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PRINCIPLES OF
HUMAN PHYSIOLOGY
PRINCIPLES OF
HUMAN PHYSIOLOGY
ERNEST H. STARLING
C.M.G., F.R.S.
M.D., HON. SC.D. (CAMBRIDGE AND DUBLIN), F.R.C.P.
JODRELL PROFESSOR OF PHYSIOLOGY IN UNIVERSITY COLLEGE, LONDON
THE CHAPTER ON THE SENSE ORGANS REVISED AND
LARGELY REWRITTEN BY
H. HARTRIDGE, M.A., M.B. Cantab.
THIRD EDIT I OS
With jj. Leaf-hair of Cucurbtta ; non-
nucleated fragment, with membrane, connected with nucleated fragment of adjoining
cell.
that the power of morphological as well as of chemical synthesis depends on
the presence of a nucleus. On this account the nucleus, as we shall learn
later on, must be regarded as the especial organ of inheritance. The trans-
mission of the paternal qualities from one generation to the next is effected by
the entrance simply of the nuclear material of the male cell, the spermato-
zoon, into the ovum. In the words of Claude Bernard, " the functional
phenomena in which there is expenditure of energy have their seat in the
protoplasm of the cell (i.e. the cytoplasm). The nucleus is an apparatus for
organic synthesis, an instrument of production, the germ of the cell."
Similar conclusions may be drawn from a study of the changes in the
nucleus which accompany different phases in the activity of the whole cell.
THE STRUCTURAL BASIS OF THE "BODY 31
Thus in growing plant cells the nucleus is always situated at the point of
most rapid growth. In the formation of epidermal cells the nucleus moves
towards the outer wall and remains closely applied to it so long as it is growing
in thickness. When this growth is finished the nucleus moves to another
part of the cell. In the formation of root hairs the outgrowth always takes
place in the immediate neighbourhood of the nucleus, which is carried forward
and remains near the tip of the growing hair. The active growth of cyto-
plasm, which accompanies the activity of
secreting cells, is always associated with
changes in the position and in the size of
the nucleus. Where the nutritive activity
of the cell is very intense, as in the silk
glands of various lepidopterous larvae, the
nucleus is found to be very large and much
branched (Fig. II) so as to present the
greatest possible extent of surface through Flo ,, Branched nucleus from
which interchanges can go on between the spinning gland of butterfly
, j . , larva (Pieris). (Korschelt.)
nucleus and cytoplasm. v ' (
The important changes which the nucleus undergoes in the process
of cell division we shall have to consider more fully in the later chapters
of this work. In the function of assimilation it is natural to assume that
it is those constituents of the nucleus which are peculiar to it both morpho-
logically and chemically, namely, the chromatin filaments, which are most
directly concerned. This assumption receives support from the changes
which have been observed to occur in these filaments during various phases
of nutritive activity of the cell. The staining powers of chromatin are in
direct proportion to the amount of nuclein it contains. In the eggs of the
shark it has been shown that the chromosomes undergo characteristic changes
during the entire growing period of the egg. At first I bey are small and stain
deeply with ordinary nuclear dyes, but during the period of growth they
undergo a great increase in size and at the same lime lose their staining
capacity,* their surface being increased by the development of long threads
which grow out in every direction from the central axis. As the egg
approaches its lull size, the chromosomes diminish in size and are finally
reduced to minute intensely staining bodies which take part in the first
division of the egg preparatory to its fertilisation (Fig. 12). We must
conclude that whereas the processes of destructive metabolism or dissimila-
tion, which determine the activity of the cell, have their immediate seat in
the cytoplasm, the processes of constructive metabolism which lead to the.
formation of new material, to the chemical and morphological building up of
the cell, are carried out in or by the intermediation of the nucleus.
HISTOLOGICAL DIFFERENTIATION OF CELLS. Even within the
limits of a single cell, differentiation of structure can take place by the
setting apart of distinct portions of the cell for isolated functions. Thus in
an organism such asvorticella the cell is shaped somewhat like a wine-glass,
* Ruckert, citad by Wilson.
32
PHYSIOLOGY
the .stem being composed <>f a spiral contractile fibre which lias the function
of withdrawing the rest of the organism when necessary towards its point of
attachment. The main portion of the cell presents at its free extremity a
part which is the seat of ingestion of food, and is therefore spoken of as the
' mouth.' This is surrounded by a circle of cilia whose function it is to set
up currents in the surrounding fluid and so favour the passage of food parti-
cles towards the mouth. Food when ingested at this end passes only a
Fig. 12. Chromosomes of the germinal vesicle in the shark Pristiniits, at different periods
drawn to the same scale. (BtJCKEET.)
A. At the period of maximal size and minimal staining-capacity (egg 3 mm. in
diameter). B. Later period (egg 13 mm. in diameter). C. At the close of ovarian life,
of minimal size and maximal staining-power.
short distance into the body of the vorticella. Here fluid is secreted around
it which serves for its digestion. This portion of the cell may therefore be
regarded as the alimentary canal or stomach. The indigestible residue of the
food is excreted in close proximity to the mouth. In addition to these organs
we have the usual differentiation of the protoplasm into an external and
internal layer, and the development within the protoplasm of contractile
vacuoles which serve to keep up a circulation of fluid and therefore to pass
the products of digestion through all parts of the cell body. Within the
limits of the single cell which forms the vorticella we may therefore speak
of organs for contraction, for digestion, for circulatiqp, and so on.
The organs which are thus formed in unicellular animals or plants can be
divided into two classes, namely (1) temporary organs, which are formed out
THE STRUCTURAL BASIS OF THE BODY 33
of a common structural basis and can therefore be replaced at any time by
the cytoplasm if destroyed. Examples of such organs are the cilia, the
commonest motor apparatus of unicellular organisms ; the pseudopodia,
which, as we have seen, can be made and destroyed at will ; the mouth of
animals such as Volvox or Vorticella ; and the stinging cells or nectocysts,
which surround the mouth of many of these animals and serve to paralyse
or kill the smaller living organisms brought by the cilia within reach in
order that they may serve as food. In contradistinction to these organs
are (2) a number of others which must be regarded as permanent. These
cannot be formed by differentiation from the cytoplasm of the cell, but are
derived by the division of pre-existing organs of the same character, and
are therefore transmitted from one generation to another. As examples of
such cell-organs may perhaps be mentioned the nucleus, with its chromo-
somes, and the plastids, of which the chloroplasts of vegetable cells are the
most conspicuous. Certain cell organs may fall into either class. Thus
the contractile vacuoles are sometimes derived by the division of the pre-
existing vacuoles in a previous generation, at other times are certainly formed
out of the common cytoplasm. The centrosome, a small particle generally
situated in the cytoplasm, which plays an important part in cell-division,
is generally derived by the division of a pre-existing centrosome, but under
certain conditions and in some organisms can be developed in situ in the
cytoplasm itself.
The possibility of histological differentiation and of the adaptation of
structure to definite functions becomes much more pronounced as we pass
from the unicellular to the multicellular organisms or metazoa. The lowest
of the metazoa, such as the sponges, consist of little more than an aggregation
or colony of cells. All the cells are still bathed with the outer fluid, and any
differentiation of structure or function seems to be entirely conditioned by
tin- position of the cell. In the ccelenterata the differentiation is already
much more marked. The hydra, one of the simplest of the group, consists
of a sac formed of two layers of cells and attached by a stalk to some firm
basis. Round the mouth of the sac is a circle of tentacles. The inner layer,
or hypoblast, represents the digestive and assimilatory layer, while the
epiblast, or outer layer, is modified for the purposes of protection, of reception
of stimuli, and of motor reaction. In the jelly-fish the differentiation of the
outer layers leads to the formation of the first trace of a nervous system, i.e.
a system fitted especially for the reception of stimuli and for their trans-
mission to the reactive tissues, namely, the muscles.
In all these classes of animals the external medium of every cell forming
the organism is the sea-water or other medium in which they li\e. This can
penetrate through the interstices between the cells, and every cell is there-
fore exposed to all the possible variations which may occur in the composition
of the surrounding medium. A great step in evolution was accomplished
with the formation of the ccelomata, the class to which all the higher animals
belong. In these, by the formation of a body cavity containing fluid, an
internal medium is provided for all the working cells of the body. The com-
3
34 PHYSIOLOGY
position of this internal medium is maintained constant by tne activity of the
cells in contact with it, and the stress of sudden changes in the chemical com-
position of the surrounding medium is borne entirely by the outer protective
layer of epiblast cells. These are rendered more or less impermeable by the
secretion on their surfaces of a cuticular layer, and only such of the con-
stituents of the surrounding medium are allowed to enter the organism as can
be utilised by it for building up its living protoplasm. Out of the ccelom
is later on formed a circulatory system which, by the circulation of the ccelo-
mic fluid or of blood through the whole body, can procure a still more per-
fect uniformity in the chemical conditions to which every cell is exposed. It,
is not till much later that the organism achieves an independence of external
conditions of temperature. In the mammalia, by means of the reactive
nervous system, the heat produced in every vital activity by the chemical
changes of combustion and disintegration is so balanced against the heat
lost through the external surface to the environment that the temperature of
the internal fluid is maintained practically constant. One of the main results
of the differentiation of function and structure is therefore a gradual setting
free of the majority of the cells of the body from the influence of variations in
the environment ; and in the highest type of all animals, in man, this inde-
pendence of external conditions is carried to a much further extent by
conscious adaptations, such as the use of clothes, dwellings, artificial heating,
and so on.
The differentiation of the cells which compose the organs of the body is
determined in the first place by the different conditions to which they are
exposed in virtue of their positions in the course of development. All the
higher animals may be considered as built in the form of a tube, the external
surface of which is modified for the purpose of defence and for adaptation to
changes in the environment. From this layer there are developed not only
the protective cuticle, but also tin 1 organs of motor reaction, namely, the
special senses and the nervous system. The internal surface of the tube
is modified for purposes of alimentation. From it are developed all those
structures which serve for the digestion of the food-stuffs, for their absorption
into the common circulating fluid, for their elaboration after absorption, and
their preparation for utilisation by other cells of the body. Between these
two surfaces are situated the supporting tissues of the body as well as the
organs for the conversion of the potential energy of the body into motion and
work, namely, the muscles. Here also is the cesium or body cavity, repre-
sented in the higher animals by the pleural and peritoneal cavities. The
alimentary canal projects for a considerable part of its course into this ccelum,
being attached to the body wall only by one side. From the ccelom is also
developed the blood vascular system, surrounded by contractile and con-
nective cells which maintain a constant circulation of the blood throughout
the body. By this differentiation the body becomes divided into a number
of organs, each of which is composed of like cells, modified for a common
function and bound together by connective tissue, the latter serving also to
carry the blood-vessels which convey the common medium for the working
THE STRUCTURAL BASIS OF THE BODY 35
cells. In the study of physiology our task consists, firstly, in the description
of the special part taken by each organ in the general functions of the body,
and, secondly, in the determination of the limiting conditions of such func-
tions and of the physical and chemical factors which determine them.
Finally, we have to endeavour to form a complete conception of the chain of
events concerned in the discharge of each function and of their causal
nexus.
In the foregoing lines we have compared the higher animal to a colony
of cells, and we often speak of an isolated cell of the body as if it were an
independent elementary organism. A better term for such an aggregation of
cells as presented by the higher animals is not however ' cell colony,' but
' cell state,' since, just as in the state politic, no cell is independent of the
activities of the others, but the autonomy of each is merged into the life of the
whole. With increasing differentiation there is increasing division of func-
tion among the various members of the state, and each therefore becomes
less and less fitted for an independent existence or for the discharge of all its
vital functions. The more highly civilised a man becomes and the greater
his specialisation in the work of the community, the smaller chance would he
have of existing on a desert island. Thus the life of the organism is essen-
fcially composed of and determined by the reciprocal actions of the single
elementary parts. It is evident that, if the process of specialisation has gone
far enough, a discussion whether each unit has or has not an independent life
is beside the mark, since it cannot possibly exist apart from the activities of
the other cells. Of late years histologists have brought forward evidence
which seems to imply that an actual structural interaction exists, in addition
to the functional dependence which is a necessary resultant of specialisation.
Even in the case of plant cells with their thick cellulose walls, fine bridges of
protoplasm can be made out passing from one cell to another through pores
in the cellulose wall. In animals protoplasmic bridges are known to exist
joining up adjacent cells in unstriated muscle, epithelium and cartilage
cells, and in some nerve-cells. The conclusion has therefore been drawn
that the morphological unit is not the cell, but the whole organism, and that
the division of the common cytoplasm into cells is merely a question of size
and convenience. There can be no doubt that the determining factor in the
division of cells is their growth : the cell divides because it grows. With
increased mass of living substance it is necessary to provide for increase of
surface both of cytoplasm and of nucleus. Whether all the tissues of the
higher animals remain in structural continuity by protoplasmic bridges, &e.,
must be to us a matter of indifference, since all that is necessary for the
interdependent working of the different cells of the body is a functional
continuity, and this in the higher animals is effected by the presence of a
common circulating fluid and a reactive nervous system connected by
conducting strands with all the cells of the bodv.
CHAPTER III
THE MATERIAL BASIS OF THE BODY
SECTION 1
THE ELEMENTARY CONSTITUENTS OF
PROTOPLASM
The material basis of which living organisms are built vrp is derived from
the surrounding medium, and the elements which compose the framework
of the body must therefore be identical with those found in the earth's crust.
Not all the elements are so utilised in the formation of living matter. Every
living organism without exception contains the following elements : carbon,
hydrogen, oxygen, nitrogen, sulphur, phosphorus, chlorine, potassium,
sodium, calcium, magnesium, and iron. In addition to these twelve elements
others are found in certain organisms, sometimes to a large extent, but it is
not known how far they are necessary to the proper development of these
organisms, and it is certain that they do not form an integral constituent
of all organisms. Of these elements we may mention especially silicon,
iodine, fluorine, bromine, aluminium, manganese, and copper. Dealing with
the first class, which includes those essential to all forms of life, we find that
their relative proportions in living organisms have little or no relation to
their proportions in the environment of the organisms. Their presence,
however, in the latter is a necessary condition of life. In the case of plants
which have a fixed habitat and camiot move in search of food, the growth
of the plant is limited by the amount of the necessary element which is
present in smallest quantities in the surrounding medium. This is what is
meant by the agriculturist's ' Law of the Minimum.' Of the elements derived
from the earth's crust, those present in the smallest amounts in most soils
are potassium, nitrogen, and phosphorus. The growth of a crop in any given
soil is determined by the amount of that one of these three substances which
is present in smallest quantities, and the aim of agriculture is to supply to
every soil the ingredient thus present in minimal amount.
Carbon forms the greater part by weight of the solid constituents of
living protoplasm. The proximate constituents of living organisms are
practically all carbon compounds, so that organic chemistry, which was
originally the chemistry of substances produced r by the agency of living
organisms, has come to be synonymous with the chemistry of carbon com-
36
THE ELEMENTARY CONSTITUENTS OF PROTOPLASM 37
pounds. The carbon compounds which make up the living cell are com-
bustible, i.e. they can unite with oxygen to form carbon dioxide with the
evolution of heat. In the inorganic world practically all the carbon occurs
in a completely oxidised form, namely, carbon dioxide. A small amount,
4 parts in 10,000, is present in the atmosphere, while vast quantities are
buried in the crust of the earth as carbonates of the alkaline earths, &c, in
the form of chalk and limestone. In this condition the carbon dioxide is
practically removed from the life cycle, the whole of the carbon contained in
the tissue, of living beings, whether plant or animal, being derived from
the minute proportion of carbon dioxide present in the atmosphere. The
energy for the conversion of carbon dioxide into the oxidisable forms with
high potential energy, which make up the tissues of plants and animals, is
furnished by the sun's rays. The machine for the conversion of the radiant
energy into the potential chemical energy of the carbon compounds is
represented by the chlorophyll corpuscles in the green parts of plants. In
these corpuscles, under the influence of the sun's rays, the carbon dioxide of
the atmosphere, together with water, is converted into carbohydrates, viz.
starch (C 6 rl lu 5 ), and the oxygen liberated in the process is set free into the
surrounding atmosphere.
6C0 2 + 5H 2 = C 6 H 10 O 5 + GO,.
In this process a large amount of energy is absorbed, an energy which
can be set free later by the oxidation of the starch to carbon dioxide. In
the oxidation of one gramme of starch about 4500 calories are evolved, and
this represents also the measure of the solar energy which must be absorbed
by the chlorophyll corpuscle in the process of formation of starch from the
carbon dioxide of the atmosphere. By this means the world of life is pro-
vided with a source of energy. At the expense of the energy of the starch
further synthetic processes are carried out. By the oxidation of a part
of the carbohydrates, sufficient energy may be supplied to deoxidise other
portions of the carbohydrates with the production of fats. Thus
3C 6 H 12 6 -80 2 = C 18 H 36 2
(Glucose) (Stearic acid)
The potential energy of a fat is still greater than that of a carbohydrate,
one gramme of fat giving on complete combustion to carbonic acid and
water as much as 9000 calories. By the introduction of ammonia groups
(NH 2 ) into the molecules of fatty acids, amino-acids may be produced, from
which the complex proteins are built up to form the chief constituents of the
living protoplasm.
The synthesis of carbon compounds from the inert carbon dioxide of
the atmosphere can be effected only by chlorophyll corpuscles. All animals
take in carbon, hydrogen, nitrogen, oxygen, and sulphur in the form of the
carbohydrates, fats, and proteins which have been built up in the living
plants. In the animal organism these food-stuffs serve as sources of energy.
They undergo a gradual oxidation, and finally leave the body in the form of
38 PHYSIOLOGY
carbon dioxide, water, ammonia or some related compound, and sulphates.
A sharp distinction lias therefore often been drawn between the metabolism
of plants and animals, plants being regarded as essentially assimilatory in
character while animals are dissimilatory, utilising the stores of energy which
have been accumulated by the plant. There is however no definite line
of demarcation. Although, generally speaking, the green plant breaks up
carbon dioxide, giving oft oxygen and storing up carbon compounds, and
the animal taking in carbon compounds oxidises them with the help of the
oxygen of the atmosphere to carbon dioxide, which is redischarged into the
surrounding medium and is available for further assimilation by plants, yet
this process of respiration is common to all living organisms, whether plants
or animals. In the green plant it may be masked by the assimilatory process
occurring under the influence of the sun's rays, but in the dark all parts of
the plant, and in the light all parts which are free from chlorophyll, display
a process of respiration, i.e. they are constantly taking up oxygen from the
atmosphere and using it for the oxidation of carbon compounds in their
tissues, with the production of carbon dioxide
The sum total of the processes of life tend therefore to maintain a
constant proportion of carbon dioxide and oxygen in the atmosphere, the
decomposition of carbon dioxide by the green plants being balanced by the
oxidation of the carbon compounds and the continual discharge of carbon
dioxide by animals. It is not certain however that this balance will be
maintained throughout all time. As Bunge has pointed out, there are
cosmic factors at work which are apparently tending to cause a constant
diminution in the quantity of carbon dioxide in the atmosphere, which alone
is of value to the plant. One of these factors is the variable affinity of the
silica and carbon dioxide respectively for the chief liases of the earth's crust.
At a high temperature silica can displace carbon dioxide from its compounds.
Thus chalk heated with silica will give rise to calcium silicate with the evolu-
tion of carbon dioxide. At an early geological epoch therefore, it is prol >a ble
that the greater part of the silica was present in combination with bases and
that the proportion of carbon dioxide in the atmosphere was very much
higher than it is now. At temperatures at present ruling on the earth's
surface carbon dioxide is a stronger acid than silica. The action of water
charged with carbon dioxide on a silicate is to cause its gradual decomposi-
tion with the formation of carbonate and silica. Both these products, being
insoluble, are deposited as part of the earth's crust, the silica in the form of
sandstone, the carbonate as chalk or limestone. The carbon dioxide is
being constantly removed by water from the atmosphere and being locked
up in this way in the earth's crust, the process of separation of calcium car-
bonate being aided to a marked extent by the agency of living organisms
themselves. The whole of the extensive deposits of limestone and chalk
have been separated from the sea-water by the action of living organisms.
With the cooling of the earth's crust which is supposed to be going on, the
discharge of carbon dioxide by volcanoes must get less and less, so that one
can conceive a time when the whole of the carbon dioxide will be bound up
THE ELEMENTARY CONSTITUENTS OF PROTOPLASM 39
with bases in the earth's crust, and life, without any source of carbon, must
become extinct.
Hydrogen exists almost exclusively in the form of water. In this form
it is taken up by plants and animals, with the exception of a small proportion
al >s< irbed in the form of ammonia. In this form too it is discharged by living
organisms. Oxygen is the only element which, in all the higher organisms at
any rate, is taken up in the free state. It forms one-fifth of the atmosphere
and, as the oxides of the various metals, a considerable fraction of the earth's
crust. It takes a position apart from the other food-stuffs in that its
presence is the essential condition for the utilisation of their potential energy.
In the living cells it combines with the oxidisable compounds formed by the
agency of the living protoplasm, with the production of carbon dioxide and
water, and the evolution of energy. This process is spoken of as respira-
tion.
•Like the three elements we have already considered, nitrogen is also
derived directly or indirectly from the surrounding atmosphere. In conse-
quence of its feeble combining power for other elements and the instability of
i's compounds, very little nitrogen is to be found in the combined state in the
earth's crust, whereas it constitutes four-fifths of the atmospheric gases.
It can be taken up by most plants only in the form of ammonia, nitrites.
or nitrates. To animals these compounds are useless, and their only
source of nitrogen is the protein which has been built up by the agency
of the plant cell. Since nitrogen in the free state is useless to nearly all
living organisms, the existence of life must depend on the amount of com-
bined nitrogen which is available. In view of the small tendency presented
by this element to enter into combination, it becomes interesting to inquire
into the source of the combined nitrogen which is the common capita] of the
living kingdom. There are certain cosmic factors which result in the pro-
duction of combined nitrogen. The passage of electric sparks or of the
silent discharge through moist air leads to the production of ammonium
nitrite.
N, + 2H 2 = NH 4 NO,.
Every thunderstorm therefore will result in the production of small quan-
tities of ammonium nitrite, which will be washed down with the rain and
serve as a source of combined nitrogen to the soil. Every decaying vegetable
or animal tissue serves as a source of ammonia, so that from various causes
the soil may contain nitrogen in the form of ammonia, or of ammonium nitrite.
These forms of combined nitrogen are not however suitable for all classes of
plants. Most moulds can assimilate ammonia as ammonium carbonate or
as amino-acids or amines, provided that they are supplied at the same
time with sugar, the oxidation of which will serve them as a source of energy.
Some moulds, many of the higher plants, and especially the Graminese;
which include the food-producing cereals, require then nitrogen in the
condition of nitrates. It is necessary therefore that the ammonia or
nitrites in the soil shall be converted into this highly oxidised form. This
40
PHYSIOLOGY
conversion is effected by a group of micro-organisms. There are a number
of bacteria (bacterium nitrosomonas) which have the power of converting
ammonia into nitrites. Others (bacterium nitro-
monas) convert nitrites into nitrates. If sewage
matter rich in ammonia is allowed to percolate
through a cylinderpacked with coke and the process
be continued for several weeks, it is found after a
time that in its passage through the filter the fluid
has lost its ammonia and contains the whole of its
nitrogen in the form of nitrate. If the cylinder be
tapped (Fig. 13) half-way down, say at K, the fluid
will be found to contain, not nitrates, but nitrites.
In this conversion the two kinds of microbes men-
tioned above are concerned. At the top of the
cylinder the nitrous bacterium is present, in the
bottom of the cylinder the nitrate bacterium is
present. The conversion of ammonia into nitrates
by the agency of bacteria has been made the basis
of a method of treatment of sewage which is now
very largely employed. These different bacteria
play an important part in all soils in preparing
them for the cultivation of crops.
Is the total capital of combined nitrogen, which
is worked over by these bacteria and utilised by
the whole living world, confined to the small quanti-
ties produced by atmospheric discharges ? Of late
years definite evidence has been brought forward
that such is not the case and that organisms exist
which can utilise and bring into combination the
free atmospheric nitrogen itself. Thus certain soils
have been found to undergo a gradual enriching
in nitrogen although no nitrogenous manure has
been applied to them. Winogradsky has shown
that this fixation of nitrogen by soils is effected by
a distinct micro-organism. which may be isolated by
growing it on gelatinous silica free from any trace
of combined nitrogen, so that the organism has
to procure its entire nitrogen from the atmo-
sphere. Under such conditions the numerous other
micro-organisms of the soil die of nitrogen starva-
tion, and only the microbe survives which is able to utilise free nitrogen.
This organism, which he called Clostridium pasieurianum, grows well on sugar
solution if free from ammonia and enriches the solution with combined
nitrogen. It is anaerobic, i.e. only grows in the absence of oxygen. In the
soil, where oxygen is constantly present, it occurs associated in a sort of
symbiosis with two species of bacteria which are aerobic and protect it from
Fig. 13. Arrangement for
studying the nitrifica-
tion of sewage. (Miss
H. Chick.)
THE ELEMENTARY CONSTITUENTS OF PROTOPLASM 41
the surrounding oxygen. The mechanism by which this organism is able
to fix free nitrogen, and the nature of the first product of the assimilation are
not yet ascertained. Such an assimilation will serve to the organism as ;i
source of energy, since the application of heat is necessary for the dissociation
either of ammonium nitrite or of nitrous acid into nitrogen and water, as is
seen from the following equation :
HN0 2 Aq. + 308 Cal. = H + N + O a + Aq.
NH 4 N0 2 Aq. + 602 Cal. = 2N + 4H + 20 + Aq.
In addition to this spontaneous fixation of nitrogen by humus, a method
has long been known to farmers by which the fertility of a soil can be in-
creased without the application of nitrogenous manures.
If a plot of land is to be left fallow it is a very usual
custom to sow it with some leguminous crop such as sain-
foin. Careful experiments by Boussingault, Lawes and
Gilbert, and others, have shown that the growth of almost
any leguminous crop in a soil poor in nitrogen may result
not only in the production of a crop containing much com-
bined nitrogen, but also in an actual increase of nitrogen in
the soil from which the crop is taken. It was then shown
by the last two observers, as well as by Schloesing and
Laurent, that the power of a leguminous crop to enrich the
soil with nitrogen was dependent on the presence on the
roots of certain small nodules which had been described
long before by Malpighi (Fig. 14). They showed also that
the production of these nodules took place only as a result
of infection. Beans grown in sterilised sand produced a
plant free from nodules, which however grew very scantily
unless nitrogenous manure were added to the sand. Such a
crop derived the nitrogen for its growth from the added
nitrogen, the total amount of which in the soil was there-
fore diminished by the crop. If however the sterilised
sand were treated with an infusion of root nodules from
another plant without the addition of any combined 'vetch with nod-
nitrogen at all, the beans developed nodules on their roots ules.
and grew luxuriantly, and at the termination of their
growth the soil was richer in nitrogen than at the commencement. On
microscopic examination the protoplasm which makes up these nodules
is found to be swarming with small rods (Fig. 15), and it was shown by
Beyerinck that these rods are bacteria and can be cultivated in media
apart altogether from the plant. We have thus an example of a class of bac-
teria which, like those of humus, are able to assimilate the free nitrogen of the
atmosphere, but, unlike them, can only effect this assimilation in a condition
of symbiosis, i.e. living in the growing tissues of a leguminous plant. Similar
nodules have been described on the roots of other plants which can grow in a
42
PHYSIOLOGY
soil free from combined nitrogen, e.y. conifers, but it is in the legurninosae
that their presence is most widespread.
The source of the combined nitrogen, which can be built up by plants
into proteins and utilised in this form by animals, is thus not only the
ammonium nitrite produced by the agency of electric discharges in the
Fig
15. Section of a root oodiile « >t Doryehnium. (Vi u.rx.uis.)
a. cortical tissue; l>. cells containing bacteria.
atmosphere, but also the free nitrogen of the atmosphere assimilated by
various types of bacteria.
Sulphur is found in all soils in the form of sulphates, generally of lime.
As sulphates it is taken up by plants. In the plant cell a process of deoxida-
tion takes place at the expense of the energy derived either from the starch
or, in the case of bacteria, from other ingredients of their food-supply. It is
built up, together with nitrogen, carbon, and hydrogen, to form sulphur
derivatives and amino-acids such as cystine, and these, together with other
amino-acids, are synthetised to form proteins. Practically the whole of the
sulphur taken in by animals is in the form of proteins. It shares the oxida-
tion of the protein molecule in the animal body winch it leaves in the form of
sulphates. The output of sulphates by an animal can therefore be regarded,
like the nitrogen output, as an index of the protein metabolism. It is
returned to the soil in the form in which it was taken by the plant, and the
cycle can be continuously repeated.
Iron, although forming but a minute proportion of the materia] basis'
of living organisms (the whole body of man contains only six grammes), is
nevertheless indispensable for the maintenance of life. It is necessary, for
instance, in two important functions, viz. the formation of chlorophyll in the
green plant and the respiratory process in the higher animals. Although iron
forms no part of the chlorophyll molecule, plants grown in the absence of this
THE ELEMENTARY CONSTITUENTS OF PROTOPLASM 43
substance remain etiolated, but form chlorophyll if the smallest trace of iron
is added to the soil in which they are growing or even if the leaves are wash* d
with a very dilate solution of an iron salt. In animals iron forms an essential
constituent of haemoglobin, the red colouring-matter of the blood, whose
office it is to carry oxy T gen from the lungs to the tissues. It is probable too
that the minute traces of iron in protoplasm exercise an important function
in the processes of oxidation which are continually going on. Even in the
inorganic world iron plays the part of an oxygen carrier. In the earth's
crust it occurs as ferrous salts and as ferric oxide. The ferrous silicate, for
instance, may be decomposed by water containing carbon dioxide into silica
and ferrous carbonate ; the latter then absorbs oxygen from the atmosphere,
liberating carbon dioxide and forming ferric oxide. In the presence of
decomposing organic matter, the ferric oxide parts with its oxygen to oxidise
the organic substances and is converted once more into ferrous carbonate,
and this may be decomposed by the oxygen of the air as before. In the
presence of sulphates and decomposing organic matter, ferrous sulphate,
which is first formed, undergoes deoxidation to ferrous sulphide, and this may
again be oxidised to sulphates and ferric salts on exposure to the atmosphere,
so that both the sulphur and the iron act as oxygen carriers between the
atmosphere and the organic matter. Iron is obtained by plants from the
soil as ferrous or ferric salts. In the protoplasm it is built up into highly
complex organic compounds, and m this form is taken up by animals. It is
probable that the main requirements of the animal for iron, which are very
small, may be satisfied entirely at the expense of these organic compounds,
but there can be little doubt that the animal can, if need be, also utilise the
iron salts presenl in its food. The animal proceeds extremely economically
with its supply of iron. Any excess of iron above that needed to supply
the iron lost to the body is excreted almost entirely with the faeces in the
form of sulphide. In the soil this undergoes oxidation and returns once nunc
to the form in which it was originally taken up by the plant.
Phosphorus is absorbed by the plant as phosphates. In the cell proto-
plasm it is built up with fatty acids and other organic radicals to form com-
plex compounds such as lecithin, a phosphorised fat, and nuclein, a com-
bination of phosphorus with nitrogenous bases of great variety. Both leci-
thin and nuclein are essential constituents of living protoplasm. Practically
the whole of the phosphorus income of animals is represented by these
lecithin and nuclein compounds. After absorption into the animal body they
are broken down by processes of dissociation and oxidation, with the pro-
duction, as a final result, of phosphates, which are excreted with the urine
or fasces and return to the soil.
Chlorine, potassium, sodium, calcium, and magnesium are taken up by
the plants in the form of salts. Although playing an essential part in all
vital processes, they do not seem to" be built up into organic combination
with the protein and other constituents of the cell protoplasm. They are
therefore taken up also by annuals in the form of salts, and as such are again
excreted with the urine.
44 PHYSIOLOGY
Little is known about the significance, if any, of the other elements which
I have mentioned as occasional constituents of living beings. Silicon, which
is of universal distribution, is assimilated as silica, probably in colloidal
solution, and is distributed in minute quantities through all plant and
animal tissues. It forms a very large percentage of the mineral basis of
grasses, but even here it does not seem to be indispensable, since these will
grow in a medium devoid of silica as luxuriantly as under normal conditions.
Fluorine is found in the enamel of the teeth and in minute traces in other
tissues of the body.
Bromine, though present in quantity in some seaweeds, appears to play
no part in the edonomy of higher animals.
Iodine is found in large quantities in many seaweeds and is present as an
organic iodine compound in the skeleton of certain horny sponges. An
organic iodine compound is also found in the thyroid gland of the higher
animals, and may possibly be the active principle by means of which these
glands are able to affect the nutrition of the whole body. Iodine, therefore,
would seem to be an essential constituent of the higher animals.
Aluminium is found in large quantities in certain lycopods. Whether
it is essential to their growth is not known.
Copper is certainly not a necessary constituent of a large number of
plants and animals. In one class, the cephalopods, it appears to take the
part of iron in the formation of a blood pigment. The hsemocyanine, which
was described by Fredericq, plays the same part in the blood of cephalopods
that is played by haemoglobin in the blood of vertebrates. When oxidised
it is of a blue colour, but gives off its oxygen and is reduced to a colourless
compound on exposure to a vacuum.
Among these elementary constituents of the body, a definite line of
demarcation can be drawn between the carbon and hydrogen on the one
hand and all the other constituents on the other. The first two elements are
built up in a deoxidised form into the living structure of the protoplasmic
molecule. The products of their complete oxidation are volatile, namely.
carbon dioxide and water, and leave the body in these forms. The nitrogen
set free by the breaking down of the proteins will pass off as free nitrogen or
;is ammonia. The sulphuric acid formed by the oxidation of the sulphur
combines with the basis to form non-volatile salts. We may therefore divide
t he ultimate constituents of the body into those which are combustible and
are driven off on heating, and those which are left behind as the ash.
SECTION II
THE PROXIMATE CONSTITUENTS OF THE
ANIMAL BODY
In spite of the enormous variety of the proximate constituents of living
organisms, they are all members or derivatives of three classes of compounds.
Since living organisms form the entire food of the animal kingdom, a study
of these proximate constituents includes the study of all the food-stuffs.
These classes are :
(a) Proteins, containing the elements carbon, hydrogen, nitrogen, oxygen,
and sulphur ; in some cases also phosphorus.
(b) Fats, containing carbon, hydrogen, and oxygen.
(c) Carbohydrates, containing carbon, hydrogen, and oxygen, the two
latter elements being present in the proportions in which they form water.
THE CHIEF TYPES OF ORGANIC COMPOUNDS OCCURRING
IN THE ANIMAL BQDY
The full consideration of the various modifications undergone by these three classes
of food-stuffs in the body, especially if we include the by-products occurring both
in plants and in animal metabolism, involves a wide knowledge of organic chemistry
which indeed at its origin was simply the chemistry of the products of living (i.e.
organised) beings. The most important substances with which we shall have to deal
belong to a comparatively restricted number of groups. For the convenience of the
reader a short summary of the relationships of these groups to one another and to the
hydrocarbons is given here.
THE HYDROCARBONS (Fatty Series). These form a continuous homologous
series, and may be saturated or unsaturated. Examples of the saturated series are
CH 4 methane
C 2 H 6 ethane
C 3 H 8 propane
C 4 Hj butane, and so on,
the general formula for the group being
P n H., n + 2 .
These paraffins, the lower members of which are gaseous, while the higher members
form the petroleum ether, the heavy petroleums, vaseline, and the paraffin Max with
which we are all familiar, are entirely inert in the animal body. If taken with the
food they pass through the alimentary canal unchanged. In order to render them
accessible to the action of the living cell they must first undergo oxidation.
The unsaturated hydrocarbons have the general formulae ^H,,,, C n H 2 „_„
45
46 PHYSIOLOGY
Examples of the first two groups are ethylene CH,
II
CH 2
and acetylene CH
III
CH
Derivatives of all these groups occur in the body.
THE ALCOHOLS. The first product of the oxidation of hydrocarbons is the
series of bodies known as the alcohols. Examples of these are :
CH 3 OH methyl alcohol
C 2 H 6 OH ethyl
C 3 H 7 OH propyl „
C 4 H 9 OH butyl
C 5 H u OH amyl „
C H 13 OH capryl ., and so on,
the general formula for the group being
C„H 2D + iOH.
In all these alcohols the OH group is, so to speak, more mobile than the other atoms
connected with the carbons, and can therefore be replaced by other substances or
groups with comparative ease. In this respect therefore an alcohol can be compared
to water HOH or to alkaline hydroxide NaOH or KOH. The best-known example
of the group is ethyl alcohol, the ordinary product of fermentation of sugar. In these
alcohols the H of the OH group can be replaced by Na. Thus, water with metallic
sodium gives sodium hydroxide and hydrogen as follows :
2HOH + 2Na = 2NaOH + H 2 .
In the same way alcohol treated with metallic sodium gives off hydrogen, and the
remaining fluid contains sodium, ethylate, thus :
21 ,H 5 OH + 2Na = 2C 2 H 5 ONa + H,
(sodium ethylate)
On the other hand, the OH group may be replaced by acid radicals. Thus, if ethyl
alcohol be treated with phosphorus pentachloride, ethyl chloride is formed together
with phosphorus oxychloride and hydrochloric acid. Thus :
Et.OH + PC1 5 = POCI3 + HC1 + Et.Cl
(ethyl chloride)
With concentrated sulphuric acid the reaction is similar to that which obtains between
sodium hydrate and this acid, and we have formed ethyl hydrogen sulphate and water.
Thus :
Et.OH + H 2 S0 4 = Et.HS0 4 + HOH
If alcohol be warmed with acetic acid and strong sulphuric acid, among the products
of the reaction is ethyl acetate, which is volatile, and therefore passes off. Thus :
Et.OH + HCH3O, = Et.C 2 H 3 2 + HOH.
These compounds of the hydrocarbon group of the alcohol, such as methyl, ethyl,
propyl, &c, with an acid, in which the ethyl takes the part of a base, are known as
esters.
An ester treated with an alkali is decomposed with the formation of an alkaline
salt of the acid, and the corresponding alcohol which, being volatile, is given off on
warming the mixture. Thus :
Et.C 2 H 3 2 + NaHO = NaC 2 H 3 2 + Et.OH.
(ethyl acetate) (potassium acetate) (alcohol)
This process of decomposition of an ester with the formation of the alkaline salt of an
acid is often spoken of as saponification, i.e. soap formation, though the term ' soap '
PROXIMATE CONSTITUENTS OF THE ANIMAL BODY 47
is applied only to the compounds of alkalies with the higher fatty acids. The series of
alcohols we have just dealt with containing one OH group replaceable by metals or
acid radicals are known as monatomic alcohols. If in the molecule of the paraffin two
or more atoms of hydrogen have been replaced by the group OH, we speak of diatomic
or polyatomic alcohols. Thus, derived from the paraffin propane C,H 8 we may have
the monatomic alcohol C s H 7 OH, propyl alcohol, or the triatomic alcohol C 3 H 5 (OH) 3 ,
which is known as glycerin, or glycerol.
Other alcohols of physiological importance are cholesterol and cety] alcohol. Cho-
lesterol is a monatomic alcohol with the formula 27 H 15 OH. It is very complex in
structure, and belongs to the aromatic scries. Recent work points to an affinity of
cholesterol with the terpenes, which have hitherto been found only as the product of
the metabolism of plant cells. Cholesterol is a constant constituent of protoplasm.
It occurs in large quantities in the medullary sheath of nerves; it is a normal con-
stituent of bile and may form concretions (biliary calculi) in the gall bladder. In
combination with fatty acids it is an important constituent of sebum and of wool'fat.
CH 3
I
Another alcohol— cetyl alcohol — C 16 H sl O — (OH„)i 4 occurs in the feather glands of
I
CHjjOH
the duck and tonus ,m important constituent of the wax, spermaceti, obtained from
a cavity in the skull of the sperm whale.
ALDEHYDES. By oxidation of any of the alcohols we obtain another group of
compounds the aldehydes. From ethyl alcohol, for instance, by warming with potas-
sium bichromate and dilute sulphuric acid, ethyl aldehyde is produced and given off. In
H
H I
these aldehydes the group C— H is converted into the group C = O, and it is the
I "OH |
possession of this group which determines the aldehyde character of any compound,
as well as the reactions which are typical of this class of compounds.
Some of the typical reactions of aldehydes may be here shortly summarised :
(1) They act as reducing agents, the CHO group being converted into the group
COOH, which is distinctive of an acid. We may therefore say that on oxidation
aldehydes are converted into the corresponding fatty acids as follows:
i +0= |
CHO COOH
(ethyl aldehyde) (acetic acid)
On account of the case with which this oxidation takes place, aldehydes act as strong
reducing agents. Warmed with an alkaline solution of cupric hydrate, they take up
oxygen, reducing the cupric to a red precipitate of cuprous hydrate. If warmed with
an ammoniacal solution of silver (i.e. silver nitrate solution to which ammonia has
been added until the precipitate first formed is just redissolved), they reduce the silver
nitrate with the formation of a mirror of metallic silver on the surface of the glass
vessel in which they are heated.
(2) On warming with phenyl hydrazine, they give the typical compounds, hydra-
zones and osazones. which are also given by the sugars and will be mentioned in
connection with these bodies.
(3) They also form addition products. With ammonia, they yield the group of
compounds known as aldehyde ammonia. Thus :
CH 3 CH 3
I + NH 3 = | NH 2
CHO CfH
48 PHYSIOLOGY
With sodium hydrogen sulphite the following reaction takes place :
CH 3 CH 3
| + NaHSO = | X)H
CHO CH^
X S0 3 Na
These compounds of aldehydes with sodium sulphite can be readily obtained in a
crystalline form and furnish a convenient means of separating the aldehydes from their
solutions.
(4) All the aldehydes possess a strong tendency towards polymerisation. Ethyl
or acetic aldehyde treated with strong sulphuric acid gives the compound paraldehyde.
Thus :
3(' 2 H 4 C 6 H 12 3 .
(acetic aldehyde) (paraldehyde)
If warmed with strong potash the polymerisation occurs to a still further extent with
the formation of resinous substances of unknown composition, but at any rate of a
very high molecular weight, the so-called ' aldehyde resin.' Formic or methyl aldehyde,
CHoO, may in the same way undergo polymerisation with the formation of a mixture
of substances belonging to the group of sugars, namely, the hexoses, as follows :
6CH 2 = C 6 H 12 O .
This formation of sugar from formic aldehyde probably plays an important part in the
assimilation of the carbon from the carbonic acid of the atmosphere by the green parts
of plants.
ACIDS. By the oxidation of the group CHO of the aldehydes we obtain the group
C'OOH, which is characteristic of an organic acid. Thus, formic aldehyde on oxidation
gives the compound HCOOH, formic acid. Ethyl or acetic aldehyde, CH 3 CHO, with
an atom of oxygen, gives the compound CH 3 COOH, acetic acid.
CH 3 CH 3
1+0= |
CHO COOH.
Since these acids are derived from the paraffins a whole series of them exists corre-
sponding to the series of paraffins, and known as the fatty acids. Examples of this
group are :
Formic acid Acetic acid Propionic acid Butyric acid
HCOOH CH 3 CH 3 CH 3
I I I
COOH CH 2 CH 2
I I
COOH e.g. :
CHj CH 3
from
CO.NH 2 COOH.
(acetamide) (acetic acid)
AMINES. These may be regarded as formed from ammonia NH 3 by replacing
one or more of the H atoms by an organic radical. Thus we may have :
GHg < '| 1 CH 3
N-H N^CH 3 N^CH 3
V H "H X CH 3
i met liy Limine) (dimethvlamine) (trimethylamine)
Under the action of living organisms primary amines may be formed from a-amino
acids by a process of decarboxylation. Thus :
CH 3 CH 3
I
CH.NH, - CO., - CH„.NH,
I
COOH
(o-amino-propiouic acid) (ethylamine)
AROMATIC COMPOUNDS
These all contain a nucleus, made up of six carbon atoms, which is extremely stable,
so that processes of oxidation, reduction, &c, can be carried out in the compound
without destruction of the nucleus. The simplest aromatic compound is benzene
C 6 H 6 . It behaves as a saturated compound. It is represented as a hexagon with a
hydrogen atom at each angle.
H
h/\h
H^H
50 PHYSIOLOGY
All the hydrogen atoms are of equal value. They may he replaced hy other groups,
such as OH, CI, NH.>. or by more complex groups belonging to the fatty serieB, e.g.
CH 3 , C 2 H S , &c. Monosubstitution derivatives exist only in one form :
C 6 H 6 .X
Disubstitution compounds exist in three forms, according to the relative position of the
substituted H atoms. These are known as the ortho, meta, and para compounds, and
have the formulse :
X
X
X
„Ax
H f>
H C
H
«U H
„IJx
<
H
H
H
X
ortho-
nieta-
para-
The following are some of the most important monosubstitution derivatives of
benzene :
Nitrobenzene (.' 6 H 6 .N0 2 .
Aniline <"' n H 5 .NH 2 .
Benzene sulphonic acid C 6 H 5 .S0 3 H.
Phenol ( ', ; H 5 .OH.
Toluene C r ,H 5 .CH 3 .
Benzyl alcohol C 6 H s .CH 2 OH.
Benzylaldehyde C 6 H 5 .GHO.
Benzoic acid C 6 H 5 .COOH.
Of the disubstitution compounds, we need mention only the following :
The di/u/dro.ri/benzenes :
Pyrocatechin or catechol Resorcinol Hydroquinone
OH OH OH
OH
OH
para-
,OH
.Salicylic acid (o-hydroxybenzoic acid) C 6 H 4
X COOH.
Tyrosin (parahydroxyphenyl alanine) :
OH
CH 2 .CH(NH 2 )COOH.
Examples of trisubstitution derivatives of benzene are :
OH
. <>H
Pyrogallol
TQH
PROXIMATE CONSTITUENTS OF THE ANIMAL BODY 51
OH
Homogentisic acid
Adrenaline
CH.,.COOH
OH
OH
OH
CH.OH
I
(-H..XHM H :
OH
Picric acid
NO,
NO.,
OPTICAL ACTIVITY
Most of the compounds produced by the agency of living organisms exhibit optical
activity, i.e. have the property of rotating the plane of polarised light either to the
right Or to the left. ,
In an ordinary wave of light the vibrations of the waves take place in all planes
perpendicular to the direction of its propagation. When such a ray is passed through
a Nicol's prism (made of Iceland spar) it emerges as a plane polarised beam, i.e. waves
in one plane only are transmitted. Another Nicol's prism will allow such a ray to pass
only if it is parallel to the first prism. If it is rotated through a right angle, no light
will pass. A Nicol's prism may thus be used to determine the plane of polarisation
of any beam of light.
In the polarimeter two Nicol's prisms mounted parallel to one another are employed.
One of them (the polariser) is fixed ; the other (the analyser) can be rotated round
s,
^ |c S,
©c
Flo. 16. Diagram of polarimeter.
B, polariser ; D, analyser ; O, tube containing solution under examination.
the axis of the beam of light passing through the first. When both prisms are parallel
light passes through the analyser. On interposing a solution of an optically active
substance between the two prisme, the plane of polarisation of the beam is rotated,
so that the light passing through the analyser is diminished. The light may be brought
to its original intensity by rotating the analyser either to the right (clockwise) or to the
left. In this way the direction and degree of the optical activity may be determined.
Optical activity is connected with the molecular arrangement of the substance exhibiting
this property, and depends on the presence of one or more ' asymmetric carbon atoms '
in the molecule.
CH 3 (H ;
Thus in lactic acid H.COH, or in alanine HCXH... the middle carbon atom is
I I
COOH COOH
asymmetric, i.e. it is unequally loaded on the four sides,
52 PHYSIOLOGY
We can imagine such a carbon atom as occupying the interior of a tetrahedron.
A B
Fig. 17
In this tetrahedron, if we represent the four groups combining with the carbon by
Rj, R 2 , R 3 , R 4 , they can be arranged either as in A or B. It is evident that no amount
of turning about will convert the tetrahedron A into tetrahedron B, but that, if we
hold A before a mirror, its image in the mirror will be represented by B. One arrange-
ment is therefore the mirror image of the other, and a compound containing one such
carbon atom will be capable of existing in two forms, namely, one form corresponding
to A, the other form corresponding to B. It is found that the unequal loading of the
carbon atom, which is present in such an asymmetric arrangement, causes the com-
pound containing the asymmetric carbon to have an action on polarised light. One
of the varieties will rotate polarised light to the right, while its mirror image will rotate
polarised light to the left. A mixture of equal parts of the two compounds will rotate
equally to left and right, i.e. will have no action on polarised light.
The variety rotating to the right is dextrorotatory, and the other laevorotatory,*
while the mixture of the two is known as the racemic or inactive variety. The three
forms are- said to be stereoisomeric, and are distinguished as the d, I, and i forms
respectively. If two asymmetric carbon atoms are present in a compound, we may
have four stereoisomers ; and generally if there are n asymmetric atoms in a molecule,
there will be 2" possible stereoisomers. These will not all be necessarily optically active,
since the dextrorotation due to one asymmetric carbon atom may be exactly neutralised
by the l;evorotation due to another, so that ' internal compensation ' takes place and
the substance is optically inactive. Thus in tartaric acid four forms are known, namely,
d, I, racemic or i, and mesotartaric, also inactive, in whicli internal compensation occurs.
These four varieties may be represented as follows :
COOH COOH
HCOH HOCH
HOCH HCOH
COOH COOH
d-tartaric acid 7-tartaric acid
COOH
HCOH
HCOH
COOH
mesotartaric acid
inactive tartaric acid
Several methods may be employed to separate the racemic form into its two optically
active components. One of these methods, first employed by Pasteur, is to grow
moulds in the solution. One of the optical isomers is destroyed, leaving the other
unchanged. Another method is the fractional crystallisation of the salts with alkaloids,
e.g. strychnine in the case of lactic acid.
* The specific rotatory power of a substance is equal to the number of degrees
through which the plane of polarisation is rotated when it passes through a 100 per cent,
solution of the substance in a tube 1 decimetre long. Thus polarised light passing
through such a tube of 10 per cent, glucose solution would show a rotation of 5-25
degrees, i.e. its specific rotatory power is + 52-5.
SECTION III
THE FATS
These substances are widely distributed throughout the animal and vege-
table kingdoms. In the higher animals they are the main constituents of
the fatty or adipose tissue lying under the skin and between the muscles,
and often forming large accumulations around the viscera. In the marrow
of bones they may amount to 96 per cent. They also occur in fine particles
distributed through the protoplasm of cells and probably also in combination
with the other constituents which make up protoplasm. Large amounts are
also found in certain members of the vegetable kingdom, as, for instance,
in the fatty seeds and nuts, e.g. linseed, olives, Brazil nuts.
CHEMISTRY OF THE FATS
The fats are esters of glycerol and the fatty acids. Glycerol is a trihydric
or triatomic alcohol and can therefore form esters with one, two, or three
of its hydroxyl groups ; thus with acetic acid the following compounds are
known :
(1) (2)
CH a OH CH..OH
I I
CHOH CH— 0— OC.CH 3
I I
CH 2 0— OC.CH3 CH 2 OH
a -monacetin d-monaeetin
nionoglycerides
(3) (4) (5)
CH 2 — 0— OC.CH, CH 2 OH OH,— 0— OC.CH 3
1 1 r
CHOH CH— 0— OC.CH3 CH— O— OC.CH 3
I' I I
CH 2 — 0— OC.CH3 CH 2 — 0— OC.CH3 . CH 2 — O— OC.CH 3
o, a diacetin a, § diacetin triacetin
diglyceridea
triglyceride
In these compounds the phenomenon of isomerism occurs owing to the
presence of primary and secondary alcohol groups in glycerol. In the case
53
54 PHYSIOLOGY
of the diglycerides and the triglycerides mixed esters, in which the fatty acid
radical varies, are possible :
(6) (7)
CH 2 — 0— OC.CH 3 CH 2 OH
I I
CHOH ' CH— 0— OC.CH 3
I' I
CH 2 — 0— OC.CH 2 .CH 3 CH 2 — 0— OC.CH 2 CH 3
(8)
CH„— O— OC.CH3
I
( JH— 0— OC.CH 2 .CH 3
I
CH 2 — O— OC.CH 2 .CH 2 .CH 3
The glyceryl esters which compose the fatty material of living matter —
whether animal or plant — are mainly triglycerides, the monoglycerides and
diglycerides being seldom found in nature. The natural fat is usually
found to consist of a mixture of triglycerides ; these triglycerides, instead
of being mixed esters as in formula (8), are generally simple esters as in
formula (5). The differences in the composition of the natural fats depend
therefore on the variety of the fatty acid radical combined with the glycerol.
The fatty acids which enter into the composition of the triglycerides
belong to two main homologous series :
A. The saturated fatty acids, namely :
Formic acid, H.COOH
Acetic acid, CH 3 .COOH
Propionic acid, CH 3 .CH 2 .COOH
Butyric acid, CH 3 .CH 2 .CH 2 .COOH
Valerianic acid, CH 3 .(CH 2 ) 3 .COOH
Caproic acid, CH 3 .(CH s ) 4 .COOH
Caprylic acid, CH 3 .(CH 2 ) 6 .COOH
Capric acid, CH 3 (CH 2 ) 8 .COOH
Laurie acid, CH 3 (CH 2 ) 10 .COOH
Myristie acid, CH 3 (CH 2 ) 12 .COOH
Palmitic acid, GH s (CH 2 ) 14 .COQH
Stearic acid, CH s (CH 2 ) 16 .COOH
Arachidic acid. CH 3 (GH 2 ) 18 .COOH
Behenic acid, CH 3 (CH 2 ) 20 .COOH
Lignoceric acid, CH 3 (CH 2 ) 22 .COOH
B. The unsaturated fatty acids, namely :
(1) Acrylic serie's, e.g. oleic acid (C n rL n . 2 2 )
(2) Linoleic series, e.g. linoleic acid (C n H 2n ". 4 2 )
(3) Linolenic series, e.g. linolenic acid (C n H, u _ n 2 )
Of the long list of fatty acids given above only a few occur to any extent
THE FATS 55
in the animal body. In milk, although the greater part of the fat consists
of the triglycerides of oleic, palmitic, and stearic acids, other members of the
series given above are present in small amounts. On the other hand, the
adipose tissue, strictly so called, consists almost exclusively of the fats de-
rived from the fatty acids, palmitic, stearic, and oleic, i.e. tripalmitin, tri
stearin, and triolein. The great differences in the appearance of the fat of
different animals are due to the varying amounts in the relative quantities of
these three fats which may be present. While triolein is liquid at 0° C, tri-
stearin and tripalmitin are solid at the temperature of the body. According
to the relative amounts of these three substances therefore, we may have a
fat which like mutton suet is solid at the body temjDerature, or a fat con-
taining much olein which is still fluid and runs away when the body is opened
after death, even when it has ahead)' cooled.
PROPERTIES OF THE FATS. The fats are colourless substances
devoid of smell. They are insoluble in water, in which they float. They are
soluble in warm absolute alcohol, but separate out into crystalline form on
cm ding. They are easily soluble in ether. If they are strongly heated with
potassium bisulphate they give v off pungent vapours of acrolein derived from
the decomposition of the glycerin of their molecule.
C 3 H 5 (OH) 3 2HLO = C 3 H 4
11 they are heated with water or steam or submitted to the action of certain
leinieiits, they undergo hydrolysis, taking up three molecules of water, and
are split into three molecules of fatty acid and one molecule of glycerin, e.g.,
C 3 H 5 (C 10 H 31 O 2 ) 3 + 3H 2 -3HC 16 H 31 2 + C 3 H 5 (OH) 3
(neutral fat — tripalmitin) (palmitic acid) (glycerin)
This process may occur spontaneously when fat is left exposed to the air.
Fat which has been artificially split in this way is said to be rancid. Most
natural fats generally contain a small amount of fatty acid which gives them
an acid reaction.
On boibng a neutral fat for a long time with an aqueous solution of
potassium or sodium hydrate, or better still with an alcoholic solution of
potassium or sodium ethylate, the fat undergoes saponification, giving the
alkaline salt of a fatty acid and glycerin. The former compound is spoken of
as a soap. In water the soaps form a sort of pseudo-solution on heating which
sets to a solid jelly on cooling. From a dilute watery solution the soap can
be thrown down in the solid form by the addition of neutral salts. Fats are
insoluble in and non-miscible with water. If shaken up with water the
droplets rapidly run together and rise to the surface, forming a continuous
layer of the oil or fat. The same thing happens if an absolutely neutral fat
be shaken up with a dilute solution of sodium carbonate. If however the
fat be slightly rancid, i.e. if fatty acid be present, the latter combines with
the alkali with the expulsion of ('0 2 to form a soap. The presence of soap
in colloidal solution in the water at once diminishes or abolishes the surface
tension between the neutral fat and the water. Like many other colloidal
56 PHYSIOLOGY
solutions, a soap solution presents the phenomenon of surface aggregation,
i.e. the concentration of the soap at the surface is increased to such an extent
as to form practically a solid pellicle of molecular dimensions on the surface of
the fluid. The same pellicle formation occurs at the surface of every oil
globule, so that on shaking up rancid oil with dilute sodium carbonate, the
whole of the oil is broken up into fine droplets, which show no tendency to
run together again and remain in suspension in the water. The suspension
of fine oil droplets, which has the appearance of milk, is spoken of as an
emulsion. It can be at once destroyed by adding acid. This decomposes
the soap, setting free the fatty acids, which are insoluble in the water. The
pellicle around each globule is destroyed, and the globules run together as
neutral oil would in pure water.
In order to characterise any given animal fat or mixture of fats the following reactions
are made use of :
(1) The ' acid number ' of the fat, i.e. its content, in free fatty acids, is determined
N
by titrating it in ethyl alcohol solution with alcoholic solution of potash, using
phenolphthalein as an indicator. ,
(•2) The ' saponification number.' This represents the number of milligrammes
of potassium hydrate necessary to saponify completely one gramme of fat.
(3) The percentage of volatile fatty acids is determined by saponifying the fat,
then treating it with a mineral acid to set free the fatty acids and distilling over the
volatile acids in a current of steam.
(4) The iodine number is the amount of iodine which is taken up by a given weight
of fat. It is a measure of the amount of unsaturated fatty acid present, i.e. in ordinary
fat, oleic acid.
Besides the glycerides, a certain number of substances occur in the body
derived, not from a combination of fatty acids with glycerol, but from a
formation of esters of the fatty acids and other alcohols, e.g. cholesterol or
cetyl alcohol. Thus, spermaceti is a mixture of cetyl palmitate with small
quantities of other fats. The fatty secretion of the sebaceous glands in
man and the higher animals, which furnishes the natural oil of hair, wool,
and feathers, consists of cholesterol esters with small traces of glycerides.
Lanoline, which is purified wool fat, consists almost entirely of cholesteryl
stearate and palmitate. These cholesterol fats are attacked with extreme
difficulty by ferments or micro-organisms. It is probably on this account
that they are manufactured in the body for protective purposes. So far as
we know, when once formed, they are incapable of further transformation in
the body. They are not appreciably altered by the digestive ferments of the
alimentary canal, and the cholesterol is said to pass through the latter
unaltered.* Cholesterol is also found in combination with fatty acids in
every living cell. Whenever protoplasmic structures are extracted with
boiling ether, a certain amount of cholesterol is present with the fats which
are so extracted. In view of the great stability of this substance when
exposed to the ordinary mechanisms of chemical change in the body, it seems
probable that the part played by cholesterol is that of a framework or
* According to Gardner, cholesterol may be absorbed from the intestine.
THE FATS 57
skeleton, in the interstices of which the more labile constituents of the
protoplasm can undergo the constant cycle of changes which make up the
phenomena of life.
PHOSPHOLIPINES OR PFOSPHATIDES
The fats form the chief constituent of the deposited and reserve fat
throughout the animal kingdom and are also contained in the protoplasm of
the living cell. The chief fatty constituents of protoplasm differ from the
above fats in the following particulars : they contain phosphoric acid and an
amine. On this account they have been called phosphorised fats. Thudi-
chum, who isolated various compounds of this nature from brain, suggested
the term phosphatides as a general name for them. The term lipoid has also
been used, but it includes all the substances composing a cell which are soluble
in ether, e.g. cholesterol, cetyl alcohol, and the fats. Leathes has suggested
the term phosphobpine for those compounds, for it denotes that the com-
pound is partly fat (lip), that it contains phosphorus, as well as a nitrogenous
basic radical (ine). The phospholipines comprise the substances lecithin.
cephalin, cuorine, sphingomyeline. In brain and other tissues similar com-
pounds, which contain no phosphorus, occur, and in the place of glycerol w e
may find galactose. Leathes has proposed calling these compounds lipines
and galactolipines.
Lecithin, the chief phospholipine, is an ester compounded of two fatty
acid radicals, phosphoric acid, glycerol, and the amine, choline. The
various lecithins may be distinguished, according as they contain different
fatty acid radicals, as oleyl-lecithin, stearyl-lecithin. The following formula
represents distearyl-lecithin :
CH a — 0— OC.(CH 2 ) 18 CH 3
|
CH— O— OC.(CH 2 ) le CH 3
I
CH 2 -0 O
W
HCK x O.CH 2 .CH 2 .N(CH 3 ) 3
OH
On warming with baryta water lecithin is broken down into fattv acid,
glycerophosphoric acid, and choline. The latter base, which is trimethvl-
| C 2 H 4 OH
oxethvl-ammoniuni hvdrate, N • (CH 3 ) 3 must be distinguished from
(oh
|C 2 H 3
neurine. N (CH 3 ) 3 which is triniethvl-vinvl-aimnonium hydrate, and is
I OH
much more poisonous than choline. Choline forms a salt with hydrochloric
acid which, with platinum chloride, yields a double salt of characteristic
crystalline form, insoluble in absolute alcohol. The universal distribution of
lecithin seems to indicate that it plays an important part in the metabolic
58 PHYSIOLOGY
processes of the cell. There is no doubt that it may serve, inter alia, as a
source of the phosphorus required for building up the conrplex nucleo-proteins
of cell nuclei. It seems to represent an intermediate stage in the utilisation
of neutral fats by protoplasm, and its occurrence in the brain as a constituent
of more complex molecules, which contain also a carbohydrate nucleus
(galactosides, such as cerebrin), might be interpreted as indicating some
share also in the metabolism of carbohydrates.
Lecithin may be extracted from tissues by boiling with absolute alcohol.
On cooling the alcoholic extract in a freezing mixture, the lecithin separates
out as granules or semi-crystalline masses. When dried in vacuo, it forms
a waxy mass, which melts at 40° to 50° C. In water it swells up to form a
paste which, under the microscope, is seen to consist of oily drops or threads,
the so-called myelin droplets. In a large excess of water it forms an emulsion
or a colloidal solution. Its power of taking up water on the one hand, and
i! s solubility in alcohol and similar media on the other, give it an intermediate
position between the water-soluble crystalloids and the insoluble fats, and
enable it to play an important part both as a vehicle of nutritive substances
and as a constituent of the lipoid membrane, which bounds and determines
the osmotic relationships of all living cells.
The phospholipids are provisionally classified according to the proportions of
N and P in their molecule, as follows :
(a) Mono-amino-monoi)hosphatides,N : P= 1 : 1 (includinglecithin andcephalin).
(b) Diamino-mono-phosphatides, N:P =2: 1 [e.g. sphingomyelin).
(c) Mono-amino-diphosphatides, N : P = 1 : 2 (e.g. cuorin, a lipine extracted from
" heart muscle by Erlandsen).
(d) Diamino-diphosphatides, N : P =2:2.
(e) Triamino-monophosphatides, N : P = 3 : 1 (an example has been reported as
occurring in egg yolk).
All these bodies (except cuorin) are obtained by the extraction of the brain or of nerve
fibres. Many also occur in egg yolk. The galacto-lipines include two substances
extracted from the brain, viz. phrenosin and kerasin. Both these on decomposition
yield galactose, a nitrogenous base called sphmgosine and a fatty acid. We know
little or nothing of their significance.
SECTION IV
THE CARBOHYDRATES
The carbohydrates are a group of bodies of wide distribution and great
importance in both the vegetable and animal kingdoms. In plants the first
product of assimilation of carbon is a carbohydrate, and in animals these
substances form one of the most important sources of energy. They consist
of the elements carbon, hydrogen, and oxygen, the two last-named being
almost invariably in the proportions necessary to form water. It is on this
account that the term carbohydrate has been given to the group. Their
general formula might be expressed C n H, n O n . Certain derivatives of the
group, obtained by the substitution of methyl and other radicals for a
hydrogen atom, though necessarily classified with carbohydrates on account
of their reactions, do not conform to this general formula, e.g. rhamnose,
C r ,Hi 2 6 . All the carbohydrates which are of importance in the animal
economy contain six carbon atoms or a multiple of this number. Analogous
substances however can be prepared containing less or more than this
number of carbon atoms. A series of compounds exist which contain in their'
molecule 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms, and are termed dioses, trioses,
tetroses, pentoses, hexoses, heptoses, and so on ; the termination ' ose ' with
the Greek numeral prefixed, indicating the number of carbon atoms, gives
them a distinct designation. These are all oxidation products of polyatomic
alcohols, being either ketones or aldehydes of these alcohols. Thus from
COH
I
glycerol we may obtain glyceryl aldehyde CHOH and dioxvacetone
I
CH 2 OH OH ..OH
I
CO. Both these substances behave as sugars and belong to the group of
I
CH 2 OH
i rinses. They are generally obtained together and are called glycerose.
CH.OH
I
From the hexatomic alcohol (OHOH), we may obtain either the aldehyde
OH..OH
;>4
60 PHYSIOLOGY
CH 2 OH
I
COM CO
I I
(CHOH) 4 or the ketone (CHOH) 3 . These two oxidation products of tl
I I
CH 2 OH CH 2 OH
polyatomic alcohols are known as aldoses and ketoses respectively. All thet
compounds are distinguished by the termination ' ose.' It is convenien
to call those compounds containing six carbon atoms the sugars, becausi
it is to this group that the natural sugars belong.
Stereoisomerism in the Sugars. It will be noticed that of the six carbon
CH 2 OH
I
atoms contained in the sugar molecule, e.g. the aldose (CHOH) 4 , four are
I
COH
asymmetric, i.e. their four combining affinities are saturated with groups
of different kinds, viz. several carbon atoms, one H atom, and one OH
group .
C
I
H— O— OH
They must therefore present many stereoisomers forms. If n represent the
number of asymmetric carbon atoms in a compound, the possible number of
stereoisomers is 2 n . Thus an aldehexose with four asymmetric carbon atoms
(CHOH) 4 must present 2 4 isomers, i.e. sixteen isomeric compounds, so that
there must be sixteen sugars all possessing the formula CH 2 OH(CHOH) 4 COH,
in addition to the inactive sugars obtained by a mixture of two oppositely
active members of this group. Of the sixteen possible sugars of this formula,
as many as fourteen have been found or have been artificially prepared.
Only a small number are however of any physiological importance. These
include the aldoses, glucose, mannose, and galactose, and the ketose, fructose
or levulose. All the other sugars are unassimilable by the animal cell and
are not manufactured by plants.
Since these sugars can be divided into the optically active and the inactive
varieties, an obvious mode of designation would be to represent them as
d-, 1-, and i- varieties respectively, i.e. dextro-rotatory, lsevo-rotatory, and
inactive. On Fischer's suggestion however, this mode of nomenclature has
been altered in favour of representing, by the letter prefixed, not the optical
qualities of the substance in question, but its relation to other substances,
especially glucose. Thus, d-fructose means that fructose is the ketose corre-
sponding to the dextro-rotatory glucose, d-fructose itself being lsevo-rotatory,
though its active asymmetric C atoms are identically arranged with those in
glucose. With this limitation one may say that it is only the d-hexoses of a
THE CARBOHYDRATES 61
articular form which are assimilable, and therefore of physiological im-
irtance. The small differences in the configuration of the four d-sugars
n be readily seen if their graphic formula? be compared :
CHO CHO f!H,OH CHO
I I I I
H.C.OH HO.C.H CO H.C.OH
I I I I
HO.C.H HO.C.H HO.C.H HO.C.H
I I I I
H.C.OH H.C.OH H.C.OH HO.C.H
I I I I
H.C.OH H.C.OH H.C.OH H.C.OH
I ,1 I I
CH 2 OH CH 2 OH CH 2 OH CH 2 OH
d-glucose d-mannose d-fructose d-galactose
THE PENTOSES. C 5 H 10 O 6
These bodies occur largely in plants in the form of complex polysaccharides, the
pentosanes, which give pentoses on hydrolysis with acids. Two forms of pentose
have been found in the animal body, namely, i-arabinose, which has been isolated
from the urine in cases of pentosuria, and 1-xylose (or d-ribose, Levene), which occurs
built up into the nucleic acid molecule of the pancreas and perhaps other organs. The
pentoses can apparently be utilised by herbivora as food-stuffs. We know nothing as
to the part they play in the animal body or as to the causation of the rare condition of
pentosuria. Since however they are reducing substances and the presence of pentose
in urine might therefore lead to a suspicion of diabetes, it is necessary to mention the
tests by which the presence of pentoses may be detected. The two following are the
chief tests for pentoses :
(1) The solution supposed to eon tain a pentose is mixed with an equal volume of
concentrated hydrochloric acid. To the mixture is added a small quantity of solid
orein and the whole is heated. If pentose is present the solution becomes at first
reddish-blue and later bluish-green. The colour can be extracted on shaking the
fluid with amyl alcohol, the solution, on spectroscopic examination, showing an absorp-
tion band between C and D.
(2) Instead of adding orcin, we may add phloroglucin to the mixture of hydrochloric
acid and pentose. The solution on heating becomes first cherry red and then cloudy.
On shaking with amyl alcohol a red solution is obtained which shows a band between
D and E.
THE HEXOSES AND THEIR DERIVATIVES
The most important of the carbohydrates belong to this class and are
either hexoses or formed by a combination of two or more hexose molecules.
They are divided into three main groups :
(1) Monosaccharides, with the formula C 6 H 12 6 , examples of which pre
glucose, fructose, &c.
(2) Disaccharides, which are derived from two molecules of a monosac-
charide with the elimination of a molecule of water, as follows :
2C 6 H 12 6 - H 2 = C 12 H 22 O n .
(Examples, maltose and cane sugar.)
62 PHYSIOLOGY
(3) Polysaccharides, composed of three or more molecules of a mono-
saccharide. The number of molecules which are associated in the com-
pounds of this group may be very large. We can regard their general
formation as represented by the following equation :
nC,H 12 6 -nH 3 = (C.H 1 ,0,)n-
(Examples, starch, dextrin, &c.)
THE MONOSACCHARIDES
Only four hexoses out of the large number which have been synthetised
are assimilable by the animal body. These are mannose, glucose, galactose,
and fructose, the three former being aldoses, while the last is a ketose. All
of them are derivatives of d-glucose. They may be synthetised in several
ways. The most interesting, because it probably represents the mechanism
of synthesis of hexoses in plants, is the formation from formaldehyde. In
alkaline solutions formaldehyde polymerises with the formation of a mixture
of hexoses known as acrose. From this mixture a-acrose can be isolated by
the formation of its osazone and the reconversion of this osazone into sugar.
It is found to be identical with i-fructose. If a solution of this i-fructose be
treated with yeast, d-fructose is fermented, leaving 1-fructose behind. For
the preparation of d-fructose it is necessary to convert the inactive sugar into
the corresponding acid, mannonic acid. This with strychnine or morphia
forms salts which can be separated into the d- and 1- groups by fractional
crystallisation. From the d- modification d-mannose can be obtained, and
this by conversion into the osazone and reconversion into a sugar gives
d-fructose.
All the monosaccharides, however many carbon atoms they contain, present certain
general reactions determined by their chemical composition.
(a) Like ordinary aldehydes and ketones, the sugars act as strongly reducing sub-
stances, and, like aldehydes, reduce ammoniacal solution of silver to metallic silver,
and many of the higher oxides of metals to lower oxides. On this behaviour is founded
the commonest of all the tests for the presence of reducing sugar — Trommel's test.
(6) On oxidising a monosaccharide the COH group becomes converted to COOH.
Thus glucose on oxidation gives gluconic acid :
COH(CHOH) 4 CH 2 OH + O = C'0()H(CHUH) 4 CH 2 OH.
On further oxidation the end group CH 2 OH also is affected, and we obtain a dibasic
acid. Thus glucose gives saccharic acid.
(c) By means of nascent hydrogen the monosaccharides can be reduced to the
corresponding polyatomic alcohol. Thus the three hexoses, glucose, fructose, and
galactose give the corresponding three alcohols, sorbite, mannite, and dulcite C 6 H 14 6 .
(d) Another important general reaction of the monosaccharides depending on the
COH or the CO group is the reaction with phenyl hydrazine. On warming a solu-
tion of sugar with a solution of phenyl hydrazine in acetic acid, the following reactions
take place. The first reaction results in the production of a hydrazone :
CH„OH(CHOH) 3 CHOHCHO + H,N.NH.C 6 H 5 =
CH 2 OH(CHOH) 3 CHOH.CH : N.NH.C 6 H 5 + H 2 0.
The hydrazone then reacts with another molecule of phenyl hydrazine with the pro-
duction of an osazone :
THE CARBOHYDRATES 63
CH.,(()H)(CHOH) 3 CHOH.CH: N.NH.C 6 H 5 + H,N.NH(' 6 H 5 -
CH„OH(CHOH) 3 C.CHN.NH.C H 5
II
N.NH.C 6 H 6 + H 2 + H 2 .
The hydrogen formed in this reaction acts upon a second molecule of phenyl hydrazine,
splitting it into aniline and ammonia. On this account it is always necessary to have
an excess of phenyl hydrazine in the operation.
The osazones form well-defined crystalline products which are generally yellowish
in colour and differ in their melting-point and in their crystalline form. They are
therefore of extreme value in the separation and identification of different carbohy-
drates. They can be also used for the artificial preparation of certain sugars. Under
the influence of acetic acid and zinc dust they form osamines, which on treatment with
nitrous acid are reconverted into the corresponding sugar, generally a ketose.
GLUCOSE, DEXTROSE or GRAPE SUGAR, is the chief constituent of the
sugar of fruits, especially of grapes. It occurs in the body as the end-
product of the digestion of starch. When pmc it forms white crystals which
melt at 100° C, and lose the one molecule of water of crystallisation at
1 10° C. It is easily soluble in water, and the solution shows bi-rotation.
Its final specific rotatory power at 20° C. is 52 '74.
TESTS FOR GLUCOSE. Trommer's test depends on the power possessed in
common with the other sugars of reducing cupric hydrate to cuprous oxide. The
sugar solution is made alkaline with caustic potash or soda, and a few drops of copper
sulphate solution added. On heating the blue solution thus obtained to boiling, it
turns yellow, and a yellowish-red precipitate of cuprous hydrate is produced. This
test is generally performed with Fehling's solution, which consists of an alkaline solution
of cupric hydrate in Rocheile salt. The proportions in making the solutions are so
arranged that 10 c.c. of Fehling's solution are completely reduced by -05 gramme glucose.
This reaction is made use of for the quantitative determination of glucose in solution.
The determination may be carried out either volumetrically, as in Fehling's or Pavy's
method, or gravimetrically, as in Allihn's method.
Moore's Test. A solution of glucose treated with a little strong caustic potash
or soda and warmed, becomes first yellow and then gradually dark brown, and gives
off a smell of caramel.
With ordinary yeast, glucose solutions ferment readily, giving off C0 2 , and form
alcohol with small traces of amyl alcohol, glycerin, and succinic acid.
With phenyl hydrazine glucose gives well-marked needles of glucosazone. These
are precipitated when the liquid is still hot, the precipitate being increased as the
liquid cools. The crystals form bundles of fine yellow needles which are almost in-
soluble in water, but are soluble in boiling alcohol. When purified by recrystallisation
they melt at 204-205° C.
On treating a watery solution of glucose with benzoyl chloride and caustic soda
and shaking till the smell of benzoyl chloride has disappeared, an insoluble precipitate
is produced of the benzoic ester of glucose. This method has been often used for
isolating glucose from fluids in which it occurs in minute quantities.
Molisch's Test. On treating 0-5 c.c. of dilute glucose solution with one drop of a
10 per cent, alcoholic solution of a-naphthol, and then pouring 1 c.c. of concentrated
sulphuric acid gradually down the side of the tube, a purple ring is produced at the
junction of the two fluids, which on shaking spreads over the whole fluid. This reaction
depends on the formation of furfurol from the glucose.
In order to identify glucose in a normal fluid, the following tests may be applied,
after removing any protein which may be present:
(1) Reduction of cupric hydrate or Fehling's solution.
64 PHYSIOLOGY
(2) Estimation of reducing power of solution.
(3) Estimation of rotatory power of solution on polarised light.
(4) Formation of osazone crystals with phenyl hydrazine. These crystals must
come down while the fluid is still hot. They must be purified and their melting-point
taken. A determination by combustion of their nitrogen content will give direct
information whether the sugar is a monosaccharide or disaccharide. <
(5) The solution is made acid and boiled for some time. It is then made up to its
former volume and its reducing power and effect on polarised light once more taken.
In the case of a disaccharide, which would be converted into monosaccharide by boiling
in acid solution, these two readings would be altered, whereas neither the rotatory
power nor the reducing power of glucose would undergo any change.
(6) Fermentation with ordinary yeast.
A positive result would exclude glycuronic acid.
D-FRUCTOSE, or LiEVULOSE, occurs mixed with dextrose in honey
and in fruit sugar. It is also, with glucose, formed by the digestion or inver-
sion of cane sugar. It is crystallisable with difficulty. Its watery solution
is laevo-rotatory, and reduces Fehling's solution somewhat less strongly than
glucose, its reducing power being 92, if we take that of glucose as 100. It
ferments readily with yeast ; with phenyl hydrazine it gives the same osazone
as is formed from glucose.
GALACTOSE is formed by the digestion or hydrolysis of milk sugar or
lactose. It is also obtained on hydrolysing cerebrin, a constituent of the
brain, with dilute mineral acids, and by the hydrolysis of certain vegetable
gums. It is much less soluble in water than glucose. It is dextro-rotatory
and shows marked bi-rotation. With ordinary yeast it ferments but ex-
tremely slowly. One species of yeast is known, namely, saccJiaromyces apicu-
latus which, while fermenting d-fructose and glucose, has no effect on galac-
tose. This yeast can therefore be used to isolate galactose from a mixture of
the monosaccharides. It reduces Fehling's solution, its reducing power
being somewhat less than that of glucose. Yeasts can be trained to ferment
galactose.
MANNOSE. Mannose, though an assimilable sugar, is of such rare occurrence in
our food-stuffs that it plays practically no part in animal physiology. It is dextro-
rotatory, reduces Fehling's solution, ferments easily with ordinary yeast, and gives
an osazone which is identical with that derived from glucose.
DERIVATIVES OF THE HEXOSES
Two derivatives of glucose are of considerable physiological importance, namely,
glucosamine and glycuronic acid.
Glucosamine, C 6 H 13 N0 6 , has the structural formula :
CH 2 OH
I
(CH.OH) 3
I
CH.NH 2
I
CHO
THE CARBOHYDRATES 65
It is obtained from chitin, which forms the exoskeleton of large numbers of the inver-
tebrata, by boiling this with concentrated hydrochloric acid. It is stated to have
been obtained as a decomposition product of certain proteins and their derivatives,
such as the mucins. It is of special interest as affording an intermediate product
between the carbohydrates and the oxy-ainino acids which can be obtained by the
disintegration of proteins. In solution it is dextro-rotatory, reduces Fehling's solu-
tion, and gives an osazone resembling that derived from glucose.
GLYCURONIC ACID. O 6 H 10 O,, may be regarded as one of the first results of
oxidation of the glucose molecule. The group which has undergone oxidation is not the
readily oxidisable CHO group, but the CH 2 OH group at the other end of the molecule.
The formula of this acid is therefore :
COOH
I
(CH.OH) 4
I
CHO.
In the free state it does not occur in the animal body. It is constantly found in the
urine after administration of certain drugs such as phenol, camphor, or chloral, and
then occurs as a conjugated acid with these substances. These conjugated acids are
laevo-rotatory, though the free acid is dextro-rotatory. In the free state it reduces
Fehling's solution and gives an osazone which is not sufficiently characteristic to dis-
tinguish from glucosazone. It does not undergo fermentation with yeast. This test
is therefore the best means of distinguishing the acid in urine from glucose.
THE FORMATION OF GLUCOSIDES
The graphic formulae given on p. 61 do not explain all the possible modes of arrange-
ment of the groups of the sugar molecules. Many of these sugars, when dissolved in
water, present the phenomenon known as multi-rotation. If their rotatory power
be taken immediately after solution, it is found to be greater or less than the rotatory
power taken some hours or days later. Glucose, for instance, immediately after solu-
tion, has a high specific rotatory power, which diminishes rapidly if the solution be
boiled, and more slowly if it be allowed to stand. Finally, the specific rotatory power
becomes constant at + 52-5° D. This change in rotatory power seems to be associated
with a change in the arrangement of the groups, the aldose for example assuming,
by the shifting of a mobile oxygen atom, what is known as a lactone arrangement.
Thus glucose COH(CHOH) 2 CHOH.CHOH.CH 2 OH becomes
CHOH.(CHOH) 2 .CH.CHOH.CH,OH
This change in the arrangement of the molecule renders a further stereoisomerism
possible, owing to the fact that now the end group which was formerly COH becomes
H
I
0— C— OH
I
c
so that now there are five instead of four asymmetric carbon atoms. The two isomers
5
1,1,
PHYSIOLOGY
if glucose, which are thus rendered possible, are represented by (he following structural
formulae :
OH— C— H
BOCH
In these molecules the OH attached to the end group can be replaced by other radicals,
including other sugar molecules. In this way we get the formation of glucosides. Thus,
if glucose be dissolved in methyl alcohol and be treated with hydrochloric acid, we
obtain a and j'i methyl glucosides, the formula; of which would be represented as follows :
H— C— OCH, CH 3 0— C— H
HOCH
HCOH HCOH
I I
CH..OH 0H,OH
Instead of methyl we might insert other groups, and even other hexose groups, such
as glucose or galactose, obtaining the two sugars maltose and lactose, which may thus
be regarded as glucosides — maltose as the a-glucoside of glucose, lactose as the /3-galae-
toside of glucose. The mode of combination of the two hexose groups to form these
disaccharides may be represented as follows :
H H OH H H
CH 2 OH— C— C — C— C — C glucose rest
OH HOH
HO H HO HO
OHC — C — C — C — C — CH, glucose rest
H OH H H
O
maltose.
CH,OH -
H OH H
- C — C— C — C -
OH H H OH
• C galactose rest \
lactose
HO H HO HO
OHC — C — C — C — C— CH 2 glucose rest
H OH H H
THE CARBOHYDRATES 67
A very large number of glucosides occur as plant products. Among these we may
mention amygdalin, salicin, phloridzin, indican, &c.
THE DISACCHARIDES
The disaccharides are formed by the union of two molecules of mono-
saccharides with the elimination of one molecule of water, and can be re-
garded, according to the manner in which the molecules are combined, as
glucosides, galactosides, &c. On hydrolysis, e.g. on heating with acids, they
take up one molecule of water and are split up into the corresponding mono-
saccharides. Thus cane sugar gives equal parts of glucose and fructose,
maltose gives equal parts of glucose and glucose, while milk sugar or lactose
gives equal parts of glucose and galactose.
CANE SUGAR, sometimes known as saccharose, is widely distributed
throughout the vegetable kingdom, and forms an important article of diet.
It has no reducing power on Fehling's solution. It is strongly dextro-rcta-
tor)' and has a specific rotatory power of + 66 "5°. On hydrolysis it is
converted into equal molecules of glucose and fructose. Owing to the fact
that fructose rotates polarised light more strongly to the left than glucose
does to the right, the mixture of the two monosaccharides so obtained is
laevo-rotatory. On this account the change from free cane sugar to the
mixture of monosaccharides is known as inversion, and the mixture is often
spoken of as ' invert sugar.' The term ' inversion ' has since been loosely
applied to the process of hydrolysis itself, so that we often speak of the
inversion of maltose or of lactose, meaning thereby the hydrolysis of these
sugars with the production of their constituent monosaccharides. With
veast , cane sugar first undergoes inversion by a special ferment present in the
yeast (invertase), and the mixture of fructose and glucose is then fermented.
MALTOSE is formed during the hydrolysis of starch by acids or by
digestive ferments, and is also the chief sugar in germinating barley or malt.
It is strongly dextro-rotatory, ferments easily with yeast, and reduces
Fehling's solution ; its reducing power is about 70 per cent, of that of
glucose. With phenyl hydrazine it gives phenyl maltosazone, which forms
definite yellow crystals with a melting-point of 206° C.
MILK SUGAR or LACTOSE is found only as a constituent of milk.
It forms colourless rod-like crystals, which are much less soluble in water
than are the two other disaccharides. On account of this solubility it is much
less sweet than either cane sugar or maltose. It is dextro-rotatory and
shows bi-rotation. It is not fermented by ordinary yeast. Before fermen-
tation can occur the lactose must be split by the agency of acids or by a
ferment, lactase, which occurs in the animal body and in certain moulds, into
the monosaccharides glucose and galactose. Lactose reduces Fehling's
solution and gives with phenyl hydrazine lactosazone, which is easily soluble
in hot water and therefore does not come down until the fluid is cold.
THE POLYSACCHARIDES
These play an important part throughout the whole vegetable kingdom,
where all the supporting tissues of the plants, their protective substances,
68 PHYSIOLOGY
an<] many of their reserve materials consist of members of this group. In
the animal body, where the supporting tissues are composed chiefly of deriva-
tives of proteins, the sole significance of polysaccharides lies in their value as
food-stuffs. In plants, anhydrides both of hexoses and pentoses occur in
bewildering variety. Here however we may confine our attention to those
members of the group of polysaccharides which are important as food-stuffs.
STARCH (CJIioOt) is present in large quantities in nearly all vegetable
foods, and is an important constituent of the cereals, from which flour and
bread are derived, as well as of tubers, such as the potato. In the plant cells
it occurs as concentrically striated grains within minute protoplasmic
structures— the amyloplasts, the office of which it is to manufacture starch
from the glucose present in the cell sap. When freed, by breaking up the
cells and washing with water, it forms a white powder consisting of micro-
scopic grains, each of which presents the characteristic concentric striation.
It is insoluble in cold water. In hot water the grains swell up and burst.
forming a thick paste, which sets to a jelly on cooling. This semi-solution,
as well as the original starch-grains, gives an intense blue colour on the
addition of iodine. On treating starch with cold alkalies or cold dilute acid,
it is converted into a soluble modification, the so-called soluble starch or
amylodextrin, which also gives a blue colour with iodine. This modification
is also produced as the first stage of the action of diastatic ferments upon
starch. On boiling with dilute acids, starch is converted first into a mixture
of dextrins, then into maltose, and finally into glucose. On acting upon
starch with various ferments, such as the diastase which may be extracted
from malt or germinating barley, or with the amylase occurring in saliva or
pancreatic juice, it undergoes hydrolysis, the final result of the action being a
mixture of four parts of maltose to one part of dextrin. As to the inter-
mediate stages in this reaction opinions are still divided. The first product
is soluble starch, amylodextrin, giving a blue colour with iodine. This
breaks up into a reducing sugar, and another dextrin, erythrodextrin, which
gives a red colour with iodine ; and this dextrin, on further hydrolysis,
yields reducing sugar and achroodextrin, which is not coloured by the
addition of iodine. Thus there are a series of successive hydrolytic decom-
positions of the molecule, each resulting in the splitting off of a molecule
of sugar and the production of a lower dextrin.
The DEXTRINS are ill-defined bodies which are difficidt to separate.
They are amorphous white powders, easily soluble in water, forming solutions
which, when concentrated, are thick and adhesive. They are insoluble in
alcohol and ether. With cupric hydrate and caustic alkali they form blue
solutions, which reduce slightly on boiling. They are not precipitated by
situration with ammonium sulphate. On boiling with dilute acids, they are
converted entirely into glucose.
The changes undergone by starch during its hydrolysis by means of diastase have
been used by Brown and his co-workers as a method of arriving at some idea of the
size and structure "of the starch molecule. Proceeding from the discovery that the
end-products of this reaction consisted of 81 per cent, maltose and 19 per cent, dextrin,
THE CARBOHYDRATES 69
they concluded that starch must consist of five dextrin-like groups, four of which are
arranged symmetrically round the fifth. At each stage one of these groups is split off and
hydrolysed to form malto-dextrin : { ,_, *£ 2 J. " • one molecule of water being
' J U C 12 H 2oOlo)2j
taken up. The malto-dextrin group is then changed into maltose by the further
assimilation of two molecules of water. The central dextrin-like group is attacked
with great difficulty by the ferment, and therefore remains at the end of the reaction as
achroodextrin. The malto-dextrin, the penultimate stage in the action of diastase,
can be regarded as formed by the condensation of three molecules of maltose attached
by the oxygen of two CHO groups, so that one CHO group remains free and determines
the reducing power of the malto-dextrin molecule. Its formula may therefore be
represented as follows :
W-9n^-'a
Ci 2 H 21 O 10 <'
the sign ( being used to denote the open terminal CHO group.
N
They further found that the stable dextrin remaining at the end of the diastatic
hydrolysis of starch probably had the formula of •40C 6 H 10 O 5 H 2 O, and might be regarded
as a condensation of forty glucose molecules with the elimination of thirty-nine mole-
cules of water. The starch molecule cannot be less than five times that of the stable
achroodextrin. Since the latter has a molecular weight of 6498, the molecular weight of
starch cannot be less than 32,400, and its empirical formula can be represented by :
100C 12 H 20 O 10 . or (80C 12 H 20 O 10 .40C 6 H 10 O 5 ).
INULIN. Another kind of starch, known as inulin, occurs in dahlia
tubers. Tt is easily hydrolysed by weak acids, and is entirely converted into
d-tiuctose, or lsevulose.
GLYCOGEN, or animal starch, is found in the liver, muscles, and other
tissues of the body, and occurs in large quantities in all foetal tissues. It is
a white powder, soluble in water, forming an opalescent solution. It is
precipitated from its solution on the addition of alcohol to 60 per cent., or by
saturation with solid ammonium sulphate. On boiling with acids, it is
entirely converted into glucose. It is affected by the ferments diastase and
amylase, in the same way as vegetable starch, giving first dextrins and finally
a mixture of maltose and dextrin. With iodine it gives a mahogany-red
colour which, like the blue colour produced in starch, is destroyed by boiling,
to return again on coobng. We shall have occasion to consider its properties
more fully when we are dealing with the functions of the liver.
THE CELLULOSES. Cellulose (C 6 H 10 6 ) x is a colourless, insoluble
material, or mixture of materials, which forms the cell walls of the younger
parts of plants, and is therefore a constituent of most of our vegetable
foods. It is insoluble in water or dilute acids or alkalies, its only solvent
being an ammomacal cupric oxide solution. On boiling with strong acids,
it gradually undergoes hydrolysis and yields sugar, the nature of which
varies according to the source of the cellulose. In herbivorous animals cellu-
lose undergoes digestive changes and forms an important constituent of their
70 PHYSIOLOGY
food. The solution of the cellulose in this case is effected by the agency, not
of ferments secreted by the wall of the gut, but of micro-organisms which
swarm in the paunch of ruminants and in the caecum of other herbivora. In
some cases the effective agent is a cytase present in the vegetable cells
themselves. Since this ferment is destroyed by boiling, cooked hay is much
less digestible than hay in the raw condition. In certain invertebrata it seems
probable that a true cellulose-digesting ferment, or cytase, is secreted by the
walls of the alimentary canal. In man cellulose undergoes practically no
change in digestion, and serves merely by its bulk to promote peristalsis and
the normal evacuation of the bowels. A further consideration of its chemical
properties, as well as of the closely allied vegetable materials, gums, pectins,
mucilages, derived for the most part from the condensation of pentose
molecules, may be dispensed with here.
SECTION V
THE PROTEINS
As sources of energy to the organism all three classes of food-stufls are
valuable in proportion to their heat equivalents, and it is often a matter of
indifference whether the main bulk of the energy required is supplied at
the expense of fat or at the expense of carbohydrate. The proteins however
form the most important constituent of living protoplasm. On this account
protein must always be present in the food to supply the material necessary
for building up new protoplasm in the growing animal and for replacing
the waste of living material which is taking place in the discharge of its
normal functions. Regarding the complexity of reaction presented by living
protoplasm as determined in the first instance by the chemical and physical
complexity of this material itself, we should expect to find that the proteins
forming its main constituents would themselves partake of some of this
quality. The carbohydrates and fats, although in many cases made up of
huge molecules, are nevertheless built up on a very simple type. Starch,
for instance, with a molecular weight of over 30,000, is formed simply by the
polymerisation of glucose molecules. The ordinary fats, stearin and
palmitin, consist of fatty acids with long straight chains of CH 2 groups
combined with the glyceryl radical. Their molecular weight is very large,
but their molecules are simple in structure. When however we break up a
protein molecule we meet with a great number of subsidiary groups, the
presence of which is essential to the making of a nutritive protein.
Owing to this complexity of structure it is not easy to give a simple
definition in chemical terms of what we mean by the term ' protein.' It is
necessary rather to describe certain of the qualities presented by this group,
the possession of which we regard as essential to the conception of a protein.
Elementary Composition. All proteins contain oxygen, hydrogen, nitro-
gen, carbon, and sulphur. The proportion of these elements in the various
proteins may be represented as follows :
C 50 "6-54 "5 per cent.
H 6-5- 7-3 „ „
N 150-176 „ „
S 0-3- 22 „ ,.
O 21-5-23-5 „ „
Nearly all the proteins contain a small trace of phosphorus varying from
0'i to 0'8 per cent. It is doubtful however how far this phosphorus forms
an integral part of the protein molecule.
71
72 PHYSIOLOGY
I J /n/sical Characters. The proteins are amorphous indiffusible substances
belonging to the class of bodies known as colloids. Most of them are soluble
either in water, weak salt solutions, or in dilute acids or alkalies. They are
inert bodies and tasteless. Although they form compounds with various
metallic salts, acids, or alkalies, these compounds are but ill defined, and the
relative proportions of the ingredients vary according to the conditions under
which the compound was formed. As is the case with most colloids when
in solution or pseudo-solution, they can be brought into an insoluble form
by various simple agencies, such as shaking, change of temperature, altera-
tion of reaction, or addition of neutral salts. Coagulation by heat forms a
distinguishing feature of a number of members of this class, which are there-
fore spoken of as ' coagulable proteins.' For instance, white of egg is a
solution of different proteins. On diluting it with weak salt solution no
precipitation takes place. If however the solution be heated to about 80° C.
a precipitate of coagulated protein is formed. If a strong solution be boiled
the whole fluid sets to a solid white mass (hydrogel). This change is irrever-
sible, i.e. it is not possible by lowering the temperature to bring the white of
egg again into solution, and many properties of the protein have been changed
in the act of coagulation. With certain proteins and their allies the coagula-
tion on change of temperature is a reversible process. Thus an alkaline
solution of caseinogen, the chief protein of milk, if treated with a little cal-
cium chloride and heated, undergoes coagulation and sets into a jelly, but on
cooling the mixture the coagulum once more enters into solution. Ordinary
gelatin, which is closely allied to the proteins, with water forms a solid jelly
below 20° C, and a fluid solution above this temperature.
If a protein be heated in a current of air or oxygen it undergoes com-
bustion. In all cases a certain amount of incombustible material is left,
consisting of inorganic salts which were closely attached to the protein
molecule. If a solution of protein be subjected to long-continued dialysis,
the proportion of ash may be diminished very largely, but in no case has
any experimenter succeeded in obtaining a preparation of protein absolutely
ash-free. On this account it has been thought that the salts of the ash must
be in chemical combination with the protein ; but having regard to the
physical character of colloidal solutions, which we shall study in the next
chapter, and the power of adsorption of substances possessed by such solu-
tions, there is no need to regard these salts as essential constituents of the
protein.
Crystallisation of Proteins. Although the indiffusibility of protein solutions differen-
tiates them from the crystalloid substances such as sugar or sodium chloride, under
certain conditions it is possible to obtain crystals consisting, largely at any rate, of
proteins. Thus in the seeds of certain plants, e.g. hemp seeds, Brazil nut, pumpkin
and castor-oil seeds, the so-called aleurone crystals may be seen under the microscope
enclosed in the protoplasm of the cells. These crystals consist of proteins belonging to
the class of globulins. By chemical means they can be separated from the surrounding
tissues and, after washing, dissolved in a solution of magnesia. Drechsel showed that
on dialysing such a solution against alcohol, the fluid undergoes gradual concentration,
and crystalline granules of the magnesia compound of the protein separate out. These
THE PROTEINS 73
crystals contain 1-4 p.c. MgO. A better method of obtaining such crystals has been
devised by Osborne. The ground seeds are extracted with 10 per cent, sodium chloride
solution, and filtered. The filtrate is diluted with water heated to 50° or 60° C. until a
slight turbidity forms. After warming the diluted solution until this turbidity dis-
appears, and then allowing it to cool slowly, the protein separates in well-developed
crystals. It is possible also to obtain crystals of animal proteins. Haemoglobin, the
oxygen -carrying protein of the red blood corpuscles, can be made to crystallise with
extreme ease. With some animals, such as the rat, it is only necessary to bring the
haemoglobin into solution, by the addition of a little distilled water and ether to the
blood, to cause the crystallisation of the liberated haemoglobin.
Egg albumin and serum albumin may also be crystallised with ease by a method
devised by Hofmeister and improved by Hopkins. If, for instance, we wish to crystallise
egg albumin, white of eggs is treated with an equal bulk of saturated solution of ammo-
nium sulphate in order to precipitate the globulin. It is then filtered, and the filtrate
is treated with saturated ammonium solution until a slight permanent precipitate
is produced. This precipitate is then just redissolved by the cautious addition of water,
and dilute acetic acid (10 per cent.) is added drop by drop until a slight precipitate is
produced. The flask is now corked and allowed to stand for twenty-four hours, when
the precipitate, which will have increased in quantity, will be found to consist entirely
of acicular crystals. A similar method may be used for seruni albumin. In each case
the crystals contain a considerable proportion of ammonium sulphate. This may be
replaced by sodium chloride by washing the crystals with a saturated solution of
this salt. By absolute alcohol the crystals may be coagulated and may be then washed
practically free from salt, but it is not possible to obtain crystals of coagulable protein
free from the presence of some salt.
Although by repeated crystallisation of egg albumin a product may be obtained
which is absolutely constant in both its physical and chemical characters, we cannot
ascribe to crystallisation the same importance in securing purity and homogeneity of
the substance that we can when we are dealing with inorganic salts. This is due to the
fact that these crystals take up other colloids with great ease. When haemoglobin, for
instance, is crystallised from blood, the first crop of crystals, although thoroughly
washed from their mother liquor, always contain a considerable proportion of serum
albumin. Indeed, the presence of colloidal material seems to render the production
of the so-called mixed crystals much more easy. Thus Schultz has shown that in
urine mixed inorganic crystals can be obtained. Human urine is allowed to stand
twenty-four to forty-eight hours with dicalcium phosphate and then filtered. On
allowing the filtrate to evaporate slowly, a crystalline precipitate is produced consist-
ing of whetstone-shaped crystals which are doubly refracting. On treating these
crystals with dilute acetic acid this acid extracts calcium phosphate from the crystals.
The original shape of the crystals is however retained. The only difference under
the microscope consists in the fact that they have now lost their doubly refracting
power on polarised light. They consisted of a mixture of calcium sulphate and calcium
phosphate from which, on treatment with acid, only the calcium phosphate was dis-
solved out.
The Molecular Weight of Proteins. We may arrive at an approximate idea
of the minimum size of the protein molecule in various ways, though in all
cases our calculations are apt to be vitiated by the difficulty of obtaining a
preparation which is homogeneous, i.e. chemically pure, and by the ease
with which molecules of the size which we must assume for proteins form
adsorption combinations in varying proportions with other substances.
If we assume that each molecule of the respective protein contains only one
atom of sulphur, we can calculate its molecular weight. It is evident that
the protein which contains 1 per cent, of sulphur will have a molecular weight
74 PHYSIOLOGY
of 3200. In this way the following molecular weights have been arrived at
(Abderhalden) :
Sulphur per cent. Molecular weight.
Edestin 0-87 . . 3680
Oxyhemoglobin . . . 43 . . 7440
(horse)
Serum albumin . . . 1-89 .. 1700
(horse)
Egg albumin . . . . 1-30 . . 2460
Globulin 1-38 .. 2320
The greater part at any rate of the sulphur in the protein molecule occurs
as a constituent of a substance, cystine, each molecule of which contains two
atoms of sulphur. Each molecule of protein must also contain two atoms of
sulphur, and we must regard double the molecular weight given in this Table
as the minimum molecular weights of these various proteins. Some idea of
the molecular complexity represented by these weights may be gained by
writing out the empirical formula? of the various proteins, e.g.,
Egg albumin ....... C 20 4H 322 N 52 O 66 S 2
Protein in haemoglobin (from horse) . . C 680 H 10!(fi N 210 (),, 1 S ,
Protein in haemoglobin (from dog) . . . C, 25 H 117 iNic, 4 21 4S„
Crystallised globulin (from pumpkin seeds) . C 202 H 481 N 20 S3 S 8
With some proteins we may make use of other elements to arrive at an
idea of the approximate molecular weight. Thus oxyhemoglobin contains
between 0'4 and 0'5 per cent. iron. If we assume that each molecule of
oxyhemoglobin contains one atom of iron, its molecular weight must be
from 11,200 to 14,000.
Attempts have been made to solve the same question by studying the compounds
of proteins with inorganic salts or oxides. Thus, the crystals of globulin from pumpkin
seeds prepared with magnesia contain 1-4 per cent. MgO. Assuming that one mole-
cule of protein has combined with one molecule MgO, the molecular weight of the
protein must be about 2800.
(If x be the molecular weight
x _ 100 - 1-4
40 hi
. • . x = 2817)
Harnack has shown that many proteins are precipitated from their solutions as
copper compounds by the addition of copper sulphate. Harnack found that this pre-
cipitate of copper contained either 1-34 — 1-37 Cu. or 2-48 — 2-73 per cent. Cu. The
smaller percentage would correspond to a molecular weight of 4700, while the second
number might be accounted for on the hypothesis that each molecule of protein was
combined with two atoms of copper. Similar attempts have been made by determining
the amount of acid or alkali necessary to keep certain types of protein in solution.
We shall see later on however that the amounts vary largely with the physical con-
dition and previous history of the colloidal substance. We are dealing here not with
compounds in the strict chemical sense of the term, but with adsorption compounds,
where the quantities taken up are determined not only by the chemical nature of the
protein itself, but by the state of aggregation of its molecules. It is therefore impossible
to lay any great stress on the determinations of the molecular weight which have been
effected in this way.
THE PROTEINS 75
Some clue to the size of the protein molecule is afforded by determinations
of the osmotic pressure or molecular concentration of their solutions by
physical methods. When we determine the freezing-point or boiling-point
of protein solutions, the depression of freezing-point, or elevation of boiling-
point is so small that it falls within the limit of experimental error or is
no greater than can be accounted for by the inorganic salts present in the
solution. Since however colloidal membranes, such as films of gelatin
or vegetable parchment, are impervious to proteins, we can directly deter-
mine the osmotic pressure of their solutions. In many cases no osmotic
pressure whatever is found. In other cases, e.g. egg albumin or serum, the
colloidal constituents of these solutions are found to give an osmotic pressure
of such a height that 1 per cent, protein corresponds to about 4 mm. Hg.
pressure. Such an osmotic pressure would indicate a molecular weight for
the serum proteins of about 30,C( 0. A determination of the osmotic pressure
of haemoglobin by Hiifner gave a molecular weight about 16,000. These
results however must be received with caution, since we are not, justified
in applying to these gigantic molecules data derived from a study of smaller
molecules such as salt or sugar. Even if we accept these determinations of
osmotic pressure as indicating the molecular weights I have just quoted, it is
evident that a very slight degree of aggregation of the molecules into larger
complexes will bring the osmotic pressure below the point at which it is
measurable, and would transform the solution into a suspension of particles
in which one could not expect to find any osmotic pressure whatsoever.
THE STRUCTURE OF THE PROTEIN MOLECULE.
We can arrive at some idea of the manner in which the protein molecule
is built up only by breaking it down bit by bit, employing methods which,
while resolving the large molecule into its proximate constituents, will not
act too forcibly in changing the whole arrangements of these constituents.
The relation of the starches or polysaccharides to the sugars was found by
studying the hydrolysis of the former, and it is by the hydrolysis of the pro-
teins that we have arrived at most of our present knowledge of their con-
stitution. Contributory evidence may also be gained by the use of oxidising
agents or by employing the refined methods of analysis possessed by certain
liviug organisms — bacteria, by which means we can effect limited oxidations
or reductions or can replace an NH, group by H, or a COOH group
by H.
ACID HYDROLYSIS OF PROTEINS. For this purpose rather stronger
acids are used than for the hydrolysis of starch. The protein is heated for
twenty-four hours in a flask fitted with a reflux condenser either with con-
centrated hydrochloric acid or with a 25 per cent, sulphuric acid. Hydro-
chloric acid was first made use of by Hlasiwetz and Habermann, who added a
certain amount of stannous chloride to the mixture in order to prevent any
oxidation taking place. We obtain in this way an acid fluid containing an
extremely complex mixture of various substances, all of which belong to the
76 PHYSIOLOGY
class of amino-acids, and must be regarded as the proximate constituents of
the protein molecule.
A similar hydrolytic change may be effected by the use of digestive
ferments obtained either from the alimentary canal of higher vertebrates or
from certain plants. Thus we may use pepsin, the active constituent of the
gastric juice, trypsin, the proteolytic ferment secreted by the pancreas,
papain, or other vegetable ferments obtained from papaya, from pineapple
juice, and so on. These ferments are all milder in their action than the
strong acids. Pepsin for instance effects only a partial decomposition of the
protein molecule. Its action results in the formation of substances which
still present all the protein reactions and are classified as hydra ted proteins
or as proteoses and peptones. Trypsin carries the protein a stage further
and gives a mixture of amino-acids. Certain groups however of the protein
molecule present a considerable resistance to the action of trypsin, so that
when its action is complete these groups are still found not yet broken down
into their constituent amino-acids.
The putrefactive processes determined by the process of bacteria in
solutions of proteins are somewhat too complicated in their results to throw
much illumination on the structure of the protein molecule itself. This
method is however of extreme value when it is applied to isolated con-
stituents of the proteins. Under the action of these bacteria we may have a
process of deamination which may be accompanied by simple hydrolysis or
by reduction. In the former case an ammo-acid may be converted into
an oxyacid, in the latter case into a fatty acid.
Thus tyrosine under the action of bacteria of putrefaction may split up
into ammonia and oxyphenyl propionic acid.
OH.C 6 H 4 .CH 2 .CHNH 2 .COOH + H =
HO.C 6 H4.CH 2 .CH 2 .COOH + NH 3
Under the action of yeasts an amine may become an alcohol.
C 5 H n .NH 2 + H.,0 - C s H u .OH + NH 3
(amylamine) (amylalcohol)
On the other hand, the effect of the bacteria may be to split off carbon
dioxide from the amino-acids. Thus, the diamino-acid, lysine,
CHJSTH, CHJSTH.,
I " I
CH„ CH S
I I
CH, becomes CH 2 pentamethylene* diamine.
I ' I
CH 2 CH 2
I I
CH.NH 2 CH 2 NH 2
I
COOH
Tyrosine becomes p. oxyphenylethylamine, a substance having marked
THE PROTEINS 77
physiological effects, and an important constituent of ergot. Phenylalanine
C,H«.CH t .CH.NH,.COOH, becomes phenylethylamine C 6 H 5 .CH 2 .CH 2 .NH 2 .
These reactions are therefore of value in determining the exact grouping of the
atoms in the more complex of the proximate constituents of the proteins.
Since all the known disintegration products of the proteins belong to the
class of amino-acidSj it may be of value to point out some of the distinguishing
features of this class of bodies.
PROPERTIES OF AMINO-ACIDS. An amino-acid is derived from an
organic acid by the replacing of one atom of hydrogen by the amino group
NH 2 . Thus from the acids,
acetic acid propionic acirl
CH 3 CH 3
I I
COOH CH 2
I
COOH
we may obtain the mono-ammo-acids,
amino-acetic acid alanine or et-amino-propionic acid
CH 2 NH 2 CH 3
I I
COOH CH.NH 2
I
COOH
It will be noticed that in the fatty acids with more than two atoms of carbon
the position of the NH 2 group may be varied. Thus, instead of alanine
we may have another amino-propionic acid, namely :
CH 2 NH 2
I
CH 2
I
COOH
This acid would be spoken of as ^-amino-propionic acid, alanine being
a-amino- propionic acid. This nomenclature is always used to distinguish
the position of the NH 2 group, so that we may have mono-amino-acids a,
/?, y, d, e . . . and so on. Practically all the amino-acids which occur as
constituents of the protoplasmic molecule belong to the a group.
On inspection of the formula of glycine it is evident that only one isomer
of this body is possible. In alanine, however, the carbon atom to which
NH 2 is attached, is asymmetric, since its four combining affinities are each
attached to different groups. Thus :
C
I
H— C— NH„
In this case, therefore, there is a possibility of stereoisomerism, and alanine
must have an influence on polarised light. If the compound
78 PHYSIOLOGY
CH,
I
HCNH 2
]
COOH
is dextro-rotatory, then its stereoisomer
CH 3
I
HjNCB
I
COOH
will be laevo-rotatory, and it will be possible to obtain ;i racemic modification
without any influence on polarised light by mixing equal molecules of these
two isomeric forms. Ail the amino-acids derived from proteins are optically
active, whereas those obtained by synthesis are inactive, and special means
have to be devised in order to obtain from the artificially formed racemic
amino-acid either the d- or Z-amino-acid.
If more than one hydrogen atom in an organic acid be replaced by NH 2
we obtain diamine- and triamino-acids. Thus ornithine, obtained by the
splitting up of arginine, one of the commonest disintegration products of
protein, is a-(5:diamino-valerianic acid.
CH,NH„
I
CH,
CH.NH 2
I
(dull
The presence in the amino-acids of the basic radical NH 2 and of the acid group
COOH lends to these bodies a double character. In themselves devoid of strong
chemical qualities, possessing neither acid nor alkaline reaction, they are able in the
presence of strong acids or bases to act either as base or acid. When in solution by
themselves it is possible that there is an actual closing of the ring by a soluble union
between the NH 2 group and the COOH group, so that e.g. the formula of glycine
may be :
CH 2 — NH 3
I I
CO — o
When such a neutral compound is treated with acid this bond is loosed and we have
the salt of the amino-acid. Thus, with hydrochloric acid, glycine forms glycine
hydrochlorate :
CHijNH^Cl
I
COOH
a salt which still possesses an acid group and which is therefore capable of combining
with ethyl to form the hydrochlorate of the ester of the amino-acid. Thus :
CH 2 .NH,HC1
I
COOCoH s
THE PROTEINS 79
With liases the amino-acids form salt-like compounds such as potassium amino- acetate :
CH,NH,
I
COOK
Amino-acids also combine with one another. This power of combination much increases
the difficulty of separating the constituents from a mixture of amino-acids. Amino-
acids, which singly are extremely insoluble, are readily soluble when in the presence
of other amino-acids.
On account of the dual nature of the ammo-acid molecule, these substances act
as feeble conductors of the electric current, i.e. as electrolytes. The charge carried
by an amino -acid and its ionisation depends upon the conditions in which it is placed.
Since it may act either as the cation or the anion, it is spoken oi i as an ampJioterir,
electrolyte.
One reaction of the amino-acids is of special interest in connection with the respira-
tory functions of the body, namely, the formation of carbamino-acids. If a stream of
carbon dioxide he passed into a mixture of an amino-acid, e.g. glycine, with lime, the
carbon dioxide is taken up. On filtering the mixture a clear liquid passes through which
gradually in course of time deposits a precipitate of calcium carbonate. The filtrate
first obtained contains a compound of calcium, calcium glycine carbonate. The
formula is as follows :
CH..NH
>
;o.co
COO Ca
METHODS OF SEPARATING AMINO-ACIDS. By the hydrolysis of protein
!>\ means of acid or of trypsin, we obtain a complex mixture of amino-acids. From
this mixture certain amino-acids are separated with ease. Thus tyrosine, which is ex-
tremely insoluble, crystallises out on concentrating the fluid, and further concentration
leads to the separation of leucine. The other acids, which keep each other mutually
in solution, are however very difficult to isolate. We owe to Fischer the first general
method for their separation. We may take one experiment as an example.
Five hundred grammes of casein are heated for some hours under a reflux con-
denser with li litres of strong hydrochloric acid. The liquid is then saturated with
gaseous hydrochloric acid and allowed to stand for three days in the ice-chest. Crystals
of hydroehlorate of glutamic acid separate out. The filtrate from these crystals is
evaporated at 40 5 (_'. under diminished pressure to a syrupy consistence, and is then
dissolved in 1J litres of absolute alcohol. Hydrochloric acid is then passed into the
solution to complete saturation, the mixture being warmed for a short time on the
water bath, and the mixture is once more evaporated to a syrupy consistence. By this
treatment all the amino-acids have been converted into the hydrochlorates of their
esters, e.g. :
(HoNHoHCl C 2 H 4 NH,HC1
I I
COOC,H 5 COOC 2 H 6 &c.
From the hydrochlorates the esters are set free' by the addition of potassium carbonate,
the mixture being cooled in a freezing mixture. By this means the esters of aspartic
and glutamic acids are separated and are extracted by shaking with ether. The
remaining esters are then liberated by the addition of 33 per cent, caustic soda together
with potassium carbonate, and are again extracted by ether. The combined ethereal
solutions are dried by standing over fused sulphate of soda and then evaporated, when
a residue containing the free esters is obtained. These esters are then separated by
fractional distillation under a very low pressure obtained by means of the Fleuss
pump, the second receiver of the apparatus being cooled in liquid air. The various
fractions of aminoesters obtained in this way are hydrolysed — the lower fractions by
80 PHYSIOLOGY
boiling for some hours with water, the higher fractions by boiling with baryta. The
acids obtained by the hydrolysis can then be further purified by means of fractional
crystallisation.
THE DISINTEGRATION PRODUCTS OF THE PROTEINS.
By the methods just described the following substances have been
isolated from proteins :
A. FATTY SERIES
(1) Mono-amino-acids (Monobasic)
GLYCINE or GLYCOCOLL This, the simplest member of the group, is
amino-acetic acid :
CHjNHj
I
COOH
It occurs in considerable quantities among the disintegration products of
gelatin and to a slight extent among those derived from certain of the pro-
teins. Like the other a-amino-acids, it has a sweetish taste, whence its name
was derived (yXvxocr = sweet, icoXkr) == glue).
ALANINE is a-amino- propionic acid :
CH 3
I
CH.NH,
I
COOH
It is optically active, the alanine derived from proteins being dextro-
rotatory.
Closely allied to alanine is the amino-acid SERINE, which was first
obtained by the hydrolysis of silk and has since been found as a constituent
of a large number of proteins. Its formula is :
CH 2 OH
I
CH.NH 2
I
COOH
i.e. it is amino-oxypropionic acid. Its special interest lies in the fact that
it was one of the first of the amino-oxyacids to be isolated, and it is possible
in these acids that we must seek the intermediate stages between carbo-
hydrates and proteins.
AMINO-VALERIANIC ACID has the formula
CH 3 CH 3
V
CH
I
CH.NH 2
I
COOH
It occurs only in small quantities in the protein molecule.
THE PROTEINS 81
LEUCINE, one of the oldest known members of the group of amino-acids,
is obtained in large quantities from the disintegration of nearly all the animal
proteins, of which in some cases it may form as much as 20 per cent. It
has the formula
CH 3 CH 3
\y
CH
I
CH 2
I
CH.NH 2
I
COOH
i.e. it is amino-isobutyl acetic acid. On evaporating a tryptic digest of
protein, impure leucine crystallises out in the form of imperfect crystals,
the so-called ' leucine cones.'
Lately another isomer of leucine has been discovered, namely, a-amino-methyl
ethyl propionic acid. This is called isoleucine.
(2) Mono-amino Derivatives of Dibasic Acids
Of these two are known, namely, aspartic and glutamic acids.
ASPARTIC ACID is a-amino-succinic acid :
COOH
I
CH.NH 2
I
CH 2 !
I
COOH
and glutamic acid is the next homologue, namely, a-amino-glutaric acid :
COOH
I
CH.NH 2
I
CH 2
I
CH 2
I
COOH
Owing to the possession of two carboxyl groups these amino-acids have a
much more pronounced acid character than is the case with the other
members of the group which we have been studying.
Aspartic acid was first found in the shoots of asparagus in the form of the amide,
asparagine :
mull
I
CHNH 2
I
CH 2
I
CONH,
82 PHYSIOLOGY
This substance is very widely distributed throughout the vegetable kingdom and
is present in seedlings in very large quantities, as much as 25 per cent, of the dried
weight. In plants it apparently serves either as a reserve material or as the form
in which the greater part of the nitrogen is conveyed from the reserve organs to be
Imilt up into the protoplasm of the growing parts of the plant.
(3) Diamino-ccids
Of these two are known, namely, lysine and ornithine. Owing to the
presence of two NH 2 groups in their molecule, they possess marked basic
characters, and are precipitated from the acid solution obtained by the
hydrolysis of proteins on adding phosphotungstic acid. Since lysine, argi-
nine, and histidine (another amino-acid which will be described later) all
contain six carbon atoms in their molecule, these three bodies were classed
together by Kossel as the ' hexone ' bases. Apart however from their high
content in nitrogen, the chemical resemblance between these bodies is no
closer than between them and the other members of the amino-acid series.
Another body isolated by Fischer in small quantities is supposed to
belong to this class and to have the composition diamino-trioxydodecoic acid.
LYSINE C g H 14 N 2 2 is a-£-diamino-caproic acid having the formula
CH.,NH,
I
(CH 2 ) 3
I
CH.NH 2
I
C'OOH
ARGININE, which was first discovered in plants (the cotyledons of
lupins), is not a simple amino-acid, but a compound of an amino-acid with
guanidin. If boiled with baryta water it splits up into urea and a substance
reacting as a base which was called ornithine.*
ORNITHINE, diamino-valerianic acid, has the formula
CH 2 NH 2
I
(CH 2 ) 2
C'H.NH,
I
C'OOH
The constitution of arginine is analogous to that of creatine, one of the
most abundant nitrogenous extractives of muscle, which has the formula
HN = C — N(CH 3 )CH 2 COOH
I
H,N
It is methyl guanidine acetic acid.' On boiling creatine with baryta water
it takes up a molecule of water and splits in the situation of the dotted line
in the formula, giving
* Ornithine had been previously discovered in the urine of fowls after the admini-
stration of benzoic acid, in the form of an acid known as ornithuric acid.
THE PROTEINS
83
H.,N
Vo (urea) and NH(CH s )CH 2 COOH (methyl glycine).
H 2 isr
This latter substance is known as sarcosine and is derived from glycine by
the replacement of one atom of hydrogen by a methyl group CH 3 .
Arginine has a similar formula. On the left-hand side of the dotted line
the formula would be identical with that of creatine. On the right-hand
side the sarcosine group is replaced by a diamino-acid of the fatty series,
diainino-valerianic acid or ornithine.
DIAMINO-TRIOXYDODECOIC acid is, as its name implies, a derivative of
a twelve carbon acid. Its constitutional formula has not yet been made out.
B. AMINO-ACIDS CONTAINING AN AROMATIC NUCLEUS
The best known of these is TYROSINE, which has the formula
OH
/\
',.11,
I'lU'H.NHoCOOH
It is paraoxyphenyl a-alanine It is one of the first of the amino-acids to be
split off from the protein molecule under the influence of hydrolytic agents.
Owing to its insolubility it
rapidly separates out as
bundles of fine needle-shaped
crystals at the sides and
bottom of the vessel.
When tyrosine is treated
with an acid solution of
mercuric nitrate containing a
little nitrous acid, a precipi-
tate is produced, and on
boiling, the precipitate and
the supernatant fluid assume
a deep red colour. This re-
action is given by all benzene
derivatives in which one atom
of hydrogen in the ringis re-
placed by one OH group. This
is known as Hoffmann's test,
hut is identical with Millon's reaction, which is given by all proteins con-
taining tyrosine in their molecules.
Closely allied to the foregoing compound is another aromatic amino-acid
namelv. PHENYL ^-ALANINE ;
Fia. 18. Tyrosine crystals. (Plim.mkh.)
84 PHYSIOLOGY
CH 2 CH.NH 2 COOH
It is an almost constant constituent of proteins.
TRYPTOPHANE was known long before it had been isolated, owing to
the fact that with bromine water it gives a rose-red colour. It had long
been observed that this substance was to be obtained at a certain stage in the
digestion of proteins by pancreatic juice, but nothing was known about its
constitution until Hopkins succeeded in isolating it by precipitation with
mercuric sulphate dissolved in 5 per cent, sulphuric acid. Cystine is also
precipitated by this reagent, but comes down with a less concentration of the
salt than tryptophane, so that it is possible to separate the two substances
by a species of fractional precipitation. Tryptophane can be isolated by
decomposing the mercury salt with sulphuretted hydrogen, and is obtained
in a crystallised form. On distillation it gives an abundant yield of indol and
skatol, bodies also obtained during the putrefaction of proteins. Trypto-
phane itself is indol amino-propionic acid :
iC.CH !! CHNH i! .COOH
\/\/ CH
NH
C. AMINO-ACIDS OF HETEROCYCLIC COMPOUNDS
Three of the disintegration products of proteins can be grouped in this
class. Two of them contain the pyrrol ring, namely, proline and oxyproline.
PROLINE, which was first isolated by Fischer, is a-pyrrolidin carboxylic
acid and has the formula
CH 2 — CH 2
I I
CH 2 CH.COOH
V
NH
OXYPROLINE is the oxy-derivative of this body and has the formula
C 5 H 8 N0 3 , the exact position of the oxy-group having not yet been deter-
mined. Doubts have been expressed whether the pyrrol group is present
as such in the protein molecule, or whether proline, for example, is not
formed by the closing of an open chain of a compound belonging to the
amino-acids in the fatty series. Thus from an oxy-amino-valerianic acid
CH 2 OH.CH 2 .CH 2 .CH.NH 2 .COOH we can by dehydration make the com-
pound CH 2 CH 2 .CH 2 .CH.COOH, the formula of which will be seen to be
NH
identical with that given for proline.
The third member of this group contains the iminazol ring
THE PROTEINS 85
CH— NH
II /CH
CH W
and is known as HISTIDINE. Its structural formula is as follows :
CH— NH v
II ) CH
. I
CH 2 .CH.NH 2 .COOH
i.e. it is iminazol a-amino-propionic acid or iminazol alanine. Since it occurs
in the phosphotungstic precipitate from the products of acid disintegration
of proteins and contains six carbon atoms, it was formerly classified with
lysine and arginine as a hexone base.
D. SULPHUR-CONTAINING AMINO-ACIDS
Sulphur forms an integral part of the molecule of all classes of proteins
except protamines. In some substances allied to proteins, such as keratin,
it may occur to the extent of 3 per cent. On boiling proteins with caustic
potash or soda, a portion of the sulphur is split off to form a sulphide, which
gives a black precipitate on addition of copper salts. On this account it was
formei'ty thought that the sulphur must be present in two forms, the oxidised
and the unoxidised, in the protein molecule. Recent investigation has
showu however that practically the whole of the sulphur is present in the
form of CYSTINE, and that this body on boiling with alkaline solutions gives
up only a little more than half its content in sulphur.
This substance, which has been known for many years as the chief con-
stituent of a rare form of urinary calculus and as occurring in the urine in
certain cases of disordered metabolism, is again a derivative of 'the three-
carbon propionic acid. On reduction it gives a body known as cysteine,
which is a-amino-thiopropionic acid.
CH,SH
i
CH.NH,
I
COOH
Cystine itself is compounded of two cysteine molecules joined together by
their sulphur atoms and has the formula
CH 2 — S — S — CH *
I I "
CH.NH 2 CH.NH 2
I I
COOH COOH
E. OTHER CONSTITUENTS OF THE PROTEIN MOLECULE
When we add together the total amino-acids obtainable by the acid
disintegration of any given protein, a considerable proportion of the original
protein remains unaccounted for. This remainder must have a greater
content in hydrogen and oxygen than the amino-acids envmerated above,
86 PHYSIOLOGY
and it has been suggested that among the missing unascertained con-
stituents of proteins may be oxyamino-acids, of which serine would form
one of the lowest members. The isolation of such substances would present
considerable interest, in that it would supply the intermediate stages between
the constituent groups of the protein molecule and the carbohydrates, the
first product of assimilation by living organisms. Only one such intermediate
body has so far been isolated, namely, glucosamine, an amino-derivative of
glucose. It was first shown by Pavy that from the products of disintegration
of a protein such as egg-white it was possible to obtain a reducing substance
and to isolate an osazone resembling in its characters those derived from
the sugars. Since then various observers have shown that this reducing
substance is most probably glucosamine :
CH 2 OH
I
M'HOH) 3
I
<'H.NH„
Although this substance may be obtained from crystallised egg albumin or
crystallised serum albumin, authorities are not yet convinced that it forms
an integral part of these proteins. Both egg-white and serum contain
proteins belonging to the class of mucins, ovomucoid and serum mucoid, each
of which yields on acid hydrolysis from 16 to 30 per cent, glucosamine. Since
various observers have obtained results varying from 1 to 16 per cent, gluco-
samine for crystallised egg albumin, it seems possible that in every case
the crystals carried down with them some of the carbohydrate-rich mucoid,
and that the varying results were due to the different amounts of mucoid
present in the crystals. By our ordinary methods it is impossible to prepare
a specimen of either egg albumin or serum albumin which is entirely free from
this amino-derivative of carbohydrate.
Connected with this group of proteins may be reckoned the diamino-
trioxydodecoic acid already mentioned as occurring among the disintegration
products of proteins.
THE BUILDING UP OF THE PROTEIN MOLECULE
By simple hydrolysis the protein molecule may be broken down into a
large number of amino-acids. Analyses of various proteins show that these
amino-acids are present in different proportions in the individual proteins,
so that in many cases a large number of identical amino-acid groups must
be present in the protein molecule with smaller numbers of other groups.
In endeavouring to form an idea of the manner in which the amino-acids can
be linked together into one gigantic molecule, Hofmeister first put forward
the idea that the linkage follows the general formula :•
— CH 2 — NH— CO—
or — NH— CH„— CO— NH—
THE PROTEINS 87
This theory of the constitution of proteins was based on the fact that a
similar grouping was known to occur in leucinimide, obtained by the con-
densation of two molecules of leucine,
r 4 H 9
I
/'"
NH CO
I I
00 NH
C 4 H 9
and also by the. fact that only a small proportion of the NH 2 groups present
in the separated amino-acids exist free in the protein molecule. By the
action of nitrous acid the terminal NH 2 groups are split off and replaced by
OH. When proteins are treated with nitrous acid only a small proportion of
the total nitrogen is split off in this way. The linking of the amino groups
must therefore take place by means of the nitrogen, i.e. by NH groups.
Synthetic experiments have fully confirmed this hypothesis. In 1883
Curtius obtained a substance giving the biuret reaction, the so-called
' biuret base,' by the spontaneous polymerisation of glycocoll ester. This
base has been shown by recent researches to consist of four glycine molecules
arranged together in an open chain. The clue to the structure of this base
was given by Fischer, who has devised a number of ingenious methods for
combining together amino-acids of any character and in an}' number. Thus
from two molecules of glycine we may obtain the compound glycyl glycine,
as follows :
NH 2 .CH,.COOH + HNH.CH,.COOH - H 2 =
NH 2 .CH 2 .CO.NH.CH,.COOH
This may be prepared in various ways. In one method glycine is converted into
its ester CH 2 .NH,.CO.OCH 3 . In a watery solution this undergoes spontaneous con-
version into glycine anhydride which belongs to the class of bodies known as diketo-
piperazins, as follows :
.OH,— CO
2NH 2 .CH 2 CO.OCH 3 = 2CH 3 OH + NH<( \NH
methyl alcohol \ CO— CH„
On treating this with dilute alkali it takes up water, splitting in the situation of the
dotted line and forming glycyl glycine, NH 2 CH 2 CO.NH.CH 2 COOH.
More general methods have been devised by Fischer for the same purpose, depending
on the use of the halogen acyl chlorides.
Thus chloraeetylchloride and alanine yield chloracetalanine :
C1.CH 2 .C0C1 + NH,.CH(CH 3 ).COOH =
C1.CH 2 .C0 - NH.CH(CH 3 )COOH + HC1.
By the subsequent action of ammonia, the halogen group is replaced by the amino
group, and a dipeptide results :
88 PHYSIOLOGY
Cl.CH 2 .CO - NH.CH(CH 3 )COOH + 2NH 3 =
NH 2 .CH 2 .CO - NH.CH(CH 3 )COOH + NH 4 C1.
Different halogen acyl chlorides are used for introducing the various amino-acid
radicals, e.g. chloracetylchloride for glycyl, a-brornopropionylchloride for alanyl, &c.
By various such methods Fischer has succeeded in combining compounds
containing as many as eighteen amino-acids, e.g. alanyl leucine, glycyl
tyrosine, dialanyl cystine, dileucyl cystine, leucyl pentaglycyl glycine, and
so on. The last named would be built up out of one molecule of leucine and
six molecules of glycine. These compounds have been designated by
Fischer as poly peptides, to signify their close connection with the peptones
produced by the agency of digestive ferments on the proteins. He dis-
tinguishes di-, tri-, tetra-, &c, peptides according to the number of individual
amino-acids taking part in the formation of the compound. The poly-
peptides resemble in all respects the peptones. Most of them, even if
derived from relatively insoluble amino-acids, are soluble in water, insoluble
in absolute alcohol. They dissolve in mineral acids and in alkalies with the
formation of salts, thus resembling in their behaviour the amino-acids.
They have a bitter taste, although the amino-acids from which they are
formed have a slightly sweet taste, in this way again resembling the natural
peptones. The higher members of the series give certain reactions, such as
the biuret reaction, which are regarded as characteristic of peptones, and like
the latter are precipitated by phosphotungstic acid. Their behaviour with
trypsin depends on the optical behaviour of the amino-acids from which they
are formed. If synthetised from the amino-acids identical with those
occurring in the disintegration of natural proteins, they resemble the pep-
tones in undergoing hydrolysis and disintegration into their constituent
amino-acids. Trypsin however has no influence on polypeptides com-
pounded of the inactive amino-acids, or of the amino-acids which are the
optical opposites of those which form the constituents of normal proteins.
Though most of the amino-acids which occur naturally are laevo-rotatory,
the polypeptides formed from them are generally strongly dextro-rotatory.
Thus in the building up of the protein molecule there is an almost indefi-
nite coupling up of numerous amino-acid groups, the connecting element in
each case being the nitrogen. Of the two or more optical isomers possible of
each amino-acid containing more than two carbon atoms, only one is made
use of for this purpose. A still further flexibility in its reactions to its
environment is conferred on the protein molecule by changes occurring with
great readiness in the intra-molecular grouping of its constituent atoms.
Thus, if we take the simplest member of the class of polypeptides, glycyl
glycine, four structural formulae are possible, namely :
(1) NH 2 CH 2 CO - NH.CH 2 .COOH
(2) NH.CHo.CO
I >o
CO.CH 2 .NH 3
(3) NH 2 .CH 2 .C(OH) = N.CH 2 .COOH
THE PROTEINS
89
W
N.CH.CO
C(OH)CH,.NH 3
>
(2) and (4) being the intramolecular form of the formulae (1) and (3). (3) and
(4) are sometimes spoken of as the enolic form. If we consider that perhaps
some hundred of the amino-acid groups may go to making up a single
protein molecule, it is possible to form some conception of the enormous
variability in reaction possible to such a compound.
THE CONSTITUTION OF DIFFERENT PROTEINS
All the proximate constituents of proteins, so far as we know, are amino-
acids. Of these the following have been isolated, namely, glycine, alanine,
amino-valerianic acid, leucine, isoleucine, proline, oxyproline, serine, phenyl
a
5 3
««
•3
3
2
3
a
|
s
B
S 3 c
Glycine
3-S
0-9
16-5
4-7
Alanine .
2-7
8-1
3-6
2-7
1-5
4-2
—
—
0-8
1-5
Serine
0-6
—
0-33
0-12
0-5
0-6
7-8
—
0-4
0-6
Amino- valeri-
anic acid
—
—
present
0-3
7-2
—
4-3
—
10
0-9
Leucine .
20-0
71
20-9
6-0
9-35
290
—
21
7-1
Proline
10
2-25
1-7
2-4
6-70
2-3
110
—
5-2
3-4
Oxyproline
—
—
20
—
0-23
1-0
—
—
3
—
Glutamic acid .
7-7
8-0
6-3
36-5
15-55
1-7
—
—
0-88
3-7
Aspartic acid .
3-1
1-5
4-5
1-3
( l-39
4-4
—
—
0-56
0-3
Phenylalanine .
31
4-4
2-4
2-6
:3-2_
4-2
—
—
0-4
Tyrosine .
21
11
21
2-4
4-5
1-5
—
— •
3-2
Tryptophane
present
present
present
10
1-50
present
—
—
—
Cystine
2-3
0-2
0-25
0-45
?
,0-3
—
—
—
10+
Lysine
—
2-15
10
5-95
4-3
12-0
2-75
11
Arginine .
214
11-7
3-4
3-81
5-4
87-4
58-2
7-62
4-5
Histidine .
11
1-7
2-5
110
12-9
0-4
0-6
alanine, glutamic acid, aspartic acid, tyrosine, tryptophane, cystine, lysine
histidine, arginine, and ' di-amino-trioxydodecoic ' acid.
The question now arises whether all the different varieties of protein owe
their peculiarities to the presence of different amino-acids or whether the
greater number of the amino-acids above mentioned are present in all pro-
teins, the differences between the latter being determined by differences in the
arrangement and relative amounts of their proximate constituents. . A large
number of analyses of different proteins have been made by Abderhalden,
Osborne, and others, utilising the methods for the isolation of amino-acids
devised by Fischer. The constitution of some representative proteins as
determined in this way is given in the Table above.
90 PHYSIOLOGY
These results show that all tin- proteins contain a very considerable
proportion of the total number of amino-acids which have as yet been
isolated from acid digests of proteins. The differences in various proteins
cannot therefore be determined by qualitative differences in their constituent
molecules, but must depend on the relative amounts of the amino-aeids
which are present and on their arrangement in the whole molecule. As regards
relative amounts of amino-acids we find very striking differences, i Thus
glutamic acid, which forms 8 per cent, of egg albumin and only f '7 per cent,
of globin (derived from haemoglobin), amounts to 36"5 per cent, in gliadin,
the protein extracted from wheat flour. Striking differences are also notice-
able in the relative proportions of the cUamino-acids and bases, the so-called
hexone bases. Whereas in casein they form about 12 per cent, of the total
molecule, in globin they form about 20 per cent. ; and in the protamine's,
salmine and sturine, about 85 per cent, of the total molecule consists of t bese
bodies. On this account the two last-named bodies have a strongly basic
character. From these figures it is evident also that certain of the amino-
acids must occur many times over in the protein molecule. Thus in globin.
if we assume the presence of one tyrosine molecule, then' must be at. least
thirty-two leucine and ten histidine molecules. On these data the molecular
weight of haemoglobin would come out at about 14,000, a figure which agrees
with that derived from a study of the amounts of sulphur and iron respec-
tively in its molecule.
THE DISTRIBUTION OF NITROGEN IN THE PROTEIN
MOLECULE
Attempts have been made to differentiate among the proteins by a
method which, while less laborious than the isolation and recognition of the
individual amino-acids, may yet throw some light on the manner in which
the nitrogen is combined within the molecule, and on the relative amounts of
the different classes of nitrogen groups which may b? present. One method,
which was devised by Hausmann. is carried out as follows. One gramme of
the protein is dissociated by boiling with strong hydrochloric acid. The
nitrogen, which has been split off as ammonia and is present in the solution
as ammonium chloride, is then distilled off with magnesia and received
into decinormal acid, where its amount can be determined by titration. This
nitrogen is variously designated as amide nitrogen, ammonia nitrogen, or
easily displaceable nitrogen. The remaining fluid, freed from ammonia, is
precipitated with phosphotungstic acid. By this means all the diamino-acids
and bases are thrown down. The nitrogen in the precipitate is determined
by Kjeklahl's method and is called diamino- or basic nitrogen. In the
remaining fluid, which contains mono-amino-acids, the total nitrogen, the
mono-amino-nitrogen, is determined by Kjeldahl's method. Table I., p. 91.
gives some' of I he results obtained in this manner, and shows that there are
considerable differences in the distribution of the different kinds of nitrogen
among the various classes of proteins. The method is however only a
rough one as compared with the separation of the individual maino-acids.
THE PROTEINS
Table I.
91
Amide Amino
Protamines
Salmi
Salmon-roe
Sturgeon-roi
Sturine
Histones Histone Thymus
Albumins
and [Ovalbumin Egg-white
phospho- l Caaeinogen Milk
proteins
Globulins
Alcohol -
soluble
proteins
Globulin
I Edestin
I Zein
i Gliadin
, Prot-
I albumose
■ Hetero-
' albumose
Wheat
Hemp seed
Maize
Wheal and rye
Witte's
peptone
Witte's
peptone
-
3-3
15-51
8-64
15-62
10-36
18-39
7-72
18-64
1008
1613
18-40
17-66
23-78
—
714
6-45
87-8
83-7
■AS-
6813
21-27
6600
22-34
53-40
37-10
57-83
31-70
77-56
3 03
7(1-27
5-54
68-17
25-42
57-4
38-93
1-87
1-34
1-52
0-64
0-99
0-79
Table II. — Distribution of the Nitrogen in Various Proteins
(Van Slyke)
Gliadin
Edestin
Hair
(dog)
Gelatin
Fibrin
ll;t' -
cyanin
Ox haemo-
globin
Ammonia N .
25-52
9-99
10-05
2-25
8-32
5-95
5-24
Melanine N .
0-86
1-98
7-42
0-07
317
1-65
3-60
Cystine N
1-25
1 49
6-60
0-99
0-80
?
Arginine N
5-71
27-05
15-33
14-70
13-86
15-73
7-70
Histidine N
5-20
5-75
3-48
4-48
4-83
13-23
12-70
Lysine N
0-75
3-86
5-37
632
11-51
8-49
10-90
Amino N of the
nitrate
51-98
47-55
17-50
56-30
54-30
51-30
57-00
Non-amino \ oi the
filtrate (proline,
oxyproline, !,
tryptophane)
8-50
1-7(1
310
14-90
2-70
3-80
2-90
99-77
99-37
99-85
99-02
99-58
100-95
10000
An improved means of determining the distribution of nitrogen in the
protein molecule bas been devised by Van Slyke. Some of his results art-
given in Table II., above.
* When a protein is boiled for a long time with strong aeid, a black precipitate maj
occur which contains nitrogen. This is known as humin nitrogen.
92 PHYSIOLOGY
TESTS FOR PROTEIN
A. COLOUR REACTIONS OF THE PROTEINS
These are of importance since in many cases they are an indication of the nature
of the groups present in the protein molecule.
(1) THE BIURET REACTION. When a solution of a protein is made strongly
alkaline with caustic potash or soda, and dilute copper sulphate added drop by drop,
a colour varying from pink to violet is produced. In the case of the proteoses and
peptones (the hydrated proteins) the colour is pink ; in the case of the coagulable
proteins, violet. According to Schiff this colour is given by all compounds containing
the following groups :
XO.NHj,
NH<(
X CO.NH 2
CO.NH 2
CH 2 <
CO.NH 2
CO— NH 2
I
CO— NH,
and the group
(NH 2 )C— CO— NH— C
We have already seen that this grouping is typical of the protein molecule.
(2) THE XANTHOPROTEIC REACTION. On adding strong nitric acid to
a solution of protein and boiling, a yellow colour is produced which turns to a deep
orange when excess of caustic alkali or ammonia is added. The production of this
reaction points to the existence of benzene derivatives in the protein molecule, and
it is therefore a general test for the presence of aromatic groups.
(3) MILLON'S REACTION. Millon's reagent is a solution of mercuric nitrate
in water containing free nitrous acid. On adding a few drops of this to a protein solu-
tion a white precipitate is produced which turns a brick-red colour on boiling. It
depends on the presence in the protein of a hydroxy-derivative of benzene, and is
determined hi the protein by the tyrosine, which is oxyphenylalanine.
(4) SULPHUR REACTION. On warming a solution of protein with caustic
soda in the presence of lead acetate, a black colour is produced owing to the precipi-
tation of lead sulphide. The depth of coloration gives a rough indication of the amount
of sulphur in the protein under investigation.
(5) THE HOPKINS AD AMKIEWICZ REACTION. It was stated by Adam-
kiewicz that on the addition of acetic acid and concentrated sulphuric acid to protein,
a violet colour was produced. Hopkins and Cole showed that the success of this reaction
depended on the presence of glyoxylic acid CHO.COOH as an impurity in the acetic
acid used. The test is therefore performed now as follows :
Glyoxylic acid is prepared by the action of sodium amalgam on a solution of oxalic
acid. A few drops of this solution are added to the solution of protein, and strong
sulphuric acid poured down the side of the tube. A bluish violet colour is produced
at the junction of the two fluids. This reaction is due to the presence in the protein
of tryptophane.
The so-called Liebermann's reaction has been shown by Cole to be essentially a
modification of the above, and is due also to the presence of tryptophane. In this
test the protein is precipitated by alcohol, washed with ether, and heated with con-
centrated hydrochloric acid, when a blue colour is produced, glyoxylic acid being
derived from the alcohol and ether.
THE PKOTEINS 93
(6) REACTIONS INDICATING THE PRESENCE OF CARBOHYDRATES.
Molisch's test is applied as follows. A few drops of alcoholic solution of a-naphthol
and then strong sulphuric acid are added to a protein solution. A violet colour is
produced, which on addition of alcohol, ether, or potash turns yellow. The reaction
is determined by the presence, either as an impurity or a constituent part of the mole-
cule, of a carbohydrate radical which, under the influence of strong sulphuric acid, is
converted into furfurol. The furfurol gives the colour reaction with the a-naphthol.
Another test for the carbohydrate radical is the orcin reaction. A small quantity
of the dried albumin is added to 5 c.c. of fuming hydrochloric acid, and the mixture is
then warmed. When the albumin is nearly all dissolved, a little solid orcin is added
on the point of a knife, and then a drop of ferric chloride solution. After warming
this mixture for some minutes, a green colour is produced which is soluble in arnyl
alcohol and gives a definite absorption spectrum.
B. METALLIC SALTS
The following metallic salts form double insoluble compounds with proteins, and
therefore cause a double precipitation when added to solutions of these bodies : ferric
chloride, copper sulphate, mercuric chloride, lead acetate, zinc acetate.
C. ALKALOIDAL REACTIONS
Proteins, like the polypeptides and the amino-acids of which they are composed,
may function either as weak acids or as weak bases, according as they are treated with
bases or acid radicals respectively. In the presence of strong acids therefore,
proteins act like organic bases, and are thrown down in an insoluble form by the various
alkaloidal precipitants. With certain proteins, such as the protamines, where there
is a preponderance of basic groups, it is not. necessary to add mineral acid in order
to ensure the precipitation. The following are the principal alkaloidal precipitants
which may be employed :
(a) Phosphotungstic acid.
(6) Phosphomolybdic acid,
(c) Tannic acid.
{d) Potassium mercuric iodide,
(e) Acetic acid and potassium ferrocyanide.
(/) Trichloracetic acid. (In order to precipitate all the coagulable proteins from
a solution, it is treated with an equal volume of 10 per cent, trichloracetic acid,
well shaken and filtered.)
(g) Metaphosphoric acid.
(h) Salicyl-sulphonic acid.
These two latter are generally employed in a 5 per cent, solution.
(i) Picric acid.
A mixture of picric and citric acids is largely employed, under the name of
Esbach's reagent, as a precipitant for coagulable proteins in the urine.
D. TESTS DEPENDING ON THE COLLOIDAL CHARACTER OF THE
PROTEIN
(1) HEAT COAGULATION. On boiling proteins in a very slightly acid solution
some are coagulated and form an insoluble white precipitate. This test is applicable
to albumins, globulins, and under certain conditions to the derived albumins. In
order that the separation of protein in this way may be complete, it is necessary to
provide for the presence of neutral salts and also for the maintenance of a slight acidity.
The best method of carrying out this test therefore is to boil the protein in slightly
alkaline or neutral solution after the addition of 2-5 per cent, of sodium chloride or
sodium sulphate. While the solution is in active ebullition, 1 per cent, acetic acid i«
added drop by drop until the reaction is just acid to litmus. By this means a nearly
perfect separation of all the coagulable proteins may be effected.
'.H PHYSIOLOGY
(2) HELLER'S TEST. On pouring a solution of protein carefully down the Bide
of a test-tube containing strong nitric acid so as to form a layer on the top, a white
layer of coagulated protein is produced at the junction of the two tluids. A similar
coagulative effect is given by other strong mineral acids.
(3) PRECIPITATION BY NEUTRAL SALTS. On addition of a neutral salt in
excess to a colloidal solution, the relation between the solvent and the particles which
are in suspension or pseudo-solution is altered. II is therefore possible in many
cases by the addition of neutral salts to separate out the dissolved colloid without
otherwise altering its characters in any way, so that, on collecting the precipitate
and separating the salt carried down with it, it can be dissolved again by adding water.
Some classes of proteins can be salted out very readily, while others require a much higher
concentration of salt before they are precipitated.
The salts which are generally employed for salting out proteins have been divided
by Schryver into three classes :
Class I. Class II. Class-III.
Sodium chloride. Potassium acetate. Ammonium sulphate.
Sodium sulphate. Calcium chloride. Zinc sulphate.
Sodium acetate. Calcium nitrate.
Sodium nitrate.
Magnesium sulphate.
The two calcium salts are however rarely employed, as they tend to render the
precipitated protein insoluble.
The salts of the first class require much higher concentration for the precipitation
of the proteins than those of the second, and these than those of the third. Since the
degree of concentration of any salt necessary for the precipitation of any particular
protein is characteristic for this body, it is possible to employ a fractional process of
salt precipitation in order to separate mixtures of proteins into their components.
Owing however to the tenacity with which different colloids adhere to one another,
it is difficult, even after many repetitions of the process of fractional salting out, to
obtain products which can be regarded as free from admixture. For the purpose of
fractional precipitation the salts most frequently employed are those of the third class,
namely, ammonium sulphate and zinc sulphate. We shall have to deal with results
obtained by this method when treating of the separation of albumoses and peptones.
The precipitability of different proteins with neutral salts serves also as the basis of
the ordinary classification of these bodies.
THE CLASSIFICATION OF PROTEINS
It is possible that in the future, when we know all the disintegration
products of the various proteins and the manner in which they are arranged
in the molecule, the classification of these bodies will be based on their con-
stitution. At the present time it is obviously impossible to make any classi-
fication on such a basis, since the necessary knowledge is wanting, and
we have therefore to use a purely artificial classification, such as that adopted
by the Chemical and Physiological Societies in 1907, based chiefly on the
solubilities of the various proteins in water and salt solutions. We shall
here only indicate the characters of the main groups into which proteins
are conventionally divided, and leave the closer study of the individual
proteins to be dealt with in connection with the organs or tissues in which
they are found.
(1) THE PROTAMINES. These occur in the body only in combination
with other groups. They are obtained from the ripe spermatozoa of certain
THE PROTEINS 95
fishes, where they are in combination with nucleic acid. They are charac-
terised by the very large amount of bases contained in their molecule,
amounting to 85 per cent, of the total substance. It was formerly thought
by Kossel that the protamines contained only diamino-acids and bases, but
it has been shown later that a small proportion of mono-amino-acids may
also be obtained from their disintegration (v. Table, p. 98). On account of
their constitution they possess strongly basic characters and form well-
marked salts, e.g. sulphates and chlorides, as well as double salts with
platinum chloride. They contain no sulphur and do not coagulate on
heating.
(2) HISTONES. This class of proteins, like the protamines, only occurs in
combination with other groups, such for instance as nuclein and haematin.
They may be obtained from red blood-corpuscles, where they form the
globin part of the haemoglobin molecule, or from the leucocytes of the thymus
gland, or from the spermatozoa of fishes. The histones are precipitated
from their watery solutions by addition of ammonia, but are soluble in
excess of this reagent. In the presence of salts they are coagulated on boiling.
With cold nitric acid they give a precipitate which dissolves on warming, but
is thrown down again on cooling. The most characteristic feature of this
class of bodies is however the high proportion of diamino-acids and bases
contained in their molecule.
(3) ALBUMINS. These are soluble in pure water and are precipitated
by complete saturation with ammonium sulphate, zinc sulphate, or sodio-
magnesium sulphate.
Egg Albumen forms the greater part of the white of egg. It gives
the ordinary protein tests, coagulates on heating at about 75° C, and
is precipitated from its solutions if shaken with a drop of dilute acetic
acid in excess of ether. It is lsevo-rotatory, its specific rotatory power
being— 35'5°.
Serum Albumen occurs in large quantities in the blood plasma, serum,
lymph, and tissue fluids of the body. It coagulates at 75° C, and is dis-
tinguished from egg albumen by its greater specific rotatory power, —56°,
and by the fact that it is not precipitated by ether and sulphuric acid. Some
vegetable proteins belong to this class, e.g. the leucosin of wheat.
(4) GLOBULINS. These bodies are insoluble in pure water and require
the presence of a certain amount of neutral salt to dissolve them. They are
precipitated from their solutions by complete saturation with magnesium
sulphate or by half-saturation with ammonium sulphate. The chief members
of this class are :
Crystallix. obtained from the crystalline lens by passing a stream of
carbon dioxide through an aqueous extract of this body.
Serum Globulin or Paraglobulin, a constituent of blood plasma and
blood serum.
Fibrinogen, which occurs in blood plasma and is converted into fibrin
when the blood clots.
Paramyosinogen, a norma] constituent of muscle.
96 PHYSIOLOGY
Midway between these two groups may be placed the muscle protein,
myosin (or myosinogen), which, though soluble in pure water, resembles
the class of globulins in the ease with which it is precipitated by the addition
of neutral salts.
In addition to the members of the globulins named above and derived
from the animal body, proteins allied to this class form an important con-
stituent of plants, and are found in large quantities in many seeds used as
articles of food. These are vegetable globulins. Prominent members of the
group are the edestins, which may be obtained from hemp seeds, cotton seeds,
and sunflower seeds, zein from maize, legumin from beans.
(5) GLIADINS, contained in cereals, and soluble in alcohol.
(6) GLUTELINS, proteins also obtained from cereals and soluble in weak
alkalies.
(7) DERIVATIVES OF PROTEINS. A. METAPROTEINS. These may
be regarded as compounds of the protein molecule or of part of the molecule
with acid or basic radicals.
Acid Albumin, or acid metaprotein, is formed by the action of warm dilute
acids or of strong acids in the cold on any of the preceding bodies. If a weak
alkali be added so as nearly to neutralise the solution of acid metaprotein,
this latter is precipitated. If the precipitate be suspended in water and
heated, it is coagulated and becomes insoluble in dilute acids or alkalies.
Alkali Albumin, or alkaline metaprotein, is formed by the action of
strong caustic potash on white of egg or on any other protein, or by adding
alkali in excess to a solution of acid metaprotein. It is precipitated on
nsutralisation of its solution.
In close association with this group may be included the proteins as they occur
in combination with the metallic salts, such as copper sulphate. On splitting off the
copper moiety from these compounds, the protein left is practically free from ash, and
behaves in many respects like an albuminate, being insoluble in absolutely pure water,
but easily dissolved by the addition of a trace of free acid or alkali.
A group of protein derivatives described by Hopkins is produced by the action
of the free halogens on protein solutions. We get in this way two definite classes of
compounds. One class, which contains the largest percentage of halogen, is obtained
by treating a protein solution with chlorine, bromine, or iodine, dissolving up the
resultant precipitate in alcohol and pouring the alcoholic solution into ether, when the
halogen compound is thrown down as a fine white precipitate. By dissolving this
precipitate in weak soda and precipitating with acid, we obtain a series of compounds
containing only about one-third as much of the halogen as is contained in the first
precipitate, suggesting that the halogen forms both substitution and additive com-
pounds with the protein molecule.
Albumins, globulins, and metaproteins are often associated together as
the coagulable proteins, since they may be thrown down entirely from their
solution on boiling in slightly acid medium in the presence of neutral salts.
B. HYDRATED PROTEINS. When proteins are subjected to the
action of superheated w-ater or steam, or heated with acids, or acted on at
the body temperature by certain ferments, e.g. pepsin, trypsin, or papain,
they undergo a change which is attended by the addition of a number of
THE PROTEINS 97
molecules of water to the protein molecule (hydrolysis). This action, when
carried to its end, results in the production of the amino-acids which we have
already dealt with.
These hydrolytic changes proceed by a series of stages, so that the
intermediate products still present many of the protein reactions. The
hydrated proteins are divided into two groups, proteoses and peptones.
The formation of these intermediate products is especially marked with the
proteolytic ferments. Pepsin with hydrochloric acid, the ferment of the
gastric juice, for example, only breaks down the protein molecule as far as the
proteoses and peptones. Trypsin also gives rise to both proteoses and pep-
tones as intermediate products. The action of these ferments on proteins is
in fact closely analogous to the action of diastase on the great polysaccharide
molecule of starch. In this case, as intermediate products we have first
dextrins of various complexity, secondly maltose, and finally, if the ferment
maltase be also present, dextrose. The monotony of the starch molecule
determines a great similarity of composition between its various disintegra-
tion products. It may be regarded as an anhydride of many (100 or more)
molecules of a hexose, and the intermediate stages in this hydrolysis are also
hexoses and their anhydrides. The protein molecule is distinguished by the
variety of the groups which enter into its formation, and this heterogeneous
character of the molecule renders possible a much greater variety of inter,
mediate products than we find in the starches. Thus a protein molecule may
consist of the groups, A, B, C, D, E, F, G, H, &c. When hydrolysis occurs
it may result in the immediate splitting off, say, of part of group A, while
the residue breaks up into a series of proteoses whose composition may be
represented as ABF, ABC, DFG, BDEF, &c. With further hydrolysis these
groups are broken into still smaller ones, and the penultimate stages of the
hydrolysis will be polypeptides similar to those which have been synthetised
by Fischer from the ultimate products of protein hydrolysis. No sharp
dividing line can be drawn between the proteoses, peptones, and poly-
peptides. Of the last group we have already seen that the higher members
give the biuret reaction as well as the other protein reactions, if the necessary
groups, e.g. tyrosine, tryptophane, are present in the molecule. The prote-
oses and peptones are however ill-defined bodies. We have at present no
satisfactory means of isolating the different members of these groups and
obtaining them in a state of chemical purity. Their classification is there-
fore, like that of the proteins generally, a conventional one, depending on
their solubilities and their precipitability by neutral salts, especially ammo-
nium sulphate. Both proteoses and peptones give the xanthoproteic and
Millon's reactions common to all proteins, and, like these, are precipitated
by such reagents as mercuric chloride, potassio-mercuric iodide, or phospho-
tungstic acid. On adding excess of caustic potash and a drop of dilute
copper sulphate to solutions of either of these classes of bodies, a pink colour
is produced which deepens to a violet on addition of more copper (the biuret
reaction). Their solutions can be boiled without undergoing coagulation.
Many of them may be thrown down from then solutions by absolute alcohol,
7
98 PHYSIOLOGY
but are not rendered insoluble even by prolonged standing under the alcohol.
The characters of the different members of these groups will be considered
at greater length when dealing with the changes undergone by the proteins
during the process of digestion. At present we may merely summarise the
distinguishing features of these two classes.
(a) Proteoses, e.g. albumose from albumin, caseose from casein, elastose
from elastin. All of these are precipitated from their solutions on saturation
with ammonium sulphate. In the presence of a neutral salt they give a
precipitate on the addition of nitric acid. This precipitate is dissolved
on heating the solution, but reappears on cooling. All, with the exception of
heteroalbumose, are soluble in pure water, and all are soluble in weak
salt solutions or dilute acids or alkalies. They are slightly diffusible through
animal membranes.
(b) Peptones, e.g. fibrin peptone, gluten peptone. These are all soluble
in pure water, diffuse fairly readily through animal membranes, but other-
wise give the same reactions as albumoses. From the latter class peptones
are distinguished by the fact that they are not precipitated on saturation of
their solutions either in acid or alkaline reaction with ammonium sulphate
or any other neutral salt. Many of them are soluble in alcohol.
(8) THE PHOSPHOPROTEINS. In this class may be grouped a number
of substances of very diverse properties, which however resemble one
another in containing phosphorus as an integral part of their molecule.
When subjected to digestion with pepsin and hydrochloric acid they are
dissolved, but a small quantity of a phosphorus-containing complex may
remain behind undissolved. This residue has been called paranuclein or
pseudonuclein. It is in reality derived from nucleoprotein, which is present
in the phosj^hoprotein as impurity and should be called simply nuclein. The
phosphoproteins have markedly acid characters. They are insoluble in pure
water, easily soluble in alkalies and ammonia from which the original body
is thrown down' again on addition of acid. Their solutions in alkali are not
coagulated by heating. To this class belong caseinogen, the chief protein of
milk, vitellin, the. main protein in the yolk of egg, and the vitellins in the eggs
of fishes and frogs. The vitellins are generally associated with a large amount
of lecithin. The phosphoproteins differ from the nucleoproteins, which also
contain phosphorus, in the facts that they are readily decomposed by caustic
alkali with the liberation of phosphoric acid, and do not contain purine
bases. The phosphorus of the nucleoproteins is not split off by alkali
(1 per cent.), and on hydrolysis the nucleic acid constituent gives rise to
purine bases.
(9) CONJUGATED PROTEINS. Various complex bodies which play an
important part in building up cells and in the various processes of the body
make up this group of compounds. They resemble one another only in the
fact that in each of them a protein radical is combined with some other body,
often spoken of as the prosthetic group.*
* By the Germans the term ' proteid ' is often applied to this group. In English
however the term ' proteid ' has been generally used for the simple protein known
THE PROTEINS 99
(a) Chromoproteins. Of this class, consisting of a colouring-matter
combined with a protein, the most important is haemoglobin. This substance,
which is the red colouring-matter of the red corpuscles of the blocd and plays
an important part in the processes of respiration, acting as an oxygen carrier
from the lungs to the tissues, is composed of the protein, globin, united with
an iron-containing body, hsematin. Oxyhaemoglobin contains from 4-5 per
cent, haematin (C 32 H3 2 N 4 4 Fe). It is easily crystallisable, and its physical
and chemical characters have therefore been more precisely determined than
is the case with most other members of the group of conjugated proteins. We
shall have to deal more fully with its properties in the chapters on Blood and
Respiration.
(h) The Nucleoproteins. These are formed by the combination of a
phosphorised organic acid, nucleic acid, with a protein which may belong to
any of the classes we have enumerated above. Some of the best-marked
members of this group consist of compounds of nucleic acid with basic histones
or protamines. The combination between protein and the prosthetic group
seems to take place in two stages. If a nucleoprotein be subjected to gastric
digestion a large amount of the protein goes into solution as proteose or
peptone, leaving an insoluble remainder. This precipitate is not however
nucleic acid, but still contains a protein group, the compound being spoken
of as nuclein. From the latter nucleic acid can be split off by heating with
strong acids or other means. The nucleoproteins are soluble in water and
salt solutions, and are easily soluble in dilute alkalies. They have acid
characters and are precipitated by the addition of acids. The nucleins, on
the other hand, are insoluble in water and salt solutions, but are easily
dissolved by dilute alkalies. The nucleins and nucleoproteins form the chief
and invariable constituent of cell nuclei. They may be therefore prepared
from the most diverse organs. The heads of the spermatozoa of the salmon
consist entirely of nuclein. Miescher and Schmiedeberg found that the
nuclein obtained from this source contained 60 -5 per cent, nucleic acid and
35*56 protamine, and was in fact a nucleate of protamine. The nuclein
derived from the spermatozoa of echinoderms has been found to be a com-
pound of nucleic acid and histone. From organs rich in cells, such as the
thymus and the pancreas, and from nucleated red blood-corpuscles, nucleo-
proteins may be obtained which can be broken down into nuclein and protein,
the nuclein again being composed of a protein residue with nucleic acid.
As first extracted from the animal cell the nucleoproteins are associated with a
considerable proportion of lecithin, and in this labile compound form the ' tissue
fibrinogen ' of Wooldridge. To prepare this substance an organ rich in cells, such as
the thymus, is minced and extracted with water or normal salt solution. After separa-
ting the cells by means of the centrifuge, the clear fluid is decanted off and acidified
with acetic acid. A precipitate is produced consisting of ' tissue fibrinogen.' This
substance is soluble in excess of acid and is easily soluble in alkalies. All the tissue
to the Germans as ' Eiweisskorper.' On account of the confusion which has risen
from this double use of the term ' proteid,' I have attempted to avoid it altogether in
this volume.
100 PHYSIOLOGY
fibrinogens arc highly unstable bodies and undergo changes in the mere act of pre-
cipitation and re Bolution. When injected into the blood they cause intravascular
clotting. On digestion with gastric juice they yield a precipitate of nuclein, and this
precipitate contains a large proportion of the lecithin present in the original substance.
In the nucleoproteins nucleic acid is combined with proteins in two degrees, a large
portion of the protein being separable by gastric digestion, while the remainder needs
stronger reagents for its dissociation. The relation of the two portions of the nucleo-
protein may be represented therefore by the following schema :
Nucleo-protein
Protein Nuclein
Protein Nucleic acid
(generally histone
or protamine)
By various means, all .of which involve hydrolysis, the nucleic acid may
be broken up into its proximate constituents. These differ according to
the source of the nucleic acid. Whatever the source, the disintegration
products belong to closely allied groups of substances. These may be
grouped as follows :
(1) Phosphoric Acid. The proportion of phosphorus varies within but
narrow limits in the different nucleic acids, the average being about 10 per
cent. It is probable that the phosphoric acid represents, so to speak, the
combining medium for the groups contained in the nucleic acid molecule, as
is the case with the various groups w T hich make up the lecithin molecule.
(2) The Purine Bases. Among the products of disintegration of nucleic
acid we find constantly one of the bases adenine, C 5 H 5 N 5 , and guanine
(C 5 H 5 N 5 0). These substances, with the products of their oxidation, xan-
thine. C 5 H 4 N 4 2 , hypoxanthine, C 6 H 4 N,0, have long been known to be
closely allied to uric acid, C 5 H 4 N 4 3 , but their true relationships have only
been thoroughly known since the researches of Fischer on this group.
According to Fischer they can be all regarded as derivatives of the body
purine,
!N= 6 CH
I I
2 HC 5 C— NH 7
II I! >H8
3 N— K'— N 9 ''
Each grouj) in this purine ring is generally designated with a number indicated
in the structural formula, in order that it may be possible to represent the
position of any substituted groups in its derivatives. Uric acid itself is
2-6-8- trioxyp urine with the following formula :
HN— CO
I I
OC C— NH
I II >co
HN— C— NH
THE PROTEINS ■ 101
It can be synthetised by fusing together in a sealed tube trichlorolactamide
and urea. Thus :
NH, CONH 2 NH— CO
r i ii
CO + CHOH + NH„ = CO C— NH + NH 4 C1. + 2HC1
I I >CO I || >CO
NH 2 CC1 3 NH./ NH— C— NH X
The relation of xanthine, hypoxanthine, guanine, and adenine to uric acid
is shown by the following formulae :
NH— CO HN CO
II II
CO C— NH CO— C— NH
I II >co Vh
NH— C— NH HN C— N ''
Uric acid Xanthine
2-6-8-trioxypurine 2-6-dioxy purine
HN— CO
i i
N
i
- C.NH 2
i
NH— CO
1 1
HC C— NH
1
HC
1
C— NH
1 1
NH 2 C C— NH
II II V'H
N— C — N *
II
N-
II )c»
- C— N ^
II II JCH
N— C— N #
Hypoxanthine
Adenine
Guanine
6-oxypurine
6-amino-purine
2 -amino 6-oxypurine
Closely allied to this gronp of bodies are the chief constituents of tea,
coffee, and cocoa, namely caffeine, which is trimethyl dioxypurine, and
theobromine, which is dimethyl dioxypurine. From the structural formulae
given it will be seen that the purine radical contains two nuclei. The
nucleus
N— C
I I
c c
I I
N— C
is spoken of as the pyrhnidine nucleus, pyrimidine havmg the formula
1 N= 6 CH
I I
2 HC 5 CH
I II
3 N— 4 CH
The other is the radical which we have met with already in histidine, a
disintegration product of proteins, namely imuiazol :
HC— NH
II )CH
HC— N ''
Besides the purine bases proper, we find among the disintegration products
of nucleic acid a series of bases derived from the pyrimidine ring. These
are uracil, thymine, and cytosine.
Uracil is 2-6-dioxvpvrimidine,
102
PHYSIOLOGY
NH- •( II )
I I
CO— CH
Thymine is 5- methyl uracil,
NH— CH
NH— 'CO
I I
CO Ci'H.,
I II
NH— CH
while oytosine is G-amino-2-oxvpvrimidine,
N =C.NH,
I I
CO CH
I II
NH- CH
Besides these two groups of nitrogenous compounds derived from the
purine and pyrimidine rings, many nucleic acids yield on hydrolysis a carbo-
hydrate. Thus Hammarsten has isolated a pentose from the nucleo-
proteins of the pancreas. It is supposed that the nucleic acid of the thymus
gland contains a hexose, since it is possible to split off from it lsevulinic acid,
which is one of the first products of the decomposition of a hexose. The
complex constitution of the nucleic acids and nucleoproteins may be
rendered clearer from the following schema :
on digestion yields
Nucleo-protein
nuclein proteoses and peptones
dissolved in alkali and precipitated with hydrochloric acid
yields
nucleic acid acid derivatives of protein, histories or protamines
hydrolysed yields
phosphoric acid
reducing sugar
pentose or
hexose
purine bases
adenine
guanine
pyrimidine
uracil
thymine
cytosine
It must not be imagined, however, that all these disintegration products
are present in all nucleic acids. Thus the nucleic acid derived from the
pancreas, the so-called guanylic acid, yields of the purine bases only guanine,
and of the pyrimidine bases only thymine and uracil, and every variety is
met with as we analyse the nucleic acids of different origin. The fact that
nucleic acid is a characteristic and necessary constituent of all nuclei adds
interest to the divergence of its constituent radicals from those which dis-
tinguish the proteins of the cell protoplasm. Further importance is lent to
THE PROTEINS 103
this section of the chemistry of the body by the close relationship which we
shall have to study later between the nuclein metabolism of the body and
the production and excretion of uric acid.
The researches ofLevenehave thrown light on the manner in which these different
groups are bound together to form nucleic acid. In the acid obtained from the thymus
the carbohydrate group Hexose is joined to a nitrogenous ring compound, forming
what is termed a 'nucleoside.' Four of these nucleosides, in thymic acid, join
with four molecules of phosphoric acid to form a ' tetra-nucleotide.' The formula
provisionally assigned to thymic acid is therefore as follows :
HO
O = PO-C 6 H 10 O 4 C 6 H 4 N 5
guanine group
HO O
I
= PO C„H a O, C,,H,N.,0
HO
HO
thymine group
O
PO - C 6 H 8 0, e^N-jO
eytosine group
HO
0=PO C s H 10 O 4 -C ? H 4 N B
adenine group
HO
Other nucleic acids are simpler in constitution and may be composed of only one
or two nucleotide groups. Thus the inosinie acid of muscle is a mono-nucleotide, con-
sisting of phosphoric arid linked by a pentose group with hypoxanthine. The defi-
nition of a nucleotide would thus be a compound in which a carbohydrate group links
a phosphoric acid group witli a purine or a pyrimidine group. Nucleic acids are simple
or compound nucleotides. The pentose in inosinie acid is d-Ribose. The same
pentose occurs in yeast nucleic acid. The nucleic acid of the pancreas, also called
Guanylic acid, ((insists of phosphoric acid linked with guanine by a molecule of d-Ribose.
(c) The Glycoproteins. In the glycoproteins the prosthetic group is
represented by. a carbohydrate radical, generally containing nitrogen, such
as glucosamine or galactosamine. They are split into their two constituents,
protein and carbohydrate radical, on prolonged boiling with dilute mineral
acids or by the action of alkalies. They may be divided into the two main
groups of mucins and mucoids.
The mucins play a large jjart in the animal kingdom as protective agents.
They form the slimy secretion which covers the inner surface of the mucous
membranes and the outer surface of many marine animals, and is secreted
either by the goblet cells of the epithelium or by special groups of cells
collected together to form a mucous gland.'.; They may be precipitated from
their solutions or semi-solutions by the addition of acids, and after precipita-
tion need the addition of alkalies for their re-solution. They are not coagu-
104 PHYSIOLOGY
lable by heat. The presence of their protein moiety causes them to give
the various typical protein tests, such as the xanthoproteic, Millon's, the
biuret reactiou, ami so on, Prolonged boiling with acids splits the molecule,
with the production of acid metaprotein and albumoses and glucosamine.
From the mucin of frogs' eggs a similar treatment results in the production
of galactosamine.
With the mucins may be classified certain bodies which have been derived from
ovarian cysts, namely, pseudomucin and paramucin. Pseudomucin occurs as a con-
stituent of the colloid material from ovarian tumours. It forms slimy solutions which
do not coagulate by heat and are not precipitated by acetic acid. It is precipitated
by alcohol, the precipitate being soluble in water even after standing a long time under
the alcohol. On boiling with ,acid it gives a reducing substance. Paramucin differs
from the above in reducing Fehling's solution before boiling with acids. Otherwise
it resembles pseudomucin. Leathes, in investigating this body, isolated from it a
reducing substance which apparently was an ammo-derivative of a disaccharide,
perhaps in combination with glycuronic acid.
The mucoids include a number of substances which may be extracted
from, various tissues by the action of weak alkalies, e.g. from tendons, bone,
and cartilage. The best studied example of this group is the chondromueoid
which, w T ith collagen, forms the ground substance of cartilage. Chondro-
mueoid is especially rich in sulphur and gives protein by long treatment with
weak alkali. On boiling for a short time with acid it is decomposed into
sulphuric acid and chondroitin, and this latter, on further action of the acid,
is converted into a substance chondrosin, which is certainly an amino-
derivative of a polysaccharide containing the elements of glycuronic acid
and an amino-disaccharide. Chondroitin-sulphuric acid occurs not only in
cartilage but also in bone, yellow elastic tissue, white fibrous tissue, and as a
constant constituent of the lardacein or amyloid substance which occurs as a
deposit in the middle coat of the blood-vessels as the result of syphilis or
long-continued suppuration, and gives rise to the condition known as ' lar-
daceous disease.' Another example of this class of mucoids is ovomucoid,
which is a constituent of egg-white. In order to prepare ovomucoid the
globulin and albumin are precipitated by boiling diluted egg-white. From
the filtrate ovomucoid can then be thrown down by alcohol. A similar body
has been prepared from blood serum. Both these mucoids yield a large
amount of reducing substance on hydrolysis. Thus from 100 grm. of ovo-
mucoid it is possible to prepare 30 grm. of glucosamine.
(10) THE ALBUMINOIDS OR SCLERO-PROTEINS. Under this heading
are grouped a number of diverse substances which play an important part
in building up the framework of the body. Their value as skeletal tissue
seems to be determined by their insoluble character. On this account it is
practically impossible to speak of purifying them. In every case w r e can
simply take the residue of a skeletal tissue which is left after extraction of
the soluble constituents. When broken down by the action of strong acids,
they yield a series of disintegration products which are included among those
we have already studied as the disintegration products of proteins. Their
difference from the proteins w ? hich are employed in metabolism for their
THE PROTEINS 105
nut ritive value is caused either by the absence of certain groups common to
all the nutritive proteins, by the presence of an excess of one or two groups,
or by the presence of certain polypeptides which present considerable resist-
ance to the action of digestive ferments. This class plays the part in the
animal economy which in the vegetable kingdom is rilled by the anhydrides
of the hexoses and pentoses, e.g. the celluloses, lignin, the pentosanes, &c.
Collagen forms the main, constituent of white fibrous tissue and the ground
substance of bone and cartilage. It is insoluble in water, hot or cold, and in
trypsin. Under the action of acids or when subjected to prolonged boiling
with water, especially under pressure, it is converted into gelatin, which is
soluble in hot water, forming a colloidal solution liquid at high temperatures,
but setting to a jelly when cold. When subjected to acid hydrolysis it gives
a series of amino-acids from which tyrosine and tryptophane are wanting.
On this account gelatin does not give any reaction either with Millon's
reagent or with glyoxylic acid. On the other hand, there is a preponderance
of such groups as glycine and phenylalanine, and it is probable that glycine,
phenylalanine, and leucine are joined together, perhaps with other amino-
acids, to form a polypeptide which is not attacked by digestive ferments, and
therefore determines the resistance of the original collagen molecule to solu-
tion. Gelatin is precipitated by tannic acid, but not by acetic acid. It is
dissolved with hydrolysis by gastric juice or by pancreatic juice, whereas
collagen, its anhydride, is unaffected by the latter. On prolonged boiling in
water it is converted into a modification which does not form a jelly on
cooling. Under the action of formaldehyde it is converted into an insoluble
modification which does not melt on warming.
Beticulin. This name has been applied to the tissue which forms the supporting
network of adenoid tissue, and has also been described in the spleen, the mucous mem-
brane of the intestine, liver, and kidneys. It differs from collagen in resisting digestion
by gastric juice, and also in containing phosphorus in organic combination. According
to Halliburton there is no essential difference between reticulin and collagen.
The keratins are produced by the modification of epithelial cells and
form the horny layer of the skin as well as the main substance of hairs,
wool, nails, hoofs, horns, and feathers. They are distinguished by their
insolubility in water, dilute acids or alkalies, and in the higher animals
pass through the alimentary canal unchanged. Although differing in their
elementary composition, according to the tissue from which they are pre-
pared, they are all distinguished by the very large amount of sulphur present
in their molecule. The greater part of this sulphur is in the form of cystine,
i if which as much as 10 per cent, can be extracted from keratin. They also
yield, on acid hydrolysis, tyrosine in larger quantities than is the case with
the ordinary proteins.
Neurokeratin, which forms the basis of the neuroglial framework of the
central nervous system, must be grouped by its general behaviour as well as
by its origin with the keratins. It resembles the other members of this class
in its insolubility and in its high content in sulphur. It is extracted from
nervous tissues by boiling these with alcohol and ether and then submitting
io<>
PHYSIOLOGY
tin- tissue to prolonged tryptic digestion, which leaves the neurokeratin
unaffected.
Elastin is a constant constituent of the connective tissues, where it forms
the elastic fibres. In some localities, as in the ligamentum nuchse, practically
Fibroin
Keratin
Keratin
Keratin
of
Elastin
from
from
from
Gelatin
silk
horn
horsehair
feathers
Glycine ....
3(50
25-75
0-45
4-7
2-6
16-5
Alanine .
2111
6-6
1-6
1-5
1-8
0-8
Amino-valerianic acid
on
Ml
4-5
0-9
0-5
10
Proline .
present
1,7
5-2
Leucine .
1-5
21 4
15-3
71
8-0
21
Phenylalanine
1-5
3-9
1-9
0-0
lid
0-4
Glutamic acid
0-0
0-8
17-2
3-7
2-3
0-88
Aspartic acid
present
prewut
2-5
0-3
11
0-56
Cystine .
—
7-5
—
—
Serine
1-6
—
11
0-6
0-4
0-4
Tyrosine .
10-5
0-34
3-6
3-2
30
0'C
Tryptophane
—
—
—
—
—
00
Lysine .
traces
—
0-2
11
—
2-75
Arginine.
10
0-3
2-7
4-5
—
7-62
Histidine
small
—
—
0-6
-~
o-4
Oxypniliiic
—
—
—
—
—
30
the whole tissue is made up of these fibres. Elastin is insoluble in water,
alcohol, or ether, or in dilute acids and alkalies. It is slowly dissolved on
'prolonged treatment with gastric juice, but is practically unaffected in the
alimentary canal. It gives the xanthoproteic and Millon's tests.
Other members of this group are fibroin, which forms the main substance of silk,
spongin, the horny framework of sponges, conchioiin, the ground substance of shells,
and perhaps the amyloid substance or lardacein which we have already mentioned in
connection with the mucoids. All these sclero -proteins present considerable differ-
ences in their qualitative and quantitative composition in amino-acids. Their proxi-
mate composition is shown in the Table given above (Abderhalden).
We have finally to mention a miscellaneous' collection of bodies which are allied
to the proteins and are distinguished by their extreme insolubility. They are often
designated as albumoids. Of their composition we know practically nothing. Under
this name are grouped such substances as those forming the membrana propria of
glands, the sarcolemma of striated muscle, the albumoid of the crystalline lens, the
ground substance of the chorda dorsalis, the organic basis of fish scales, and many
similar substances. In every case the substance is characterised necessarily according
to its place of origin, little or nothing being known as to its chemical composition.
SECTION VI
THE MECHANISM OF ORGANIC SYNTHESIS
THE ASSIMILATION OF CARBON
The building up of protoplasm from the material which is available at the
earth's surface must be an endothermic process. The food presented to the
plant contains the necessary elements, but as a rule in a state of complete
oxidation. The energy of the living plant, as of animals, is derived almost
entirely from the oxidation of its constituents. The building up of un-
organised into organised material must therefore be effected at the expense
of energy supplied from without. The source of this energy is the sun's rays.
The machine for the conversion of solar radiant energy into the chemical
potential energy of protoplasm is the green leaf. Here a deoxidation of the
carbon dioxide of the atmosphere takes place, with the production of carbo-
hydrates, generallv in the form of starch. The formation of starch must be
regarded as the first act in the life-cycle, since this substance serves as a
source of energy to the already formed protoplasm in its work of building up
all the other constituents of the living cell. It is the solar energy captured
by the green leaf which is utilised by all plants devoid of chlorophyll, as well
as by the whole animal kingdom.
There are one or two exceptions to this statement. Thus the bacterium nitro-
somonas, described by Winogradsky, grows on a medium devoid of all organic con-
stituents, and derives the energy for its constructional activity from that set free in
the conversion of ammonia into nitrites. The sulphur bacteria apparently derive
their energy from the decomposition of hydrogen sulphide and the liberation of sulphur.
The fundamental importance of this process of assimilation for the whole
of physiology justifies some account of the researches which have been
directed to the elucidation of its mechanism. The production of oxygen by
the green plant w r as discovered by Priestley in 1772, and a few years
later Ingenhaus showed that this production occurred only in the light and
was effected only by green plants. ' De Saussure (1804) pointed out that the
essential process concerned was a setting free of the oxygen from the carbon
dioxide of the atmosphere, and recognised that the co-operation of water
was also necessary. Mohlin 1851 observed the formation of starch grains
in the chlorophyll corpuscles, and regarded these as the first products of
assimilation. The organs of carbon dioxide assimilation are the chloroplasts.
These, which are responsible for the green colour of plants, are generally
small oval bodies embedded in the cytoplasm, but sometimes, as in spirogyra,
ma) 7 have the form of spiral bands. In a plant which has been kept for some
time in the dark, or in an atmosphere free from carbon dioxide, they present
107
108 PHYSIOLOGY
no enclosed grannies. Within three to five minutes after exposure to light
in the presence of carbon dioxide, starch granules make their appearance
within them, and grow rapidly, assuming the typical laminated structure.
Bngelmann has pointed out a means by which it can be proved that the
chloroplasts carry out this process without the co-operation of the rest of the
cytoplasm. Certain bacteria have a great avidity for oxygen and present
movements only in the presence of this gas. If a filament of spirogyra be
placed in a suspension of these bacteria and be examined under a microscope,
the bacteria will be seen to congregate in the immediate neighbourhood of the
chlorophyll bands. The same phenomenon is observed in the case of
chlorophyll corpuscles isolated by breaking up the cells in which they were
contained. These corpuscles therefore take up carbon dioxide and water,
and form carbohydrate and oxygen, as follows :
n(6C0 2 + 5H 2 0) = (C,H 10 O 6 ) n + n(60 2 )
The whole structure of the green leaf is directed to the furthering of this
process. Its cells contain chlorophyll corpuscles, which change their position
according to the intensity of the illumination. A free supply of air to all
the cells is provided by means of the stomata on the under surface of the
leaf. Horace Brown has shown that the rate at which carbon dioxide diffuses
through such fine openings is as great as if the whole leaf were an absorbing
surface. We get therefore optimum absorption of ( carbon dioxide by the
leaf, with the maximum protection of the absorbing tissue and the necessary
limitation of loss of water by transpiration.
In view of the very small amount of carbon dioxide in the atmosphere,
the extent of the assimilatory process is remarkable. One square metre of
leaf of the catalpa can lay on 1 grm. of solid per hour, using up for this pur-
pose 784 ccm. carbon dioxide. The rapidity of assimilation is increased
within limits by increasing the intensity of the light falling on the plant,
though an over-stimulation of the process is prevented by the movements of -
the chloroplasts just mentioned. It is also increased by raising the per-
centage of carbon dioxide in the atmosphere supplied to the leaf. Ihe
optimum percentage of carbon dioxide will of course vary with the other
conditions of the leaf. In certain experiments Kreusler found the optimum
to be about 1 per cent. Taking the amount of assimilation in normal air with
•03 per cent, carbon dioxide at 100, the assimilation in an atmosphere con-
taining 1 per cent, was 237, and was not increased by raising the percentage
of carbon dioxide to 7 per cent. Owing to the decomposition of the organic
matter of the soil, the percentage of carbon dioxide near the ground is always
greater than in the higher strata of the atmosphere — a fact which is taken
advantage of by the low-growing plants and herbage. Other necessary con-
ditions of assimilation are the presence of water and the maintenance of a
certain external temperature. The absorption of the sun's rays by the leaf
raises the temperature of the latter above that of the surrounding medium,
and so quickens the process of assimilation.
The assimilation of carbon dioxide, the formation of starch, and the
THE MECHANISM OF OKGANIC SYNTHESIS 109
evolution of oxygen will go on in the isolated chloroplast. In the absence
of chlorophyll, as in an etiolated leaf, the formation of starch will take place
if the plant be supplied with a sugar such as glucose, and this conversion
represents the main function of the hucoplasfs present in all the cells of the
reserve organs of plants. In the absence of chlorophyll no decomposition of
carbon dioxide takes place, so that this pigment is evidently essential for
the utilisation of the sun's energy. Chlorophyll may be extracted from
leaves by means of absolute alcohol. A solution is thus obtained which is
green by transmitted and red by reflected light, i.e. chlorophyll is a fluorescent
substance. It presents four absorption bands, the chief being an intense
black band between Fraunhofer's lines B and C. If the chlorophyll is the
means of conversion of the solar into chemical energy, the conversion must
take place at the expense of the light which is absorbed by the pigment.
One would expect therefore the process of assimilation to be most' pro-
nounced in those parts of the spectrum corresponding to the absorption
bands — an expectation which has been realised by experiment.
As to the exact chemical changes effected by these absorbed rays physio-
logists are still undecided. There can be no doubt that an early product of
the process is a hexose, which is rapidly converted into cane sugar or into
starch. It was suggested by Baeyer in 1870 that carbon dioxide was
reduced to formaldehyde, which later by condensation yielded sugar. We
know that formaldehyde easily polymerises to form a mixture of hexoses,
but until recently no evidence had been brought forward of its presence as
an intermediate product in the assimilatory process. For most plants,
indeed, formaldehyde is extremely poisonous, though certain algse, as well
as the water-plant, Ebdea, can stand a solution containing -001 per cent,
formaldehyde. Bokorny stated that spirogyra could form starch out of such
derivatives of formaldehyde as sodium oxymethyl-sulphonate, or from
methylal. The difficulty in these cases is that possibly a spontaneous
formation of sugar from the formaldehyde had taken place in the solution and
that the plants were using up the sugar rather than the formaldehyde as the
source of their starch.
One must assume, with Timiriazeff , that the function of chlorophyll in
the process of assimilation is that of a sensitiser. Just as the addition of
eosin to the emulsion used for coating photographic plates will render these
sensitive to the red and green parts of the spectrum, i.e. will excite change in
the silver salt when light from these parts of the spectrum falls upon it, so
the chlorophyll serves as a means by which the absorbed solar energy can b'e
utilised for the production of chemical change in the chloroplast. Attempts
have been made to imitate this process outside the plant. Thus Bach passed
a stream of carbon dioxide through a 1-5 per cent, solution of a fluorescent
substance, uranium acetate, in sunlight. As a result there was a precipitate
of uranium oxide and peroxide, with the formation of traces of formaldehyde.
Usher and Priestley, on treating a solution of carbon dioxide with 1-5 per
cent, uranium acetate or sulphate in bright sunlight, obtained uranium
peroxide and formic acid, but no formaldehyde. The formation of peroxides
110 PHYSIOLOGY
in these conditions suggests that the first change in the chloroplast may be
as follows :
C0 2 + 3H 2 = 2H 2 2 + CH 2
Such a reaction must be regarded as reversible since the hydrogen per-
oxide first formed would tend to oxidise the formaldehyde again. Moreover
it would have a destructive influence on the chlorophyll itself, which is easily
oxidised. In order therefore that the reaction should go on in one direction
only, i.e. that of assimilation, means must be present in the chlorophyll cor-
puscles for the removal of both hydrogen peroxide and formaldehyde as soon
as they are formed. The removal of the hydrogen peroxide can be effected
by a catalase, which is fairly widely distributed in plants and has been shown
by the last-named authors to be present in the chloroplasts. In order to
demonstrate the production of the first result of assimilation, i.e. formalde-
hyde, the further stages in its conversion must be stopped by killing the plant
and the catalase it contains. They therefore placed leaves, which had been
boiled, in water saturated with carbon dioxide and exposed them to bright
sunlight. The leaves were bleached by the oxidation of the chlorophyll, and
some substance of an aldehydic nature was produced, as shown by the
red colour obtained on placing them in rosaniline, previously decolorised
with sulphurous acid.
Two proofs were brought forward that this substance was formaldehyde :
(o) Some of the bleached leaves were soaked for twelve hours in aniline water. The
chloroplasts under the microscope were seen to contain crystals resembling methylene
aniline.
(b) The leaves were distilled in a current of steam. The distillate was shown to
contain formaldehyde by the formation of methylene aniline crystals on treatment
with aniline, and by the preparation from it of the characteristic tetrabrome derivative
of hexamethylenetetramine.
Usher and Priestley conclude that the first products of the photolysis
of carbonic acid are hydrogen peroxide and formaldehyde. Both these
substances are rapidly removed from the reaction. The hydrogen peroxide
is broken up by the catalase into water and oxygen which is turned out by the
plant. The formaldehyde is at once polymerised in the protoplasm of the
chloroplast with the formation first of a hexose and then of starch. The
formaldehyde, if not removed in this way, destroys the catalase. The
hydrogen peroxide, if not broken up by the catalase, destroys the
chlorophyll.
The relations between the various factors in this process may be dia-
grammatically expressed thus :
THE MECHANISM OF ORGANIC SYNTHESIS 111
Carbon dioxide + Water
I f
(// not removed, destroys)^. Chlorophyll
r
Hydrogen peroxide + Formaldehyde
, (// not removed, poisons) *
Enzyme Living protoplasm
i 4
Oxygen ( 'arbohydrates
In thus reducing certain of the stages in the assimilation of carbon
to phenomena which can be imitated outside the living organism, we have
made considerable strides in the ' understanding ' of the process. The stage
for which the vitality of the chloroplast is absolutely essential is the formation
of starch from formaldehyde. Outside the body, our polymerisation of
formaldehyde results in the formation of a mixture of sugars which are optic-
ally inactive. The same process, in the living cell, leads to the production
of optically active sugars which are connected stereochemically and mutually
convertible one into the other, e.g. fructose and glucose. The derivatives of
protoplasm, containing asymmetric carbon atoms, are in the same way
optically active, and it seems that the asymmetry of the protoplasmic
molecule conditions a corresponding asymmetry in the substance which it
builds on to itself. The protoplasm furnishes, so to speak, a mould in which
polymerisation of formaldehyde can result only in the production of sugars
of certain definite stereochemical configurations.
Few, if any, chemical reactions are pure. Nearly all are attended with
by-reactions, so that the yield of end product never attains 100 per cent, of
the theoretical yield. Even if the above mechanism be regarded as the
chief one, it is probable that side reactions take place at the same time, so that
we may have the formation of substances such as glyoxylic acid and other
derivatives of the fatty acid series. Such by-products might play an im-
portant part in the other synthetic activities of the cell, and especially in the
formation of fats and proteins.
THE FORMATION OF PROTEINS
Our knowledge of the mechanism by which proteins are synthetised in
plants is still more incomplete than that of the synthesis of carbohydrates,
and we are reduced in most cases to a discussion of the possible ways in
which, from our knowledge of the chemical behaviour of the constituents of
the protein molecule, we might conceive of its formation. We can at any
rate state the problems which have to be solved and study the conditions
under which the synthesis of protein is possible in plants and in animals.
We know that plants are independent of any organic food for building
up their various constituents, whether carbohydrate, protein, or fat, pro-
vided only that they possess chlorophyll corpuscles and so are able to utilise
112 PHYSIOLOGY
the energy of the sun's rays. Most plants will grow in the dark if supplied
with sugar and with combined nitrogen either in the form of ammonia or of
nitrates. The higher plants are especially dependent on the presence of
nitrogen in the latter form, and it is on this account that the nitrifying bac-
teria of the soil acquire so great an importance for agriculture. From the
carbon dioxide of the atmosphere or from the hexose formed by the assimila-
tion of carbon, and from nitrogen, in the form either of ammonia or nitrates,
together with inorganic sulphates, the plant cell is able to build up all the
various types of protein which are distributed throughout the vegetable
kingdom. Our study of the disintegration products of proteins has shown
that this class of bodies contains a large number of the most diverse groups,
having as a common character the possession of nitrogen in their molecule,
generally as an NIL or NH group. These disintegration products can be
classified as follows :
(a) Open chain amino-acids.
(b) Heterocyclic compounds, including :
(1) Pyrrol derivatives.
(2) Pyrimidine derivatives.
(3) Iminazol derivatives.
These two last groups co-exist in all the purine compounds.
(c) Benzene derivatives.
(d) Indol derivatives.
The first step in the synthesis of proteins is probably the formation of these
constituent groups. Just as in digestion the protein molecule is taken to
pieces with the formation of the different amino-acids, so in the synthetic
action of protoplasm the reverse process of dehydration occurs, resulting
in a coupling up of the different groups, as has been effected by Fischer in the
case of the polypeptides. Wherever transport of protein from one part of the
organism to another is necessary the protein is carried, not in its original
form, but in the hydrolysed condition of amino-acids. Thus the germination
of seeds which contain rich stores of protein is accompanied by a liberation
of proteolytic ferments within the cells of the seeds, and the breakdown
of the reserve protein into its constituent amino-acids. As amino-acids it
is transported into the growing tip and leaves of the seedling, analysis of the
latter showing a very large percentage of nitrogen in the form of amino-acids.
This is especially the case if the synthetic functions of the growing tip are
hindered by interference with assimilation, as, e.g. by keeping the plant in the
dark. Under these circumstances, asparagine may form as much as 25
per cent, of the total dried weight of the seedling. In animals the greater
part of the protein of the food is broken down into its constituent amino-
acids in the intestine. These are absorbed and probably carried to the
different organs of the body, where they are resynthetised, generally in
different proportions from those of the original protein, into the protein
specific for the organ or tissue. The same process of hydrolysis and
subsequent synthesis occurs whenever the transport of protein is neces-
sary from one organ to another. We shall later on have to discuss the
THE MECHANISM OF ORGANIC SYNTHESIS
113
possibility of synthesis of the different amino-acids in animals. We need
therefore at present deal only with the possible methods by which, from the
glucose or substances produced in the assimilation of carbon and
from the ammonia or nitrates derived from the soil, the plant is able
to make the different groups which go to the building up of the protein
molecule.
All the amino-acids contain the NH, group in the a position. We can
therefore consider them as formed by the interaction of an a-oxyacid and
ammonia. Thus :
CH 3
I
CH.OH + NH S
I
COOH
lactic acid
r 'H 3
I
CH.NH, + H 2
I
COOH
alanine
This particular example, namely, the formation of alanine, may occur
at the expense of the glucose produced as the first product of assimilation
of carbon dioxide. If a solution of glucose together with lime be exposed to
sunlight for a considerable time it undergoes decomposition with the forma-
tion of lactic acid. Thus :
C 6 H 12 0, ; 2C 3 H 6 3
glucose lactic acid
This change of glucose to lactic acid under the catalytic influence of the
alkaline calcium hydrate probably occurs by means of a shifting of the
elements of the water, a process which in many long chains seems to occur
with considerable facility, and is dependent on the spatial configuration of
the molecule involved. Thus the change of sugar to lactic acid is readily
effected by means of many micro-organisms in the case of glucose, fructose,
and mannose, but with considerable difficulty in the case of galactose. In
the three former sugars the atoms round the two middle carbon atoms of the
chain are disposed thus :
I I
OH.C.H H.C.OH
H.C.OH
OH.C.H
When either of these arrangements reacts with water, thus
CH..OH
I
CHOH
I
OH.C.H
HCOH
I
CHOH
I
COH
OH
<'H,OH
I
CHOH
COH + H 2
CH.OH
I
CHOH
I
COH
114 PHYSIOLOGY
we obtain two molecules of glyceric aldehyde, which then by a further
shifting of the OH and H groups becomes
CH 8
I
CH.OB
I
GOOH
lactic acid
Lactic acid with ammonia and some dehydrating agent will give amino-
propionic acid or alanine. The formation of the higher amino-acids in-
volves a process of reduction of the sugar first formed in the chlorophyll
granules. It is possible however that the starting-point for the amino-acid
synthesis may be, not a hexose itself, but some other substances, formed,
so to speak, as by-products in the assimilation of sugar from carbon dioxide.
We have seen reason to believe that the first result of the action of the sun's
rays within the chlorophyll corpuscle is formaldehyde. This substance in
the presence of calcium carbonate when exposed to the light gives a mixture
of glyceryl aldehyde and dihydroxyacetone. If we can assume that acetone
is formed from the latter by a process of reduction, we might possibly derive
leucine from an interaction of this substance with lactic acid and ammonia.
Thus :
CH 3 CH 3
CH 3 OH 3 OH /
I I I
CO + CH.OH + NH 3 + H, = CH 2 +2H,0
• I I I
CH 3 COOH CH.NH 2
I
COOH
As an intermediate product in the synthesis of starch, glvoxylic acid
CHO
has been described as occurring in the green parts of plants. This
COOH
substance with ammonia gives formyl glycine, and by the splitting off of
formic acid, glycine or amino-acetic acid. Why nitrates are necessary for
certain forms of plants is not at present understood. In the proteins nitrogen
always occurs in an unoxidised form as NH or NH 2 , and the nitrates taken
up from the soil must therefore undergo reduction before they can be built
into the protein molecule. It is supposed that they may pass through a series
of reductions, namely :
HN0 3 HNO, HNO H 2 N— OH
nitric acid nitrous acid hypoiiitrous acid hydroxylamine
and that the latter substance then reacts with formaldehyde or other sub-
stance derived from the carbon dioxide assimilation to form amino-com-
pounds. - In general we may say that the probable mechanism of formation
of amino-acids is the production of a-oxyacids, which then react with
ammonia to form the amino-acids of the protein molecule ; but of the
THE MECHANISM OF ORGANIC SYNTHESIS 115
exact steps in this process we are at present ignorant. Knoop's work would
point to the ketonic acids as forming one step, and as interacting with
ammonia, with simultaneous reduction, to form amino-acids.
The pyrrol ring which occurs in proline and in oxyproline may possibly
be derived from an open chain amino-acid, and it has in fact been suggested
that the proline found in the products of the acid digestion of proteins is
derived from ornithine by a process of condensation with the loss of ammonia.
Thus :
CH.NH 2 .CH 2 .CH 3 .CH.NH 2 COOH becomes
CH 2 .CH 2 .CH 2 .CH.COOH
NH
or, as it is generally written :
CH„— CH 2
I I
CH„ CH.COOH
NH
Its pre-existence in the protein molecule is however practically assured, and
it plays an important part in the building up both of chlorophyll and of
hsematin, the prosthetic group of haemoglobin.
CH— NH
Iminazol || JCH
CH— N "
occurs in histidine (which is iminazol alanine), and can be formed fairly
readily by the action of certain catalytic agents on a mixture of glucose and
ammonia. Thus, if a solution of glucose with ammonia and zinc oxide be
exposed to light, methyl iminazol is formed in large quantities. Windaus
and Knoop imagined that in this process glyceric aldehyde and formaldehyde
are first formed, and that these then interact with ammonia to form methyl
iminazol.
CH 3
I
C — NH
II >CH
CH— N
It is interesting to note that, if we attach to this compound carbamide
or urea, we obtain a body belonging to the class of purines. Xanthine,
for instance, would have a formula
NH— CO
I I
CO C— NH
I II >'H
NH— CH— N "
Thus by the action of simple catalytic agencies on sugar and ammonia
we can obtain the iminazol nucleus, and by easy transitions pass through
116 PHYSIOLOGY
this to the purine nucleus with its contained ring, the pyrimidine nucleus,
found in the bases cytosine, uracil, &c, which occur in the nucleins.
With regard to the formation of the aromatic constituents of the protein
molecule, i.e. those containing the benzene and indol rings, we have at
present very little indication even of the lines along which it might be
1 1. isai ble to prosecute our researches. It has been suggested that inosite may
represent some stage in the formation of the benzene ring from the open chain
found in the carbohydrates. Inosite has the same formula as glucose,
namely, C 6 H 12 6 , but is a saturated ring compound :
CHOH
CHOH fN CHOH
CHOH \y CHOH
CHOH
and may be expected to be formed as a result of polymerisation of formalde-
hyde. We have no evidence however of the possibility of such a formation,
and the relations of this substance with the benzene compounds are by no
means intimate. It is of such universal occurrence, both in plants and
animals, that it is difficult to refrain from the suspicion that it may play some
part as an intermediate stage between the fatty and the aromatic series.
Since plants are able to manufacture all these varied substances out of
the products of assimilation of carbon and ammonia or nitrates, they must
also find no difficulty in transforming one amino-acid into another, and we
know that most plants can procure their nitrogen from a solution of a single
amino-acid as well as from a nutrient fluid containing the nitrogen in the form
of ammonia. In animals the power of transforming one amino-acid into
another, of one group into another, is probably strictly limited. So far as
we know, nearly all the amino-acids utilised in the building up of the animal
proteins are derived directly from those contained in the food. On the
other hand, we have evidence in the animal body of synthesis of the purine
bodies, and therefore of the pyrimidine and iminazol rings. The hen's egg
at the beginning of incubation contains very little nuclein, nearly the while
of its phosphorus being present in the form of phosphoproteins and lecithin.
As incubation proceeds these substances disappear, their place being taken
by the nucleins which form the chief constituent of the nuclei of the developing
chick. In the same way the ovaries and testes of the salmon are formed
during their sojourn in fresh water at the expense of the skeletal muscles,
especially those of the back. Here again there is a transformation of a tissue
poor in purine bases into a tissue which consists almost exclusively of nucleins
and protamines. Whether in this case there is a direct conversion of the
monc-amino-acids of the muscle proteins into the diamino-acids and bases
typical of protamines, we do not know. It is more probable that only
diamino-acids and bases previously existing in the muscle are utilised for the
THE MECHANISM OF ORGANIC SYNTHESIS 117
formation of the generative glands, the other amino-acids being oxidised
and utilised for the ordinary energy requirements of the animaL
THE SYNTHESIS OF FATS
In some plants fat globules have been stated to appear as the first products
of the assimilation of carbon dioxide under the influence of sunlight, but
there is no doubt that as a rule the formation of fats as reserve material in
seeds or fruits occurs at the expense of carbohydrates. In the higher animals
too, although a certain amount of the fat of the body is derived from the fat
taken up with the food, the organism can also manufacture neutral fat out
of the carbohydrates presented to it in its food. The problem therefore
of the synthesis of the fats is the problem of the conversion of a sugar such
as glucose into glycerin and the fatty acids. Although this conversion
is armarently so easily effected by the living organism, it is one which from the
chemical standpoint involves considerable difficulties. On account of the
fact that the higher fatty acids consist largely of oleic and stearic acids, i.e.
acids containing eighteen carbon atoms in their chain, it has been thought
that the synthesis might be brought about by the linking together of three
molecules of a hexose. Such a change would involve a series of difficult
chemical transformations. For instance, no less than sixteen out of the
eighteen oxygen atoms present in the three glucose molecules woidd have
to be dislodged in order to convert the chain into stearic acid. Moreover,
although these two acids contain a multiple of six carbon atoms, a whole
array of fats are found both in plants and animals which could not be derived
by a simple aggregation of glucose molecules ; and it is worthy of note that, of
all the fatty acids which occur in nature, all those with more than five carbon
atoms contain an even number of carbon atoms. Thus in milk, -in addition
to the three common fats, tristearin, tripalmitin, and triolein, we find the
glycerides of caproic, caprylic, capric, lauric, and myristic acids, i.e. acids
with 6, 8, 10, 12, and 14 carbon atoms. In all cases these acids are the
normal acids with straight unbranched chains. It seems probable that in
the transformation of carbohydrate into fatty acid the latter is built up, not
by six carbon atoms, but by two carbon atoms at a time. It has been
suggested by Magnus Levy and by Leathes that the transformation may
occur by way of lactic acid. We have seen already that glucose and the
sugars of analogous composition may be converted under the influence either
of sunlight or of micro-organisms into lactic acid. Lactic acid breaks down
with readiness into aldehyde and formic acid.
CH 3 CH 3
I I
CHOH = CHO + H
I I
COOH COOH
Aldehyde undergoes condensation to form aldol.
118
PHYSIOLOGY
CHO
CH,
I
i Hull
CH,
I
CHO
aldehyde aldol
Aldol reacts with water and undergoes a shifting of its OH and H groups,
in a manner with which we are already familiar as occurring in the conversion
of glucose into lactic acid, forming butyric acid. We may represent the
reaction in the following way, placing the water molecules opposite those
groups of the aldol molecule with which they react :
OH,
I
H HO CH H
OH
gives
CH,
O C H OH
CH,
CH,
| " + 2H 2
CH,
I
COOH
It will be seen that although water must enter into the reaction there is
no addition of water to the aldol in order to form the butyric acid.
It has been suggested that similar reactions might account for the forma-
tion of the higher fatty acids, in which case one molecule of acetic aldehyde
would be added to the fatty acid in order to build up the acid which is next
highest in the series. Although certain of the higher acids have been pre-
pared in this way, proof is still wanting that a continuous series of syn-
theses may be effected by the continuous addition of aldehyde. Such a
hypothesis is however more probable than the direct conversion of three
molecules of sugar into one molecule of stearic acid. The latter change
would be associated with a very great absorption of energy, whereas a con-
tinuous building up of fatty acids, by the addition of aldehyde obtained
through lactic acid from the disintegration of hexose molecules, requires only
a small expenditure of energy, which could be obtained by the combustion
of the formic acid formed as a by-product in the process. If we suppose that
the synthesis of the higher fatty acids from sugar is carried out in this way,
the energy equations would be as follows (Leatb.es ) :
1 g. rnol. glucose ) |2 g. mols. aldehyde + 2 g. mols. formic acid.
677-2 cals. j ~ "*" ( 2 + 275-5 + 2 X 61-7
= 674-4 cals.
THE MECHANISM OF OEGANIC SYNTHESIS 119
2 g. mols. aldehyde ) (1 g. mol. aldol | |1 g. mol. butyric acid.
551 cals. j "*"{ 546-8 cals. j *\ 517-8 cals.
Or, tracing the same change on as far as palmitic acid :
4 g. mols. glucose ) (1 g. mol. palmitic acid + 8 g. mols. formic acid.
2708 cals. j { 2362 cals. + 494 cals.
= 2856 cals.
In the first stage of the synthesis, the reaction leading to butyric acid, the
net result would be, supposing the formic acid to be oxidised, that some 160
calories or nearly 25 per cent, of the whole energy, would be rendered avail-
able for other purposes. In the latter stages leading to palmitic acid some
of the energy derived from the oxidation of the formic acid would be required
for effecting the synthesis, and only about 12-5 per cent, of the original
amount contained in the sugar would be set free. It is worth noting that
in the butyric fermentation of sugar by micro-organisms there is a production
first of lactic acid, and this substance then disappears to give place to butyric
acid. At the same time carbonic acid and hydrogen are evolved, both gases
being derived from the decomposition of the formic acid. In the process a
certain amount of caproic acid is always produced, and the crude butyric
acid of fermentation is used as the source from which commercial caproic
acid is derived.
Attempts to produce the higher fatty acids by the condensation of successive
molecules of aldehyde have so far resulted only in the production of branched chains
of carbon atoms, whereas the normal fatty acids of the body are straight chains ;
though Raper has shown that the normal caproic acid may be formed by the condensa-
tion of aldol with itself. Miss Smedley has suggested that a more probable line of
synthesis. lies through pyruvic acid. Pyruvic acid, which may be produced in the body
from lactic acid, and so from carbohydrate, is fermented by yeast with the production of
acetaldehyde and carbon dioxide, by means of a ferment carboxylase. If we assume
the existence of a similar ferment in the cells of the body, it would split this acid into
aldehyde and C0 2 . Aldehyde however combines with a molecule of pyruvic acid to
form a higher keto =acid, which might either be oxidised to the fatty acid containing one
carbon atom less, or might be again transformed by enzymes into an aldehyde capable
of reacting with another molecule of pyruvic acid. These changes are represented in the
following equations:
CH 3 CO.archment, which is hung up in a large bulk of distilled water (Fig. 2G), all
the salts diffuse out, and if this be frequently changed, we obtain finally a
fluid within the dialyser free from salts and other crystalloid substances, but
containing the whole of the colloidal proteins originally present.
PASSAGE OF WATEE AND DISSOLVED SUBSTANCES 135
Thus the transference of fluids and dissolved substances across membranes
is determined not only by the osmotic pressure of the solutions, but also by
the diffusion coefficient of the solutes and the permeability of the membrane.
This permeability may be of the same character as the permeability of water,
in which case the rates of passage of the dissolved substances across the
Fig. 26. Dialyser, consisting of a tube of parchment paper immersed in a vessel
through which a constant stream of sterile distilled water can be passed.
(Wroblesui.)
membrane vary as, their diffusibilities, and are therefore probably some func-
tion of their molecular weights. On the other hand, the membrane may
exhibit a certain attraction for, or power of dissolving, some of the solutes to
the exclusion of others, in which case there will be no relation between the
diffusibilities and the rates of passage of the dissolved substances.
Bayliss has drawn attention to certain other factors which may determine permanent
inequality of distribution of a salt on the two sides of a membrane permeable to the salt.
If Congo red, which is a compound of an indiffusible colloid acid with sodium, be placed
in an osmometer which is immersed in water, a certain osmotic pressure is developed.
On adding sodium chloride either to the inner or outer fluid, there is a fall in the osmotic
pressure if time be allowed for equilibrium to be established. At this point it is found
that the outer fluid, which is free from dye, contains a larger percentage of sodium
chloride than the inner solution of dye. This difference is permanent and is more
marked the greater the concentration of the dye salt. In the following Table is given
the concentrations of the two fluids with different percentages of salt. The numbers
indicate the litres to which each gramme molecule of the salt is diluted. Apparently
136
PHYSIOLOGY
Dye
Chlorine
Inside
mil i,i,
30
52
30
30
465
73-6
30
<5500
180
100
32-9
29-5
the difference depends on the fact that the non-dissociated salt must be equal on the I w< .
sides of the membrane and that the dissociation is much impeded on the inner side on
account of the presence there of another salt of sodium. A sodium salt of any
other indiffusible substance, e.g. of, a protein such as caseinogen, would behave in a
precisely similar fashion.
SECTION III
THE PROPERTIES OF COLLOIDS
Although the chemical changes involved in the various vital phenomena
occur between substances in watery solution, the solution in every casj is
bound up within the meshes or adsorbed by the surfaces of a heterogeneous
mass of colloids. The complex chemical molecules which make up
protoplasm itself are all colloidal in character. The participation of
colloids in chemical reactions introduces conditions and modes of reaction
differing widely from those which have been studied in watery solutions.
Our knowledge of these conditions is still very imperfect, but the important
part played by colloids in the processes of life renders it necessary to discuss
in some detail their properties and modes of interaction.
The term colloid, from xoWy, glue, was first introduced by Thomas
Graham, Professor of Chemistry at University College from 1836 to 1855.
Graham divided all substances into tw T o classes, viz. crystalloids, including
such substances as salt, sugar, urea, which could be crystallised with ease,
diffused rapidly through water, and were cajiable of diffusing through animal
membranes ; and colloids, which included substances such as gelatin or
glue, gum, egg-albumin, starch and dextrin, were non-crystallisable, formed
gummy masses when their solutions were evaporated to dryness, diffused
with extreme slowness through water, and would not pass through animal
membranes. The process of dialysis was therefore introduced by Graham
for the separation of crystalloids from colloids. Although the broad dis-
tinction drawn by Graham between colloids and crystalloids still holds good,
some of the criteria by wdiich he distinguished the two classes are no longer
strictly applicable. For instance, it has been shown that many typical
colloidal substances, such as haemoglobin, can be obtained in a crystalline
form. On the other hand, all gradations exist between substances, such as
egg-albumin, which are practically indiffusible, and those, such as common
salt, which are very diffusible. Graham pointed out that colloids exist under
two conditions :
(1) In a state of solution or pseudo-solution, in which they form sols, and
are distinguished as hydrosols, when the solvent is water ; and
(2) In a solid state, in which a relatively small amount of the colloid
sets with a large amount of a fluid, such as water, to form a jelly. This
solid form is known as a gel. The most familiar instance is the jelly which
is obtained on dissolving a little gelatin in hot water and allowing the mixture
137
138 PHYSIOLOGY
to cool. Such a jelly is known as a hydrogel. In many of these gels the
water can be replaced by other fluids, such as alcohol, without any alteration
in the appearance of the solid, which is then known as an alcogel. An
example of an alcogel is the jelly which can be made by dissolving soap in
warm alcohol and allowing the mixture to cool.
A number of these colloidal substances can be shown on purely chemical
grounds to consist of monstrous molecules. Thus the molecular weight
of haemoglobin is at least 16,000, and one must ascribe similar high molecular
weights to such substances as egg-albumin and globulin. Still greater must
be the molecular size of such substances as the cell proteins, which may
be made up of more than one type of protein built up with various
nucleins, with lecithin and cholesterin, to form a gigantic complex, to
which it would probably not be an exaggeration to ascribe a molecular
weight of over 100,000. This chemical complexity is not however a
necessary condition of the colloidal state, as is shown by the existence
of colloidal silica, of colloidal ferric hydrate and alumina, and even of
colloidal metals.
On neutralising a weak solution of sodium silicate or water-glass by means of HC1,
we obtain a solution which contains sodium chloride and silicic acid. On dialysing this
mixture for some days against distilled water, the whole of the NaC'l passes out, and a
solution of silicic acid or colloidal silica is left in the dialyser. This solution can be
concentrated over sulphuric acid. When concentrated to a syrupy consistence it
becomes extremely unstable. The addition of a minute trace of sodium chloride
or other electrolyte to the solution causes it to set at once to a solid jelly (gelatinous
silica), the change being accompanied by an appreciable rise of temperature. The
change is irreversible, in that it is not possible to bring the silicic acid into solution
again by removal of the electrolyte by means of dialysis. If however it be allowed
to stand with weak alkali for some time, it gradually passes into solution. Analogous
methods are employed for the preparation of colloidal Fe 2 3 and A1,0 3 .
Of special interest are the colloidal solutions of the metals. Faraday
long ago pointed out that, on treating a weak solution of gold chloride with
phosphorus, it underwent reduction with the formation of metallic gold.
The gold was not precipitated, but remained in suspension or pseudo-
solution, giving a deep red * or a blue liquid, according to the con-
ditions under which the reaction was effected. This solution was homo-
geneous in that it could be filtered without change, and could be kept for
months without deposition of the gold. The latter was however thrown
down on addition of mere traces of impurity, though greater stability could
be conferred on the solution by adding to it a little ' jelly,' i.e. a weak solution
of gelatin. In 1899 Bredig showed how similar hydrosols might be prepared
from a number of different metals, viz. by the passage of a small arc or
electric sparks between metallic terminals submerged in distilled water.
If, for example, the terminals be of platinum, the passage of the current
is seen to be accompanied by the giving off of brown clouds, which spread
into the surrounding fluid. These clouds consist of particles of platinum
* Ruby glass is a colloidal ' solid ' solution of gold in a mixture of silicates.
THE PROPERTIES OF COLLOIDS 139
of all sizes. The larger settle at the bottom of the vessel, the smaller — ■
which are ultra-microsccpic in size, i.e. from 5 ^ to 40^* — remain in sus-
pension, and we obtain a brown fluid which can be filtered through paper
or even through a Berkefeld filter without losing its colour. It may be
kept for months without any deposit taking place. The addition of minute
traces of electrolytes precipitates the platinum particles, leaving a colourless
fluid. We shall have to return later on to the consideration of the behaviour
of these metallic sols.
Colloidal solutions or sols may be divided into two classes, emidsoids
and suspensoids, accord'ng as they may be regarded as suspensions of liquid
in liquid or as suspensions of solid particles.
Most protein solutions are emulsoids, while the metallic sols belong to
the class of suspensoids. Dilute egg-white is an emulsoid, but if it be boiled,
although no visible precipitation is produced, the fine particles are coagulated
and it behaves as a suspensoid.
PROPERTIES OF GELS. A typical hydrogel is the firm mass in which
a solution of gelatin sets on cooling. It is clear, hyaline, apparently structure-
less, and possesses considerable elasticity, i.e. resistance to deforming force.
It may be regarded as formed by the separation of the warm pseudo-solution
of gelatin into two phases : first a solid phase, rich in gelatin and forming
a tissue or meshwork, in the interstices of which is embedded the second
phase, consisting of a very weak solution of gelatin.
If the process be observed under the microscope, according to Hardy minute drops
first appear which, as they en Urge, touch one another and form networks. In stronger
solutions the first structures to make their appearance consist, not of the more con-
centrated phase, but of droplets of the dilute solution of gelatin ; the stronger solution
collects round these drops and solidifies to a honeycomb structure.
In many cases the more fluid part of the gel is practically pure water.
In such a case immersion in alcohol causes a diffusion outwards of the water,
which is replaced by alcohol with the formation of an alcogel. In a dry
atmosphere the gel loses water and becomes shrivelled and dry, but in
some cases, e.g. gelatin, it can resume its former size and characters on
immersion in water. Other gels, such as silicic acid or ferric hydrate, lose
the power of swelling up after drying. The change in them is therefore
irreversible. A gel adheres tothe last traces of water with extreme tenacity.
In consequence of its structure, it presents an enormous extent of surface
on which adsorption can take place. At this surface the vapour-tension of
fluids is diminished, as well as the osmotic pressure of dissolved substances.
On this account gelatin must be heated for many hours at a temperature
of 120° C. in order to be thoroughly dried. When dry, it, as well as other
solid colloids, can exert a considerable amount of energy when caused to
swell up by moistening. This energy was made use of by the ancient
Egyptians in the quarrying of their stone blocks by the insertion of wedges
* One fj. is one-thousandth of a millimetre ; one yu./x is one-thousandth p, i.e. one-
millionth of a millimetre.
140 PHYSIOLOGY
of wood ; water was poured on the wood, and the swelling of the wedges
split the rock in the desired direction.*
On account of the extent of surface it is practically impossible to wash
out the inorganic constituents from a gel. The diminution of the osmotic
pressure of many dissolved substances at surfaces causes the concentration
at the surface of the solid phase to be greater than that in the surrounding
medium. Thus if dry gelatin be immersed in a salt solution it will swell
up, but the solution which it absorbs will be more concentrated than the
solution in which it is immersed, so that the proportion of salt in the latter
will be diminished. When however equilibrium is established between a
gel and the surrounding fluid, it is found to present no appreciable resistance
to the passage of dissolved crystalloids. Thus salt or sugar diffuses through
a column of solid gelatin as if the latter were pure water. On the other
hand, gels are practically impermeable to other colloids in solution. This
impermeability is made use of in the separation of crystalloids from colloids
by dialysis, membranes used in this process being generally irreversible
and heterogeneous gels (i.e. vegetable parchment, animal membranes).
Other gels, such as tannate of gelatin or copper ferrocyanide, are not only
impermeable to colloids, but also to many crystalloid substances. These
membranes therefore were used by Pfeffer for the determination of the
osmotic pressure of such crystalloids as cane sugar.
PROPERTIES OF HYDROSOLS. Substances such as dextrin or egg-
albumin may be dissolved in water in almost any concentration. If a
solution of egg-albumin be concentrated at a low temperature, it becomes
more and more viscous and finally solid. But there is no distinct point
at which the fluid passes into the solid condition. Such solutions are known
as hydrosols. Much discussion has arisen whether they are to be regarded
as true solutions or as pseudo-solutions or suspensions. The chief criterion
of a true solution is its homogeneity. In a solution the molecules of the
solute are equally diffused throughout the molecules of the solvent, and
it is impossible, without the application of energy, to separate one from
the other. Thus filtration, gravitation leave the composition of the solution
unchanged. It is true that, by the employment of certain kinds of mem-
branes, e.g. the semi-permeable copper ferrocyanide membrane, it is possible
to separate solute from solvent, but in this case the force required to effect
the filtration is enormous and grows with every increase in the strength
of the solution. The measure of the force required is the osmotic pressure
of the solution, and it becomes natural therefore to regard the possession
of an osmotic pressure as a distinguishing criterion of a true solution.
Is there any evidence that colloidal solutions also display an osmotic
pressure ?
I have shown that it is possible to determine the osmotic pressure of
colloidal solutions directly, taking advantage of the fact that colloidal mem*
* According to Rodewald, the maximal pressure with which dry starch attracts
water amounts to 2073 kilo, per sq. cm.
THE PROPERTIES OF COLLOIDS
141
branes, while permitting the passage of water and salts, are impermeable
to colloids in solution.
The method originally adopted was as follows : In order to determine the osmotic
pressure of the colloidal constituents of blood-serum, 150 c.c. of clear filtered serum are
filtered under a pressure of 30-40 atmospheres through a porous cell which has been
previously soaked with gelatin. The first 10-20 c.c. of filtrate, which contain the
water squeezed out of the meshes of the gelatin and have also lost salt in consequence
of absorption by the gelatin, are rejected. The filtration is allowed to go on for another
twenty-four hours, when about 75 c.c. of a clear colourless filtrate are obtained, per-
fectly free from all traces of protein, but possessing practically the same freezing-point
as the original serum. (Although the colloids, if they possess an osmotic pressure, must
also cause a depression of the freezing-point, any such depression would be within
the errors of observation, since a pressure of 45 mm. Hg would correspond only to
0*005° C.) The concentrated serum left behind in the filter is then put into the osmo-
meter, the filtrate being used as the inner fluid. The construction of the osmometer
is shown in the diagram (Fig. 27).
The tube BB is made of silver gauze, connected at each end to a tube of solid silver.
Round the gauze is wrapped a piece of peritoneal membrane, as in making a cigirette.
This is painted ail over with a solution of gelatin (10 per cent.) and then a second layer
of membrane applied. Fine thread is now twisted many times round the tube to
prevent any disturbance of the membranes, and the whole tube is soaked for half an
hour in a warm solution of gelatin. In this way one obtains an even layer of gelatin
between two layers of peritoneal membrane and supported by the wire gauze. The
tube so prepared is placed within a wide tube, AA, which is provided with two tubules
at the top. One of these, O, is for filling the outer tube ; the other is fitted with a
mercurial manometer, M. Two small reservoirs, CC, are connected with the outer
ends of BB, by means of rubber tubes. The whole apparatus is placed in a wooden
cradle, DD, pivoted at X, and provided with a cover so that it may be filled with fluids
at different temperatures if necessary. The colloid solution is placed in AA, and the
reservoirs, CC, and inner tube, BB, are filled with the filtrate, i.e. with a salt solution
approximately or absolutely isotonic with the colloid solution. The apparatus is then
made to rock continuously for days or weeks by means of a motor. In this way the
fluid on the two sides of the membrane is continually renewed, and the attainment
of an osmotic equilibrium facilitated. With this apparatus I found that the colloids
in blood-serum, containing from 7 to 8 per cent, proteins, had an osmotic pressure of
25 to 30 mm, Hg, which would correspond to a molecular weight of about 30,000.
142 PHYSIOLOGY
A more convenient form of osmometer has been devised by B. Moore,
using parchment paper as the membrane. With this osmometer, the
existence of an osmotic pressure in colloidal solutions has been definitely
established both by Moore in the case of haemoglobin, proteins, and soaps,
and by Bayliss in the case of colloidal dyes, such as Congo red. The osmotic
pressure of haemoglobin was found I y Hiifner to correspond to a molecular
weight of about 10,000, i.e. a molecular weight already deduced from its
composition and its combining powers with oxygen. Often however the
osmotic pressure is very much smaller than would be expected from the
molecular weight of the substance, owing to the fact that colloids in solution
may be in many different conditions of aggregation. Thus the molecule
of colloidal silica must be many, probably thousands of times larger
than the molecule as represented by H,Si0 3 . The osmotic pressure
being proportional to the number of molecules in a given volume of solution,
the larger the aggregate the smaller would be the total number of molecules,
and the smaller therefore the osmotic pressure of the solution.
It is in consequence of the huge size of the molecular aggregates that
colloidal solutions, such as starch or glycogen, and probably globulin, display
no appreciable osmotic pressure. We cannot divide colloidal solutions into
two classes, viz. those which form true solutions and present a feeble osmotic
pressure, and those which form only suspensions and therefore exert no
osmotic pressure. In inorganic colloids, such as arsenious sulphide, Picton
and Linder have shown that all grades exist between true solutions and
suspensions. With increasing aggregation of the molecules, the suspension
becomes coarser and coarser until finally the sulphide separates in the form
of a precipitate.
The measurement of the osmotic pressure of the colloids of serum points
to their having a molecular weight of about ?)0,CC0. Chemical evidence
shows that haemoglobin has a molecular weight of about 16,0(0, and we
have every reason to believe that the much more complex molecules forming
the cell proteins may have molecular weights of many times this amount.
When however we arrive at molecular weights of these dimensions, the
disproportion between the size of the molecules and those of the solvent,
water, becomes so great that a homogeneous distribution of the two sub-
stances, solute and solvent, is no longer possible. The size of a molecule
of water has been reckoned to be -7 x 10 — 8 mm. A molecule 10,((0
times as large would have a diameter of -7 x 10 — 4 mm. = -07^, a size
just within the limits of microscopic vision. Long before molecules attained
such a size they would no longer react according to the laws which have
been derived from the study of the behaviour of the almost perfect gases,
but would possess the properties of matter in mass. They have a surface
of measurable extent, and their relations to the molecules of water or solvent
will be determined by the laws of adsorption at surfaces rather than by
the laws of interaction of imleeules. As a matter of fact we find that such
solutions present an amazing mixture of properties, some of which betray
them as mechanical suspensions, while others partake of the nature of the
THE PROPERTIES OF COLLOIDS 143
chemical reactions such as those studied in the simpler compounds usually
dealt with by the chemist.
OPTICAL BEHAVIOUR OF HYDROSOLS. Nearly all colloidal solu-
tions present what is known as the Faraday- Tyndall phenomenon. When
a beam of light is passed through an optically homogeneous fluid, the course
of the beam is invisible. A beam of sunlight falling into a dark room is
rendered visible by impinging on and illuminating the dust particles in its
course. Each of these particles, being illuminated, acts as a centre of dis-
persion of the light, so that the course of the beam is apparent to a person
standing on one side of it. Tyndall showed that, if the particles were
sufficiently minute, the fight dispersed by them at right angles to the beam
was polarised. This can be easily tested by looking at the beam through
a Nicol's prism. If the prism be slowly rotated, it will be found that,
while at one position the light is bright, in the position at right angles to this
it becomes dim or is extinguished. The production of the Tyndall pheno-
menon may therefore be regarded as a test for the presence of ultra-micro-
scopic particles, varying in size from 5 to 50 /iu. The phenomenon is perhaps
too sensitive to be taken as a proof that a fluid presenting it is a suspension
rather than a solution. It is shown, for instance, by solutions of many
bodies of high molecular weight, such as raffinose (a tri-saccharide) or the
alkaloid brucine (Bayliss).
A particle having a diameter less than half the wave-length of light,
i.e. about 300 / or -3 //,, cannot be clearly distinguished under any power of
the microscope. The fact that an ultra-microscopic particle may serve
as a centre for dispersal of light may be used for rendering such particles
visible under the microscope. For this purpose a strong beam of light is
passed in the plane of the stage of the microscope through a cell containing
the hydrosol, which is then examined under a high power. On examining
with this apparatus a dilute gold sol, we see a swarm of dancing ] oints
of light. ' like gnats in the sunlight," which move rapidly in all directions,
rendering it almost impossible to count their number in the field. The coarser
particles present slight oscillations similar to those long known as the Brown-
ian movements. The smallest particles which can be seen show a combined
movement, consisting of a translatory movement, in which the particle
passes rapidly across the field in one-sixth to one-eighth of a second, and a
movement of oscillation of much shorter period. The representation of the
course of such a particle is given in Fig. 28.
The size of the smallest particles seen in this way may amount to -f 05 //.
Not all colloidal solutions show these particles in the ultra-microscope.
In some cases this is due simply to the small size of the particles, and
the addition of any substance, which causes aggregation and therefore
increase in the size of the particles, will bring them into view. In others
the absence of optical inhomogeneity may be due to the coincidence of
the refractive indices of the two phases of the hydrosol, or to the ab ence
of any surface tension and therefore dividing surfaces between the two
phases.
144
PHYSIOLOGY
ELECTRICAL PROPERTIES OF COLLOIDS
In the case of many hydrosols the ultra-microscopic particles of which
they are composed carry an electric charge which, according to the nature
of the solution, may be either positive or negative. On this account, the
particles move if placed in an electric field, and the direction of their move-
ment reveals the nature of their change. Thus colloidal ferric hydrate is
electro-positive and travels from anode to cathode. Silicic acid, in the
presence of' a trace of alkali, is electro-negative, and the same is true of a
hydrosol of gold. When a current is passed through these hydrosols, the
colloidal particles travel to. the anode, where they are precipitated. In
certain colloids the charge varies according to the conditions under which
they are brought into solution. If for instance, egg-white be diluted ten
times with distilled water, filtered and boiled, no precipitate occurs, but
Fig. 28. Movements of two particles of india-rubber latex in colloidal solution, recorded by
cinematograph and ultra-mi roBcope. (Hentu.)
we obtain a colloidal suspension of albumin. When thoroughly dialysed,
this protein is insoluble in pure water, but is soluble in traces of either acid
or alkali. In acid solution the protein particles carry a positive charge,
whereas in alkaline solution their charge is negative. The charged condi-
tion of these particles must play a considerable part in keeping them asunder
and therefore in preventing their aggregation and precipitation. This is
shown by the fact that any agency which will tend to discharge them will
cause precipitation and coagulation. Among such agencies is the passage
of a constant current, just mentioned. To the same action is due the
coagulative or precipitating effects of neutral salts. Thus any of the
colloids we have mentioned, ferric hydrate, silica, gold, or boiled albumen,
are thrown down by the addition of traces of neutral salts, and it is found
that in this process they carry with them some of the ion with the opposite
charge to that of the colloidal particle. Thus, in the precipitation of the
THE PROPERTIES OF COLLOIDS • 145
electro-positive ferric hydrate the acid ion of the salt is the determining
factor, the coagulative power increasing rapidly with the valency of the acid.
On the other hand, in the precipitation of a gold sol the electro-positive ion
is the effective agent, and here again the coagulative effect is enormously
increased by a rise in valency. This is shown in the following Tables,
where it will be seen that in the coagulation of gold, barium chloride with
the divalent Ba", is seven times as powerful as K 2 S0 4 containing the
univalent K'. On the other hand, in the precipitation of the electro- positive
ferric hydrate. K,S0 4 with a divalent S0 4 ", is 400 times as effective as
BaCL.
Amount of Salt necessary to Precipitate Colloidal Solutions
To coagulate Gold To coagulate Fe 2 3
K 2 S0 4 1 g. mol. in 4,000,000 c.c.
MgS0 4 „ „ „ 4,000,000 „
BaCl s „ „ „ 10,000 „
Nad .. ., „ 30,000 ..
BaCl 2 1 g. mol. in 500,000 c.c.
NaCl „ „ „ 72,000 „
K,S0 4 „ „ „ 75,000 „
The presence of a charge is not however a necessary condition for the
stability of a colloidal solution. Thus the proteins of serum, globulin in a
weak saline solution, or gelatin, present no drift when exposed to a strong
electric field. In such cases one must assume the stability of the solution
to be determined by the absence of any surface tension between the two
phases in the solution, or between the particles of solute and solvent.
Thus no force is present tending to cause aggregation of the particles.
The charged condition of a colloidal particle makes it behave in an
electric field in much the same way as a charged ion of an electrolyte, and
this similarity extends also to its chemical behaviour, so that we have a
class of compounds formed resembling in many respects chemical com-
binations, but differing from these in the absence of definite quantitative
relations between the reacting substances. This class of continuously
varying chemical compounds has been designated by Van Bemmelen absorp-
tion compounds. Since, however the interaction must take place at the
surface layer bounding the charged particles, it will be perhaps better, as
Bayliss has done, to use the term adsorption. The huge molecules or aggre-
gates of molecules which distinguish the colloidal state form a system with
a considerable inertia, so that we have a tendency to the establishment
of conditions of false equilibrium. Once a configuration is established, it
is necessary, in consequence of the inertia, to overstep widely the conditions
of its formation in order to destroy it. Thus a 10 percent, gelatin solution
sets at 21°C, but does not melt until warmed to 2y-ti°C. Solutions of agar
in water set at about 35°C, but do not melt under 90°C. A gel of
gelatin takes twenty-four hours after setting to attain a constant melting-
point.
The factors involved in the formation of adsorption or absorption com-
binations are therefore :
(1) Extent of surface. In a colloidal solution this must be enormous
in proportion to the mass of substance in solution. Thus a 10 c.c. sphere
10
146
PHYSIOLOGY
with a surface of 22 sq. cm., if reduced to a fine powder consisting of spherules
of -C0000025 cm. in diameter, will have a surface of 20,CC0,CC0 sq. cm.,
i.e. nearly half an acre. At the whole of this surface adsorption may
take place, involving the concentration of dissolved electrolytes, ions, or
(2) Chemical nature of particle.
(3) Electric charge on the surface. The sign of this may be determined
by the chemical nature of the colloid and its relation to the electrolytes in
the surrounding medium.
Another factor which may determine the character of the charge on the particles
has been pointed out by Coelin. This observer finds that, when various non-con-
ducting bodies are immersed in fluids of different dielectric constants, they assume a
positive or negative charge according as their own dielectric constants are higher or
lower than the fluid with which they are in contact. For instance, glass (5 to 6) is
negative in water (80) or alcohol (26), whereas in turpentine (2-2) it is positive. In
water, as Quincke has found, nearly all non-conducting bodies take on a negative charge.
Among these are cotton-wool and silk. Particles of these in water, exposed to an
electric field, move towards the anode. The same is true, as Bayliss has shown, of paper.
The conditions which determine the formation of these adsorption com-
pounds can be studied in their simplest form on the adsorption of dyestuffs
by substances such as paper. If we take a series of solutions of a dye,
such as Congo-red, in progressively diminishing concentration, and place
in each solution the same amount of filter-paper, we find that a part of the
dye is taken up by the paper, and the proportion taken up is larger the more
dilute the solution. This relation has been spoken of by Bayliss as the law
of adsorption. This is illustrated by the following Table of results of such
an experiment :
Concentration of
solution
Proportion of dye
in solution
Proportion of dye-
in paper
Initial Final
0-014 00056
Per cent.
40
Per eent.
60
0-012 0-0024
0010 00009
20
9-3
80
90-7
0-008 00003
4
96
0-006 0-00008
0-004
0-002
13
trace
trace
98-7
practically all
practically all
If put into the form of a curve, where the ordinates represent the per-
centage of dye left in solution, and the abscissae the original concentration
of the solution, the curve only approaches the ax,is (i.e. zero concentration)
asymptotically. In other words, however dilute the original solution may
be, there will always be a certain amount of the dye left unabsorbed by
the paper. Similar relations are found to exist between proteins and electro-
lytes. By continuously washing a protein or gelatin with distilled water,
THE PROPERTIES OF COLLOIDS 147
the removal of electrolytes becomes slower and slower, but it is practically
impossible within finite time to get rid in this way of the last traces of ash.
Although the chemical behaviour of colloids is largely determined by
surface phenomena, it presents at the same time analogies with more strictly
chemical reactions, since it is conditioned by the chemical structure, of the
colloid molecule as well as by the charge carried by the latter. A good
example of these adsorption combinations is presented by globulin, the
behaviour of which has been studied by Hardy. This may be obtained
from diluted blood-serum by precipitation with acetic acid. Four states
can be recognised in both the solid condition and in solution, viz. globulin
itself, compounds with acid or with alkali, and compounds with neutral
salt. The amount of acid and alkali combining with the globulin is in-
determinate, the effect of adding either acid or alkali to the neutral globulin
being to cause a gradual conversion of an opaque, milky suspension into a
limpid, transparent solution. On drying HC1 globulin, the dried solid is
found to contain all the chlorine used to dissolve it. The acid may therefore
be regarded as being in true combination. Both acid and alkali globulins
act as electrolytes, the globulin being electrically charged and taking part
in the transport of electricity. In order to produce the same extent of
solution, the concentration of the alkali added must be double that of the
acid. The relation of globulin to acids and alkalies is similar to that of the
so-called amphoteric substances, such as the amino-acids. An amino-acid,
such as glycine, can react as a basic anhydride with other acids, thus :
NH 3 NH 2 HC1
CH,/ + HC1 = CH /
N CO,H C0 2 H
or as an acid anhydride with bases :
CH 2 .NH 2 CH 2 .NH 2
+ NaHO = | +H a O
COOH COONa
Like these too, globulin forms soluble compounds with neutral salts. An
amphoteric electrolyte thus acts as a base in the presence of a strong acid,
and as an acid in the presence of a strong base.
From true electrolytes, colloidal solutions differ in the fact that their
particles are of varying size according to the conditions in which they exist
and carry varying charges of electricity, whereas an ion such as Na or CI
has a mass which is constant for the ion in question, and always carries
the same electric charge. The charged particles of an acid- or alkali-globulin
may be distinguished therefore as pseudo-ions.
In these adsorption combinations, although the chemical nature of the
colloidal molecules is concerned, there is an absence of definite equilibrium
points, such as we are accustomed to in most chemical reactions. The inertia
of the system and the large size of the molecules determine the occurrence
of false equilibria and of delayed reaction, so that the condition and behaviour
of a colloidal system at any moment are determined, not entirely by the
148 PHYSIOLOCxY
quantitative relations of its components, but also by the past history of the
system.
COMBINATIONS BETWEEN COLLOIDS
Besides the compounds between colloids and electrolytes, combination,
or at least interaction, takes place between different colloids. Many colloids
are precipitated by other colloidal solutions. This effect is always found to
occur when the colloidal solutions carry different charges. Thus ferric
hydrate in colloidal solution is precipitated by colloidal silica or colloidal
gold, both colloids being thrown out of solution. On the other hand, certain
colloids may exercise a protective influence on other colloidal solutions.
Thus, as Faraday first showed, colloidal gold is much more stable in the
presence of a little gelatin. The colloids of serum can dissolve a considerable
amount of purified globulin. Although the latter in solution shows a drift
in the electric field, the resulting solution is quite unaffected by the passage
of a current through it. In these cases the protective colloids carry no
charge, but the same protective effect may be observed if a large excess
of. e.g. an electro-positive colloid be added to an electro-negative colloid.
This interaction between different colloids probably plays an important
part in many physiological phenomena. We have reason to believe that
the reactions between toxin and antitoxin, and between ferment and sub-
strate, which we shall study later, are of this character, and that the
compounds formed belong to the class of adsorption combinations.
THE COAGULATION OF COLLOIDS
Most colloidal solutions are unstable, and the relations between the
suspended particle or molecule and the surrounding fluid may be upset by
slight changes of reaction or the presence of minute traces of salts. As a
result the hydrosol is destroyed, the suspended particles aggregating to
form larger complexes. These aggregations may settle to the bottom of
the fluid as a precipitate, or may form a species of network, the result
varying according to the nature of the colloid and its concentration. Thus
gelatin changes from the condition of hydrosol to hydrogel with fall of
temperature. The same is true of agar. On the other hand, by adding
calcium chloride to an alkaline solution of casein, we obtain a mixture which
sets to a jelly on warming, but becomes fluid again on cooling. Other agen-
cies may lead to the production of changes which are irreversible. Thus
a strong solution of colloidal silica sets to a solid jelly on the addition of
a trace of neutral salt, and it is not possible to reform the hydrosol, however '
long the jelly is submitted to dialysis.
Two methods of bringing about coagulation of hydrosols deserve special
mention. The first of these is heat- coagulation. If a solution of egg-
albumin or globulin be heated in neutral or slightly acid medium and in the
presence of neutral salt, the whole of it is thrown down in an insoluble form.
This coagulated protein is insoluble in dilute acids or alkalies. The same
coagulative effect of heating is observed in the metallic sols. With con-
THE PROPERTIES OF COLLOIDS 149
centrated solutions of protein, heat coagulation results in the formation of a
gel, i.e. a network of insoluble protein, containing water or a very dilute
solution of protein in its meshes. In dilute solutions the result is the
production of a flocculent precipitate.
Another method is the so-called mechanical coagulation. If a solution
of globulin or albumin be introduced into a bottle, which is then violently
shaken, a shreddy precipitate makes its appearance in the solution, and this
precipitate increases, so that by prolonged shaking it is possible to throw
down 80 or 90 per cent, of the dissolved protein in the coagulated form.
Ramsden has shown that this mechanical coagulation is a surface pheno-
menon. It depends on the fact that a large number of substances in solution
(viz. any which lower the surface tension of their solutions) undergo concen-
tration at the free surface of the fluid. Such substances are proteins, bile-
salts, quinine, saponin, &c. In the case of proteins the concentration reaches
such an extent, and the molecules at the surface are so closely packed
together, that they form an actual solid pellicle, which hinders the movement
of any object, such as a compass needle, suspended in the surface. When the
solution is violently shaken, new surfaces are constantly being formed, and
as the older surfaces are withdrawn into the fluid, the solid pellicle, on them
is rolled up into a fine shred of coagulated protein, and this process will
continue until there is no protein left to form a pellicle.
We must conclude that colloidal solutions, although differing so widely
from true solutions in many of their properties, are connected with these by
all possible grades. In a solution of an ordinary crystalloid or electrolyte
the molecules of the dissolved substance are distributed equally and homo-
geneously among the molecules of the solvent. In the various grades of
solution a colloid solution or hydrosol may be assumed to begin when the
size of the molecule is increased out of all proportion to that of the molecules
of the solvent. The ' dissolved ' ^olecules now have the properties of
matter in mass and to present surfaces with all their attendant attributes.
The same sort of solution may be formed with smaller molecules, such as
Si0 2 , when these are aggregated together with adsorbed water into huge
molecular complexes or, as in metallic sols, by the division of the solid metal
into ultra-microscopic particles. The distinguishing features of a colloidal
solution are due to this lack of homogeneity, and to the fact that in every
solution there are two phases-— a fluid phase, and a second phase which is
either solid or a concentrated or supersaturated solution of the colloid. The
huge size of the molecules and the development of surface not only determine
the formation of adsorption combinations but, on account of the inertia of
the system, cause a delay in changes of state, and tend to the formation of
false equilibria dependent on the past history of the system.
IMBIBITION
All colloids, even those such as starch or gelatin, which are insoluble
in cold water, exhibit a phenomenon, viz. ' Quellung ' or imbibition, which
in many cases it is impossible to distinguish from the process of solution.
150 PHYSIOLOGY
This phenomenon, which was long ago studied by Chevreul and has been
the subject of a series of careful experiments by Overton, is exhibited by
all animal tissues and all colloids. Thus elastic tissue dried in vacuo absorbs
from a saturated solution of common salt 36-8 per cent, of water and salt. If
dried colloids be suspended in a closed vessel over various solutions, they
will take up water in the form of vapour from the solution, and the osmotic
pressure of the solution in question will inform us as to the amount of work
which would be necessary in order to separate the water again from the
colloids.
Thus it has been reckoned that to press out water from gelatin containing
284 parts of water to 100 parts of dried gelatin would require a pressure of
over two hundred atmospheres. The imbibition pressure of colloids in-
creases rapidly with the concentration of the colloid and at a greater rate than
the latter. In this respect however imbibition pressure resembles osmotic,
or indeed gaseous, pressure. At extreme pressures the pressure of hydrogen
rises more rapidly than its volume diminishes. In solutions this effect is
more marked the larger the size of the molecule. Thus a 6-7 per cent,
solution of cane sugar has the same vapour- tension, and therefore the same
osmotic pressure, as a -67 per cent. NaCl solution. A 67 per cent, cane-sugar
solution has however the same osmotic pressure as an 18-J per cent, solution
of common salt. It is impossible to draw any hard line of distinction between
imbibition pressure and osmotic pressure, or to say where a fluid ceases to be
a solution and becomes a suspension. All grades are to be found between a
solution such as that of common salt with a high osmotic pressure and optical
homogeneity, and a solution such as that of starch, which scatters incident
light and is therefore opalescent, and has no measurable osmotic pressure.
The close connection between the processes of imbibition and of solution
is shown also by the fact that the latter occurs only in certain media, the
nature of the media being dependent on the chemical character of the sub-
stances in question. Thus all the crystalline carbohydrates — such as grape
sugar and cane sugar — are easily soluble in water, only slightly soluble in
alcohol, and practically insoluble in ether and benzol. The amorphous
carbohydrates which must be regarded as derived by a process of condensa-
tion from the crystalline carbohydrates — e.g. starch, cellulose, gum arabic,
&c. — have a strong power of imbibition for water. This power may be
limited, as in the case of cellulose, or may be unlimited, as in the case of
gum arabic, so that a so-called solution results. On the other hand, they
swell up but slightly in alcohol, and are unaffected by ether and benzol.
In the same way proteins all take up water and in man}' cases form a so-called
solution, but are unaffected by ether and benzol — a behaviour which is
repeated in the case of the amino-acids, out of which the proteins are built
up, and which are easily soluble in water but are practically insoluble in ether
and benzol. On the other hand, india-rubber and the various resins take up
ether, benzol, and turpentine often to an indefinite extent, while they are un-
touched by water. With this behaviour we may compare the easy solubility
of the hydrocarbons, the aromatic acids, and esters in ether and benzol, and
THE PROPERTIES OF COLLOIDS 151
their insolubility in water. As Overton has pointed out, the power of
amorphous carbohydrates to take up fluids is modified by alteration of their
chemical structure in the same direction as the solubility of the corresponding
crystalline carbohydrates. Thus, if the hydroxyl groups in the sugars be
replaced by nitro, acetyl, or benzoyl groups, they become less soluble in
water, while their solubility in alcohol, acetone, &c, is increased. In the
same way the replacement of the hydroxyl groups in cellulose by N0 2 groups
diminishes the power possessed by this substance of taking up water, but
renders it capable of swelling up or dissolving in alcohol and acetone.
SECTION IV
THE MECHANISM OF CHEMICAL CHANGES IN
LIVING MATTER. FERMENTS
All the events which make up the life of plants and animals are accompanied
and conditioned by chemical changes of the most varied character. In a
previous chapter we have endeavoured to form an idea of the ways in which
some of the synthetic processes that occur in the living body may be effected.
We saw that, although it was possible to imitate in many respects the vital
syntheses by ordinary laboratory methods, the imitation fell far short of the
process as it actually occurs in the living cell, both in completeness of the
reaction and in the ease with which it could be effected. We can, for
instance, by passing carbon dioxide over red-hot charcoal, convert it into
carbon monoxide, and this gas, acting on dry potassium hydrate, forms
potassium formate. Formate of linie, on dry distillation, gives a small
proportion of formaldehyde which, under the influence of dilute alkalies,
will condense to the mixture of sugars known as acrose. The green leaf
in sunlight absorbs the minimal quantities of carbon dioxide present in the
atmosphere and converts it almost quantitatively into starch within a few
minutes, and this change is effected in the absence of any concentrated
reagents and at the ordinary temperature of the atmosphere. Many of the
chemical transformations effected by living cells we have so far been quite
unable to imitate. The problem of the synthesis of camphor, of the terpenes,
of starch, of cellulose, is still unsolved ; and even in the case of those sub-
stances which we can manufacture outside the living cell our methods involve
the use of powerful reagents and of high temperatures, and result in most
cases in the production of many side reactions, besides that reaction which
it is our special object to imitate. The distinguishing characteristics of the
chemical changes wrought by the living cell are :
(i) The rapidity with which they are effected at ordinary tempera-
tures.
,(2) The specific direction of the process, which is therefore almost
complete, with a surprising absence of the side reactions which interfere
to such an extent with the yield of the methods employed in a chemical
laboratory.
This second characteristic may however be regarded as a consequence
of the first, since an increase in the velocity of any given reaction will deter-
152
CHEMICAL CHANGES IN LIVING MATTER. FERMENTS 153
mine a preponderance of this reaction over all other possible ones. A funda-
mental question therefore in physiology must relate to the manner in which
the cell is able to influence the velocity of some specific reaction.
In spite of the enormous diversity of chemical reactions occurring in the
body, they may be divided into a relatively small number of types. Nearly
all the reactions are reversible. The chief types of chemical change are as
follows :
(1) HYDROLYSIS. In most cases this involves the taking up of water
and a decomposition into smaller molecules. Thus the proteins are broken
down in the intestine into their constituent amino-acids. The disaccharid.es,
such as maltose or lactose, take up one molecule of water and give rise to
two molecules of monosaccharide. The fats take up three molecules of
water with the formation of fatty acid and glycerin. Hippuric acid is broken
down into benzoic acid and glycine. The reverse change, that of dehydra-
tion, is also effected apparently with equal facility by the living cell, the
hexoses losing water and being converted into a complex starch or glycogen
molecule, while the amino-acids are built up first into polypeptides, and
these again into the complex proteins of the cell. Besides the reactions in
which there is a difference in the amount of free water on the two sidts of
the equation, it seems probable that hydrolysis and simultaneous dehydrolysis
at different parts of the molecule determine a number of chemical transforma-
tions, which at first sight seem to involve a simple splitting of the molecule.
An example of such a process is afforded by the conversion of glucose into
lactic acid described on p. 113.
(2) DEAMINATION. This process involves the splitting off of an NH 2
group from an amino-acid as ammonia, and its replacement by H or OH.
Many tissues of the body appear to have this power. In most cases the
nature of the change in the remaining fatty moiety of the molecule has not
yet been ascertained. If, for instance, to a mass of liver cells some amino-
acid, such as glycine, alanine, or leucine, be added, ammonia is set free in
proportion to the amount of amino-acid which was added. This ammonia is
therefore assumed to be derived from the amino-acid, and it has been sug-
gested that here also the process of splitting off ammonia is a hydrolytic one
and that the NH 2 group is replaced by OH. Thus —
CH 3 CH 3
I I
CH.NH 2 + H 2 = CH.OH + NH 3
I I
COOH COOH
(alanine)
Recent work by Neubaue'r tends to show that deamination is accompanied
in the first place by oxidation, so that the first intermediate product formed
is not an a oxy-acid, but an a ketonic acid. A second atom of oxygen is
then taken up, and carbon dioxide is split off, with the production of the
next lower acid of the series.
154 PHYSIOLOGY
We might represent these changes as follows :
(1) CH 3 CH a
I I
CHNH 2 + = CO + NH 3
I I
COOH COOH
(2) CH„
I CH 3
CO +0=| + co„
I COOH
I'UUII
Is the reverse change ever effected in the animal body ? If it were
possible to replace the OH group in an oxy-fatty acid by NH 2 or the in an
a ketonic acid by HNH 2 , it ought also to be possible to nourish an animal
from a mixture of carbohydrates and ammonia, or at any rate by supplying
him with a mixture of the appropriate oxy-acids or ketonic acids and am-
monia. Until recently there was no evidence that the animal body is able to
utilise nitrogen, except in organic combination as amino-acids or the complex
aggregate of amino-acids known as proteins. In the plant the process
of synthesis of protein from ammonia and a carbohydrate such as hexose is
continuously going on, and it is probable that the formation of amino-acid
occurs by a process the reverse of that which we have just been studying.
Knoop has shown that the same reversed change may occur even in a
mammal, and that here again the intermediate substance is an a ketonic
acid. On administering benzylpyruvic acid (C 6 H 5 .CH 2 .CH 2 .CO.COOH)
to a dog, a certain amount of benzylalanine (C' 6 H5.CH 2 CH2CHNH 2 .COOH)
appeared in the urine. The first phase of the oxidative deamination of
amino-acids is thus a reversible one and may be represented :
R R R
I I OH ||
CHNH 2 + 1 -> C< < > CO + NH 3
I | NU 2 |
COOH COOH COOH
(3) DECARBOXYLATION. Many amino-acids when subjected to the
agency of bacteria lose a molecule of carbon dioxide and are converted into
a corresponding amine.
For instance, lysine, which is diamino-caproic acid, is converted into
pentamethylene diamine or cadaverine. Thus :
CH 2 .NH 2 CH 2 .NH 2
I I
CH 2 CH 2
I I
CH 2 becomes CH 2
I I
CH 2 CH 2
I I
CH.NH 2 CH 2 .NH 2
I
COOH
CHEMICAL CHANGES IN LIVING MATTEE. FERMENTS 155
In the same way ornithine derived from the breakdown of arginine is con-
verted by putrefactive bacteria into tetra-methylene diamine or putrescine.
Other examples of this process of decarboxylation are :
Isoamylamine from leucine, (CH 3 ) 2 .CH.CH,.CH 2 .NH 2 .
(5 phenylethylamine from phenylalanine, C 6 H 5 .CH 2 ,CH 2 .NH 2 .
Para-oxyphenylethylamine from tyrosine, OH.C 6 H 4 .CH 2 .CH 2 .NH 2 .
A similar process has been supposed to take place as a step in the suc-
cessive oxidation of the carbon atoms in the long chain fatty acids or carbo-
hydrates, but a thorough study of this process as it occurs in the higher
animals is still wanting, and its very existence is indeed still hypothetical.
In the case of the fats the oxidation takes place chiefly or entirely in the
/S position. On the other hand, decarboxylation certainly takes place in
substances such as the a amino-acids, where the first oxidation change occurs
in the a group, and probably closely follows this oxidation change. The
reverse reaction, namely, the insertion of the group CO.O at the end of the
long carbon chain, is not known to take place, but would furnish a means
by which the organism with apparent simplicity could build up long carbon
chains and so imitate the process which in the laboratory is generally effected
bv attaching a CN group to the end of the molecule. In the case of the
fats the building up, like the oxidative breakdown, appears to occur by
two carbon atoms at a time ; hence all the fatty acids met with in the body
have an even number of carbon atoms in their chain.
It is worthy of note that all the changes which we have been considering
— changes which not only account for the greater part of the chemical re-
actions of the living body, but may lead to the production of the most
complex substances known — are performed with little expenditure or evolu-
tion of energy. This is evident if we examine the heat evolved by the
total combustion of one gramme molecule of the initial and final substances
in a number of typical reactions. In the following Table these are given
for the substances involved in typical instances of the three classes of
chemical change that we have just been considering :
(1) Hydrolysis
Initial
substance
Maltose
Heat of com-
bustion per
gram molecule
. 1350
Final
substance
2 Glucose
Heat
of
combustion
1354
Glucose
. 677
2 Lactic acid
659
Hippuric acid
. 1013
( Glycine
^ Benzoic acid
£} '» 8
(2) Deaj
IINATION
Initial
substance
Alanine
Heat of
combustion
. 389-2
Final
substance
Lactic acid .
Heat of
combustion
329-5
Leucine
Aspartie acid
. 855
. 386
Caproic acid
Succinic acid
837
354
156 PHYSIOLOGY
(3) Decarboxylation
liiitnil Seal oi
nil i i im i combustion
Alanine .... 389
Leucine .... 855
Final Heat ol
substance combustlc
Ethylamine . . . 409
Isoamylamine . . 867
(4) OXIDATION AND REDUCTION. The fourth class of chemical
reactions differs from those just described in being attended with a very
considerable energy change. This class involves the processes of oxidation
and reduction. In almost every living cell, by far the largest amount of
the energy available for the discharge of the functions of the cell is derived
from the oxidation of the food-stuffs, and even in the plant the energy, is
obtained from the oxidation of the food-stuffs, built up in the first instance
at the cost of the energy of the sun's rays. If we take the final changes
in the food-stuffs, the very large evolution of energy attending their oxida-
tion is at once apparent. Thus in the conversion of glucose into C0 2 and
water there is an evolution for each gramme molecule of 077 calories. In
the combustion of glycerin 397 calories are evolved. In the oxidation of a
fat such as trimyristin there are 6650 calories evolved. The change does
not in the living cell occur all at once, but the molecule is oxidised step by
step. In each step the heat change will however be probably greater than
the heat changes in the other types of chemical change which we have been
considering.
Since the mechanism of oxidation in the animal body will have to be
discussed at length in a subsequent part of this work, we may at present
confine our attention to the other types of chemical change. Of these,
all which involve a splitting of a large molecule into smaller ones with the
taking up of one or more molecules of water, as well as, in all probability,
those in which the reverse change of dehydration and synthesis occur, are
effected in the body by means of ferments. To the same agency are also
. ascribed the process of deamination which takes place in many organs of
the body and, though with less certainty, the processes which involve
decarboxylation.
FERMENTS
Under the name ferments we include a number of substances of indefinite
composition whose existence is chiefly known to us by their action on other
substances. A ferment has been defined as a body which .on addition to a
chemical system is able to effect changes in this system without supplying
any energy to the reaction, without being used up, and without taking
any part in the formation of the end products. It differs therefore from
the reacting substances in the absence of any strict quantitative relation-
ships between it and the substances included in the system in which its
effects are produced. Minimal quantities of ferment can induce chemical
changes involving almost indefinite quantities of other substances, the only
result of increasing the quantity of ferment being to quicken the rate of
the change. Since they are effective in minimal doses they occur in living
tissues in minute quantities, and it is partly due to this fact that it has
CHEMICAL CHANGES IN LIVING MATTEE. FERMENTS 157
hitherto proved impossible to obtain any preparation of a ferment which
could be regarded as a pure substance. The difficulty in their isolation
is increased by the fact that all of them are colloidal or semi-colloidal in
character, and present therefore the tendency common to all colloids of
adhering to other colloidal matter as well as to surfaces such as those pre-
sented by a precipitate. A common method of isolating, or rather obtaining
a concentrated preparation of a ferment, is to produce in its solution an inert
precipitate such as cholesterin or calcium phosphate. The ferment is
carried down on the precipitate and may be obtained in solution on washing
the precipitate with water. A further difficulty in their preparation lies
in the unstable character of many members of the group. Although they
are not coagulated by alcohol, they are nevertheless gradually changed, so
that every act of precipitation of a ferment tends to rob it of some of its
powers, i.e. of the only characteristic by which we can establish its identity.
Of these ferments a large number have already been described as taking
part in the ordinary chemical processes of life. So wide is their dominion
in cell chemistry that many physiologists have thought that the whole of
life is really a continual series of ferment actions. The following list repre-
sents some of the ferments whose existence has been definitely established
in the animal body. The greater part of them are involved in the processes
of digestion in the alimentary canal. The preponderance however of
digestive ferments in the list is due to the fact that we know more about
digestion than about the other chemical processes taking place within the
cells of the body.
List of Fekments.
Ferment
Converting
Into
Amylase (of saliva, pancreatic
Starch
Maltose and dextrin
juice, liver, blood serum, &o.) .
Pepsin .....
Proteins .
Proteoses and pep-
tones
Trypsin .....
Proteins .
Peptones and amino-
acids
Enterokinase . .
Trypsinogen
Trypsin
Erepsin .....
Proteoses
Amino-acids
Lipase ■ (of pancreatic juice, liver.
Neutral fats
Fatty acid and
&c.)
glycerin
Maltaae .....
.Maltose .
Glucose .
La itase .....
Milk sugar
Glucose and galactose
Invertase or sucrase .
Cane sugar
Glucose and kevulose
Arginase .....
Arginin .
Urea and ornithine
Urease ......
Urea
Ammonium carbonate
Lactic acid ferment
Glucose .
Lactic acid
Zymase (? present in the body)
Glucose .
Alcohol and C0 2
Deaminating ferment (?), v. p. 153
Amino-acids
Oxy -acids (?)
158 PHYSIOLOGY
Many other ferments will probably be distinguished with increase in
our knowledge of cellular metabolism. The long list which is here given
suffices to show how great a part these bodies must play in the normal
processes of life. A study of the conditions of ferment actions is therefore
essential if we would form a conception of the chemical mechanisms of the
living cell.
It is important to note that all the changes wrought by ferments can
be effected by ordinary chemical means. Thus the disaccharides can be
made to take up a molecule of water and undergo conversion into mono-
saccharides. If a solution of maltose be taken and bacteria be excluded
from the solution, it undergoes at ordinary temperatures practically no
change. If the solution be warmed, a slow process of hydration takes place
which is quickened by rise of temperature, so that if the solution be heated
under pressure to, say, 110° C, hydrolysis occurs with considerable rapidity.
If however a little maltase be added to the solution, the change of maltose
into glucose takes place rapidly at a temperature of 30° C. In the same
way a solution of protein may be kept almost indefinitely without undergoing
hydrolysis, which however can be induced by heating the solution under
pressure. The action of the ferments in these two cases is to quicken a
process of hydrolysis which without their presence would take an infinity
of time for its accomplishment.
In this respect their action is similar to that of acids, and indeed of a
whole class of bodies w r hich are spoken of as catalysers or catalysts. A
catalyser is a substance which will increase (or diminish) the velocity of a
reaction without adding in any way to the energy changes involved in the
reaction, or taking any part in the formation of the end-products. Since
the catalyser is unchanged in the process, a very small quantity is able to
influence reactions involving large quantities of other substances. By
adding acids to a watery solution of the food-stuffs, the process of hydrolysis
is quickened in proportion to the strength and concentration of the acid.
The effective catalytic agents in this process appear to be the hydrogen ions
of the free acid. There are many other bodies, besides the free acids, which
may act as catalysers, and a study of the conditions under which catalysis
takes place may throw some light on the essential nature of the action of
ferments.
The velocity of almost any reaction in chemistry can be altered by the
addition of some catalytic agent, and there are few of the ordinary reactions
in which catalysis does not play some part. Among such processes we may
instance the action of spongy platinum on hydrogen peroxide. Hydrogen
peroxide undergoes slow spontaneous decomposition into water and oxygen.
If a little spongy platinum be added to it, it is at once seen to decompose
rapidly with the evolution of bubbles of oxygen, and the action does not
cease until the whole of the hydrogen peroxide has been destroyed. Spongy
platinum is able in the same way to quicken a very large number of chemical
reactions. Thus sulphur dioxide and oxygen when heated together will
combine very slowly ; the combination becomes rapid if a mixture of the
CHEMICAL CHANGES IN LIVING MATTER. FERMENTS 159
two gases be passed over heated platinum. The same reaction, namely,
the combination of sulphur dioxide with oxygen, may be quickened by the
addition of a small trace of nitric oxide, and this fact is made use of in the
manufacture of sulphuric acid on a commercial scale by the ordinary lead-
chamber process. Hydrogen peroxide and hydriodic acid slowly interact
with the formation of water and iodine. This reaction may be quickened
by the addition of many substances, among which we may mention molybdic
acid.
There is moreover a specificity in the action of catalysers, though not
so well marked as with ferments. Whereas all the disaccharides are con-
verted by acids into the corresponding monosaccharides, a ferment such as
invertase acts only on cane sugar, and has no action on maltose or lactose,
each of which requires a specific ferment (maltase, lactase) to effect their
' inversion.' But we find many examples of a restricted action even among
inorganic catalysers. Thus potassium bichromate will act as the catalyser
for the oxidation of hydriodic acid by bromic acid, but not for the oxidation
of the same substance by iodic acid. Iron and copper salts in minute traces
will quicken the oxidation of potassium iodide by potassium persulphate,
but have no influence on the course of the oxidation of sulphur dioxide
by potassium persulphate. Tungstic acid increases the velocity of oxida-
tion of hydriodic acid by hydrogen peroxide, but has no effect on the velocity
of oxidation of hydriodic acid by bromic acid, and these examples may be
multiplied to any extent. One cannot 'therefore regard the limitation of
action of the ferments as justifying any fundamental distinction being
drawn between the action of this class of substances and catalysts.
Whereas the influence of most catalysers on the velocity of a reaction
increases rapidly with rise of temperature, in the case of ferments this in-
crease occurs only up to a certain point. This point is spoken of as the
optimum temperature of the ferment action. If the mixture be heated above
this point the action of the ferment rapidly slows off and then ceases. This
contrast again is only apparent. The ferments are unstable bodies easily
altered by change in their physical conditions, and destroyed in all cases
at a temperature considerably below that of boiling water. Thus ferment
actions, like catalytic actions, are quickened by rise of temperature, but
the effect of temperature is finally put a stop to by the destruction of the
ferment. The same applies to those inorganic catalysers whose physical
state is susceptible, like that of the ferments, to the action of heat. Thus
the colloidal platinum ' sol ' exerts marked catalytic effects on various
reactions, e.g. on the decomposition of hydrogen peroxide and on the
combination of hydrogen and oxygen. The reaction presents an optimum
temperature, owing to the fact that the colloidal platinum is altered, coagu-
lated, and thrown out of solution when this is heated to near boiling-point.
We may therefore employ either class of reactions in trying to form some
conception of the processes which are actually involved.
Very many theories have been put forward to account for this action
of catalysers or of ferments. Many of them are merely transcriptions in
160 PHYSIOLOGY
words of the processes which actually occur, and fail to throw any light
on their real nature. The essential phenomena involved fall directly into
two classes. In the first class we must place those which are determined
by the influence of surface. In many cases the combination of gases can
be hastened by increasing the surface to which they are exposed, as by
passing them over broken porcelain or over powdered charcoal. This cata-
lytic effect is certainly connected with the power of a solid to condense
gases at its surface, and is therefore proportional to the extent of surface
exposed. Thus the efficacy of platinum in hastening the combination of
hydrogen and oxygen is in direct proportion to its fineness of subdivision,
and is best marked when the metal is reduced to ultra-microscopic dimen-
sions, as in the colloidal solution of platinum. Every colloidal solution
must be regarded as presenting an enormous surface in proportion to the
mass of substance in solution. There is therefore a direct proportionality
between the power of a substance to condense a gas on its surface and its
power to quicken the velocity of chemical changes in which the gas is in-
volved. The same process of condensation may occur with dissolved sub-
stances. In all cases where the presence of a substance in solution diminishes
the surface tension of the. solvent, there is a diffusion of dissolved substances
into the surface, i.e. a concentration of dissolved substances at the surface
of contact. It was suggested by Faraday that the catalytic property of
surfaces was due to this condensation of molecules, and the consequent
bringing of the two sets of molecules within each other's sphere of influence.
Whether this is the sole factor involved is doubtful, since mere compression
of gases or increased concentration of solutions does not in the majority
of cases result in such a quickening of the velocity of reaction as is brought
about by the effect of the surface.
It is possible that this condensation effect or adsorption may be in every
case combined with the second factor which we must now consider, namely,
the formation of intermediate products. If we boil an alkaline solution
of indigo with some glucose, the indigo is reduced with oxidation of the
glucose. The mixture therefore becomes colourless. On shaking up with
air, the c :>lourless reduction product of the indigo absorbs oxygen from the
atmosphere, and is re-transformed into indigo. These two processes can
be repeated until the whole of the glucose is oxidised, and the process can
be made continuous if air or oxygen be bubbled through a heated solution
of glucose containing a small trace of indigo. In this case the indigo does
not add to the energy of the reaction. It appears unchanged among the
final products and a small amount may be used to effect the change of an
infinite quantity of glucose. It therefore may be said to act as a ferment
or catalytic agent. Instead of an alkaline solution of indigo, we may use
an ammoniacal solution of cupric oxide for the purpose of carrying oxygen
from the atmosphere to the glucose. This is reduced to cuprous hydrate
on heating with the sugar, but cupric hydrate can be at once re-formed
by shaking up the cuprous solution with air. It has been thought that many
or all of the catalytic reactions occur in the same way by two stages, i.e.
CHEMICAL CHANGES IN LIVING MATTER. FERMENTS 161
by the formation of an intermediate product. Thus, in the old lead chamber
process for the manufacture of sulphuric acid, the Ditric oxide may be sup-
posed to combine with the oxygen of the air to form nitrogen peroxide.
This interacts with sulphur dioxide, giving sulphur trioxide and nitric oxide
once more. The nitric oxide, which we alluded to before as the catalyser,
may in this way be regarded as the carrier of oxygen from air to sulphur
dioxide. .It has been suggested that the action of spongy platinum or
colloidal platinum rests on the same process, and that in the oxidation of
hydrogen, for instance, PtO or Pt0 2 is formed and at once reduced by the
hydrogen with the formation of water.
There is a certain amount of experimental evidence in favour of this hypothesis.
According to Engler and Wohler,* platinum black, which has been exposed to oxygen,
in virtue of the gas which it has occluded, has the power of turning potassium iodide
and starch blue. This power is not destroyed by heating to 260° in an atmosphere of
Co 2 , or by washing with hot water. On exposure of the platinum black to hydrochloric
acid, a certain amount is dissolved, and the substance loses its effect on potassium
iodide. The amount dissolved corresponds with the amount of iodine liberated from
potassium iodide, and also with the amount of oxygen occluded, the (soluble) platinum
and oxygen being in the proportions necessary to form the compound PtO.
But why should a reaction take place more quickly if it occurs in two
stages instead of one ? As Ostwald has pointed out, the formation of an
intermediate compound can be regarded as a sufficient explanation of a
catalytic process only when it can be demonstrated by actual experiment
that the rapidity of formatiou of the intermediate compound and the rapidity
of its decomposition into the end-products of the reaction are in sum greater
than the velocity of«the reaction without the formation of the intermediate
body. In the case of one reaction this requirement has been fulfilled. The
catalytic effect of molybdic acid on the interaction of hydriodic acid and
hydrogen peroxide has been explained by assmning that the first action
which takes place is the formation of permolybdic acid, and that this then
interacts with the hydrogen iodide to form water and iodine. Now it has
been actually shown — (1) that permolybdic acid is formed by the action
of hydrogen peroxide on molybdic acid ; (2) that permolybdic acid with
hydriodic acid produces water and iodine ; (3) that the velocity with which
these two reactions occur is much greater than the velocity of the inter-
action of hydrogen peroxide and hydriodic acid by themselves.
Although we may find it difficult to explain why a reaction should occur more
quickly in the presence of a catalyser by the formation of these intermediate bodies,
certain simple analogies may help us to comprehend how a factor which introduces no
energy can yet assist the process. Thus a man might stand to all eternity before a
perpendicular wall twenty feet high. Since he cannot reach its top at one jump, he is
unable to get there at all. The introduction of a ladder will not in any way alter the
total energy he must expend on raising his body for twenty feet, but will enable him
to attain the top. Or we might imagine a stone perched at the top of a high hill. The
passive resistance of the system, the friction of the stone, and its inertia will tend to
keep it at rest, even though it be on a sloping surface and therefore tending to slide
or roll to the bottom. If however it be rolled to a point where there is a sudden increase
in the rapidity of slope, it may roll over, and having once started its downward course, its
* Quoted by Mellor, "Chemical Statics."
11
162 PHYSIOLOGY
momentum will carry it to the bottom. The amount of energy set free by the stone in
its fall will not vary whether the course be a uniform one, or whether it falls over a
precipice at one time and rolls down a gentle slope at another. It is evident that by
a mere alteration of the slope or, in the case of a chemical reaction, of the velocity of
part of its course, a change in the system may be initiated and brought to a conclusion
which without this alteration would never take place.
vSince the action of ferments, like that of catalysts, consists essentially
in the quickening up of processes which would otherwise occur at an in-
finitely slow velocity, it is possible that in their case also the formation
of an intermediate compound may be involved in the reaction. Light may
be thrown upon this question by a study of the velocity of the reaction
induced by the action of a ferment.
It is well known that the velocity of a rexction depends on the number of molecules
involved. As an illustration, we may take first the case of a reaction involving a
change in one substance. If arseniuretted hydrogen be, heated, it undergoes decom-
position into hydrogen and arsenic. This decomposition is not immediate, but takes
a certain time, and the velocity with which the change occurs depends on the tempera-
ture. At any given temperature the amount of substance changed in the unit of time
varies with the concentration of the substance. If, for instance, one-tenth of the gas
be dissociated in the first minute, in the second minute a further tenth of the gas will
also be dissociated. Thus, if we start with 1000 grammes of substance, at the end
of the first minute 100 grammes will have been dissociated, and 900 of the original
substance will be left. In the second minute one-tenth again of the remaining substance
will be dissociated, i.e. 90 grammes, leaving 810 grammes. In the third minute 81
grammes will be dissociated, leaving 729 grammes. The amount changed in the
unit of time will always bear the same ratio to the whole substance which is to be
changed, and will therefore be a function of the concentration of this substance. Put
in the form of an equation, we may say that <^>, the amount changed in the unit of time,
will be equal to KC, where K is a constant varying with the substance in question and
with the temperature, and C represents the concentration of the substance. The
equation = KC applies to a monomolecular reaction.
If two substances are involved, the equation will be rather different. In this case
the amount of change in a unit of time will be a function of the concentration of each
of the substances, and the form of the equation will be <& = K(C, + C y ). In the case
of the unimolecular reaction, halving the concentration of the substance will halve the
amount of substance changed in the unit of time. In the case of a bimolecular reaction,
halving each of the substances will cause the amount of change in the unit of time to be
reduced to one-quarter of its previous amount. If now either a unimolecular or a
bimolecular reaction be quickened by the addition of a catalyser or ferment, and the
ferment enter into combination with one of the substances at some stage of the reaction,
it is evident that our equation must take account also of the concentration of the
ferment or catalyser. In the case of the catalytic effect of molybdic acid on the inter-
action between hydrogen peroxide and HI, there was definite evidence of a reaction
taking place between the molybdic acid and the peroxide, resulting in the formation
of an intermediate compound, namely, permolybdic acid. Brode has shown that the
interaction of the molybdic acid is revealed in the equation representing the velocity
of the reaction. ' 6 Without the addition of molybdic acid the equation would be :
4>=K(C H2 o 2 XC HI )
After the addition of molybdic acid, the equation becomes :
4> = K(C H ,0, + y C molybdic = KG, where C is the concentration of the ferment. This concen-
tration is always being renewed, and kept constant by the breaking down
of the intermediate product, so that the rate of change would be continuous
throughout the experiment.
On the other hand, when the amount of ferment is relatively large, the
rate of change, though at first very rapid, tends continuously to diminish.
This is shown by the following Table representing the rates of change,
during succeeding intervals of ten minutes, in a caseinogen solution to which
a strong solution of trypsin had been added (Bayliss) .
Velocity of Trypsin Reaction
' N
6 c.c. 8 per cent, caseinogen + 2 c.c.-r^ AmHO -f 2 c.c. 2 per cent.
trypsin at 39°C.
1st 10 minutes K =0-0079
2nd
3rd
4th
5th
7 M.
0-0046
0-0032
0-0022
0-0016
0-0009
The cause of this rapid diminution in the velocity of change is probably
complex. One factor may be an auto-destruction of the ferment, which is
known to occur in watery solution. That this is not the only, or even the
chief, factor involved is shown by the fact that, when the action of trypsin
on caseinogen has apparently come to an end, it may be renewed by further
dilution of the mixture or by removal of the end-products of the action by
dialysis. It is evident that, in this retardation of the later stages of ferment
action, the end-products are concerned in some way or other, and the re-
tardation can be augmented by adding to the digesting mixture the boiled
end-products of a previous digestion. The retarding effect of the end-
products resembles in many ways that observed in a whole series of reactions
which are known as reversible.
As an example of such a reaction we may take the case of methyl acetate and water.
When methyl acetate is mixed with water, it undergoes decomposition with the forma-
tion of methyl alcohol and acetic acid. On the other hand, if acetic acid be mixed
with alcohol, an interaction takes place with the formation of methyl acetate and
water. These changes are represented by the equation :
MeC 2 H 3 2 + HOH = MeOH + HC,H 3 O a .
niethylaeetate water methylalcohol acetic acid
Each of these changes has a certain velocity constant, and, since they are in opposite
directions, then- must be some equilibrium point where no change will occur, and
166 JPHYSIOLOGY
there will be a definite amount of all four substances present in the mixture, namely,
water, alcohol, ester, .and acid. This equilibrium point can be shifted by altering
the amount of any of the four substances. Thus the interaction of methyl acetate and
water can be diminished to any desired extent by adding to the mixture the products
of the interaction, namely, methyl alcohol and acetic acid.
There is evidence that some of the ferment actions are reversible. Thus
nialtase acts on maltose with the formation of two molecules of glucose.
If the maltase be added to a concentrated solution of glucose, we get a
reverse effect, with the production of a disaccharide which has been desig-
nated as isomaltose or revertose. To this reverse action may be due a
certain amount of the retardation observed in the action of trypsin on
coagulable protein. A more important factor is probably the combination
of the ferment itself with the end-products and the consequent removal
of the ferment from the sphere of action. Several facts speak for such a
m.ode of explanation. Thus the action of lactase on milk sugar is not
retarded by both its end-products, namely, glucose and galactose, but only
by galactose. In the same way the action of invertase on cane sugar is
retarded by the end-product fructose, but not at all by the other end-
product, glucose.
So far therefore a study of the velocity of ferment actions would lead
us to suspect that the ferment combines in the first place with the substrate,
and that this combination is a necessary step in the alteration of the sub-
strate. In the second place, the ferment is taken up to a certain extent
by some or all of the end-products, and this combination acts in opposition
to the first combination, tending to remove the ferment from the sphere
of action, and therefore to retard the whole reaction. Other facts can be
adduced in favour of these conclusions. Thus it has been shown that
invertase ferment, which is destroyed when heated in watery solution at a
temperature of 60°C, can, if a large excess of its substrate, cane sugar,
be present, be heated 25 3 higher without undergoing destruction. The
same protective effect is observed in the case of trypsin. Trypsin in watery
or weakly alkaline solutions undergoes rapid decomposition. At 37 °C. it
may lose 50 per cent, of its proteolytic power within half an hour. If, on
the other hand, trypsin be mixed with a protein such as egg albumin or
caseinogen, or with the products of its own action, namely, albumoses and
peptones, it can be kept many hours without undergoing any considerable
loss of power.
It has been found that, whereas maltase splits up all the a-glueosides, it has no
power on the /S-glucosides ; that is to say, maltase will fit into a molecule of a certain
configuration, but is powerless to affect a molecule which differs from the first only
in its stereochemical structure. On the other hand, emulsin, which breaks up /S-gluco-
sides, has no influence on a-glucosides. This specific affinity of the ferments for optically
active groups of bodies suggests that the ferment itself may be optically active. We
cannot of course isolate the ferment and determine its optical behaviour ; but that
it is optically active is rendered probable both by these results and certain results
obtained by Dakin on lipase, the fat-sphtting ferment. Dakin carried out his experi-
ments on the esters of mandelic aeid. Mandelic acid is optically inactive, but this
optically inactive modification consists of a mixture of equal parts of dextro-rotatory
CHEMICAL CHANGES IN LIVING MATTER. FERMENTS 167
and leevo-rotatory mandelic acid. The esters prepared from the optically inactive
acids are themselves optically inactive. Dakin found that, when an optically inactive
mandelic ester was acted upon by a lipase prepared from the. liver, the final results
of the action were also inactive ; but if the reaction were interrupted at the half-way
point, the mandelic acid which had been liberated was dextro-rotatory, while the
remainder of the ester was lsevo-rotatory. Thus the rate of hydrolysis of the dextro-
eomponent of the ester is greater than that of the kevo-component, a result which can
be best explained by the assumptions (a) that the enzyme or a substance closely associ-
ated with it is a powerfully optically active substance ; (6) that actual combination
takes place between the enzyme and the ester undergoing hydrolysis. Since the
additive compounds thus formed in the case of the dextro- and kevo-components of
the ester would not be optical opposites, they would be decomposed with unequal
velocity, and thus account for the liberation of the optically active mandelic acid.
We may conclude that in the action of ferments on the food substances,
whether carbohydrate or protein, an essential factor is the combination
of the ferment with the substrate. Only the part of the substrate, which is
thus combined with the ferment, can be regarded as the active mass and as
undergoing the hydrolytic change. What is the nature of this combination ?
Ferments, which are all of a colloidal or semi-colloidal character, cannot
be dealt with in the same way as the catalysts of definite chemical com-
position, such as molybdic acid or nitric oxide. In many cases the substrate,
e.g. starch or protein, is also colloidal, and the combination therefore falls
into the class of combinations between colloids. In this we have an inter-
action between two substances in which the adsorption by the surfaces
of the molecules of one or both substances plays an important part, though
this adsorption is itself determined or modified by the chemical configuration
of the molecules. The combination of ferments with their substrates be-
longs therefore to that special class of interactions, not entirely chemical
and not entirely physical, but depending for their existence on a co-operation
of both chemical and physical factors, which we have discussed earlier under
the name of adsorption compounds.
FERMENTS AS SYNTHETIC AGENTS
If maltase, obtained from yeast, or from the so-called takadiastase
(prepared from Aspergillus oryzw), be added to a solution of maltose, the
latter is hydrolysed to ghicose. The process of hydrolysis stops short of
complete inversion at a point varying with the concentration of the sugar
solution. Thus in a 10 per cent, solution of maltose, inversion proceeds
until 98 per cent, otthe maltose is converted into dextrose, whereas in a
40 per cent, solution the change stops short when 85 per cent, sugar has
undergone inversion. Croft Hill showed that if the maltase were added
to a 40 per cent, solution of dextrose, a change took place in the reverse
direction, which proceeded until 85 per cent, of the glucose was left. The
sugar formed, which is a disaccharide, was regarded by Croft Hill as maltose.
According to Emmerling, however, it is the stereoisomeric sugar, iso-maltose,
which is formed ; and Croft Hill in his later papers spoke of the sugar as
revertose.
In the same way it has been shown by Castle and Loewenhart that the
168 PHYSIOLOGY
hydrolysis of esters by lipase is a reversible read ion, the action of lipase
being simply to hasten the attainment of the equilibrium point between
the four substances — ester (or neutral fat), water, fatty acid, and alcohol.
Similar reversible effects have been described for other ferments. Thus
the addition of pepsin to a strong solution of albumoses causes the appear-
ance of an insoluble precipitate, which is called plastein, and has been
regarded as produced by the resynthesis of the original protein molecule.
If all ferment actions are in this way reversible, a possibibty is opened
of regarding the synthetic processes occurring in the living cell, as well
as the processes of disintegration, as determined by the action of enzymes.
It must be noted that these effects are obtained with distinctness only
when dealmg with concentrated solutions. The degree of synthesis which
would be produced in the very dilute solutions of glucose &c. occurring
in the animal cell would therefore be infinitesimal. But if a mechanism
were provided for the immediate separation of the synthetical product
from the sphere of reaction, either by removing it to a different part of the
cell or by building it up into some more complex body which was not acted
on by the ferment, the process of synthesis might go on indefinitely, and the
infinitesimal quantities be summated to an appreciable amount.
Some experiments by Bertrand on fat synthesis have been interpreted as showing
that the process of synthesis by ferments is not the mere attainment of an equilibrium
point in a reversible reaction. It has long been known that watery extracts of the
fresh pancreas split neutral fats into the higher fatty acids and glycerine. This observer
has shown that, if the pancreas be dried with alcohol and ether and powdered, addition
of the dry powder to a mixture of the higher fatty acids and glycerine brings about a
rapid synthesis of neutral fat, The process of synthesis is at once stopped by the
addition of water. In this case either there are two ferments present, one a synthetising,
the other a hydrolysing, ferment, differing in their conditions of activity, or there is
one ferment which may act either as a fat-splitting or fat-forming agent according to
the conditions under which it is placed. In the latter case the effect of the addition of
water would be simply to alter the equilibrium point of the mixture. It has been
shown that in all reversible reactions the equilibrium position is the same from which-
ever side it be approached. The action of the ferment is to hasten the attainment of
equilibrium, the position of the latter being determined by the relative concentration
of the reacting molecules.
SECTION V
ELECTRICAL CHANGES IN LIVING TISSUES
The material composing living cells and tissues is permeated throughout
with water containing electrolytes in solution. All salts, as we have seem
undergo ionic dissociation in watery solution — a dissociation which, in the
concentrations occurring in the animal body, must be nearly complete.
When an electric current passes through the living tissues it is carried by the
charged ions formed by the dissociation of the salts. Thus, n/10 solution
+ -
of sodium chloride contains almost entirely Na and CI ions. In addition to
these charged inorganic ions, the cell protoplasm contains in solution or
suspension various colloidal particles which in many cases are themselves
charged. By the presence of these colloidal particles marked differences
may be caused in the distribution of the inorganic ions owing to the power
of adsorption possessed by the colloids for many inorganic salts. It is
evident that any unequal distribution of the charged ions or colloidal particles
in a tissue or on the two sides of a membrane may give rise to corresponding
unequal distribution of electric charges, and therefore differences of potential
between different parts of the tissue, which under suitable conditions may
find their expression in an electric current. It is therefore not surprising that
practically every functional change in a tissue has been shown to be
associated with the production of differences of electrical potential. Thus all
parts of an uninjured muscle are isopotential, and any two points may be led
off to a galvanometer without any cm-rent being observed. If however one
part of the muscle be strongly excited, as for instance by injury, so that it
is brought into a state of lasting excitation, it will be found that, on leading
off from this point and a point on the uninjured surface to a galvanometer,
a current flows through the latter from the uninjured to the injured surface.
Every beat of the heart, every twitch of a muscle, every state of secretion of
a gland, is associated in the same way with electrical changes. In most
cases the electrical changes associated with activity have the same general
character, the excited part being found to be negative in reference to any
other part of the tissue which is at rest. The uniform character of the
electric response in different kinds of tissues suggests that an accurate know-
ledge of the changes in the distribution of charged ions responsible for the
response ought to throw important light on the intimate nature of excitation
generally. It may be therefore advisable to consider more closely the
169
170
PHYSIOLOGY
conditions which determine differences of potential in a complex system of
electrolytes.
As a simple case we may take an ordinary concentration cell. Two
vessels (Fig. 29), A and B, are united by a glass tube C. A contains a 10
per cent, solution of zinc sulphate and B a 1 per cent, solution of the same
salt. A rod of pure zinc is immersed in each limb. On connecting the zinc
by a zinc wire to a galvanometer a current is observed to flow from A to B
through the galvanometer, and therefore from B to A through the cell. A
solution of zinc sulphate contains partly undissociated ZnS0 4 and partly
+ —
dissociated Zn and S0 4 ions. If a rod of zinc be immersed in a watery fluid
the zinc tends to dissolve. The Zn passing into the fluid is however
directly ionised, and therefore carries a positive charge into the fluid, leaving
the zinc negatively charged (Fig. 30). This process of solution will rapidly
come to an end, since the positively charged ions in the fluid will repel back
into the zinc any ions which may be escaping from the zinc. The amount of
zinc actually dissolved in the fluid is infinitesimal, the process of solution
ceasing when the pressure (osmotic pressure) of the Zn ions in the fluid
equals what may be called the ' electrolytic solution pressure ' of the zinc.
The continued solution of the zinc is therefore possible only when means are
supplied for the Zn ions in the fluid to get rid of their positive charges.
In an ordinary Daniell cell the Zn ions which leave the zinc are dis-
charged by combining with the S0 4 ions passing to the zinc from the copper
sulphate in the outer cell. It is a well-known fact that pure zinc does not
dissolve in acid until some other metal, such as copper, is brought into con-
tact with it, so as to set up an electric couple, i.e. to provide means for the
discharge of the Zn ions passing into the solution. When the zinc is
immersed in the two solutions of zinc sulphate in the concentration battery,
the same change will occur. The ZnS0 4 solution in the two limbs of the
ELECTRICAL CHANGES IN LIVING TISSUES 171
concentration cell already contains Zn ions. Since their pressure in the 10 per
cent, solution is greater than in the 1 per cent, solution, fewer Zn ions will
leave the zinc in A than in B. The negative charge on the Zn in A will
therefore be less than that on the rod in B, and positive electricity will there-
fore flow from A to B. This will disturb the equilibrium at the surface both
of B and A, so that Zn ions will be deposited from the fluid on the surface of
the zinc in A and will continue to pass from zinc into solution in B. At the
same time there is a movement of S0 4 ions, set free at the surface of A
towards B. The ultimate result therefore is that the zinc in B dissolves
and the same amount of zinc is deposited on A. The solution of zinc
sulphate on A becomes progressively weaker, while that in B becomes
stronger, until finally the concentrations in the two limbs are identical
and the current ceases. In this process no chemical energy is involved,
the energy set free by the conversion of zinc into zinc sulphate in B being
exactly balanced by the energy lost by the deposition of zinc from zinc
sulphate in A. Yet the current which is produced has a certain amount
of energy which can be utilised for heating a wire through which it is made
to pass. Since this energy must be taken from the cell, the cell is cooled
during the passage of the current. We have here a close analogy with the
case of compressed gases. If the 10 per cent, and 1 per cent, solutions
were mixed together in a calorimeter, no change of temperature would
be produced, since no work is done in the process. In the same way no cooling
effect is observed if compressed gas be allowed to expand into a vacuum.
If however the compressed gas be allowed to expand from a narrow orifice
against the pressure of the external air, so that it does work in the process,
it is cooled, and this cooling effect is made use of in the working of refrigerat-
ing machines or for the liquefaction of gases. We may therefore regard the
concentration battery as a machine for making the substances in solution
do work as they expand from a strong into a dilute solution.
The differences of potential obtained from an ordinary concentration
cell are very small and would not ^
suffice to account for such a high
electromotive force as is set up, e.g.
in the contraction of a muscle. We
have seen earlier however that even
in isosmotic solutions differences of
pressure may be brought about by
differences in diffusibility of the sub-
stances in solution, especially if the
two solutions be separated by a mem-
brane. Very large differences may be Fig. 31.
produced if this membrane be prac-
tically impermeable to one or other of the dissolved substances. In the same
way a semipermeable membrane, i.e. a membrane with different permeabil-
ities for the different ions of the two solutions, may suffice to bring the
differences of potential of a concentration cell up to and beyond the extent
uv
B
UV
172 PHYSIOLOGY
which is observed in living tissues. Supposing we have (Fig. 31) two solu-
tions, A and B, each containing an electrolyte, UV, in different concentrations
separated by a membrane m. If u represents the velocity of transmission
of U through m, and v the velocity of V, then the electromotive force of the
cell is given by the formula
^^0-0577.1og. 1 „ C2 Volt.
If v is taken as very small, the membrane may be regarded as semipermeable
for the corresponding ion V. Supposing we take potassium chloride as the
solution, we should have to make the concentration in B eight times that in
A, in order to get a current of strength equal to that obtained from the
olfactory nerve of the pike, for example. Macdonald has made such an
assumption in order to explain the normal nerve current. He suggests that
the axis cylinder contains an electrolyte which is equivalent to a 2-6 per
cent, solution of potassium chloride. It is unnecessary however to assume
such great differences of concentration if we regard the membrane as itself
a solution of electrolytes, as has been suggested by Cremer, or if we take
different substances on the two sides of the membrane. In the case of two
electrolytes, UiVj, U 2 V 2 (U being the cation in each case), separated by a
membrane with varying permeability for the different ions, the electro-
motive force of the cell is given by the following formula :
0-0577 log.,,;'"
_ + v t
where u u v lt « 2 , v 2 , are the velocities of the corresponding ions. We assume
that the concentrations of the two solutions are identical. Now it is evident
that by making w 2 and v t very small, the expression log. 10 — - may be
U 2 + Vj
made to attain any quantity, and in the same way by making Uj + v 2
infinitesimally small, the electromotive force of the combination will also
become correspondingly small. The thickness of the membrane does not
come into the formula, so that membranes of microscopic or even ultra-
microscopic thickness, which we have seen reason to assume as present in
and around cells and their parts, could perform all the functions required
of the hypothetical membrane in the above example. This is also the case
when V! is the same as V 2 — that is to say, there is a common anion or a
common cation on the two sides of the membrane.
It must be remembered that the passage of a current through a membrane
impermeable to one or other ion in the surrounding fluid will cause an accu-
mulation of the ion at the surface of the membrane, so that this will become
polarised. Such an accumulation at any surface will naturally alter the
properties of the surface, including its surface tension. The construction of
the capillary electrometer depends on this fact. When mercury is in contact
with dilute acid or mercuric sulphate solution it takes a positive charge from
the fluid, and the state of stress at the surface of contact between the
mercury and the negatively charged fluid diminishes the surface tension of
ELECTRICAL CHANGES IN LIVING TISSUES
173
the mercury. If the mercury be in the form of a drop in a tube drawn out
to a capillary, the mercury will run down the capillary and the drop will be
deformed until the surface tension tending to pull the mercury into a
spherical globule is just equal to the force of gravity tending to make the
mercury run out through the end of the capillary (Fig. 3'2).
If the mercury be immersed in sulphuric acid it will descend to
a lower level in the capillary owing to the diminution of its
surface tension, If now the acid and the mercury be con-
nected with a source of current so as to charge the mercury
negatively, the effect will be to diminish the charge previously
taken up by the mercury. The state of tension at the contact
with the acid is therefore diminished, the surface tension is
increased, and the mercury withdraws itself from the point
of the capillary. If however the mercury be connected with
the positive pole, its charge will be increased and its surface
tension correspondingly diminished, so that the meniscus
will move towards the point of the capillary. The move-
ment of the meniscus to or away from the point may thus be
used, as in the capillary electrometer, to show the direction
and amount of any moderate electric change occurring in a
tissue, two points of which are connected with the mercury
and the acid respectively. It is possible that this electrical
alteration of surface tension may be a determining factor
in many of the phenomena of movement observed in the animal
body. We shall have occasion to discuss this question more fully when
endeavouring to account for the ultimate nature of muscular contraction.
Fig. 32.
BOOK II
THE MECHANISMS OF MOVEMENT AND
SENSATION
CHAPTER V
THE CONTRACTILE TISSUES
SECTION I •
THE STRUCTURE OF VOLUNTARY MUSCLE
The most striking features in the continual series of adaptations to the
environment, which make up the life of an individual, are the movements
carried out by contractions of the skeletal muscles. In fact, all the mechan-
isms of nutrition can be regarded as directed to the maintenance of the
neuro-muscular apparatus, i.e. of the mechanism for adapted movement.
With the growth of the cerebral hemispheres, which determines the rise
in the scale of animal life, the skeletal muscles become more and more the
machinery of conscious reaction. Even the highest of the adaptations
possessed by man, those involving the use of speech, are impossible without
some kind of movement. A man's relation to his fellows, and his value in
the community, are determined by these higher muscular adaptations.
It is not therefore surprising that the organs of the body which present
in the highest degree the reactivity characteristic of all living things should
have early attracted the attention of physiologists and have been the object
of numberless researches directed to determining the ultimate nature, of the
processes generally described as vital.
The movements of the muscles are carried out in response to changes
aroused in the central nervous system by events occurring in the environ-
ment and acting on the surface of the body. Every movement of an animal
is thus in its most primitive form a reflex action, and involves changes in a
peripheral sense organ, in an afferent nerve fibre, in the central nervous
system, and in an efferent nerve fibre, before the actual process of contrac-
tion occurs in the muscle itself and gives rise to the resultant movement
(Fig. 33). If we are to determine the nature of the changes involved in this
reflex action, we must be able to study them as they progress along the
different elements which make up the reflex arc. This analysis is facilitated
by the fact that we are able to arouse a condition of activity in the different
parts of the arc, even when isolated from one another. Thus we can excite
anv given reflex movement by stimulation of the periphery of the body,
or of the afferent nerve passing from the surface to the central nervous
177 12
178
PHYSIOLOGY
system. We can proceed further and cut the efferent nerve away from
the central nervous system and still succeed in exciting a condition of activity
in the efferent nerve or in its attached muscle. All parts of the reflex arc
possess the property of excitability, and we are thus able to arouse the
activity of each part in turn, to study its conditions, its time relations, and
the physical and chemical changes concomitant with the state of activity.
It will be convenient for our analysis to begin with the tissue whose
Sensory ll ^ Sensory nerve 9
Surface \\M — *
Central Nervous
System
Fig. 33. Diagram of a reflex arc.
reaction forms an end link in the reflex chain, namely, the muscle, and to
proceed from that to the consideration of the processes occurring in the
conducting strand between central nervous system and muscle, namely,
the nerve fibre, postponing to a future chapter the treatment of the more
complex processes associated with the central nervous system.
In the higher animals we may distinguish several varieties of muscle.
All movements that require to be sharply and forcibly carried out are
effected by means of striated muscular tissue and, as these movements
are in nearly all cases under the control of the will, the muscles are generally
spoken of as voluntary. Unstriated or involuntary muscles form sheets
or closed tubes surrounding the hollow viscera. By their slow, prolonged
contractions they serve to maintain and regulate the flow of the contents
of these organs. Such fibres are found surrounding the blood-vessels,
the alimentary canal, the bladder, &c. Intermediate in properties as
well as structure between these two classes is the heart muscle. This,
like voluntary muscle, is striated, but presents considerable variations both
in structure and function from ordinary skeletal muscle. Many of its
properties will be considered in treating of the physiology of the heart.
The properties of contractile tissues have been most fully investigated in the volun-
tary muscles, almost exclusively on the muscles of cold-blooded animals, such as the
frog. The choice of skeletal muscles for this purpose is justified by the fact that a
function is most easily investigated in the organs in which it is most highly develojied.
The choice of cold-blooded animals is guided by the fact that it is possible to isolate
the muscle from the rest of the body and to study its reactions during a considerable
time without the research being interfered with by the death of the tissue. We may
therefore deal at length with the properties of the skeletal muscles, pointing out inei-
THE STRUCTURE OF VOLUNTARY MUSCLE 179
dentally in what respects the heart muscle and involuntary muscle differ from the
skeletal muscle.
The voluntary or striated muscles form a large part of the body, and
are known as the flesh or meat. Each muscle is embedded in a layer of
connective tissue, and is made up of an aggregation of muscular fibres,
which are united into bundles by means of areolar connective tissue. The
individual fibres vary much in length, and may be as long as 4 or 5 cm.
At each end of the muscle the fibres are firmly united to tough bundles
of white fibres., which form the tendon of the muscle, and are attached as
Fio. 34. Muscular fibre of a mammal, examined fresh in serum,
highly magnified. (Schafer.)
a rule to bones. Running in the connective tissue framework of the muscle
we find a number of blood-vessels, capillaries and nerves.
On examination of a living muscle, each fibre is seen to consist of a
series of alternate light and dark strise, arranged at right angles to its long
axis, and enclosed in a structureless sheath — the sarcolemma. Lying under
the sarcolemma are a number of oval nuclei embedded in a small amount
of granular protoplasm. In some animals these nuclei occupy a central
position in the fibre. Each band may be considered to be made up of a
number of prisms (sarcomeres) side by side, with interstitial substance
(sarcoplasm) between them. The muscle prisms of adjacent discs are
connected to form long columns (primitive fibrillse, or sarcostyles). Each
muscle prism is more transparent at the two ends than in the middle, thus
giving rise to the appearance of light and dark strise. In the middle of
the light band is a line or row of dots (often appearing double), called Krause's
membrane.
The development of this regular cross and longitudinal striation is
closely connected with the evolution and specialisation of the muscular
function, i.e. contraction. Contractility is among others a function of all
undifferentiated protoplasm. Undifferentiated cells, such as the amoeba,
can effect only slow and weak contractions. Directly a specialisation of
function is necessary and some cell or part of a cell has to contract rapidly
in response to some stimulus from within or without, we find a differentiation
both of form and of internal structure. In many cases, as in the developing
muscle of the embryo or the adult muscles of many invertebrates, this
differentiation affects only part of the cell, so that while one part presents
the ordinary granular appearance, the other half is finely and longitudinally
180.
PHYSIOLOGY
striated, the striatum being apparently due to the development of special
contractile fibrillae. In the slowly contracting unstriated muscle of the
vertebrate intestine, the longitudinal striation is with difficulty made cut,
but as the muscle rises in the scale of efficiency, the longitudinal striation
becomes more apparent, and in the striated muscle of vertebrates, and still
more in the wonderful wing-muscles of insects, which can perform three
hundred complete contractions in a second, the longitudinal is associated
Fig. 35. Muscle fibre of an ascaris. a, the differentiated contractile portion of the
cell. (After Hertwig.)
Fig. 3(5. Muscle fibres from the small intestine, showing the fine longitudinal stria-
tion. (Schafee.)
with and often apparently subordinated to a transverse striation, due to
the regular segmentation of the contractile fibrillae or sarcostyles. Every
muscular fibre, which presents any trace of histological differentiation, may
be said to consist of contractile fibrillse (sarcostyles), each composed of a
series of contractile elements (sarcous elements or sarcomeres), and embedded
in a granular material known as sarcoplasm. The great divergence in the
aspect of muscular fibres from different paits of the animal kingdom is
THE STRUCTURE OF VOLUNTARY MUSCLE
181
largely conditioned by the varying relations, spatial and quantitative, cf
the sarcoplasm to the sacostytes. Thus in the higher vertebrates, two
types of voluntary muscular fibre are distinguished, according to the
Fig. 37. Transverse sections of the ])ectoral muscles of «, the falcon, b. the goose, and c,
the domestic fowl. It will be noticed that the relative amount of granular or red fibres
present varies directly as the bird's power of sustained flight. (After Knoll.)
amount of sarcoplasm they contain : one rich in sarcoplasm, more granular
in cross-section, and generally containing haemoglobin ; and the other poor
in sarcoplasm, clear in cross-section, and containing no ha?moglobin. From
the fact that the granular fibres are B
found chiefly in those muscles which
have to carry out long-continued
and powerful contractions, it seems
reasonable to regard the interstitial
sarcoplasm as the local food-supply
of the active sarcostyles, although
some authors have endowed the
sarcoplasm with a contractile power
of its own, differing onlv bv its
extremely p olonged character from
the quick twitch of the sarcostyles.
The connection between structure
and activity of the muscle-fibres is
well shown by Fig. 37.
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c
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In some animals, such as the rabbit,
we find muscles consisting almost entirely
of one or other of these varieties ; but in
most animals (amongst which we may
reckon frog and man) the two varieties
occur together in one muscle, so that what
we have to say about the properties of
voluntary muscle, which rests nearly Fig. 38
entirely on experiments with frog's
muscle, really has reference to a mixed
muscle, i.e. muscle containing both red
and white fibres.
Since the sarcous element represents the
contractile unit of the muscle, a know-
ledge of its intimate structure should be of great importance for the theory of muscular
contraction. Unfortunately however we are here at the limits of the demonstrably
Fibrils of the wing-muscles of a wasp,
prepared by Rollet's method. Highly
magnified. (E. A. Schafer.)
a, a contracted fibril. B, a stretched
fibril, with its sarcous elements separated
at the line of Hensen. c, an uncon-
tracted fibril, showing the porous struc-
ture of the sarcous elements.
182
PHYSIOLOGY
SJS.
Fio. 30. Diagram of a sarcomere in
a moderately extended condition,
A, and in a contracted condition, B ;
k, K, membranes of Krause : h,
line or plane of Hensen ; SE,
poriferous sarcous elements.
(Si rafer.)
visible. It becomes difficult to determine how far the appearances observed under
the microscope are due to actual structural differences or are produced by the unequal
diffraction of light by the Various elements of the muscle fibre. All observers are agreed
thai the essential contractile element is the row
A B of sarcous elements forming the muscle fibril or
sarcostylc. Schafer, working on the highly
differentiated wing-muscle of the wasp, concludes
that each sarcostyle is divided by Krause's
membranes (the lines in the middle of each light
stripe) into sarcomeres. Each sarcomere contains
a darker substance near the centre divided into
two parts by Hensen's disc. At each end of the
sarcomere the contents are clear and hyaline.
In the act of contraction, the clear material flows,
according to Schafer, into tubular pores in the
central dark material.
Most histologists agree in assigning to the
middle part of the sarcous clement (the sarco-
mere) a denser structure than to the two ends.
According to Macdougall, however, the lighter appearance at each end of the sarco-
mere is an optical illusion. He regards the sarcous element as a cylindrical bag with
homogeneous contents, crossed only by one or
three delicate transverse membranes. Krause's
membrane would be rigid, while the lateral wall of
the sarcous element is extensible, and is folded longi-
tudinally, so that it can bulge out and produce
a shortening and thickening of the whole sarcous
element if by any means the pressure be raised
in its interior. In favour of a differentiation
within the sarcomere itself is the fact that
under certain conditions it is possible to produce
a precipitate, limited only to central part, i.e.
to the sarcous element to which Schafer assigns
a tubular structure.
When a muscle fibre, killed by osmic acid or
alcohol, is examined under the microscope by pol-
arised light, it is seen to be made up of alternate
bands of singly and doubly refracting material.
The doubly refracting {anisotropous) substance
corresponds to the dark band, and the singly re-
fracting (isotropous) to the light band. If the
living fibre be examined in the same way, it is
found that nearly the whole of it is doubly re-
fracting, the singly refracting substance appearing
only as a meshwork with long parallel meshes
corresponding to the muscle prisms. In short, in
a living fibre the muscle prisms are anisotropous,
the sarcoplasm isotropous.
When a muscle fibre contracts, there is an ap-
parent reversal of the situations of the light and
dark stripes, owing to the fact that the interstitial
sarcoplasm is squeezed out from between the
bulging sarcomeres, and accumulates on each side
of the membranes of Krause. The accumulation of sarcoplasm in this situation
makes the previously light striae appear dark, and the dark striae by contrast lighter
Fw. 40. Motor end-organ of a
lizard, gold preparation. (Ktjhnb.)
n, nerve fibre dividing as it ap-
proaches the end-organ ; r, ramifi-
cation of axis cylinder upon b, gran-
ular bed or sole of the end-organ ;
m, clear substance surrounding the
ramifications of theaxis cylinder.
THE STRUCTURE OF VOLUNTARY MUSCLE 183
than they were before. That there is no true reversal of the striae is shown by exam-
ining the muscle by polarised light, the two substances, isotropous and anisotropous,
retaining their relative positions.
Every skeletal muscle is connected with the central nervous system
by nerve fibres, some conveying impressions from the muscle to the centre,
the others acting as the path of the motor impulses from the centre to the
muscle. These latter — the motor nerves — end in the muscular fibre itself,
by means of a special end-organ — the motor end-plate. The neurilemma
ofthe nerve fibre becomes continuous with the sarcolemma, the medullary
sheath ends suddenly, while the axis cylinder ramifies in a mass of un-
differentiated protoplasm, containing nuclei, and lying in contact with the
Tendo Aehillis
Fio. 41. Muscles of hinder extremity of frog. (After Ecker.)
contractile substance of the muscle immediately under the sarcolemma
(Fig. 40). This mass of protoplasm is known as the ' sole plate.' It is not
marked in all animals. Thus in the frog the axis cylinder ends in a series of
branches at right angles to one another, distributed over a considerable length
of the muscle fibre. The sole plate in this case seems to be limited to scat-
tered nuclei lying in close contact with the terminal branches of the nerve
fibre. So far as we can tell at present, the ultimate ramifications of the
axis cylinder end freely and do not enter into organic connection with the
contractile substance itself.
184 PHYSIOLOGY
Musi nf our knowledge on the subject of muscle has been derived from the study
ill i In- gastrocnemius and saitorius muscles of the frog. The position of these muscles
is shown in I In' accompanying diagram (Fig. 41). The gastrocnemius which, with
the attached sciatic nerve, is must frequently employed as a nerve-muscle preparation,
forms a thick belly immediately under the skin at the back of the leg, and arises by
t \vi i tendons from the lower end of the femur and the outer side of the knee-joint. The
two tendons converge towards the centre of the muscle, uniting about its middle, and
from them a number of short muscular fibres arise, passing backwards and dorsally to
be inserted into a flat aponeurosis covering the lower half of the muscle, which ends
in the tendo Achillis. On account of this irregular arrangement of the muscular fibres,
tin gastrocnemius can be employed only when the contraction of the muscle as a whole
is the object of investigation. The effective cross-area of the fibres is much greater
than the actual cross-section of the muscle, so that, while the actual shortening of the
gastrocnemius is but small, its strength of contraction is considerable.
The sartorius muscle consists of a thin band of muscle fibres running parallel from
one end of the muscle to the other. It lies on the ventral surface of the thigh, arising
from the symphysis puhlis by a thin Hat tendon, and is inserted by a narrow tendon
into the inner side of the head of the tibia. On account of the regularity with which
its fibres are disposed, this muscle is of especial value in experiments on the local con-
ditions of a muscle fibre accompanying its activity. When a greater mass of approxi-
mately parallel fibres is necessary, recourse may be had to a preparation consisting of
the gracilis and semi-membranosus muscles together. This latter muscle lies dorsally
to the gracilis muscle which is shown in the illustration.
Other muscles in the frog used for particular purposes are the mylohyoid and the
dorsocutaneous muscles. The mylohyoid muscle of the frog, which lies on the ventral
surface of the tongue, has the advantage that its fibres lie in close contact with a lymph-
space occupying the centre of the tongue. Tf any drug be injected into this lymph-
space it ails with extreme rapidity on the muscle fibres, so that the tongue-preparation
of the frog is a useful one for the study of the action of different substances on muscle-
fibres.
SECTION II
EXCITATION OF MUSCLE
A MUSCLE may be caused to contract in various ways. Normally it con-
tracts only in response to impulses starting in the central nervous system
and transmitted down the nerves. But contraction may be artificially
excited in various ways in a muscle removed from the body. If we make
a muscle-nerve preparation {i.e. a muscle with as long a piece of its nerve
as possible attached to it), such as the gastrocnemius of the frog with the
sciatic nerve, we find we can cause contraction by various forms of stimuli —
mechanical, thermal, or electrical — applied to the muscle or the nerve
(direct and indirect stimulatiou). Thus the muscle responds with a twitch
if we pass an induction shock through it or its nerve, or pinch either with a
pail of forceps. Or we may use chemical stimuli, and cause contraction
by the application of strong glycerin or salt solution to the nerve.
These experiments do not prove conclusively that muscle itself is irritable.
It might tie urged that, when we pinched or burnt the muscle we stimu-
lated, nut Hie muscle substance itself, but the terminal ramifications of
the nerve in the muscle, and that these in their turn incited the muscle to
contract. But the independent excitability of muscle is shown clearly by
the following experiment by Claude Bernard.
A frog, whose brain has been previously destroyed, is pinned on a board,
and the sciatic nerves on each side exposed. A ligature is then passed
round the right thigh underneath the nerve, and tied tightly so as effectually
to close all the blood-vessels supplying the limbs, without interfering
with the blood-supply to the nerve. Two drops of a 1 per cent, solution
of curare are then injected into the dorsal lymph-sac. After the lapse of a
quarter of an hour n is found that the strongest stimuli may be applied
to the left sciatic nerve without causing any contraction of the muscles it
supplies. On the right side, stimulation of the nerve is as efficacious as
before. Both gastrocnemii respond readily to direct stimulation, showing
that the muscles are not affected by the drug. Since both sciatic nerves
have been exposed to the influence of the curare, it is evident that the
difference on the two sides cannot be due to any deleterious effect on them
by the curare. We have also excluded the muscles themselves ; so we must
conclude that the curare paralyses the muscles by affecting the terminations
of the nerve within the muscle, and probably the end-plates themselves.
185
186
PHYSIOLOGY
This experiment teaches us that muscle can be excited to contract by
direct stimulation, even when the terminal ramifications of the nerve within
it are paralysed, so that stimulation of them would be without effect.
The same fact may be demonstrated in a different way by means of
chemical stimuli. It is found that whereas strong glycerin excites nerve
fibres, it is without effect on muscle fibres, while on the other hand weak
ammonia is a strong excitant for muscle, but is without effect on nerve.
If the frog"s sartorius be dissected out and the lower end dipped in glycerin,
no twitch is produced. On snipping off the lower third of the muscle and then
immersing the cut end in glycerin, a twitch at once occurs. The lower
end contains no nerve fibres (Fig. 42), and it is
only when a section containing nerve fibres is ex-
posed to the action of glycerin that contraction takes
place. On the other hand, mere exposure of muscle
to the vapour of dilute ammonia causes contraction
(and subsequent death), although the nerve to the
muscle can be immersed in the solution without
any excitation being produced.
Of all the different stimuli capable of exciting
muscular contraction, the electrical is that most
frequently employed. It is easy, using this form,
to graduate accurately the intensity and duration
of the stimulus. At the same time the stimulus
may be applied many times to any point on the
of the nerve fibres within muscle or nerve without killing the part stimulated,
the sartnrius muscle of w h ereas with other forms of stimulus it is difficult
the frog, showing the free- . ■ ....
doni of the lower portion to obtain excitatory effects without injuring to a
of the muscle from nerve greater or less extent the part stimulated,
fibres. (Kuhne.) *
METHODS EMPLOYED FOR THE STIMULATION OF MUSCLE AND NERVE
The two commonest forms of electrical stimuli employed are (1) the make and break
of a constant current, (2) the induction currents of high intensity and short duration
obtained from an induction coil. «
(1) Constant Current. As a source of constant current a Daniell's cell is generally
employed. This consists of an outer pot containing a saturated solution of copper
sulphate, in which is immersed a copper cylinder. To the cylinder at the top a binding
screw is attached, by which the connection of the copper with a wire terminal is effected.
Within the copper cylinder is a second pot. of porous clay, filled with dilute sulphuric
acid, in which is immersed a rod of amalgamated zinc. In this cell the zinc is the
positive and the copper the negative element. Hence the current flows (in the cell)
from zinc to copper, and if the binding screws of the two elements are connected by
a wire, the current flows in the wire (outer circuit) from copper to zinc, thus completing
the circuit. Since in the outer circuit the current flows from copper to zinc, the terminal
attached to the copper is called the positive pole, and that to the zinc the negative
pole. When the current is required to be very constant, the zinc may be immersed
in a saturated solution of zinc sulphate instead of dilute sulphuric acid. A Daniell's
cell, though very constant, gives only a small current, owing to its small electromotive
force and high internal resistance.
When a stronger current is required it is best to use a storage battery. In this,
Fia. 42. The ramification
EXCITATION OF MUSCLE 187
when charged, the two elements are lead and lead oxide, Pb0 2 . It has the advantage
that it may be used over and over again, being recharged through a resistance from the
electrical mains when it has run down.
Another useful type of cell is the Leclanche cell. This consists of a glass jar con-
taining a solution of sal ammoniac. Into this dips an amalgamated rod of zinc, which
is the positive plate. A piece of gas carbon forms the negative plate. This is sur-
rounded by peroxide of manganese (Mn0 2 ) which is kept in contact with the surface of
the carbon by being placed in a porous pot. In some forms of Leclanche the manganese
and carbon are ground up together and pressed into a cylinder which surrounds the
zinc rod. When the cell is on open circuit — that is, when the terminals are not con-
nected and no current is passing — very little action takes place ; but when the circuit
is closed and the current passes, the zinc dissolves in the sal ammoniac, forming a double
chloride of zinc and ammonia, while ammonia gas and hydrogen are liberated at the
carbon pole. The nascent hydrogen reduces the peroxide of manganese and so polarisa-
tion is prevented. On account of its great solubility in water the ammonia has no
polarising action. The Leclanche is a convenient form of cell, as when once set up it
requires a minimum of attention. If it is worked through a considerable resistance,
it will keep in order for some time, particularly if the work is intermittent ; but if it is
used with a small resistance in circuit it polarises very rapidly. The E.M.F. of one
Leclanche cell is l - 4 volt in the external circuit. The positive current is conventionally
said to run from the zinc to the carbon in the cell, and from the carbon to the zinc
in t he circuit outside. The wire attached to the carbon is the positive pole, that to the
zinc the negative pole. Dry cells are usually Leclanche cells, in which the solution of
sal ammoniac is prevented from spilling by absorption with sawdust or plaster of Paris.
The E.M.F. is the same as the Leclanche, but they polarise much more readily.
If the poles of a Daniell's cell be connected by wires with a nerve or muscle of a
nerve-muscle preparation (as in Fig. 43), the current will flow from copper to the nerve
at a, and along the nerve from a to K.
At K the current will leave the nerve to
flow to the zinc of the battery, so com-
pleting the circuit. The point at which
the current enters the nerve {i.e. the
point of the nerve connected with the
positive pole of the battery) is called the
anode, and the point at which the current
leaves the nerve is called the cathode. The
wires by which the current is conducted
to and from the nerve are called the electrodes. As electrodes we generally employ
two platinum wires mounted together on a piece of vulcanite.
For the purpose of making or breaking the current at will, various forms of keys
are employed. The ordinary make and break key consists of a hinged wire dipping
into a mercury cup. When the wire is depressed so that it dips into the mercury,
the circuit is complete. On raising the wire by means of the handle, the circuit is
broken.
Du Bois Reymond's key consists of two pieces of brass, each of which has two bind-
ing screws for the attachment of wires. These are connected by a third piece, or
bridge, which is jointed to one of the two side bits, so that it may be raised or lowered
at pleasure {v. Fig. 44). It may be used either as a simple make-and-break key, or,
as is more usual, as a short-circuiting key. In the first case one brass bank is attached
to one terminal, the other to the other terminal. If the bridge be now lowered, the
connection is made and the current passes. If the bridge be raised, the current is
broken. Fig. 44 a and B shows the way in which the key is arranged for short-circuit-
ing. It will be seen that four wires are attached to the key ; two going to the battery,
and two we may suppose going to a nerve. When the bridge is down, as in Fig. 44 A,
the current from the cell on coming to the key has a choice of two routes. It may either
go through the brass bridge, or through the "other wires and nerve. The resistance of
J!
PHYSIOLOGY
I lie nerve however is about 100,000 ohms, whereas that of the bridge is not the thou-
sandth part of an ohm. When a current divides, the amount of current that goes along
any branch is inversely proportional to the resistance. Here the resistance in the nerve-
circuit is practically infinite compared with that in the brass bridge, and so all the
A B
Fig. 44. Du Bois key. closed.
Du Bois key. open.
We say then that the
current goes through the bridge and none through the nerve.
current is shorl-circuitnl.
It is often necessary to reverse the direction of a current through a nerve-muscle
preparation or a galvanometer in the course of an experiment. For this purpose
Polil's reverser may be used. It consists of a slab of ebonite or paraffin or other in-
sulating material, in which are six small holes filled with mercury. A binding screw is
in connection with the mercury in each of these holes. Two cross-wires (not in contact
with one another) join two sets of pools together, as shown in Fig. 45. A cradle con-
sisting of two wires joined by an insulating handle carries two arcs of wire by which
the pools at a and b may be put into connection with either x and y, or the corresponding
pools on the opposite side. It will be seen
that with the cradle tipped to one side, as in
Fig. 45 a, the current from the battery enters
the reverser at a ; this proceeds up the wire
of the cradle, down towards the right, then
along the cross-wire to the pool at x. x is
therefore the anode, and y the cathode. In
Fig. 45 B the cradle has been swung over to
the other side. Here the cross-wires are not
used at all by the current, which passes from o
up the sides and down the curved wire to y.
In this case y is now the anode and x the
cathode, and the direction of the current
through the circuit connected with X and y is
reversed. By taking out the cross-wires,
Polil's reverser may be used as a simple
switch, by which the current may be led into
two different circuits in turn.
With this form of reverser difficulty is often
experienced owing to dirt accumulating on the
mercury and forming an insulating layer be-
tween it and the binding screw or copper
wire. Several improved forms of reverser
are now made where the mercury poles are replaced by brass banks, and these are
generally to be preferred in practice.
(2) Induced Currents. In using these the muscle or nerve is stimulated by the
current of momentary duration produced in the secondary circuit of an induction-coil
by the make or break of a constant current in the primary.
The construction of the induction-coil or inductorium is founded on the fact that if
a coil of wire in connection with a galvanometer be placed close to (but insulated from)
Fig. 45. Diagram of Pohl's reverser.
EXCITATION OF MUSCLE
189
another coil through which a current may be led from a battery, it is found that on
make and break of the current of the second coil a momentary current Is induced in the
first. The induced current on make is in the reverse direction, that on break in the
same direction as the primary current. The electromotive force of the induced current
is proportional to the number of turns of wire in the coils. The induction-coil consists
of two coils, each containing many
turns of wire. The smaller coil {n r ,
Fig. 46), consisting of a few turns of
comparatively thick wire, is the pri-
mary coil, and is put into connec-
tion with a battery. It has within
it a core of soft iron wires, which
has the effect of attracting the
lines of force, concentrating them,
and so increasing its power of in-
ducing secondary currents. The
secondary coil. r 2 , of a large num-
ber of turns of very thin wire,
is arranged so as to shde over the
primary ooil. It is provided with
two terminals, which may be con-
nected with the nerve or other Fl0 46 Diagram of inductorium. R[ , primary:
tissue that we wish to stimulate. e 2 , secondary coil, m, electro-magnet of Wagner's
Since the electromotive force of the hammer, w, Helmholtz's side wire.
induced current is proportional to
the number of turns of wire, it is evident that the electromotive force of the current
delivered by the induction coil may be many thousand times that of the battery cur-
rent flowing through the primary coil. The induced currents increase rapidly in
strength as the coils are approached to one another ; the strength of these therefore
may be regulated by shoving the secondary up to or away from the primary coil.
A short-circuiting key is always placed between the secondary coil and the nerve
to be stimulated. If only single induction shocks are to be used, a make-and-break
key is put in the primary battery circuit, and the two wires from the battery and key-
are attached to the two top screws of the primary coil (c and d. Pig. 46). It is then
found that the shock given by the induced current on break of the primary current
is much stronger than that on make.
In endeavouring to explain this difference in the intensity of the make-and-break
induction shocks, it must be remembered that the intensity of the momentary current
induced in the secondary coil at make or break of the primary current is proportional
il ) to the number of turns of wire in each coil ; (2) inversely to the mean distance between
the coils (i.e. the nearer the coils, the stronger the induced current) ; (3) to the rate of
change in strength of the primary current. Now, when a current is made through the
primary coil, induction takes place, not only between primary and secondary coils,
hut also between the individual turns of the primary coil itself. This current of self-
induction, being opposed in direction to the battery current, hinders and delays the
attainment by the latter of its full strength, and so slows the rate of change of current
in the primary coil. Hence the intensity of the momentary current induced in the
secondary coil is less than it would have been without the retarding effect of self-induc-
tion. At break of the current, an extra current is also produced in the primary coil
in the same direction as the battery current, and therefore tending to reduce the rate
of change of the current from full strength to nothing. In this case however the
primary circuit being broken, the current of self-induction cannot pass without jumping
the great resistance offered by the air, so that its retarding effect on the rate of dis-
appearance of the primary current may be practically disregarded. In Fig. 47 the line,
a, 6, c, d, will represent the changes occurring in the primary current at make and
break, a b corresponding to the make and c d to the break. The lower line represents
190
PHYSIOLOGY
the momentary currents induced in the secondary circuit, m being the current of low
intensity and long duration produced by the make, and \ the shock of high intensity
and short duration caused by the sharp break of the primary current.
When we desire to use faradic stimulation — that is, secondary induced shocks
rapidly reputed .VI to 100 times a second — -we make use of the apparatus attached
to the coil, known as Wagner's
hammer (Figs. 48a and 48b).
In this case the wires from the
battery are connected to the
two lower screws (a and b, Fig.
46). Fig. 48a shows the direc-
tion of the current when Wag-
ner's hammer is used. The cur-
rent enters at a. runs up the
pillar and along the spring to the
screw x. Here it passes up
through the screw, and through
the primary coil B r From the
primary coil it passes up the
small coil m, and from this to
the terminal h and back to the
battery. But in this course
the coil m is converted into an
electro-magnet. The hammer h
attached to the spring is attracted down, and so the spring is drawn away from the
screw x, and the current is therefore broken. The break of the current destroys the
magnetic power of the coil, the spring jumps up again and once more makes circuit
with the screw x, only to be drawn down again directly this occurs. In this way the
spring is kept vibrating, and the primary circuit is continually made and broken, with
the production at each make-and-break of an induced current in the secondary coil.
It is evident that, when the primary current is made and broken fifty times in the
second, there will be a hundred momentary currents produced during the same period
in the secondary coil. Every alternate one of these produced by the break of current
- T
^7-
Fig. 47
T
Uq
Fig. 48a. Diagram showing course of
current in inductorium when Wagner's
hammer is used.
Fio. 48b. Diagram showing course of
current when the Helmholtz side wire
is used.
in the primary will be much stronger than the intervening currents produced by the
make. In order to equalise make and break induction-shocks, so that a regular series
of momentary currents of nearly equal intensity may be produced, the arrangement
known as Helmholtz's is used. In this arrangement the side wire w, shown in Fig. 46,
and diagrammatically in Fig. 48b, is used to connect the binding screw o with the
binding screw c at the top of the coil. The screw x is raised, so as not to touch the
spring, and the lower screw y is moved up till it comes nearly in contact with the under
EXCITATION OF MUSCLE
191
surface of the spring. If we consider the direction of the current now, we see that
it enters as before at the terminal, travels up the Helmholtz wire w to the screw c,
thence through the primary coil R x , then through the coil to of the Wagner's hammer,
and so back to the battery. The coil to, thus becoming an electro-magnet, draws
down the hammer h. In this act the under surface of the spring comes in contact with
the screw y. The current then has a choice of two ways. It may either go through
the coil as before, or take a short cut from the terminal a, up the pillar, along the spring,
through the screw y, and down to the terminal b back to the battery. As the resistance
of this latter route is very small compared with the resistance of the primary
coil, &c, the greater part of the current takes this way. The infinitesimal
current which now passes through the coil of Wagner's arrangement is insufficient to
magnetise this, and the hammer springs up again ; thus the process is restarted, and the
• spring vibrates rhythmically. With this arrangement the primary current is never
broken, but only short-circuited, and so diminished very largely. Hence the retarding
influence of self-induction is as potent with break as with make of the current, and the
effects on the secondary coil in the two cases are approximately equal. In Fig. 47 ce
represents the change in the primary current when the current is short-circuited instead
of being broken, and 6 represents the effect produced in the secondary coil. It will be
seen that the currents to and b are practically identical in intensity and duration.
When the induction-coil is used for stimulating, it is usual to graduate the strength
of the shock administered to the excitable tissue by moving the secondary coil nearer
to or further away from the primary coil. It must be remembered that the strength
of the induced current does not vary in numerical proportion with the distance of the
two coils from one another. If one coil is some distance, say, 20 cms. from the primary
coil, the induced current produced by make or break of the primary current is very
small, and on moving the secondary from 20 up to 10 cms. the increase in strength of
the current will not bo very rapid. The increase will however become more and more
rapid as the two coils are brought closer together. Usiog the same strength of current
in the primary coil and the same resistance in the secondary coil, we can say that the
make or break current will be uniform so long as the distance of the coils remains
constant. We are not able however to say by how much the current will increase
as the secondary coil is moved, say, from 11 to 10 cms. distant from the primary coil.
If it is required to know the exact increment in the exciting current which is used, it
is necessary to graduate the induction-coil by sending the induction shocks, obtained
at different distances of secondary from primary coil, through a ballistic galvanometer.
Another method which may be adopted for the excitation of muscle or nerve is the
discharge of a condenser. The advantage of this method is that we can determine
not only the amount of electricity discharged through
the preparation, but the actual energy employed. If
two plates of metal separated from one another by a thin
insulating layer of dielectric such as air, glass, mica, or
paraffined paper, be connected with the two poles of a
battery, each plate acquires the potential of the pole of
the battery with which it is connected, and receives
therefrom a charge of electricity (positive or negative).
If the connections be broken the two plates retain their
charge. If now they be connected by a wire they
discharge through the wire, and if a nerve be inserted in
the course of the wire, it may be excited by the discharge.
The amount of electricity that may be stored up in
tills way will depend on the extent of .the plates and
their proximity to one another, as well as on the e.m.f. Fir.. 49. Diagram to show
of the charging battery. In order to get great extent t,le mo,,e of construction of
of surface, a condenser is built up, as in the diagram ' ' '
(Fig. 49), of a very large number- of plates of tinfoil,
separated by discs of mica or paraffined paper. Alternate discs are connected together :
L92 PHYSIOLOGY
thus, 1, 3, 5 are connected to one polo, while 2, -I, 6 are connected to the other.
The rheocord is used to modify the amount or strength of current flowing through
a preparation. One form of it is represented in fig. 50. A constant source of current
at B causes a flow of electricity from n to 6 through a straight wire. As the resistance
of this wire is the same throughout its length, the fall of potential from a to 6 must
be constant. The nerve, or w li.it. >\ rr preparation is used, is connected with the straight
wire at. two points, a< » and at c, by means of a sliding eontaot or rider. Supposing
thai there is an eleotromotii e difference <>f one volt between 2 ,)
and the tension due to the weight as well as the velocity on contraction is directly
proportional to the distance of the weight from the axis, it follows that it is better to
Fig. 55. 151ix apparatus for recording isometric and isotonic curves synchronically. (Miss
Buchanan.) p, the steel C3'lindrical support with jointed steel arm to bear the isotonic
lever I, which consists of a strip of bamboo with an aluminium tip. t, the isometric
lever, also of bamboo, except for a short metal part (', in which are holes for fixing the
muscle. The two wires from an induction coil are brought, one to x, which is in con-
nection with the support and hence with the metal bar t', the other to y, which is insulated
from the support but connected by a copper wire with a thin piece of copper surrounding
the isotonic lever at the point where the muscle is attached to it. CI, clamp for fixing
the lower end of the muscle when an isometric curve is to be taken. The axis of the
isotonic lever is at X, close to which is hung the weight of 50 grin.
load the muscle with 40 grams 1 milhmetre from the axis than with 1 gram 40 milli-
metres from the axis, though the tension put on the muscle will be the same in both
rases.
In tlie first ease the energy of the moving mass will be proportional to
■_'li, and in the second to — _ — - = 800, and it is this energy which deter-
2 2
mines the overshooting of the lever and the deformation of the curve. Since throughout
the contraction in the latter arrangement the lever follows the muscle in its movement,
the tension on the muscle remains the same throughout, and the method is therefore
known as the isotonic method.
It is of importance to be able to record the development of the energy (i.e. the ten-
sion) of the active muscle apart from any changes in its length. For this purpose the
muscle is allowed to contract against a strong spring, the movements of which are
magnified by means of a very long lever. Thus the shortening of the muscle is almost
entirely prevented, but the increase in its tension causes a minute but proportionate
movement of the spring, which is recorded by means of the lever. Since in this case
the length or measurement of the muscle remains approximately constant, while the
tension is continually varying throughout the contraction, it is known as the isometric
method. Tin' great magnification necessary in this method introduces serious sources of
error ; but it seems that if all due precautions be taken to avoid these errors, the isometric
PHYSIOLOGY
curve differs very little in form from the isotonic, displaying only a somewhat quicker
development of energy at the beginning of contraction. It is better to eliminate
the lever altogether and magnify the minute movements of the spring by attaching
to it a small hinged mirror by which a ray of light is reflected through a slit on to a
travelling photographic plate. Since the ray of light has no inertia, magnification
of the movements may be carried to any extent without increasing the instrumental
deformation of the curve (Fig. 56).
A simple muscular contraction or twitch, such as that in Fig. 52,
1 in ill need by a momentary stimulus, consists of three main phases:
(1) A phase during which no apparent change takes place in the muscle,
or at any rate none which gives rise to any movement of the lever. This
is called the latent 'period.
Fio. 50. Myograph for optical registration of muscular
contraction. (K. Lttcas.)
(2) A phase of shortening, or contraction.
(3) A phase of relaxation, or return to the original length.
The small curves seen after the main curve are due to elastic vibrations
of the lever, and do not indicate any changes occurring in the muscle itself.
From the time-marking below the tracing we see that the latent period
occupies about yJ )Tr second, the phase of shortening TT t ff , and the relaxation
t ^q second.
Thus a single muscle-twitch is completed in about ^ second. It must
be remembered however that this number is only approximate, and varies
with the temperature of the muscle and its condition, being much longer in
a fatigued muscle. ■ Moreover it is almost impossible to avoid some deforma-
tion of the curve due to defects of the recording instruments used. Thus the
relative period during which no mechanical changes are taking place in
the muscle must always be shorter than is apparent from a curve obtained
THE MECHANICAL CHANGES OF MUSCLE
199
bv the foregoing method. The elasticity and extensibility of the muscle must
prolong the apparent latent period, since the first effect of contraction of any
part of the muscle will be to stretch the adjacent part, and only later to
Fig. 57. Burdon Sanderson's method for photographic record of muscle-twitch.
The exciting shock is sent into the muscle by the wires d and d'.
move the tendon to which the lever is attached. Thus if we have a weight
supported by a rigid wire, and suddenly pull the upper end of the wire so as to
raise the weight, the latter will rise instantaneously. If however the
weight be suspended by a piece of elastic, it will not follow the pull exactly,
but will lag behind, the first part of the pull being occupied with stretching
the india-rubber, and only
when this is stretched to a
certain degree will the weight
begin to rise. The same re-
tardation of the pull would be
observed if, instead of india-
rubber, we used a piece of
living muscle.
It is possible to obviate
this instrumental inertia by
employing solely photographic
methods for the record and
magnification of the muscle-
twitch. In the experiments
of Sanderson and Burch
the thickening of the muscle
at the point stimulated was
recorded graphically by photo-
graphing the movement on a Fig. 58. Photographic record of muscle-twitch .
l-i. fi?- rt\ -U l:„j „l,;„i, (B. Sanderson.) The upper curve is the move-
slit (Fig. 57), behind which ^ ent of the J^ the ' middle curve the 9ignal
was a moving sensitive plate. showing the moment of excitation, and the lower
Thus avoiding all instrumental ™™J d that ° f a tuning - fork vibrating 50 ° time8
inertia, and diminishing the
inertia of the muscle to a minimum, the mechanical latent period was
found to be only(H>025 second (Fig. 58). This figure we can take as the
average latent period for the skeletal muscle of the frog at the ordinary
temperature of the laboratory (about 16°C.). We shall have occasion later
-I Ml
nnsioi,<>(;\
on to consider the changes which occur in the muscle between the application
of the stimulus and the moment at which the first mechanical change makes
its appearance.
The relaxation of muscle is helped by a moderate load, and in a normal
condition is complete. It is not active — that is to say, is not due to a con-
Fig. 50.
V. Krics' apparatus for taking 'after-loading' and 'arrested con-
traction curves.'
traction in the transverse direction — but is a passive effect of extension and
elastic rebound. This may be shown by allowing a muscle to contract while
floating on mercury. The subsequent lengthening on relaxation is very
incomplete.
Even with the most careful arrangements for securing isotonicity in the
record of the contraction there is probably a certain amount of over-shoot
of the lever whenever, as at high temperatures, the contraction is sufficiently
rapid. The effect of this is that one cannot assume the existence of an actual
pull on the lever during the
whole time of the ascent of the
latter. We can therefore speak
of a period during which there
is contractile stress — that is to
say, when the muscle is actu-
ally pulling on the lever, which
will occupy only a part of the
ascent of the curve. The dura-
tion of this period of contrac-
tile stress may be shown by
recording what is known as ' arrested ' contractions. One mechanism
for this purpose is shown in the figure (Fig. 59). The stop Su is
AAAAAAAAAAAAAAAAAAAAA
. 60. Curves of isotonic and arrested contractions
of an unloaded muscle, (Kaiser.)
THE MECHANICAL CHANGES OF MUSCLE 201
used simply for after- loading the muscle so that the weight shall not
act upon the muscle until it begins to contract. The stop So may be regu-
lated so that it suddenly checks the movement of the lever at any desired
height above the base line. We may thus get a series of contractions such
as those shown in Fig. 60. It will be seen that at the points x', x", and x"'
the muscle was still pulling on the lever, and therefore held it up against
the stop. At the point X the arrested twitch returns rapidly to the base
line, showing that the movement of the lever in the unarrested curve above
this point was due to the inertia of the moving parts and not to the actual pull
of the muscle. In this case the period of contractile stress was about 0'02
seconds.
THE ENERGY OF CONTRACTION. When a muscle contracts we may
conceive of it as converted into a body with elastic properties other than
those which it possesses during rest. Directly after it has been excited
it possesses potential energy which can be measured by the isometric method
as tension and which will degenerate in a few hundredths of a second into
heat, or can be turned into work by allowing the muscle to shorten and to
raise a weight, as in the isotonic method of recording muscular contractions.
Under the conditions of an ordinary physiological experiment, a contracted
muscle loaded only by a light lever is shorter than the non-contracted,
but can be stretched to the length of the latter by a certain weight, when
it will be in a condition of tension. In their natural position in the body
muscles may possess any length between extreme shortening and extreme
elongation whether they are in a resting or in an excited condition. Since
the relaxed muscle requires only a minimal force to extend it to the maximal
length possible in its natural relationships in the body, it is usual to speak
of the different lengths of an excited and unexcited muscle, the lengths being
in this case those which are impressed on the muscle by a minimal load.
When we measure by means of the isometric method the maximum energy
set free in a muscle as the result of excitation, we find, as Blix first pointed
out, that this energy depends on the length of the muscle fibres during
the period of contractile stress set up by the excitation. With increase
in the length of the muscle the tension developed on excitation increases
until the length of the muscle is somewhat greater than that which it possesses
in its normal relationships in the body. To lengthen the muscle beyond
this point a certain stretching force must be applied to it which rapidly
increases. The tension developed on excitation however soon begins to
diminish.
These relationships are shown by the diagram (Fig. 61), where the ordinates repre-
sent the length of the muscle and the abscissa the tension on the muscle. The left-
hand thick line represents the muscle in a state of rest, the right-hand curved line
the muscle in a state of excitation. The horizontal distance between the two lines
gives the increase of tension (as measured by the isometric method) produced when the
muscle passes from the resting into the excited state as the result of stimulation by a
single induction shock.
Since the tension set free on excitation depends on the length of the
202
PHYSIOLOGY
muscle fibres during the production of the condition of tension, the tension
developed will be diminished if the muscle be allowed to shorten before its
maximum tension has been reached. This is the case with all isotonic
records of muscular contraction, so that it becomes difficult to give any
exact expression for the total energy changes in a muscle which is allowed
to shorten. On the other hand, in the body the bony levers are so arranged
that the muscles at their greatest length work at a maximum mechanical
disadvantage which lessens continuously as the muscles shorten and approxi-
mate their points of attachment. The load on a muscle is thus lessened
-J
i
SB
r
Tension >
Fig. 61. Diagram to show the relation between the initial length of a
muscle and the tension developed in it during excitation (as measured
by the isometric method). The tension developed at each initial
length is measured by the horizontal distance between the two thick
lines, the left line representing the resting muscle, and the curved thick
line on the right the contracted muscle. (From Blix.)
continuously as the muscle contracts. A muscle is a machine primarily
for developing tension, and the potential energy thus set up may be used
for the production of work to any degree the conditions of loading allow.
The work done by a muscle when it contracts is measured by multiplying
the weight lifted by the height through which it is lifted, w X h. Since
however the result will vary according to the conditions of loading of the
muscle, a much more useful quantity is obtained by measuring the tension
produced in a muscle which is stimulated but not allowed to shorten. The
potential erjergy available due to the new elastic conditions of the fibres is
found to be approximately 1 IV, where T is the maximum tension developed
in the twitch and I is the length of the muscle (A. V. Hill).
THE MECHANICAL CHANGES OF MUSCLE
203
Living muscle
1
THE EXTENSIBILITY OF MUSCLE
a perfectly normal condition is distinguished by its slight but
perfect elasticity ; that is to say, it is con-
siderably stretched by a slight force (in the
longitudinal direction), but returns to its
original length when the extending weight
is removed. The length to which muscle is
stretched is not proportional to the weight
used, but any given increment of weight
" N gives rise to less elongation the more the
Fig. 62, Extensibility of india-rubber («) musc ] e is already stretched. The accom-
comparcd with that <>f a frogs gastroc- . ' ., ,
nemius muscle (6). panymg curves show ^grammatically the
elongation of muscle as compared with a
piece of india-rubber when the weight on it is uniformly increased.
Dead muscle is less extensible and its elasticity is less perfect. A given weight
applied to a dead muscle will not stretch it so much as when the muscle was alive, but
the de'ad muscle does not return to its original length when the weight is removed.
A contracted muscle, on the other hand, is more extensible than a muscle at rest.
A gramme applied to a contracted gastrocnemius will cause greater lengthening than
if it were applied to the ^ ^
same muscle at rest. The
relation between the exci-
tability of a muscle under
the two conditions of )
contraction and rest are
shown in the diagram in
Fig. 03.
At the point y the
muscle is unable to shor-
ten at all against a
weight. / It is evident
from this diagram that Fio. 63. Curve allowing the length of a muscle under various
the height of contraction loads in the contracted condition by, and uncontracted
of a muscle diminishes as c ° nditiot > C V- The double lines a, b, &c, represent the con-
tracted muscle, while the long single lines a c, Sec., show the
the load is increased, .very, length of the i nact ive muscle.
riipjrl1yjf__th p mp se,|e _js
after-loaded, less rapidly if the weight applied to the muscle be allowed to extend it
at rest. It is evident however that in either case the diminution in height is nut in
proportion to the load, and that the work done by the muscle, w X h, as the weight is
ineivasrd. rises at first quickly, then more slowly to a maximum to sink finally to
zero. \ By inspection of diagram (Fig. 63) it will be seen that
\_ O.h <10.h 1 <20.h 2 < 30.h 3 > 40.h 4 > 50.h 6 ,
so that in this case the maximal mechanical work is obtained when the muscle is loaded
with about 30 gms.
PROPAGATION OF CONTRACTION. THE CONTRACTION WAVE
The whole muscle does not as a rule contract simultaneously. When
excited from its nerve the contraction begins at the end-plates and spreads
in both directions through the muscle. The rate of propagation of the con-
traction wave ran only be measured by employing a curarised muscle, so as
to avoid the wide spreading of the excitatory change by means of the intra-
muscular nerve-endings. For this purpose a curarised saitorius muscle
204 PHYSIOLOGY
is taken, stimulated at one end, and the thickening of the muscle recorded by
means oftwo levers placed one near the exciting electrodes and the second
at the other end of the muscle, as shown in the diagram (Fig. 04). The
difference between the latent periods of the two curves represents the time
taken by the contraction wave in travelling from a to b. By measurements
carried out in this way it is found that the rate of propagation of the con-
traction in frog's muscle is :> to 4 metres per second ; in the muscle of
warm-blooded animals it may amount to 6 metres.
Fig. 04. Diagram of arrangement for recording the contraction wave in a
curariaed sartorius.
The actual duration of the shortening at any given point is necessarily
smaller than that of the whole muscle, and amounts in frog's muscle to only
005-009 sec, about half the duration of the contraction of a whole muscle
of moderate length. The length of the wave is obtained by multiplying the
rate of transmission by the duration of the wave at any one point. It varies
therefore in frog's muscle between 3CC0 x -05 ( = 150) and 4CC0 x -C9
(= 360) millimetres. Thus the muscle fibres in the frog are much too short
to accommodate the whole length of the wave, and the contraction of the
whole muscle must be made up of the summated effects of the contraction
wave as it passes from point to point. Hence the longer the muscle, the
more must the contraction be lengthened by the time taken up in propagation
from one end to another.
SECTION IV
THE CONDITIONS AFFECTING THE MECHANICAL
RESPONSE OF A MUSCLE
STRENGTH OF STIMULUS. If a series of single break-shocks be applied
to a muscle or nerve at intervals of not less than five seconds, it will be found
that beyond a certain distance of the secondary from the primary coil no
effect at all is produced. The shocks are said to be subminimal.
On pushing the secondary coil nearer the primary a point will
be reached at which a small contraction will be observed.
On then pushing in the coil a millimetre at a time the contrac-
tion will become greater for the next couple of centimetres
(e.g. as the coil is moved from 12 to 10 cm. distance). Further
increase of current by approximation of the coils is without
effect, although the current actually used may be increased
a hundred times in moving the coil from 10 to 0. It was
formerly thought that this limited gradation of the muscular
response according to strength of stimulus was due to a similar
gradation in the response of each individual muscle fibre of
which the muscle is composed. It seems more probable how-
ever that, when a minimal or subminimal response is obtained,
not all the fibres making up the muscle are contracting. A min-
imal contraction is in fact a contraction in which some fibres
of the whole muscle are stimulated. A maximal contraction
is one in which all the fibres are stimulated. So far as concerns
each individual muscle fibre every contraction is a maximal
contraction. The fibre either contracts to its utmost or it does
not contract at all. The rule of all or none ' which was first ^ o
enunciated for heart-muscle is probably true for every con-
tractile element. The difference between skeletal and heart
muscle lies in the fact that in the former the excitatorv process does not
spread from one fibre to its neighbours. If for instance we take a curarised
sartorius and split its lower end, as in Fig. 65, the stimulus applied to a
causes a contraction only of the left side of the muscle, while a stimu-
lus applied to b is in the same way limited to the right side. If a piece
of ventricular or auricular muscle of the frog or tortoise were treated in the
same way, a stimulus applied at a would cause a contraction which would
travel across the bridge at the upper end and extend to b. «
205
206
I'HYKIOI-Om
It was shown by Gotch that, if eaofa <>f the three roots which make up thr sciatic
nerve and send fibres to the gastrocnemius be stimulated in turn, it is often impossible
in evoke a maximal contraction of I he gastrocnemius, however strongly each root
be stimulated. Keith Lucas has shown that if stimuli in gradually increasing strength
lie applied to the motor nerve (containing only seven to nine fibres), which supplies
the dorso-cutaneous muscle of tin- frog, the contraction of the, muscle increases, not
gradually, but by a series of sic ps. This can be explained only by assuming that the
smallest effective stimulus excites perhaps four out of the seven nerve fibres, those
immediately in contact with the electrodes. With increasing strength of current
the stimulus becomes effective for the three lilacs lying next to these, and finally still
further increase of current may excite all the fibres making up the nerve (Fig. 66).
' '1 T
.
r
Fig. 66. Curve showing relation of height of contraction of dorso-cutaneous muscle
to strength of stimulus. Ordinates = height of contraction ; abscissa =
strength of stimulus. (K. Lucas.)
THE REPETITION OF STIMULUS
SUMMATION. The response of a muscle fibre to a single shock, whether
measured by the isotonic or the isometric method, i.e. as shortening or as
tension, is independent of the strength of stimulus and varies only with the
length of the fibre during the rise of the excitatory condition. If however
a second shock is sent in during this period a further evolution of energy is
possible, and the effect is still further increased by putting a series of stimuli
into the muscle or its attached nerve before the development of the contractile
stress due to the first stimulus has reached its maximum. If two shocks at
intervals of one hundredth of a second be sent into a muscle, the response,
whether shortening or rise of tension, will be greater than that produced by
one shock. If a series of shocks be sent in, the excitatory condition is main-
tained, so that instead of a simple muscle twitch rising to a maximum and
then falling, the muscle lever rises to a given point, which in the muscle con-
tracting isometrically may be double that due to a single stimulus, and then
remains at this height during the continuation of the repeated excitations.
If the muscle be allowed to contract isotonically, the continued contraction
produced by a series of stimuli may with a heavy load be three or four times
as considerable as that produced by a single stimulus. This condition of
apparently continued stimulation brought about by continued application of
stimuli is said to be summated.
REFRACTORY PERIOD. If the interval between two stimuli sent into
a muscle be successively shortened in a series of observations, we finally
yrrive at a point at which summation is no longer apparent, i.e. the effect of
THE MECHANICAL RESPONSE OF MUSCLE
207
r it
Fig. 67. Muscle curves showing summation of
stimuli, r and r'. the points at which the
stimuli were sent into the nerve. From the
first stimulus alone the curve abc would be
obtained. From r' the curve def is obtained.
These two curves are stimulated to form the
curve aejhik when both stimuli are sent in at
the interval r r'.
the two .stimuli is no greater than the effect of a single .stimulus. This
means that the second stimulus has become ineffective, and this ineffective-
ness we must ascribe to the condition set up in the muscle as the result
of the first stimulus. For a very short period of time after stimulation a
muscle is inexcitable to a second stimulus. The period during which it is
inexcitable is known as the refractory period and amounts in skeletal muscle
to about -0015 second. The same phenomenon is better marked in certain
other excitable tissues, such as the heart muscle, but it seems to be a common
property of excitable tissues generally.
When a loaded muscle is made to record its contractions isotonically we may get
summation of effects, though the interval between the stimuli is greater than that
which corresponds to the duration of
the rise of contractile stress. Thus if
the interval is just so long that the
second becomes effective just as the
contraction due to the first has com-
menced to die away, the second con-
traction seems to start from the point
to which the muscle has been raised
by the first (Fig. 67). By repeating
these stimuli in a heavily loaded
muscle, the contraction may be made
three or four times as extensive as a
single twitch. With slow stimuli the
summation is however rather mechan-
ical than physiological. The period of contractile stress, which lasts only about
03 second, is so short that it has no time to raise the weight to the maximum height
before it has passed away. This is shown by the fact that if the muscle be after-
loaded, so that the lever is raised to the top of the curve of a single twitch, application
of the stimulus will make it shorten still more, and by repeated after-loading in this
fashion, it is possible to make the muscle raise a weight in response to a single stimulus
to the same height that
it would if excited by a
series of stimuli. This
mechanical factor in sum-
mation is shown in Fig.
68. It will be noted
however that the tetanus
is not a steady one and
is probably due to stimuli
Fig. 68. Contractions of a frog's muscle. Two single (witches repeated at intervals of
are followed by a tetanus, which is almost twice as high as a about * of a second If
single contraction. After two more single twitches, the drum ,, '"
was made to rotate more slowly, and single shocks employed, tbe r . of stimulation
at the same time as the ' after-loading ' was continually were increased to 50 or
increased. It can be seen that the curve obtained in this way 100 per second, a tetanus
is as high as the original tetanus. (V. Frey.) wouM bo produoed and
the curve would be prob-
ably twice as high as that represented in the figure. We thus see that for the over-
coming of a resistance a single twitch is not economical. It is doubtful whether any
contractions of muscles which occur in the body are other than tetani of varying
duration.
TEMPERATURE. Speaking generally, the effect of warming a muscle
208
PHYSIOLOGY
is to quicken all its processes. The latenl period becomes shorter and the
muscle curve steeper and shorter.
It is very often observed that the height of contraction of the warmed muscle is
greater than that obtained at ordinary temperatures. It seems that this apparent
increase in height is really instrumental in origin, the quicker-moving muscle jerking
the lever beyond the real extent of the contraction. If proper means are taken to
eliminate this overshooting of the lever, it is found that the height of contraction is
unaltered between 5° and 20°C, the only change being in the time-relations of the
curves. This is especially well shown in the so-called ' arrest ' curves (Fig. 69).
Fig. 69. Isotonic and 'arrest ' curves of muscle-twitch : (1) unloaded at 14 ('. .
(2) at 25°C. ; (3) at 0°C. ; (4) loaded at 14°C. Note that the arrest curves
attain the same height throughout. (Kaiser.)
If a muscle be heated gradually (without stimulation) up to about 45°C.,
it begins to contract slowly at about 34°0, and this contraction reaches its
maximum at 45°C, at which point the muscle has entered into pronounced
rigor mortis.
Cold has the reverse effect. The intra-molecular processes which lie at
the root of the muscular activity are slowed, so that the latent period and the
contraction period are prolonged. The action of cold on the excitability <>l
muscle is to increase it, so that any form of stimulus is more effective at 5°C.
than at 25°C. Moreover, when maximal stimuli are being used,_and the
muscle is heavily loaded, the first effect of the application of cold may be to
increase the height as well as the duration of contraction, for the same
reason that a gentle push is more efficacious in closing a door than would be
a heavy blow with a hammer. If however a muscle be cooled for a short
time to zero or a little below, it loses its irritability, which returns if the
muscle be gradually warmed again. Prolonged exposure to severe cold
irrevocably destroys its irritability. Warming the muscle will now simply
bring about rigor mortis.
FATIGUE. A muscle will not go on contracting indefinitely. If it
be repeatedly stimulated, changes soon become apparent in the curve of
contraction. The latent period is prolonged, as well as the length of the
contractions ; the absolute height and work done are diminished. At
the same time the muscle does not return to its original length ; the shorten-
THE MECHANICAL RESPONSE OF MUSCLE
209
ing which remains is spoken of as ' contraction remainder.'' After an initial
rise during the first few contractions, these diminish uniformly in height
till they are no longer apparent, so that the muscle is now said to have lost
its irritability. At the same time there is a great prolongation of the curve,
occasioned almost entirely by a retardation -of the relaxation, so that after
forty or fifty contractions several seconds may elapse before the lever returns
to the base line (Fig. 70).
fro. 70. Muscle curves showing fatigue in consequence "!' repealed stimulation.
The first six contractions are numbered, and show the initial increase of the
first three contractions. (Brodik.)
The fact that I he relaxation part of the muscle curve is affected by various conditions,
especially fatigue, apparently independently of the contraction part, led Fick to put
forward a theory that two distinct processes were concerned in the response of a muscle
to excitation, one process causing the active shortening and the other the relaxa-
tion. (It must be noted that this is not the same as saying that the lengthening is
an active process, a statement negatived by the behaviour of a muscle when caused
to contract on mercury.) He suggested that the disintegration associated with activity
might be conceived as occurring in two stages : the first resulting in the production
of sarcolactic acid and the active shortening of the muscle ; the second in the further
conversion of the acid into C0 2 , with a consequent relaxation. A retardation of this
second phase would cause the prolonged curve with ' contraction remainder ' observed
in a fatigued muscle. We shall return to this point when discussing the chemical
and heat changes which accompany contraction.
If left to itself, the muscle which has been exhausted by repeated stimula-
tion will recover. The recovery is hastened by passing a stream of blood,
or even of salt solution, through the blood-vessels of the muscle. Recovery
in a muscle outside the body is never complete.
The phenomena of fatigue probably depend on two factors :
(1) The consumption of the contractile material or the substances avail-
able for the supply of potential energy to this material.
(2) A more important factor is the accumulation of waste products of
contraction. Among these waste products the lactic acid is probably of great
importance. Fatigue may be artificially induced in a muscle by ' feeding '
it with a dilute solution of lactic acid, and again removed by washing out
the muscle with normal saline solution containing a small percentage of alkali.
14
210
PHYSIOLOGY
THE ACTION OF SALTS
The action of sodium salts on muscle is of considerable interest. We
are accustomed to use a 0-6 per cent, solution of Nat 'I as a ' normal fluid '
to keep muscle preparations moist. If however the solution be made
with distilled water, it has a distinctly excitatory effect upon the muscle.
Fio. 71. A. Tracing of the contraction of a frog's sartorius, poisoned with veratrin,
in response to a momentary stimulus. The time-marking indicates seconds.
B. Tetanic contraction of normal sartorius in response to rapidly interrupted
stimuli. (The duration of the stimulus is indicated by the words ' on ' and
'off.') It will bo noticed that the two curves are practically identical. (Miss
Buchanan.)
so that single induction shocks may cause tetaniform contractions. The
same excitatory effect is still better marked with solutions of Na 2 C0 8 '. If
a thin muscle, such as a frog's sartorius, be immersed in a solution con-
taining 0-5 per cent. NaCl, 0-2 per cent. Na 2 HP0 4 , and 0-04 per cent. Na 2 C0 3
(Biedermann's fluid), the muscle enters into a series of frequent contractions,
so that it may wriggle from side to side, or
may even ' beat ' for a time with the regularity
of heart-muscle, though at a much greater
rate.
This excitatory action of sodium salts
is neutralised by the addition of traces of
calcium salts. Hence the normal saline used
in the laboratory should always be
made with tap water, containing
'Excitation. ca l c j um salts.
* jjuULaAj»j\ j Aj_louLaj_jlaAjljljlji Seconds.
Fig. 72. Tracing of the contraction of a Potassium salts, although form-
muscle poisoned by the injection of a strong ing SO important a constituent of
solution of veratrin. showing the double ,-, ■, r , , ,
contraction due to unequal poisoning of the ash of muscle, act as muscle
different fibres. (Biedermann.) poisons, quickly and permanently
destroying its irritability. If a
muscle be transfused with normal fluids containing minute traces of potas-
sium salts, it at once shows all the signs of fatigue, signs which may be
removed by washing out the potassium salts by means of 0-6 per cent. NaCl
solution. It is possible that the setting free of potassium salts may be one of
the factors involved in the development of the normal fatigue of muscle.
THE MECHANICAL RESPONSE OF MUSCLE 211
THE ACTION OF DRUGS
Of the drugs that have a direct action on muscle, the most remarkable is veratrin.
which causes an excessive prolongation of a muscular contraction (produced by a
single stimulus). Thus the 'twitch' of a muscle poisoned with veratrin may last
fifty or sixty seconds, instead of the normal one-tenth of a second (Fig. 71).
Barium salts have a similar, though less marked effect.
Tn order to carry out the poisoning with veratrin, very weak solutions (1 in 100,000
or 1 in 1,000,000 of normal saline) should be used and the muscle exposed to its action
for some time. We get then on a single stimulus a response lasting many seconds
and exactly similar in height and form to a tetanus obtained by discontinuous stimu-
lation. If stronger solutions be used, the action of the drug is apt to affect the fibres
unequally, so that we may have a sharp normal twitch preceding the prolonged con-
traction (Fig. 72). If the muscle be excited several times immediately after the pro
longed contraction has passed away, it responds with twitches like those of a normal
muscle, but if allowed to rest a few minutes, stimulation is again followed by the peculiar
long-drawn-out contraction.
SECTION V
CHEMICAL CHANGES IN MUSCLE
CHEMICAL COMPOSITION OF VOLUNTARY MUSCLE
Voluntary muscle consists of elongated cells, the muscle fibres being
embedded in a connective tissue framework; and. as in all cellular tissues,
proteins form its chief chemical constituents. The contents of the fibres
are semi-fluid and can be expressed from the finely divided muscle as a
viscous fluid known as muscle-plasma.
Muscle- plasma is obtained in the following way. The living muscle of frogs is
frozen, minced with ice-cold knives and pounded in a mortar with four times its weight
of sand containing •(> of common salt. The mixture is then thrown on to a filter kept
at. (V ('. when an opalescent fluid filters through. The filters soon become clogged
and therefore must be freipifiil l\ changed, and their temperature must not be allowed
to rise above 2° to 3°C.
If the temperature of the muscle-plasma be allowed to rise, clotting
takes place, the clot later on contracting and squeezing out a serum, as is
the case with blood-plasma.
The muscle-plasma is neutral or slightly alkaline. When coagulation
takes place however, it becomes distinctly acid, and this acidity is due to
the formation of sarcolactic acid in the process. Arguing chiefly from
analogy with the blood-plasma, the muscle-plasma has been said to contain
a body, myosinogen, which is converted when clotting takes place into
myosin.
The exact nature of the proteins in muscle-plasma, as well as of the protein con-
stituent of the clot, which we have called myosin, is still a subject of debate. Kiihne.
to whom we owe our first acquaintance with muscle-plasma, described the clot as
consisting of myosin, a globulin, soluble in 5 per cent, solutions of neutral salts, such
as NaCl or MgS0 4 . precipitated by complete saturation with MgS0 4 , and coagulated
on heating to 56° C. In the muscle-serum, obtained after separation of the clot, he
found three proteins, one coagulating at 45 ( '., one he called an albumate (i.e. a derived
albumen or metaprotein), and the third coagulating about 75°C. and apparently
identical with serum albumen. Halliburton extended these researches to the muscles
of warm-blooded animals. He described four proteins as existing in muscle-plasma,
of which two, paramyosinogen and myosinogen, gave rise to the clot of myosin.
In no case however is it possible entirely to dissolve up the clot when once formed,
and it seems that the so-called solution in dilute salt solutions was merely an extraction
of still soluble protein in the meshes of the clot. Von Fiirth has shown that if the
muscles of a mammal are washed free of adherent lymph and blood, the plasma obtained
by extraction with normal salt solution contains only two proteins. These proteins
are extremely unstable, and are gradually transformed on standing into insoluble
212
CHEMICAL CHANGES IN MUSCLE 213
protein, giving rise to a precipitate in dilute solutions, or forming a jelly-like clot in
strong solutions. The properties of these proteins may be summarised as follows :
(1) Myosin (paramyosinogen of Halliburton). A globulin, coagulating at about 47°-
50°C, precipitated by half saturation with ammonium sulphate or on dialysis. Trans-
formed slowly in solution, rapidly on precipitation, into an insoluble protein, myosin
fibrin.
(2) Myogen (myosinogen of Halliburton). A protein allied to the albumens in
that it is not precipitated by dialysis. Coagulates on heating at 55°-60°C. It changes
slowly into an insoluble protein, myogen fibrin, but passes through an intermediate
soluble stage called soluble myogen fibrin. This latter body coagulates on heating to
40°C, being instantly converted at this temperature into insoluble myogen fibrin.
It 'Iocs not seem that any ferment action is associated with these changes, which we
may represent by the following schema :
Muscle-plasma.
\ myosin or paramyosinogen. 1 myogen (myosinogen of Halliburton,
albumate of Kiihne).
I
Soluble myogen fibrin.
I '
Myosin fibrin. Insoluble myogen fibrin.
Muscle clot.
Soluble myogen fibrin, which in mammalian muscle-plasma forms only on standing,
exists apparently preformed in frog's muscle. Hence the instantaneous clotting of
frog's muscle-plasma on warming to 40°C.
The residue left after the expression of the muscle-plasma consists
chiefly of connective tissue, sarcolemma, and nuclei, and as such contains
gelatin (or rather collagen), mucin, nuclein, and adherent traces of the
proteins of the muscle-plasma itself.
The muscle-serum contains the greater part of the soluble constituents
of muscle.
OTHER CONSTITUENTS OF MUSCLE. A number of other sub-
stances are found in muscle in small quantities, those which are soluble
being contained to a great part in the muscle-serum. It will suffice here
to enumerate the chief of these.
(a) Colouring- matter. All red muscles contain a considerable amount of heemo-
globin. A special muscle pigment allied to haemoglobin has been described by MacMunn
as myohaematin. The only evidence for its existence is spectroscopic.
(b) Nitrogenous extractives. Of these, the most important is creatine (CH 9 N 3 0. 2 )
of which 0-2 to 03 per cent, may be found in muscle. Its significance will be the subject
of consideration later. Other nitrogenous bodies occurring in smaller quantities are
hypoxanthine, xanthine, and traces of urea and amino-acids.
(c) Non-nitrogenous constituents.
Fats, in variable amount.
Glycogen. This substance is invariably found in healthy muscle. Fresh skeletal
muscle contains about 1 per cent. In the embryo the muscles may contain many
times this quantity of glycogen.
Glucose is present in fresh muscle in minimal quantities, about -01 per cent.
When muscle is allowed to stand, especially in a warm place, the glycogen under-
goes partial conversion into glucose, so that the latter increases at the expense of the
former.
214 PHYSIOLOGY
Inosit (C 6 H 12 O 2H,0) or ' muscle sugar ' occurs in minute traces in muscle.
It does not belong to the group of carbohydrates at all, being a hexahydrobenzene.
It is nonfermentable and does not rotate polarised light nor does it reduce Fehling's
solution. Its significance is quite unknown.
(d) Inorganic constituents. Muscle contains about 75 per cent, of water. Ash
forms 1 to 1-5 per cent, and consists chiefly of potassium and phosphoric acid, with
traces of calcium, magnesium, chlorine and iron.
RIGOR MORTIS
All muscles after removal from the body, or if left in the body after
general death, lose after a time their irritability, and this loss is succeeded
by the phenomenon known as rigor mortis. The muscle, which was pre-
viously flaccid, contracts, though the shortening is not very powerful and
can be prevented by a moderate load on the muscle. Whereas the living
muscle is translucent, supple, and extensible, it becomes in the process of
rigor opaque, rigid and inextensible. When rigor has been established,
the reaction of the muscle is also found to have changed from a slightly
alkaline to a distinctly acid one, the acid being due to the presence of sarco-
lactic acid. From this condition of rigor there is no recovery. There can
be no doubt that the change in consistence of the muscle and probably also
its shortening in rigor are due to the coagulation of the muscle proteins. Both
changes can be imitated by heating the muscle, as is indicated by Brodie's
experiments. This observer found that, if a living muscle be lightly loaded
and then warmed very gradually, a series of stages in the heat contraction
could be distinguished corresponding to the coagulation temperatures of
the different proteins described by von Fiirth in muscle plasma. It seems
likely however that the main contraction at all events, that which comes
on spontaneously after death or immediately on warming the muscle to
45°C., has another component. In the coagulation of the separated muscle
proteins there is no evidence of any appreciable formation of sarcolactic acid,
whereas the formation of this substance seems to bear an important relation
to the occurrence of rigor. Thus after severe muscular fatigue, as in hunted
animals, where there has already been a considerable formation of the waste
products of muscular contraction, rigidity may come on almost imme-
diately after death. If a thin living muscle be plunged into boiling water,
it undergoes instant coagulation, but no chemical change. The reaction
of the scalded muscle, like that of fresh muscle, is slightly alkaline to
litmus. No sarcolactic acid or carbonic acid is produced. On the other
hand, in surviving muscle, after the cessation of the circulation, there is a
steady formation of lactic acid which accumulates in the muscle. The
actual coagulation of the muscle proteins occurring in rigor is largely, if not
entirely, determined by the increasing acidity of the muscle thereby pro-
duced. In fact, it is the production of the acid which causes the onset
of rigor, and not the rigor which causes a sudden formation of acid. Hence
if the accumulation of lactic acid be prevented by perfusing the muscle
with salt solutions, the onset of rigor may be postponed indefinitely, and
the muscle may begin to putrefy without having undergone rigor.
CHEMICAL CHANGES IN MUSCLE 215
THE PRODUCTION OF LACTIC ACID IN SURVIVING MUSCLE
The lactic acid formed in muscle (sarcolactic acid) is a physical isomer of the lactic
acid formed in the fermentation or souring of milk. They both have the formula
CH 3 .CH(OH).COOH, i.e. they are ethylidene lactic acids. The lactic acid of fermenta-
tion is optically inactive ; sarcolactic acid rotates polarised light to the right ; while
a third isomer which is laevo-rotatory is produced by the action of various bacilli and
vibriones on cane sugar. The sarcolactic acid can be extracted from the muscle by
means of alcohol.
It was pointed out by Hopkins and Fletcher that most of the methods previously
used for the extraction of lactic acid from muscle caused the formation of lactic acid
in this tissue. To obviate this difficulty, they adopted the precaution of cooling
the muscles before cutting them out of the body and then dropping them into alcohol
cooled to 0°C. While in this ice-cold alcohol they were finely divided with scissors
and then pounded up in a cooled mortar. In this way the tissue was destroyed at
a temperature which did not allow of the changes responsible in surviving muscle
for the production of lactic acid. It is generally separated in the form of the zinc
sarcolactate, by boiling its partially purified solution with zinc carbonate. Its presence
may be tested for by means of Uffelmann's reagent, which is made by the addition of
ferric chloride to dilute carbolic acid. The purple solution thus produced is at once
changed to yellow by the addition of even traces of lactic acid.
A much more definite colour reaction for lactic acid has been introduced by Hopkins.
The test is carried out in the following way. About 5 c.c. of strong sulphuric acid
are placed in a test-tube together with one drop of saturated solution of copper sulphate,
which serves to catalyse the oxidation that follows. To this mixture a few drops of
the solution to be tested are added, and the whole, well shaken. The test-tube is now
placed in a beaker of boiling water for one or two minutes. The tube is then cooled
under a water-tap, and two or three drops of a very dilute alcoholic solution of thiophene
(ten to twenty drops in 100 c.c.) are added from a pipette. The tube is replaced in
the boiling water and the contents immediately observed. If lactic acid is present the
fluid rapidly assumes a bright cherry red colour, which is only permanent if the tube be
cooled the moment after its appearance.
A study of the lactic acid content of muscle by Fletcher and Hopkins,
using the precautions described above, has shown that fresh muscle contains
only minimal amounts of lactic acid, the quantity being smaller, the greater
the care that is taken to avoid injury to the muscle and to keep its tempera-
ture low until sufficient time has elapsed for its vital chemical processes to be
destroyed by the action of the cold alcohol. If the muscle be left in the
body after the death of the animal or be excised, a steady formation of
lactic acid takes place, which is more rapid in the first few hours after
death, but continues until the muscle passes into rigor. With the complete
onset of rigor, frog's muscles are found to contain about 4 per cent, lactic
acid. After this time the amount does not increase. The onset of rigor
and the rate of production of lactic acid are quickened if the muscle be
kept warm. It is interesting to note that the amount of lactic acid found
in rigid muscle is almost invariable whatever the j^revious history of the
muscle. Thus, if the muscle be finely minced and then extracted with
cold alcohol, it is found to contain about -2 per cent, lactic acid. If how-
ever it be allowed to stand after mincing, there is a slow production of
lactic acid up to the maximum 4 per cent. Again, a muscle which has been
tetanised to exhaustion contains about -2 per cent, lactic acid. When
allowed to undergo rigor, the amount rises to about 4 per cent.
216 PHYSIOLOGY
It has long been known that the onset of rigor is associated with an evolu-
tion of carbonic acid by the muscle. Fletcher has shown that this increased
output of carbonic acid by a surviving muscle is due simply to the driving
off of carbonic acid from the carbonates in the muscle as a result of the
production of lactic acid. There is no evidence of a new formation of carbonic
acid in the dying muscle as a result, for instance, of oxidative changes.
THE CHEMICAL CHANGES WHICH ACCOMPANY ACTIVITY
The principle of the conservation of energy teaches us that the energy
of the contraction of muscle must be derived from chemical changes, probably
processes of decomposition and oxidation, occurring in the muscle itself.
In seeking out the nature of these changes three methods are open to us :
(1) We can examine the changes in the muscle itself, avoiding so far
as possible reintegrative changes by working on excised muscles.
(2) We can investigate the changes in the medium surrounding the
muscle. Muscle may be exposed in a vacuum or in a confined space of
air, and its gaseous interchanges during rest and activity compared. Or
we may lead a current of defibrinated blood through excised muscles, and
determine the change in the composition of the blood in passing through the
muscle under various conditions.
(3) A method, which although apparently complex has rendered the
utmost service to the physiology of muscle, is to use the changes in the total
metabolism of the animal during rest and muscular work as a clue to the
muscular metabolism itself. In such a case the respiratory exchanges of
the animal are determined (viz. its oxygen intake and its C0 2 output),
and the urine and faeces are carefully analysed, in order to judge of the
action of muscular work on the carbon and nitrogen metabolism of the body.
By the third of these methods we may show that muscular exercise
increases largely the intake of oxygen and the output of carbon dioxide
by the body. No corresponding changes are found in the nitrogenous
metabolism, so that ultimately we may regard the energy of the muscular
contraction as derived from the oxidation of the food-stuffs and especially
the carbohydrates. That it is this class of bodies which is the immediate,
or at any rate the most accessible, source of muscular energy, is shown by
the rise in the respiratory quotient which occurs during muscular exercise,
When the exercise is moderate there is no evidence of the production of any
other substance than carbon dioxide as a result of the muscular metabolism,
but with violent exercise it can be shown that lactic acid is not only pro-
duced in the muscle, but appears in the blood and is excreted in the urine.
It has been shown by Ryffel that normal urine contains 3 — 4 mg. of lactic acid
per hour. In one experiment the urine passed after the observer had run one third
of a mile with the production of severe breathlessness contained 454 mg. of lactic acid.
In another experiment blood obtained before running contained 12-5 mg. per 100 c.c,
and that obtained immediately after running one third of a mile contained 70 mg.
lactic acid per 100 c.c. On the other hand, the examination of the urines of com-
petitors in a twenty-four hours track walking race showed no increase in the output
of lactic acid above the normal 4 mg. per hour.
CHEMICAL CHANGES IN MUSCLE 217
The appearance of lactic acid thus seems to be attendant on a relative
deficiency in the oxygen supply to the contracting muscle. The same
conclusion may be drawn from experiments made many years ago by Araki,
in which lactic acid was observed in quantities in the urine in cases where
the oxidative processes of the body were interfered with by CO poisoning.
Similar results are obtained when we investigate the chemical changes
accompanying the contraction of excised muscles of the frog. If frogs'
muscle be hung up in an atmosphere of nitrogen and stimulated repeatedly
with single shocks, it will give a series of contractions gradually diminishing
in size (v. p. 209). After a time the muscle is completely fatigued, and
no further response can be elicited on stimulation. On now examining it,
it is found to be acid in reaction and to contain about 2 per cent, lactic
acid. There is no evidence that under these conditions any carbonic acid
is produced, though a certain amount may be liberated in consequence of the
acidification of the muscle. Almost the -same results are obtained when
the muscle is stimulated in ordinary atmospheric air. The penetration
of oxygen from the air through the body of the muscle is so slow that all
the muscle except the thin layer on the surface may be regarded as cut off
from the action of oxygen. By hanging the muscle, especially a thin muscle
such as the sartorius, in an atmosphere of pure oxygen, the results are quite
different. In the first place the muscle does not fatigue so soon. More-
over, a muscle which has been stimulated to exhaustion in an atmosphere of
nitrogen, if restored to one of pure oxygen, will rapidly recover its power
of contraction. In pure oxygen no lactic acid is produced, and a muscle
stimulated to exhaustion contains very little more lactic acid than does
resting muscle. On the other hand, the intake of oxygen and the output
of carbonic acid by the muscle is increased at each contraction. We thus
find that a muscle during contraction may produce lactic acid or carbonic
acid according as oxygen is absent or present. In both cases contraction
takes place apparently normally, but fatigue supervenes much more rapidly
in the absence of oxygen. The question arises whether we should regard
the formation of lactic acid and carbonic acid as alternative processes, or
whether lactic acid is first formed and is then removed under the action of
oxygen, undergoing partial or complete oxidation to carbonic acid in the
process. The evidence is distinctly in favour of the second hypothesis.
Thus Hopkins and Fletcher have found that muscle possesses in itself a
chemical mechanism for the removal of lactic acid. If a fatigued muscle
be exposed to pure oxygen, 30 per cent, of the lactic acid present in the
muscle may disappear within two hours and 50 per cent, within six to
ten hours. Thus, even apart from the circulation which of course would
remove large quantities of any lactic acid which might be produced in
the muscles, these can deal with this metabolite locally. It has been found
that a muscle may be fatigued several times and then placed in oxygen
to recover, so that lactic acid is produced and removed also several times.
If at the end the muscle be allowed to undergo rigor, it is found to contain
•4 per cent, lactic acid, i.e. exactly the same amount as if it had given
218 PHYSIOLOGY
110 contractions at all. Fletcher and Hopkins interpreted this result as
showing that under the influence of oxygen, lactic acid is put back into
the precursor from which it arose, anil would assume that part of the lactic
acid is completely oxidised to carbonic acid and water, the energy so evoh ed
being employed in the building up of the precursor from the rest of the lactic
acid. On the other hand it is possible that the lactic acid produced in the
initial stage of contraction may be ui.der normal circumstances completely
removed by oxidation, and that the energy or part of the energy so made
available is used to build up some precursor substance, not out of the lactic
acid, but out of the glycogen already present in the muscle (Parnas). It
is certain that prolonged activity of muscle, especially in the presence of
oxygen, may be associated with a diminution in the glycogen store of the
muscle. We cannot however discuss this question further without refer-
ence to the total energy changes in muscle contracting with or without
oxygen, and the clue to these changes is given by a study of the heat
production in muscle.
SECTION VI
THE PRODUCTION OF HEAT IN MUSCLE
The experience of everyday life teaches us that muscular exercise is
associated with increased production of heat. Thus a man walks fast on a
frosty day to keep himself warm. In large animals the production of heat
in muscular contraction can be easily shown by inserting the bulb of a
thermometer between the thigh muscles, and stimulating the spinal cord.
The rise of temperature produced in this way may amount to several degrees.
This observation is confirmed when we investigate the contraction of an
isolated muscle outside the body. If a frog's muscle is tetanised, its tem-
perature rises from 0-14"' to 0-18°C, and for each single twitch from 0-001°
to 0'C05°C.
It is evident that such small changes in temperature as 0001° cannot be estimated
by ordinary thermometric methods. By converting a heat change into an electrical
change however, we can estimate differences of temperature with much greater accuracy
and fineness than by the use of a thermometer.
Two main principles are employed in measuring
temperature by electrical methods. The thermo-
electrical method depends on the fact that, when
the junctions of a circuit made of two metals are Antimony
at different temperatures, a current of electricity "^^-n each ,,,..,., , „ ^, ,
side of the anode, so that on rough observation the longitudinal coat at the cathode,
it would be thought that contraction occurred The same result is observed in the
at the anode itself. earthworm and leech. But careful
observation shows in each case that the
irregularity is really only apparent, and that in the immediate neighbourhood of the
anode there is relaxation of both coats, with a contraction of the circular coat on each
side, and that at the cathode there is a contraction of both coats. The accompanying
diagram (Fig. 94) will serve to show the condition of the circular coat at each electrode.
As a matter of fact, in con-
sequence of the arrangement of
the fibres, we have in the neigh-
bourhood of the anode a num-
ber of places (virtual cathodes)
where the current is leaving the
muscle-cells to enter inert con-
ducting tissues, and in the same
way there will be in the neigh-
bourhood of the cathode a num-
ber of virtual anodes (Fig. 95).
Thus if we take the ureter and
lead a current through it while
it is slung up in thread loops
serving as electrodes, there is contraction of both coats at the cathode and relaxation
of both at the anode. If however the ureter be packed in a pulp of blotting-paper
Fia. 95. Diagram to show the spread of current which
occurs when a current is led tlirough a tube such as the
ureter by means of two electrodes applied to its surface.
It will be noticed that while + E is the anode, there are
immediately below and around it a number of cathodes,
E,, E„, E,„, E„„ due to the current leaving the muscle to
flow through indifferent tissues. (BiEDERMAira.)
OTHER FORMS OF CONTRACTILE TISSUE 245
moistened willi normal saline, thus allowing the current to leave the contractile tissues
anywhere along the ureter, we get the same aberrant results of stimulation as are
obtained with the intestine.
In voluntary muscle, if one stimulus follows another at an interval
which is not too large, a summated contraction is produced which is greater
in amplitude than that due to a single stimulus. This summation may
be mechanical or physiological, the former being observed when the stimulus
is repeated during the decline of the excitatory process and being due
simply to the after-loading of a muscle by the first contraction. It is
best marked when the muscle is heavily loaded. If however the stimuli
be sent in at sufficiently short intervals so that two stimuli fall within
the period of rise of contractile stress, an increased height of contraction
is obtained under all conditions, and under isometric conditions the tension
developed is greater than that with a single stimulus. If the interval between
two stimuli be so short that the second falls within what we have called
the refractory period due to the first stimulus, no summation is obtained,
the second stimulus being ineffective.
In the slow contraction of involuntary muscle we could hardly expect
mechanical summation to come into play. Most types of this tissue show
however the true summation, i.e. the increased liberation of energy due
to repetition of the stimulus during the rise of the excitatory condition.
As might be expected the refractory period is also longer in involuntary
muscle, since all the processes of this muscle are slowed in comparison with
those of voluntary muscle. In certain types of tissue, and especially in
heart muscle, the refractory period lasts during the whole of the period
of contraction. During this time therefore a second shock will be ineffective.
As the contraction dies away the muscle fibre gradually recovers its sus-
ceptibility to stimulation, but it does not recover its full irritability until
it has entirely relaxed. On this account it is impossible to obtain summa-
tion in or to tetanise heart muscle, the application of interrupted currents
to this tissue producing only a series of rhythmic contractions.
In all involuntary muscle we may observe summation of the effects of
stimuli even when the individual stimuli are insufficient to produce any
excitation. Thus in a muscle such as the retractor penis, we may find a
strength of induction shock which, applied singly, is just insufficient to evoke
any response. If however the shocks are repeated at intervals of a second,
it will be found that the first three or four stimuli are ineffective and then
the muscle enters into a contraction which increases with each succeeding
stimulus until it has attained its maximum. There is thus summation
before any contraction has occurred, a summation of stimuli. Each stimulus,
in fact, alters the state of the contractile tissue and makes it more ready
to respond to the next stimulus, so that the stimuli become more and more
effective. If time is allowed for the muscle to relax between successive
stimuli, this summation is evidenced by a continually increasing height
of contraction, the so-called ' staircase.' The same initial increase of
246 PHYSIOLOGY
effect is observed when voluntary muscle is excited by continually recurring
stimuli {v. Fig. 70, p. 209).
We shall meet with other examples of this summation of stimuli when
dealing with the physiology of the central nervous system. It is indeed a
fundamental phenomenon in the physiology of excitation.
CHEMICAL STIMULATION. Strong salt solution excites contractions
just as in the case of skeletal muscle. Many drugs, such as physostigmine,
ergot, salts of lead and barium, digitalis, may act directly on smooth muscle
and cause contraction. As one would expect however from the greater
independence of the smooth muscle, the action of these drugs varies from
organ to organ, muscle-fibres, which apparently are histologically identical,
reacting diversely according to their origin.
MECHANICAL STIMULATION. Smooth muscle may react to a local
pinch or blow with a local or a general (propagated) contraction. The most
important form of mechanical stimulation is that produced by tension.
The effect of increasing the tension on smooth muscle may be twofold :
causing in the first place relaxation and in the second excitation with in-
creased contraction. These two effects may be illustrated by taking the
case of the bladder. If this viscus (which is surrounded by a complete
coat of smooth muscle) has all its connections with the central nervous
system severed, it is when empty in a state of tonic contraction. If fluid
be injected into it rapidly there is a great rise of pressure in its cavity, due
to the forcible distension. If however the fluid be injected slowly, the
bladder muscle relaxes to make room for it, so that a considerable amount
of fluid may be accommodated in the bladder without any great rise of
pressure. This process of relaxation has its limit. If the injection of fluid
be continued, the walls begin to be stretched passively, and this increased
tension acts as a stimulus causing marked rhythmic contractions of the
whole bladder.
In the same way the response of a smooth muscle to an electrical stimulus
is much increased by previous increase of the tension on the muscle fibres.
PROPAGATION OF THE EXCITATORY STATE, OR WAVE OF
CONTRACTION. On stimulating any part of a voluntary muscle fibre,
a wave of contraction is started which travels to each end of the fibre, but
no further. There is no propagation from muscle fibre to muscle fibre,
the synchronous contraction of the whole muscle being brought about by
simultaneous excitation of all its fibres. It is doubtful whether this isolation
of the excitatory state is found in smooth muscle. As a rule a stimulus
applied to any part of a sheet of smooth fibres may travel all over the sheet
just as if it were a single fibre. It seems probable indeed that there is
protoplasmic continuity by means of fine bridge-like processes between
adjacent muscle cells. And even in the absence of such bridges the jjropaga-
tion of the contraction could be easily accounted for. Although in the case
of voluntary muscle the rule is isolated contraction, yet a very small change
in the muscle, such as that produced by partial drying or by pressure, is
sufficient to cause the contraction to spread from one fibre to another.
OTHER FORMS OF CONTRACTILE TISSUE 247
Indeed by cla'mping two curarised sartorius muscles together, as in the
diagram (Fig. 96), it is found that stimulation of the muscle a causes con-
traction of the muscle b. The current of action of a in this case
has served to excite a contraction in B.
It must be remembered that in all unstriated muscle the fibres are sur-
rounded by a network of non-medullated nerve fibres. Some physiologists are
inclined to ascribe to these fibres an important part in the propagation of the
contraction wave. In the case of the heart muscle however, it can be shown
almost conclusively that the propagation takes place independently of nerve Fig. 96.
fibres, and probably the same is true for many kinds of involuntary muscle.
INFLUENCE OF TEMPERATURE. Smooth muscle is extremely sus-
ceptible to changes of temperature ; as a ride warming causes relaxation,
while application of cold causes a tonic contraction. The condition of the
muscle at any given. time depends not only on its actual temperature,
but also on the rapidity with which this temperature has been reached.
Thus a rapid cooling of the retractor penis muscle of a dog from 35° to 25°
may cause a contraction as extensive as would be produced by a slow cooling
to 5°C. On warming a muscle from 30° to E0°C. it lengthens gradually up
to about 40°, and it may then undergo a marked heat contraction (varying
in degree in different muscles) at about 50°O, which may pass off at a
somewhat higher temperature. It is killed somewhere between 40° and
50 C C. It seems very doubtful whether any true rigor mortis occurs in
smooth muscle. The hard contracted appearance of the smooth muscle
in a recently dead animal is chiefly conditioned by the fall of temperature.
On excising the muscle and warming it up to body temperature it may
again relax and show signs of irritability two or three days after the death
of the animal. Different smooth
muscles however vary very much
in their tenacity of life.
DOUBLE INNERVATION.
Voluntary muscle is absolutely
dependent for its activity on the
central nervous system. Cut off
froni_this it is flabby and motion-
less. Its sole function is to con-
tract efficiently and smartly on re-
ceipt of impulses arriving along its
nerve. It is only necessary therefore
Fio. 97. Tracing from the retractor pi nis muscle that these impulses should be of one
of the dog, showing lengthening (inhibition) i . n , ,,
on stimulation of the nervus erigens, and a character — motor,andweknowthat
smart contraction on stimulating the pudic each fibre of a muscle, such as the
(motor) nerve. (Movements of muscle re- , . ~
duced $.) sar tonus, receives one efferent nerve
fibre terminating in an end-plate.
In the case of smooth muscle we have a tissue which has an activity
and reactive power of its own, and apart from its innervation may be at
one time in a state of relaxation, at another in a state of tonic contraction.
m
248 PHYSIOLOGY
In order that the central nervous system should have efficient control over
such a tissue, it must be able to influence it in two directions : it must be
able to induce a contraction or increase a contraction already present, and
it must also be able to put an end to a spontaneous contraction, i.e. to induce
relaxation. In order to carry out these two effects, smooth muscle receives
nerve fibres of two kinds from the central nervous system, one kind motor,
analogous to the motor nerves of skeletal muscle, the other land inhibitory,
causing relaxation or cessation of a previous contraction. All these fibres
belong to the visceral or ' autonomic ' system. They are connected with
ganglion-cells in their course outside the central nervous system, and their
ultimate ramifications in the muscle are always non-medullated. A typical
tracing of the opposite effects of these two sets of nerves is given in Fig. 97.
In the invertebrata many ' voluntary ' striated
muscles probably possess a double innervation.
Thus in the crayfish the adductor muscle of the claw
consists of striated muscular fibres, every fibre of
which is supplied with two kinds of nerve fibres.
By exciting these fibres one may get, according to
the conditions of the experiment, either contraction
of a relaxed muscle or relaxation of a tonically con-
tracted muscle (Fig. 98).
Fig. 98. Tracing of contraction AMCEBOID MOVEMENT
of adductor muscle of claw of
crayfish, showing inhibition re- Amoeboid movement is seen in the uni-
^rtVtTby^tfof^con! cellular organisms such as the amoeba and
stant current. The break of the m the white blood corpuscles. It can occur
current causes a second smaller . ... , • !•_•* t +,.„,.-,„„„j-,,..«
inhibition. (Biedekmank.) only within certain hmits of temperature
(about 0°C. to 40°) ; within these limits it is
the more active the higher the temperature. At about 45° the cell goes
into a condition resembling heat rigor.
The fluid in which the corpuscles are suspended is of great importance.
Distilled water, almost all salts, acids and alkalies, if strong enough, stop the
action and kill the cell.
The movements are also stopped by C0 2 or by absence of oxygen.
Artificial excitation, whether electrical, chemical, or thermal, causes
universal contraction of the corpuscle, which therefore assumes the spherical
form.
CILIARY MOVEMENT
Cilia are met with in man in nearly the whole of the respiratory
passages and the cavities opening into them, in the generative organs, in the
uterus and Fallopian tubes of the female, and the epididymis of the male, and
on the ependyma of the central canal of the spinal cord and its continuation
into the cerebral ventricles.
The cilia (Fig. 99) are delicate tapering filaments which project from the
hyaline border of the epithelial cells. There are about twenty or thirty to
each cell . The hyaline border is really made up of the enlarged basal portions
of the cilia.
OTHER FORMS OF CONTRACTILE TISSUE
249
In action the cilia bend suddenly down into a hook or sickle form, and
then return slowly to the erect position. This
movement is repeated many (twelve to twenty)
times a second, and thus serves to mova forward
mucus, dust, or an ovum, as the case may be.
The movement seems to be entirely automatic,
and it is quite unaffected by nerves, at any rate
in all the higher animals.
There seems to be a functional connection
between all the cells of a ciliated epithelial
surface, so that movement of the cilia, started in
one cell, spreads forward as a wave, just as,
when the wind blows, waves of bending pass
over a field of corn.
The conditions of ciliary action are the same Fio. 99. Ciliated columnar
*,, r i-T LfiJii epithelium from the trachea
us those tor amoeboid movement of naked cells. j a ra bbit ■ m 1 m\
The minuteuess of the object has up to now m 3 , mucus-secreting cells,
prevented us from deciding whether the cilium ( ' CHAFEK ->
is itself actively contractile, or whether it is simply passively moved by
the action of the basal part situated in the hyaline border of the cell.
CHAPTER VI
NERVE FIBRES (CONDUCTING TISSUES)
SECTION I
THE STRUCTURE OF NERVE FIBRES
On stimulating the nerve of a nerve-musele preparation at any part by
electrical, thermal, or mechanical means, the stimulus is followed, after
a very short interval, by a contraction
of the muscle. This observation illus-
trates the two functions of nerve fibres,
irritability and conductivity — that is to say,
a suitable stimulus can set up changes in
any part of the nerve, which are trans-
mitted down the nerve without any visible
effects occurring in it, and it is not until
this nervous change has reached the
muscle that a visible effect takes place in
the shape of a contraction. In the animal
body a direct excitation of the nerve
fibre in its course never takes place under
normal circumstances. The only function
the nerve fibre has , to perform is that
of conducting impulses from the sense
organs at the periphery to the central
nervous system, and efferent impulses
from this to the muscles and other of
its servants. Hence it is absolutely es-
sential that there should be vital continuity
along the whole length of the fibre. Dam-
age to any part, such as by crushing, heat,
or any other injurious condition, infallibly
causes a block to the passage of an
impulse.
A nerve fibre is essentially a long process or
arm of a nerve-cell (Fig. 100). The cell may
either be situated on the surface of the body or,
as in most cases in the higher animals, may be
withdrawn from the surface into a special
collection of cells such as the posterior root
ganglion, or may be one of the mass of cells and
250
Fig. 100. Diagram of a motor nerve-
cell with its nerve-fibre. (After
Barker.)
a.li, axon hillock ; d, dendrites ;
a.x. axis cylinder ; to, medullary
sheath ; n.R. node of Ranvier.
THE STRUCTURE OF NERVE FIBRES
251
interlacing processes making up a central nervous system. All nerves are alike in possess-
ing as their conducting part the continuous strand of protoplasm produced from the
nerve-cell and known as the axon or axis cylinder. By special methods the axon may be
shown to be made up of fibrillar or neuro-fibrils, embedded in a more fluid material (Fig.
101). These neuro-fibrils are supposed to be continuous throughout the cell and the axis
Fio. 101. Medullated nerve fibres, showing continuity of the neuro-fibrils across
the node of Kanvier. (Bethe.)
o, longitudinal ; b, transverse section.
cylinder and to represent the essential conducting constituents of the nerve. In the
course of growth the nerves develop certain histological differences, which appear to
bear some relation to the nature of the processes they conduct or to the character of
their parent cell. Thus all the fibres which are given off from and which enter the
central nervous system, i.e. the brain and spinal cord, belong to the class known as
medullated. In this type the conducting core or axis cylinder is surrounded with a
layer of apparently insulating material known as myelin, forming the medullary sheath,
or the sheath of Schwann. This sheath consists of a fatty material composed largely
of lecithin, and staining black with osmic acid, supported in the interstices, of a network
formed of a horny substance known as neurokeratin. The medullary sheath is sur-
rounded by a structureless membrane, the primitive sheath or neurilemma. At regular
intervals a break occurs in the medullary sheath, the neurilemma coming in close
contact with the axis cylinder. This break is the node of Ranvier, the intervening
portions of medullated nerve being the intemodes. In each internode, lying closely
under the neurilemma, is an oval nucleus embedded in a little granular protoplasm.
The medullated nerve fibres vary considerably in diameter, the largest fibres being
distributed to the muscles and skin, the smallest carrying impulses from the central
nervous system to the viscera. The latter all come to an end in some collection of
ganglion- cells of the sympathetic chain or peripheral ganglia, the impulses being carried
on to their destination by a fresh relay of non -medullated nerve fibres.
252
PHYSIOLOGY
The non-medullated fibres (Fig. 102) differ from the niedullated simply in the
absence of a medullary sheath. They possess, in many cases at any rate, a primitive
sheath, under which we find nuclei lying clbsely on the side of the fibre and bulging out
the sheath. In their ultimate ramifications they tend to form close networks or
plexuses and appear to lose the last traces of a sheath.
The medullated nerves are bound together by connective tissue (endoneurium)
into small bundles, which :'re again united by tougher connective tissue into larger
nerve-trunks. These fibres as a rule branch only when in close proximity to their
destination, and then the branching always occurs at a node of Ranvier.
Fig. 102. Non-medullated nerve fibres. (SchAfer.)
As to the functions of the myelin sheath in the medullated nerve fibre very little
is known. It does not make its appearance until the axis cylinder is formed, and is
apparently derived from a series of cells which grow out from the spongioblasts of the
central nervous system and form a chain surrounding the out-growing axons. .In the
regeneration of a nerve fibre after section the myelin sheath appears later than the
axon in the peripheral part of the nerve. It has been supposed by some to act as a sort
of insulator ensuring isolated conduction within any given nerve fibre. We have how-
ever no proof that equally isolated conduction is not possible in the non-medullated
fibres of the visceral system, although it is certainly true that a finer ordering of move-
ments is required in the skeletal muscles than in the visceral mistriated muscles. More-
over in the central nervous system the main tracts cannot be shown to be functional
before the date at which they acquire their medullary sheaths, suggesting that pre-
viously any impulse making its way along the tract underwent dissipation before arriving
at its destination. It is possible too that the myelin sheath may serve as a source
of nutrition to the enclosed axis cylinder winch, in the greater part of its course, is
far removed from its trophic centre, namely the cell of wliich it is an outgrowth. This
trophic f imction of the myelin sheath has a certain basis of fact in that the myelin sheath
is as a rule larger in those fibres which take the longer course.
SECTION II
PROPAGATION ALONG NERVE FIBRES
The velocity of propagation along a nerve fibre may be measured, although
in early times it was thought to be as instantaneous as the lightning flash.
To measure the velocity of propagation in a motor nerve, a frog's gastroc-
nemius is prepared, with a long piece of sciatic nerve attached. The muscle
is arranged (Fig. 103) so that its contraction may be recorded on a rapidly
moving surface, on which are also recorded, by means of electro-magnetic
Fig. 103. Diagram of arrangement of experiment for the determination of the
velocity of transmission of a motor impulse down a nerve.
The battery current passes through the primary coil of the inductorium c,
and a ' kick over ' key k. By means of the switch s, the break shock in the
secondary circuit can be sent through the nerve n, either at 6 or at a. The
muscle m is arranged to write on the blackened surface of a trigger or pendulum
myograph, and is excited during the passage of the recording surface bj the
automatic opening of the key k. (The time-marker is not shown.)
signals, the moment at which the stimulus is sent into the nerve, and also a
time-marking showing w-t-g- sec. Tracings are now taken of the contraction
of the muscle : first, when the nerve is stimulated at its extreme upper end ;
secondly, as close as possible to the muscle. It will be found that the latent
period, which elapses between the point at which the stimulus is sent into
the nerve and the point at which the lever begins to rise, is rather longer in the
first case than in the second. The difference in the two latent periods gives
the time that the nervous impulse has taken to travel down the length of
nerve between the two stimulated points. Calculated in this way, the
velocity of propagation in frog's nerve is about 28 metres per second.
In man and in warm-blooded animals the velocity has been variously
estimated at from 60 to 120 metres per second. The higher of these figures
is probably nearer the truth.
253
254
PHYSIOLOGY
On the other hand, in invertebrata the velocity of propagation along nerve fibres
may be quite slow. The following Table represents the velocity of transmission along
a number of different fibres, as determined by Carlson, compared with the duration of
a single muscle twitch in the same animal.
Species
Muscle
Nerve
Contrac-
Rate of
Muscle
tion
time in
seconds
Nerve
the Impulse
in metres
per second
Frog
Gastrocnemius
010
Sciatic
(medullated)
27-00
Snake
Hyoglossus
0-15
Hyoglossal
(medullated)
14-004
Lobster .
Adductor of
0-25
Ambulacra!
1200
(Homarus)
forceps
(non -medullated)
Hag fish .
Retractor of jaw .
018
Mandibular
(non-medullated)
4-50
Limulus .
Adductor of
forceps
1-00
Ambulacral
(non-medullated)
3-25
Octopus .
Mantle
0-50
Pallial
(non-medullated)
200
Slug (Limax) .
Foot
400
Pedal
(non -medullated )
1-25
Limulus .
Heart
2.25
Nerve plexus in heart
0.40
(non-medullated)
The velocity of propagation in sensory nerves is more difficult to deter-
mine owing to the fact that a sensory impulse, on arrival at the receiving
organ — i.e. some part of the central nervous system — does not at once give
rise to some definite recordable mechanical change, such as a muscular con-
traction. There is another method of determining the velocity of conduction
which may be used also with sensory fibres. The passage of a nerve-
impulse down a nerve, just as the passage of a wave of contraction along a
muscle fibre, is immediately preceded or accompanied by an electrical change,
which also travels along the nerve as a wave of ' negativity.' The velocity
of propagation of this wave may be measured, and is found to give the same
numbers as the velocity determined by the preceding method.
The existence of this electrical change enables us to show that a nerve-
impulse, excited at any point in the course of a nerve fibre, travels in both
directions along the fibre. The power of nerves to transmit impulses in either
direction is shown further by the experiment known as Kuhne's gracilis
experiment. The gracilis muscle of the frog is separated into two portions
by a tendinous intersection, so that there is no muscular continuity between
the two halves. The nerve to the muscle divides into two branches, one
to each half, and at the point of junction there is division of the axis cylinders
themselves. If the section a in the diagram (Fig. 104), which is quite isolated
from the rest of the muscle, be stimulated, as by snipping it with scissors,
PROPAGATION ALONG NERVE FIBRES
255
Fio. 104.
Kiihne's gracilis
experiment.
the whole muscle contracts. If the portion of the muscle which is free from
nerve fibres be stimulated in the same way, the contraction is limited to
the fibres directly stimulated, showing that in the first case the stimulus
excited nerve fibres which transmitted the impulse up the nerve to the point
of division and then down again to the other half of the muscle.
Since nerves have this power of conduction in both directions, it might
be thought that a single set of nerve fibres might very well subserve both
afferent and efferent functions, at one time conducting
sensory impulses from periphery to cord, at another time
motor impulses from cord to muscles. But this is not the
case. As a matter of fact we find in the body a marked
differentiation of function between various nerve fibres.
Thus Bell and Majendie showed that the spinal roots
might be divided into afferent and efferent, the anterior
roots carrying only impulses from spinal cord to periphery,
while the posterior roots carried impulses from periphery
to central nervous system. The law known by the name
of these observers states indeed that a nerve fibre cannot
be both motor and sensory. We may find both kinds of
fibres joined together into a single nerve-trunk, but the
fibres in each case are isolated and conduct impulses only
in one or other direction. Under normal conditions the afferent fibres
are excited only at their endings on the surface of the body, while
the efferent fibres are excited only at their origin from the spinal cord.
The difference in the function of different nerve fibres depends there-
fore not so much on the structure of the nerve fibre itself as on the
connections of the fibre. We can show this experimentally by graft-
ing one set of nerve fibres on to another. If the cervical sympathetic
be united to the lingual nerve, stimulation of the sympathetic, instead
of causing, as usual, constriction of the vessels of the head and neck, will
cause dilatation of the vessels of the tongue and secretion of watery saliva.
In the same way the finer functional differences between the various forms of
sensory nerves seem to be determined by their connections within the central
nervous system. Stimulation of the optic nerve by any means whatsoever
evokes a sensation of light. One and the same stimulus applied to different
nerves will evoke different sensations, e.g. a tuning-fork applied to the skin
will give a sensation of vibration, to the ear a sensation of sound. We shall
have occasion to return to this question of the restricted function of nerve
fibres when we deal with Midler's ' law of specific irritability ' in the chapter
on Sensations.
SECTION III
EVENTS ACCOMPANYING THE PASSAGE OF A
NERVOUS IMPULSE
In muscle we saw that the passage of an excitatory wave was accompanied
or followed by electrical changes, production of heat, and mechanical change,
all pointing to an evolution of energy from the explosive breaking-down of
contractile material.
In nerve however which serves merely as a conducting medium, we
should not expect so much expenditure of energy, or in fact any expenditure
at all. All that is necessary is that each section of the nerve should transmit
to the next section just so much kinetic energy as it has received from
the section above it. And experiment bears out this conclusion. The
most refined methods have failed to detect the slightest development of
• heat in a nerve during the passage of an excitatory process, and we know
already that there is no mechanical change in the nerve. The only physical
change in a nerve under these circumstances is the development of a current
of action. A nerve becomes, when excited at any point, negative at this
point to all other parts of the nerve and, just as in muscle, this ' negativity '
is propagated in the form of a wave in both directions along the nerve.
That the excitatory process in nerves is probably accompanied by certain
small chemical changes is indicated by the facts that, in the complete
absence of oxygen, the nerve fibres lose their irritability, and that this loss
of irritability is hastened by repeated stimulation of the nerve. When the
irritability has been abolished by stimulation in the absence of oxygen, it
may be restored within a few minutes by readmission of oxygen to the nerve.
If we connect a galvanometer to two p.oints of an uninjured nerve, no
current is observed, all points of a living nerve at rest being isoelectric. On
making a cross-section of the nerve at one leading-off point, a current is at
once set up, which passes from the surface through the galvanometer to the
cross-section. This is a demarcation current, set up at the junction between
living and dying nerve. This current rapidly diminishes in strength and
finally disappears, owing partly to the fact that the dying process started
in the nerve by the section extends only as far as the next node of Ranvier and
there ceases, so that after a short time the electrode applied to the cross-
section is simply leading off an intact living axis cylinder through the dead
portion of the nerve, which acts as an ordinary moist conductor. On making
a fresh section just above the previous one, the process of dying is again set
256
EVENTS ACCOMPANYING A NERVOUS IMPULSE 257
up, and the demarcation current is restored to its original strength. If,
while the demarcation current is at its height, we stimulate the other end of
the nerve with an interrupted current, the needle of the galvanometer swings I
back towards zero, i.e. there is a negative variation of the resting current.
In order to demonstrate the wave-like progression of the electrical change
from the excited spot along the nerve, it is necessary, as in the case of muscle,
to make use of a very sensitive capillary electrometer or a string galvano-
meter. It is then found that the change progresses along the nerve at the
same rate as the nervous impulse, i.e. 28 to 33 metres per second in the frog.
Hut it lasts only an extremely short interval of time at each spot, viz. six to
eight ten-thousandths of a second. Thus the length of the excitatory wave
in nerve is about 18 mm.
SECTION IV
CONDITIONS AFFECTING THE PASSAGE OF A
NERVOUS IMPULSE
TEMPERATURE. Below a certain temperature the propagation of the
exeitatorv process in the nerve is absolutely abolished. The exact tempera-
ture at which this occurs varies according as we use a warm- or a cold-blooded
i animal. In the frog it is necessary to cool
the nerve below 7 0°C. before conduction
is abolished, whereas in the mammal it is
sufficient to cool the nerve to somewhere
between 0° and 5°C. Since cooling the
G nerve does not excite it. this procedure forms
a convenient method for blocking the passage
of impulses along a nerve without using
the irritating procedure of section. On
warming the nerve again the conductivity
returns. The rapidity with which the excita-
tory process is propagated along either a nerve
or a muscle fibre depends on the temperature.
Thus the mean rate of conduction in the
frog's nerve at 8° to 9°C. is about 16 metres
per second. The temperature coefficient
of the velocity of nerve propagation, i.e.
velocity at Tn + in . . , , T
-. has been found bv Lucas
velocity at Tn
to be about 1-79. The same value was
found by Maxwell for conduction in molluscan
H nerve, and in frog's striated muscle Woolley
• 10 °' found the temperature coefficient for con-
duction of the excitatory process to vary between 1-8 and '2.
An ingenious method (Fig. 105) has been used by Keith Lucas for the determination
of the conduction rates in nerve at different temperatures. The glass vessel repre-
sented in the figure is filled with Ringer's solution, in which the whole nerve-muscle
preparation is immersed. The muscle used was the flexor longus digitorum, so that
the whole length of the sciatic, tibial, and sural nerves could be used. The nerve is
passed up through the constrictions in the inner glass vessels at c and D, and is attached
to the thread E. F, I, and G are three non-polarisable electrodes composed of porous
258
CONDITIONS AFFECTING A NERVOUS IMPULSE
259
clay, containing saturated zinc sulphate, in which a zinc rod is immersed. If the current
is passed in at G and out at p the effective cathode is at the lower end of the constriction
c, and similarly if the current is passed in at I and out at G, the effective cathode is at
D. The tendon of the muscle A is attached by a thin glass rod H to a very light recording
lever, the movement of which is magnified by jjlacing it in the focal plane of a projecting
eye-piece and recording itsimageon a moving sensitive plate. The whole apparatus, with
the exception of the glass rod at H, can be immersed in a water bath at any given tempera-
ture. Two records are taken with the whole apparatus, first stimulating at c, and
secondly stimulating at D. The difference between the latent periods in these two
cases is the time taken for the excitatory wave to travel from D to c. The rate of
propagation is similarly
recorded when the water
bath is raised to 18°C.
or to any desired tempera-
ture. Since we are only
dealing with differences
in latent periods the effect
of die rise of temperature
on t he latent period of the
muscle itself does not
affect the determinations.
THE INFLUENCE
OF FATIGUE. In the
description of the
phenomena of mus-
cular fatigue given in
i lie last chapter, it was
assumed that the
muscle was being
excited directly. The same phenomena are observed when the muscle
is excited through its nerve, though in this case fatigue comes on much
more quickly. If, after the muscle has been excited in this way until
exhausted, it be excited directly, it will respond with a contraction nearly as
high as at the beginning of the experiment. We see therefore that the
nervous structures are more susceptible to the influences causing fatigue
than the muscle itself, and it can be shown that the weak point in the nerve-
muscle preparation is not the nerve, but the end-plates. In fact it is not
possible to demonstrate any phenomena of fatigue in the nerve-trunk.*
This fact can be shown in mammals by poisoning the animal with curare, and
then stimulating a motor nerve continuously while the animal is kept alive
by means of artificial respiration. As the effect of the curare on the end-
plates begins to wear off in consequence of its excretion, the muscles supplied
by the stimulated nerve enter into tetanus. The action of the curare may be
cut short at any time by the injection of salicylate of physostigmine, when
the muscles will at once begin to react to the excitation.
The same fact may be shown on the excised nerve-muscle preparation
of the frog. The gastrocnemii of the two sides with the sciatic nerves are
dissected out, and an exciting circuit is so arranged that the interrupted
* Unless it be asphyxiated by total deprivation of oxygen.
)6. Curve of muscle-twitch obtained by foregoii
method. (Keith Lucas.)
moment of excitation, b = movement of muscle,
c = time-marker.
2 CO
PHYSIOLOGY
secondary currents pass through the upper ends of both nerves in series (Fig.
L07). At the same time a constant cell is connected with two non-polarisable
electrodes (np, np) placed on the nerve of b, so that a current runs in the
nerve in an ascending direction. The effect of passing a constant current
through a nerve is to block the passage of impulses through the part traversed
by the current. When the con-
stant polarising current is made,
the muscle may give a single
luamnitf 1_ twitch, and then remains quies
v^^^/ cent. The exciting current is
then sent through both nerves by
the electrodes ^ and e 2 . The
muscle a enters into tetanus,
which gradually subsides owing
to ' fatigue.' When a no longer
responds to the stimulation, the
constant current through the
nerve of b is broken, b at once
enters into tetanus, which lasts
as long as the contraction did in
the case of a, and gradually sub-
Fl °f ^ ^ rra T ment ° f f e ( \P. e " meak ior ?TTA sides as fatigue comes on. Since
strating the absence of fatigue in medullated 6
nerve fibres. both nerves have been excited
EC, exciting circuit ; or, polarising circuit. ^0^0^ it is evident that the
fatigue does not affect the nerve-trunk. We have already seen that a muscle
will respond to direct stimulation when stimulation of its nerve is without
effect, and must therefore conclude that the first seat of fatigue is the junction
of nerve and muscle, i.e. the end-plates.
In the normal intact animal the break in the neuro-muscular chain which
is the expression of fatigue occurs still higher up, i.e. in the central nervous
system, and is probably due to some
reflex inhibition of the central motor
apparatus from the muscle itself. Thus
after complete fatigue has been produced
in a muscle so far as regards voluntary
efforts, direct stimulation of the muscle
itself or its nerve will produce a contrac-
tion as great as would have been the case
at the beginning of the experiment.
THE INFLUENCE OF DRUGS. The
most important drugs with an influence
on nerve fibres are those belonging to the
class of anaesthetics. Of these we may mention carbon dioxide, ether,
chloroform, and alcohol.
The action of any of these substances on the excitability and conductivity of a nerve
may be studied by means of the simple apparatus represented in Pig. 108. The nerve
CONDITIONS AFFECTING A NERVOUS IMPULSE 261
of a nerve-muscle preparation is passed through a glass tube which is made air-tight by
plugs of normal saline clay surrounding the nerve at the two ends of the tube. By means
of two lateral tubulures a current of C0 2 , or air charged with vapour of ether or other
narcotic, can be passed through the tube. The nerve is armed with two pahs of elec-
trodes which are stimulated alternately, the pair within the tube serving to test the
action of the drug on the excitability, while the pair outside the tube show the presence
or absence of any effect on the conducting power of the nerve below it.
Of the gases and vapours mentioned above, CO., and ether both diminish
and finally abolish the excitability and conductivity of the nerve fibres.
The conductivity however persists after all trace of excitability, has dis-
appeared, before in its turn being also abolished. On removing the gas
1, - 11 ii
Fio. 109. Tracing to show the effect of ether on excitability and conductivity of nerve.
Nerve excited by single induction shocks alternately within and above ether chamber. The
vertical lines indicate contractions of the muscle (gastrocnemius.) The lower line indicates
the periods during which the nerve was exposed to the action of ether.
a. disappearance of excitability: a, reappearance of excitability; c, disappearance of
conductivity ; i>, reappearance of conductivity. (From a tracing kindly lent by Prof. Gotch.)
or vapour by blowing air over the nerve, the conductivity and excitability
gradually return in the reverse order to their disappearance (Fig. 109).
Alcohol is said to increase the excitability or leave it unaffected, while
diminishing the conductivity of the nerve.
Chloroform rapidly abolishes both excitability and conductivity. It
is a much more severe poison than the drugs just mentioned, so that in many
cases its effects are permanent, and no, or only a very partial, recovery of the
nerve is obtained on removal of the chloroform vapour from the apparatus.
SECTION V
THE EXCITATION OF NERVE FIBRES
Many different forms of stimuli may be used to arouse the activity of an
excitable tissue such as muscle or nerve. Thus we may use thermal, mechani-
cal, or chemical stimuli. If the temperature of a motor nerve be gradually
raised, no effect is noticed till about 40°C. is reached, when the muscle may
enter into weak quivering contractions. Sudden warming of the nerve
always gives rise to excitation. At about 45°C. the nerve loses its irritability
and dies. On the other hand, a nerve may be rapidly cooled without any
excitation taking place.
A nerve may be excited mechanically by crushing or cutting. These
methods destroy the nerve. It is possible to excite a nerve mechanically,
without any serious injury to it, by carefully graduated taps, and this method
has been used in investigating the phenomena of electrotonus.
All chemical stimuli applied to the nerve have a speedy effect in destroying
its irritability. The chemical stimuli most used are strong salt solutions,
glycerin, or weak acids. If any one of these be applied to a motor nerve, the
muscle enters into an irregular tetanus, which lasts till the irritability of the
nerve is destroyed at the part stimulated.
None of these forms of stimuli can be adequately controlled either as to
strength or duration. Moreover, owing to their destructive effects, any
repetition of the stimulus will fall on a nerve or muscle more or less altered
by the first stimulus. We are therefore justified in the use of electrical
stimuli not only for arousing the activity of excitable tissues, but also for
determining the conditions of excitation of muscle and nerve. For this pur-
pose we may use either the make and break of a constant current, the induced
current of short duration produced in a secondary coil of -an inductorium
by the make or break of the primary circuit, or the discharge of a condenser.
The last-named method of stimulation is especially useful when we desire to deter-
mine the total amount of energy involved in the electrical stimulation of a nerve or
muscle. The arrangement of such an experiment is shown in Fig. 110. By means
of the switch S the condenser can be put into connection either with the battery from
which it receives its charge or with the nerve through which it can discharge. By
knowing the capacity of the condenser and the electromotive force by which it is
charged, we can estimate the energy of the charge- sent through the nerve.
E (energy in ergs)* = 5PV 2
(P = capacity in microfarads ; V = electromotive force in volts).
* An erg is the amount of work produced or energy expended by the action of
one dyne -through one centimetre. A dyne is the force which will give to a mass of
one gram an acceleration of one centimetre per second.
262
THE EXCITATION OF NERVE FIBRES
263
In this way it has been found that the energy of a minimal effective stimulus for frog's
nerve is about 1 ,„',;„ of an erg.
The amount of energy necessary to excite the nerve will vary with the rate at which
the condenser is allowed to discharge through the nerve. Its rate can be modified
by altering the resistance in the discharging circuit or by altering the electromotive
force of the charge. This method has been adopted by Waller in determining the rate of
change at which excitation is obtained with a minimal ex-
penditure of energy, which he calls the " characteristic " of
the tissue in question. To this point we shall have occasion
to refer later.
FlO. 1 Ml. Arrangement of apparatus
for the excitation of a nerve by
means of condenser discharges.
c, battery ; R, rheoehord ; c, rider
of rheoehord ; s, switch (Pohl's re-
verse!- without cross wires) ; o, con-
denser ; «, nerve : m, muscle ; e. non-
polarisable electrodes.
When using the make and break of a constant
current as a stimulus, the first fact of importance is
the relation of the seat of excitation to the rjoles
I iy which the current is led into or out of the ex-
citable tissue. We have already seen that when a
current is passed through a muscle or nerve the
muscle contracts only at make or at break
of the current, no propagated excitatory
effect being produced during the passage
of the current. The excitation at make
is obtained with a smaller current than the
excitation at break.
Besides this difference in intensity, there
is a difference in the point from which
excitation starts. A make contraction starts
from the cathode, a break contraction from
the anode. This is well shown by the two following experiments :
(«) A curarised sartorius muscle of the frog (Fig. Ill), with its bony
insertions still attached, is fastened at the two ends to two electrodes, which
are able to swing when the muscle contracts, and are attached by threads
to levers which serve to record the contraction. The middle of the muscle is
then fixed by clamping it light!)'.
A circuit is arranged so that a con-
stant current can be sent through the
electrodes and the whole length of
the muscle. It is found, on making
the current, that the lever attached
to the cathode- — that is, to the elec-
trode by which the current leaves the
muscle — rises before the other lever. On the other hand, on breaking the
current, the lever at the anode rises first, showing that the anodic half of
the muscle contracts before the cathodic half.
(b) The irritability of a muscle, i.e. its power of responding to a stimulus
by contracting, is intimately dependent on the life of the muscle. If the
muscle be injured or killed at any spot, its irritability at this spot will be
therefore diminished or destroyed. Hence, if we stimulate a muscle at the
injured spot, no contraction will ensue. This fact maybe used to demon-
Fici. 111. Sartorius clamped in middle and
attached to levers at either end.
jj}
264 PHYSIOLOGY
strate the production of excitation at cathode on make, and at anode on
break of a constant current.
A muscle with parallel fibres, such as the sartorius, is injured at one
end, and a constant current passed, first from the injured to the uninjured
end, and then in the reverse direction (Fig. 112). It is found in the former
case, when the anode is on the injured part (which is therefore less excitable),
that break of the current is ineffec-
i-L-_^...^_ ' tive, and in the latter, when the
contraction at make cathode is on the injured surface,
that the make stimulus is ineffec-
tive, showing that the part excited
an0d M3fbs8» kath ° d8
Fro. 129. Diagram to show direction of the Fig. 130. Diagram of arrange-
positive polarisation current, clue to a break ment for: showing' paradoxical
excitation at the anode. contraction.
tissue is however always negative towards adjacent unexcited tissue,
and therefore if we connect a to k, there must be a current outside the
nerve from k to a, and in the nerve from a to k, viz. in the same direction
as the polarising current. We see therefore that negative polarisation is
due to polarisation occurring between an electrolytic sheath and a con-
ducting core, whereas positive polarisation is hardly a polarisation effect at
all, but is a current of action.
PARADOXICAL CONTRACTION. If the sciatic nerve of a frog be
POLARISATION PHENOMENA IN NERVE 283
dissected out, and one of the two branches into which it divides be cut,
and the central end of this branch stimulated, the muscles applied by the
other half of the nerve contract to each stimulus. Ligature or crushing
of the nerve x (Fig. 130) between the points stimulated and the point
which joins the main trunk puts a stop to this effect, showing that it is
not due to a mere spread of current.. The fibres passing down n are in
fact stimulated by the electrotonic current developed in x during the passage
of the exciting current.
SECTION IX
THE NATURE OF THE EXCITATORY PROCESS
Under this heading we have really two questions to discuss, namely, (a) the
nature of the change excited at the stimulated spot in an excitable tissue,
and (b) the propagation of the .excitatory change away from the excited spot,
e.g. down a nerve fibre. That these two phenomena are more or less in-
dependent and may be dealt with separately is shown by the result of passing
a constant current through a parallel-fibred muscle, such as the sartorius.
In this case, as we have seen (p. 192), at make of the current an excitatory
change occurs at the cathode and is transmitted throughout the whole
length of the muscle, giving rise to a twitch of the muscle. During the
passage of the current there is still an excitatory change at the cathode,
but limited to a region within one or two millimetres of the cathode.
An attempt has been made by Boruttau and other physiologists to
explain the nerve process, not as a wave of electrical change affecting the
substance of the axis cylinder itself, but as a propagated catelectrotonic
current. This observer found that, by working with a ' platinum core
model ' (' Kemleiter ') (Fig. 125) of considerable length, the catelectrotonic
current was developed at one end of the model some appreciable time after
a current had been sent in at the other end, thus resembling a current of
action. It is however impossible to explain all the electrical phenomena
of nerve as due simply to polarisation. We might go so far as to assume
that the excitatory effect at the cathode is due to negative polarisation,
and that excitation at break, i.e. at the anode, is caused by the sudden
coming into existence of a negative polarisation current ; but then it would
be difficult to imderstand how the excitation, so produced at the anode, should
give rise to a current so much exceeding the current which produced it that
it would appear in our external circuit as a current of positive polarisation.
The same objection would hold to the comparison of a nerve-fibre with
a submarine cable. An electric disturbance produced at any part of a cable
(i.e. a conducting wire in an insulating sheath) is propagated along the
cable at a certain finite velocity which can be calculated when we know
the conductivity of the core, the capacity of the cable, and the di-electric
constant of the sheath. In all these cases there must be a decrement of
the change as it is transmitted away from its seat of origin, a decrement for
the existence of which there is no evidence in a nerve fibre or other excitable
tissue* Moreover the phenomenon of propagation of an excitatory process
* It might be urged, on the other hand, that one would not expect to find any
appreciable decrement in a cable only 1 to 3 inches long.
284
THE NATURE OF THE EXCITATORY PROCESS 285
is equally well marked in tissues, such as muscle and non-medullated nerve
fibres, which show very little of the electrotonic effects described in the last
section. The absence of decrement in the excitatory process has been
taken as an indication that the axis cylinder of the nerve is the seat of energy
changes which may be let loose under the influence of chemical or electrical
changes, just as the energy of a contracting muscle is set free by the exertion
of an infinitesimal force applied as a stimulus. The nerve on this view
does not simply transmit the energy which is imparled to it, like a telegraph
wire, but itself furnishes the energy of the descending nerve-process.
Against this view might be urged the absence of phenomena of fatigue
in nerve', as showing that nervous activity is not accompanied by any ex-
penditure of energy or using up of material. But it must be remembered
that this absence of fatigue holds good only for medtdlated nerve fibres and
is not found in non-medullated nerves,* and even in medullated nerves the
persistence of irritability is dependent on the continual supply of a certain
small amount of oxygen. It may therefore possibly be explained by a
continual process of restitution taking place at the expense of the sheath.
Fatigue is absent, not because nothing is used up, but because the assimilative
changes exactly balance and make good the dissimilation involved in the
propagation of a nervous impulse.
There is thus a certain amount of justification in the comparison of a
nerve fibre to a chain of gunpowder, though in the nerve fibre the impetus
to disintegration, imparted from each particle to the next in order, consists,
not in a rise of temperature at the point of ignition, but in all probability
in an electrical change ; and the total evolution of energy is so small that
it cannot be measured as heat by the most sensitive methods at our disposal.
The excited condition at any segment of a nerve is associated with a develop-
ment of electromotive forces at the junction of the segment with the adjacent
resting segments. The current of action thereby produced can pass by the
sheath of the nerve, so that it must enter the axon at the excited spot, and
leave it at the adjacent unexcited segment. Hermann has suggested that in
this way the current of action at any excited spot may excite the adjacent
segments or molecules, causing them to become negative and thus setting up
a current of action which in its turn excites the succeeding segments. In this
way the excitatory process may travel the whole length of the nerve. Propa-
gation would thus involve the successive setting up of an excitatory process
all along the nerve or excitable tissue, though it is difficult to see why on this
theory every excitatory state should not give rise to a propagated change.
We are as yet a long way from a comprehension of the changes involved
in the process of excitation, though we are able to form some idea of many of
the factors which must be involved. Any theory of the excitatory process
must take into account the following phenomena :
(1) The excitatory state is attended with an electrical change of such
* This statement is based chiefly on experiments on the olfactory nerve of the pike.
Halliburton and Brodie found no signs of fatigue in the non-medullated fibres of the
sympathetic supply to the spleen, even after several hours' stimulation.
286 PHYSIOLOGY
a nature that the excited spot, is negative to adjacent unexcited spots. Tliis
electrical change rises rapidly to a maximum and dies away more slowly,
the rate of its rise, and still more of its subsidence, varying largely according
to the nature of the tissue under investigation.
(2) The excitatory change is aroused only at the poles of a current
passing through the tissue, i.e. at those places where polarisation can occur
in consequence of the electrical movement of ions.
(3) Excitation only occurs at the cathode at make of the current,
and only occurs if the current attains a sufficient strength within a certain
period of time, the relation of strength of current to rate of change varying
in different tissues.
(4) All living tissues are made up of colloids, divided into compartments
by membranes of various permeabilities and permeated with salts and other
electrolytes in solution.
Disregarding for the moment all considerations of structure, it is possible
to form a hypothesis of the nature of electrical excitation which takes into
account the facts just mentioned and enables us to give a quantitative or
mathematical expression to the factors involved. An electrical current
passing through a tissue containing membranes, impermeable to the dis-
solved ions, will set up differences of concentrations at and near the mem-
branes. Nernst, on the supposition that these differences of concentrations,
when sufficiently large, would cause an excitation, arrived at a formula
connecting the lowest current required to excite with its duration, and
another formula connecting the lowest amplitude of an electrical current
with its frequency. The mathematical investigation of the question has been
continued by A. V.-Hill in conjunction with Keith Lucas. For this purpose
we may suppose that the excitable unit is represented by a cylindrical space
closed at its two ends by the mem-
branes A and B (Fig. 131) and
filled with a solution of electro-
lytes. If a current be passed
from b to A, the positively charged
ions will move towards a and
FlG - 13L tend to accumulate there. The
accumulation of the ions near the membranes will be limited by the tendency
of the ions to equalise their concentration in all parts of the cell by diffusion.
If we suppose that a necessary condition for excitation is that the concentra-
tion of the ions in the neighbourhood of one of the membranes shall reach a
certain definite value, it becomes possible to calculate under what conditions
of strength, duration, &c, an electrical current will just produce excitation.
The rise of the excitatory state would here be determined by the rate at
which the ions accumulate, the subsidence of the excitatory state by the rate
of dispersal of the ions by diffusion. The formula arrived at by these
observers has this form :
X
THE NATURE OF THE EXCITATORY PROCESS 287
where i is the smallest current which will excite,
I is duration of the current;
while y, //, are constants which depend on :
(1) The distance between the membranes.
(2) The distance from the membrane at which the concentration
changes are being considered.
(3) The diffusion constant of the ion.
(4) The number of ions by which a given quantity of electricity is
carried.
(•">) A constant expressing in general terms the ease with which a
propagated disturbance is set- lip.
Investigation on these linos may give us in future sufficient infor-
mation to form a material conception of the factors involved in excitation,
factors which in the above formula have only a symbolic existence. Thus
a determination of the distance between the membranes would give us some
clue to the size of the ultimate excitatory units in the tissue involved.* The
constant it. has reference only to the position relative to the membranes at
which the changes of concentration are effective. From Lucas's experiments
it would seem that the changes of concentration occur in the immediate
neighbourhood of one of the membranes. Macdonald has brought forward
evidence that the passage of a currenl through a nerve involves the setting
free of certain inorganic, ions. The subsidence of the excitatory state
depends on the rate of diffusion of ions. If however we compare the rates
of subsidence of the excitatory state in different tissues, we find much greater
divergence than would be possible on the assumption that the diffusion is one
affecting inorganic ions. Thus between the substance /? (the intermediate
substance) of the frog's sartorius and the ventricular muscle fibre of the
same animal, the rate of subsidence of the excitatory state changes in the
ratio H'U) : 1. If the ions concerned were simple ions, such as H-, Ca--, Na-,
CI', Sec, it would be impossible to account for this wide variation, since their
velocities differ in the ratio of 10 : 1 at most. Moreover the effect, of rise of
temperature on the rate of subsidence is greater than the effect of a similar
rise on ionic velocities. It is evident therefore that the theory is one for use
as a working hypothesis only. That excitation is associated with accumu-
lation of ions in the region of the exciting electrode, that the subsidence of
the excitatory state is due to disappearance by diffusion or otherwise of
t hese ions, there can be little doubt. But the questions as to the nature of
these ions, and their relation to the colloidal constituents of the excitatory
tissue, or to other possible substances, changes in which may form an integral
part in the excitatory state, must be left- for future investigation.
* It would bo premature at present to give any histological significance to Hill
and Luoas's diagrammatic cylinder. As Hardy has pointed out, the nerve cannot
consist of a row of such cylinders, otherwise excitation would occur throughout the
whole intrapolar region, and not be confined to the cathode at make and the anode
at break. It may be that we are dealing here again with the polarisable sheath of the
' Kernh/trr,' and that the membrane A corresponds to the surface of the axis cylinder
or of its neuro-fibrils.
CHAPTER VII
THE CENTRAL NERVOUS SYSTEM
SECTION I
THE EVOLUTION AND SIGNIFICANCE OF THE
NERVOUS SYSTEM
Every vital phenomenon may be regarded as a reaction conditioned by some
change in the environment of the animal and adapted to its preservation. In
the community of cells forming the whole organism, the defence of any one
part must involve the co-operation of the whole community ; no change
in a cell of the body can be regarded as a matter of indifference to any of the
other cells. For this subordination of the activities of each part to the
welfare of the whole, as for the co-operation of all parts in maintaining the
welfare of each, a means of communication is necessary between the various
cells. For some of the lower functions the channel of communication is the
blood, which serves as a medium for carrying food material from one part of
the body to another, or for the transmission of chemical messengers which,
elaborated by one set of cells, may affect the metabolism of cells in distant
parts of the body. * This method of correlating different activities would
however be too slow and clumsy for the quick adaptation of the organism
to sudden changes of environment. Such a rapid correlation can be effected
only by a propagation of some molecular change from the seat of incidence of
the stimulus, either to all parts of the body or to some mechanism controlling
all parts of the body. The medium for the propagation of a state of excitation
is furnished by the nervous system. We have seen that stimuli of various
kinds, involving such various forces as thermal, chemical, and electrical
energy, are transformed by a muscle or nerve fibre into what we call a state
of excitation, which is propagated along the fibres, whether nerve or muscle,
at a certain definite rate, its passage in the case of the muscle being followed
by a wave of contraction.
In unicellular animals, such as the amoeba and vorticella, there is no
differentiation of any structure which can be regarded as peculiarly nervous.
A stimulus applied to any part of the amoeba may evoke responsive activity
in all other parts. A slight touch applied to any point on a vorticella will
cause an excitation which is rapidly propagated to the stalk, causing this to
288
EVOLUTION OF THE NERVOUS SYSTEM
289
contract and so withdraw the organism from any possible injury. In the
lowest metazoa, such as the sponges, we find no special nervous structures.
The cells forming the sponge may react to changes in their environment by
contraction or by alteration of their relative positions. Many of the cells can
move from one part of the sponge to the other in response to chemical
changes occurring in the body of the sponge. So far however no cells have
been distinguished as endowed above their fellows with the property of
irritability or the power of reaction to stimulus. It is in the next class, that
of the Coelenterata, where we first find a definite nervous system. The object
B
FlG. 132, Diagrammatic representation of evolution of a nervous system.
(Modified from Foster.)
ec, epithelial cell ; mp, muscular process j sc, sensory cell ; np, nerve process
or fibre : mc, muscle cell ; sn/p, sensory nerve process ; mnp, motor nerve process ;
cc, central cell.
of a nervous system is to ensure the co-operation of the whole organism in any
reaction to changes in its surroundings. At its first appearance therefore we
should expect a nervous system to be developed in connection with that layer
of the animal which is in immediate relation to the environment, namely,
the epiblast or external layer. In some species of hydra, though no typical
nervous tissues have been detected, many of the epithelial cells lying on the
surface are prolonged at their inner ends into a long contractile process (Fig.
132, a), so that stimuli applied to the surface and acting on the epithelial
cells can cause, as an immediate response, a contraction of the underlying
muscular processes. We may easily conceive that in such an animal, among
the cells forming the epiblast, certain cells might become endowed with a
special sensitiveness to external changes, other cells being developed, like
those of the hydra just mentioned, into special contractile structures. If in
the course of development the protoplasmic continuity between these two
sets of cells had not become interrupted (and we have no ground for assuming
that such an interruption occurs under normal circumstances), it is evident
f hat we should have so produced the simplest form of a reflex arc (Fig. 132, B),
namely, a sensory cell, which is stimulated by slight physical changes in its
surroundings and is thereby thrown into a state of activity similar to that
which we have already studied in muscle and nerve. This state of activity
would be propagated bv the protoplasmic channels to the muscular cell and
19
290
PHYSIOLOGY
arouse there the specific function of the muscle, namely, contraction. In such
a simple reactive tissue, lines of less resistance would be rapidly laid down
through the protoplasmic continuum, and these lines, acquiring a specific
structure or composition, would form a network uniting sensory and muscular
cells. Thus a stimulus applied to any sensory cell would spread to the ad-
jacent sensory and muscular cells, and the response of the muscle cells would
be greatest near the stimulated spot, gradually dying away as the area of the
excitation widened. A further step in the development of such a hypotheti-
cal elementary nervous system would occur when certain of the sensory cells
(Fig. 132, c) developed a special sensitiveness, not to mechanical changes in
the environment, but to the protoplasmic excitatory process arriving at them
along the nerve network. These cells would act as relays of force, picking
up the excitations arriving from
the undifferentiated sensory cells,
V and sending them on with increased
- <: ^-- _ rs^>^. vigour along the nerve network.
In such a manner a stimulus
applied at one point could be sent
on in successive relays from cell to
cell throughout the whole reactive
tissue on the surface of the body.
We cannot point to any par-
ticular animal as presenting in-
stances of either of the two types
of elementary nervous system
just described. If such exist, t hex-
have not yet been investigated,
or the undifferentiated character
of their nervous tissues has
thwarted the efforts of zoologists
to display their specific characters
by staining reagents. In the
lowest definite nervous system
with which we are acquainted,
namely, that of the jelly-fish,
all three types of cell, the sensory cell, the reactive or central cell, and
the motor cell, are already developed and have undergone among
themselves a considerable degree of differentiation. In a jelly-fish or medusa,
such as aurelia or sarsia (Fig. 133), the reactive tissue of the body is confined
to the under-surface of the so-called umbrella with the tentacles and manu-
brium. A section through the umbrella shows a layer of epithelium contain-
ing differentiated sense cells, below which is a plexus or rather network
of fine nerve fibres with a certain number of nerve cells at the nodes of the
network. From this network fibres pass more deeply to end in a finer net-
work situated among a layer of muscle fibres formed, like the sensory cells, by
a differentiation of the primitive epithelium or epiblast (Fig. 134). Besides
:g. 133. Diagrammatic view of a jelly-fish.
(Hem wig.)
umbrella ; M, manubrium ; t,. t 2 , tentacles ;
T, velum ; s, nerve ring ; it. ' marginal body.'
EVOLUTION OF THE NERVOUS SYSTK.M
291
this diffuse aervous system, there is a continuous ring of nerve fibres round
the margin of the umbrella, thickened at intervals by the accumulation of
nerve cells, which are in close relation to special collections of sensory cells in
the ' marginal bodies.' These sensory cells present a differentiation among
themselves, some being apparently determined for the reception of mechani-
Fio. 134. Diagram of subepithelial plexus of nerve fibres and nerve cells, communicat-
ing on the one side with the sensory epithelium, and on the other side with the sub-
umbrellar sheet of muscle fibres. (After Bethe.)
cal stimuli, others for the reception of light stimuli, while others again are
found in close relation with little masses of calcium carbonate crystals, by the
direction of the weight of which the cells are able to react to changes in the
position of the animal in space. In the jelly-fish therefore the nervous or
reactive system has already acquired a considerable degree of differentiation.
I'lc. 1 :!5. Figure of a jelly-fish in which all the marginal bodies except one have
been removed, and which has been incised in various diiework of fibres, which may be regarded as processes
either of the sensory nerve fibres or of the nerve cells. The typical reflex
arc in this case therefore is formed by two nerve cells with their processes.
Such a nerve cell with its processes is spoken of as a neuron. The first neuron,
the recipient neuron, or receptor, is represented by the sensory cell with its
296 PHYSIOLOGY
two processes in the granular material. The second neuron is formed by t ln j
ganglion-cell with its finely branched dendritic processes in the granular
matter and its motor axon, which passes into the muscle fibres.
As to the manner in which the impulse passes from the branches of one
cell into those of the other, opinions are still divided. The question will
have to be more fully considered when we come to deal with the vertebrate
nervous system. Many believe that there is no anatomical continuity 1 letween
the two neurons, and that the excitatory change is transmitted by a mere
contiguity, a change in one set of nerve-endings exciting a corresponding
change in another set of nerve-endings in immediate contact with them.
By certain methods however it is possible to show the existence of an anato-
mical continuum throughout the whole nervous system in these inverte-
brate animals. Apathy and Bethe have demonstrated the presence of a
continuous system of neurofibrils (much smaller than an individual nerve
fibre), which, starting in a sensory cell, pass into a network of fibrils forming
the greater part of the central granular matter. From this network neuro-
fibrils run along the dendrites into the ganglion cells, forming there a small
network through the centre of which a neurofibril is continued down the nerve
processes again, and passes out along the motor nerve to end in a network
of fibrils among the muscle fibres. In a system so constituted it is evident
that, although an excitatory process passing along a given fibril may find
certain paths easier than others, and so maintain a constant prescribed
path through the nerve system, yet it will be possible, by sufficiently increas-
ing the strength of the excitatory process, to cause it to travel in all direc-
tions in the central nervous system and to evoke in this way a general
activity of all parts of the body, a condition in fact found to obtain in the
normal animal. It is significant that, although a great number of fibrils
pass into the bodies of the ganglion cells, yet in many cases, especially in
crustaceans, fibrils are to be found sweeping from the neuropilem or nerve
network of the granular substance into a nerve process, and thence into
its motor axon without at any time entering the body of the cell (Fig. 139).
SECTION II
THE NERVOUS SYSTEM OF VERTEBRATES
In these, as in the invertebrata, the central nervous system is developed
by an involution of the epiblast, revealing thereby its primitive relations
to the surface of the body. At an early period in foetal life, shortly after the
formation of the two layers of epiblast and hypoblast, a thickening is ob-
served in the epiblast. Tliis thickening soon gives place to a groove, the
neural groove (Fig. 140), and the walls of the groove folding over form a
Fig. ]40. Transverse section of human embryo of 2"4 mm. to show developing
neural canal. (T. H. Bryce.)
lie, neural canal; me, museleplate : my, outer wall of somite;
sc, sclerotome.
(anal, the neural canal, which is dilated at the head end of the embryo to
form three enlargements known as the cerebral vesicles.
When first formed the canal is oval in cross-section, its wall being made
up of a layer of columnar cells between the outer extremities of which
an- seen smaller rounded cells. The internal layer of columnar cells sends
a process peripherally which branches at the end so as to form a close
nu'shwork of fibres. These fibres branch more and more as development
progresses, and eventually form the supporting tissue of the adult central
nervous tissue, known as the neuroglia. As the wall of the canal grows in
thickness, some of the cells may wander outwards and form neuroglia-cells
with numerous radiating branches. In the adult nervous system little is
left of these cells except their nuclei, so that the neuroglia appears as a close
felt-work of fibres, to which here and there nuclei are attached. These cells
297
298
PHYSIOLOGY
B
are formed from the most superficial layer of the invaginated epiblast, and
are spoken <>f as spongioblasts. The deeper layer of cells, which are to give
rise to the permanent nerve-cells, and are therefore known as neuroblasts,
rapidly divide and form a thick layer surrounding the internal layer of
spongioblasts, through which pass the peripheral processes of the latter.
When first formed these cells have no processes. Later on each neuroblast
acquires a pear shape, the stalk of the pear having a somewhat bulbous
extremity (Fig. 142). The stalk continually elongates, and the elongated
process may leave the spinal cord altogether and grow outwards to any part
of the body of the embryo, or may pass
to other parts of the central nervous sys-
tem. This long process of the developing
nerve cell is known as the axon. Some
time after its formation other processes
grow out from the cell, which soon branch
and end in the immediate neighbourhood
of the cell. The axons of the cells near the
ventral part of the neural tube grow out
to the different muscles of the body,
where they end in close connection with
the muscular fibres by an arborisation
1 which forms the end-plate. They provide
an efferent path for impulses running
from the central nervous system to the
musculature of the body. The afferent
channel is formed in a somewhat different
manner. Even before the neural groove
has closed in, a thickening of the epiblast
is seen immediately external to the
groove on each side. This thickening
becomes divided into a series of collections of cells lying immediately
under the epiblast on the lateral and dorsal surface of the neural
canal. The cells, which are at first round or oval, send off two pro-
cesses in opposite directions so that they become bi-polar (Fig. 142).
One process passes into the central nervous system, where it divides, some
of its branches being distributed in the nervous system at the same level,
while others run a considerable distance towards the head immediately out-
side the tube of nerve cells. The other process grows downwards, along
with the processes from the ventral cells of the tube, towards the periphery
of the body, where it ends in close connection with the surface in the various
sense organs of the skin and muscles. These collections of bi-polar cells form
the posterior root ganglia. In fishes they retain their primitive character
throughout life, but in mammals the bi-polar cell is to be found only in the
spiral and vestibular ganglia which give origin to the fibres of the eighth
nerve. In all the other ganglia the shape of the cell becomes modified
by an approximation of the points of attachment of the two processes until
Fig. 141. Neuroblast* from the spinal
cord of a chick embryo. (Cajal.)
a. three neuroblasts stained to show
neurofibrils : o. a bi-polar cell.
1!. a neuroblast showing the ' incre-
mental cone c.
THE NERVOUS SYSTEM OF VERTEBRATES
299
finally the cell becomes uni-polar. giving off one process which divides by
a T-shaped junction into two, one of which runs towards the spinal cord,
while the other takes a peripheral course as the afferent nerve fibre. The
central nervous system thus becomes provided with a ' way in : and a '*way
out ' for the chain of impulses concerned in a nervous reaction or reflex action.
The further development of the spinal cord is mainly determined by the exten-
Fig. 14i'. Section through developing spinal cord and nerve roots from chick
embryo of fifth day. (Cajal.)
a. ventral root : n. dorsal root ; c, motor nerve cells ; d, sympathetic ganglion
cells ; E. spinal ganglion cells still bi-polar : F. mixed nerve ; b, c, d, motor nerve
tilires to /. developing spinal muscles ; i. a sensory nerve-trunk.
sion of the axons of the cells outside the tube of cells themselves, and by
the provision of the ' long paths ' which are a necessary condition of increased
efficiency of the reacting organ. Some time after the outgrowth of the axon
.! medullary sheath is formed, apparently by the agency of the axon itself,
so that each group of axons leaving or entering the cord forms a bundle of
medullated nerve fibres. The long branches of the posterior or dorsal roots
running up towards the head form a mass of fibres behind the tube of cells
known as the posterior columns. Fibres starting in the spinal cord itself
run upwards and downwards to end in other parts of the cord, or in the more
anterior divisions of the central nervous system forming the brain, and
-ui round the neural tube on its ventral and lateral aspects with a sheath
oi white matter. To these white fibres are added others, which take origin
in the brain and pass all the way down the cord. Meanwhile the cells
300
I'HYSHH.OCY
themselves become separated by the ramifications between them of the
branches of axons entering the cord, as well as of the dendrites of the cells
themselves. Thus, in its adult form, the spinal cord ((insists of a central
mass" of nerve cells and fibres, known as the grey matter, which is encased
in a sheath of white matter formed of medulla ted nerve fibres. The cord
itself is cylindrical in shape, and is divided into two symmetrical halves by
the anterior and posterior fissures. In each half of the cord the grey matter
on cross-section is crescentic in shape, presenting an anterior or ventral
horn and a posterior or dorsal horn, and is connected with the corresponding
mass in the other half of the cord by grey matter known as the anterior
and posterior grey commissures. Between the two grey commissures is
the central canal, relatively very minute when compared with the condition
in the foetus and lined by a single layer of columnar ciliated epithelium,
the cells of which are directly descended from the neural epithelium lining
the medullary canal.
THE STRUCTURE OF NERVE CELLS
In the adult animal a typical nerve cell, such as those forming a prominent
feature in the anterior horn of the spinal cord, is a large cell with many
branches. It lias a large vesicular nucleus with very little chromatin,
Fir., 14.'!. Nerve cell from the spinal cord,
stained by Nissl's method.
a, axis-cylinder process or axon ; b, proto-
plasm of cell, consisting of c, fibrillated
ground substance, and e, the grannies of
Nissl ; d, nucleus. (Lenhossek.)
Fig. 144. The point of origin
of the axon, the ' nerve-
hillock, highly magnified,
to show absence of Nissl's
granules from the origin of
the process. (Held.)
which may be collected into one or two nucleoli. The body of the cell
presents different appearances according to the manner in which it has
been treated for histological examination. When separated from the sur-
rounding tissues by means of dissociating fluids it may present traces of
striation. the individual stihe running from one process to another of the
cell. "When treated fresh with methvlene blue, or hardened by alcohol
THE NERVOUS SYSTEM OF VERTEBRATES
301
or corrosive sublimate and stained with methylene blue or toluidine blue,
the protoplasm is seen to contain angular masses which are deeply coloured
with the dve (Fig. 143). These masses are known as the Nissl granules or
bodies. By other methods it is possible to demonstrate that the whole
protoplasm of the cell between the Nissl bodies is pervaded by fine fibrils,
which enter the cell from the processes and may run out of the cell by the
axon or may run into some of the other shorter processes (Fig. 146). The
processes of the cell, as is evident from their development, are of two kinds.
The axon which becomes continuous with the axis cylinder of the medullated
Figs. 145 and 140. Nerve cells from spinal cord. (Bethe.)
14."). showing Golgi network, and neurofibrils : . Spinal cord, [After Lenhossek.) (In left side of ti»\irc arc shown
the nerve cells with their axis-cylinder processes. On the right side the dis-
tribution of the chief collaterals.
I, motor cells ; 2, cells of the columns ;
processes across into direct cerebellar tract :
2a, cells of Clarke's column, sending
3, 4. and 5, commissural cells.
According to the destiny of their axons these nerve cells may be divided into four
groups (Fig. 155).
(1) THE MOTOR CELLS, the largest of all. which send their axons into the anterior
roots, where they run to supply skeletal muscle fibres. As a sub-group of these cells we
may class the somewhat smaller cells of the lateral horn, which in all probability send
their axons by the anterior roots to supply visceral muscles. Their axons can be
distinguished from the motor axons by the smaller diameter of the nerve fibres they
form. They pass later from the mixed nerve along a white ramus communicans into
the sympathetic system, in the ganglia of which they end.
(2) CELLS OF THE COLUMNS. As typical of these cells we may take those
which form Clarke's column. Their axons do not leave the central nervous system,
but pass out into the white matter to some other part of the central nervous system,
contributing thus to form the white columns of the cord.
(3) COMMISSURAL CELLS. These cells send their axon across the middle
line to the opposite side of the cord, making up a great part of the anterior white
commissure.
(4) CELLS OF GOLGI. These cells are found chiefly in the posterior horn. They
are multipolar and are distinguished from all the other cells by the fact that their
STRUCTURE OF THE SPINAL CORD
319
axon does not pass far from the cell, but rapidly breaks up into a number of blanches
which terminate in the near neighbourhood of the cell giving off the axon. They may
be regarded as association cells, i.e. as serving to establish a functional connection
between many different cells at any given level of the grey matter.
The white matter of the cord is divided by the fissures already described
into anterior, lateral, and posterior columris. The nerve fibres of which
it is composed are all of them axons of nerve cells situated at different levels
of the central nervous system or outside the cord. Since the whole object of
the study of the anatomy of the cord is the tracing out of the systems of
neurons of which it is made up, and therefore of the possible paths of any
reflexes or nerve impulses through the cord, a mere anatomical differentiation
of different columns is quite useless unless we can determine in each column
the origin and destination of the fibres of which it is composed.
IN II, i
ratral nervous
For tracing out the' course of the different axon system
system several methods are available.
(a) HISTOLOGICAL. Two methods may be employed for staining a nerve cell
with all its processes, namely, the intravitum staining with methylene blue and the
impregnation method invented by Golgi. In the latter method, of which there are
many modifications, the nervous tissue is hardened in some chromate or bichromate,
and is then soaked in a solution of silver nitrate or mercuric chloride. In this way
a precipitate of silver or mercuric chromate is formed within the nerve cells and their
processes ; but for some unexplained reason the impregnation is not general, and is
confined to a small percentage of the neurons. If
the precipitate were diffuse, even a thin section
would be absolutely opaque : since it is partial,
thick sections maybe cut and. after clearing, allow
the tracing of the processes of the few impregnated
nerve cells through the whole thickness of the section.
We may in this way get sections 01 mm. thick at
the point of entrance of a posterior nerve root, and
trace out the course and ending of a large number of
the fibres composing the nerve root, or we may in a r/i
section involving the anterior nerve root trace the
course of an axon of an anterior cornual cell out of
the cord into the root. This method is of no use in
tracing any given nerve fibre through the whole
length of the cord. For this purpose however
several methods are available.
(b) MYELINATION METHOD OF FLECHSIG.
Nerve fibres at their first formation as axons of a
nerve cell are non-medullated, the medullary sheath
being formed later with the beginning of function of
the nerve. It has been shown by Flechsig that I he
mvclination docs not occur simultaneously through
all parts of the central nervous system, but that it
is later in proportion as the nerve fibre is more
Fig. 156. Section through the cer-
vical spinal cord of a new-bora
child, stained by Weigert's
method, to show absence of
medullation in pyramidal tract.
,". anterior commissure ; Fp.
crossed pyramidal tract ; Fe, direct
cerebellar tract : Zrp. posterior
recent in the phylogenetic history of the animal. root zone ; rp \ posterior root
The cord in its most primitive form can be regarded fibres. (Bechterew.)
as a scries of ganglia presiding over the different
segments of the body. The most primitive fibres therefore would be those which run
from the periphery of the body to each segment and from each segment out to the
muscles, and so a medullary sheath is first formed in a number of the fibres entering
and leaving the cord in the nerve-roots. Next in order of myelination are those
320
PHYSIOLOGY
fibres which connect different segments of the cord, the internuncial or intra -spina I
fibres. Next come those fibres which connect the spinal cord with the cerebellum.
Last of all to receive a medullary sheath are the fibres which take a direct course from
the cerebral cortex to the spinal cord. These are called the pyramidal tracts, and in
man arc not medullated until flic first month after birth (Fig. 156).
(c) THE WALLERIAN METHOD. A nerve fibre, when cut off from the nerve
cell of which it is a process, degenerates. This degeneration is marked by a breaking
up of the medullary sheath and a conversion of the phosphorised fat, myelin, of which
it is composed, into ordinary fat. Later on the fat is absorbed and the nerve becomes
replaced by a strand of fibrous tissue in the case of peripheral nerves, of neuroglia
in the central nervous system. If the white matter of one half of the spinal cord be
divided in the dorsal region, and the animal be killed about three weeks after the opera-
tion, sections of the cord both above and below the lesion will show the presence of
degenerated fibres. In order to display these fibres pieces of the cord are hardened
in a solution containing bichromates and are then immersed in a mixture of osmic
FlG. 157. Cells from the oculo-motor nuclei thirteen days after section of the
nerve on one side.
a, cell from healthy side ; 6. cell from side on which nerve was
divided. (Flatait.)
acid and bichromate. By this method ordinary fat is stained, but myelin is left un-
stained (Marehi's method). Degenerated fibres are therefore stained black in virtue
of their content in fat. The black staining has different distribution according as we
take a section of the cord above or below the lesion. The existence of the degeneration
shows that those fibres which are degenerated in the cervical region are axons of nerve
cells situated below the lesion, while the fibres in the lumbar cord which are degenerated
must have their nerve cells in some part of the nervous system which is above the
lesion. If the animal be kept alive for a considerable time, six months or more, before
being killed, the occurrence of degeneration in any given area of the cord will be shown
by the absence of normal nerve fibres in this area. In such a case some method of
staining the medullary sheath, such as that of Weigert or Heller, is employed, when the
degenerated area will be evident owing to its inability to take the stain. This method
however is not so satisfactory as the Marchi method, since it is impossible in this way
to detect in a section the presence of one or two degenerated nerve fibres, whereas
by the use of the Marchi method they would appear as black dots in the unstained
section (cp. Fig. 164).
(d) METHOD OF RETROGRADE DEGENERATION. When a nerve fibre is
divided there is no degeneration as a rule in the part of the nerve fibre central to the
lesion. The nerve cell is however affected, and the extent to which this occurs is
STRUCTURE OF THE SPINAL CORD 321
more pronounced according as the lesion is nearer to the cell (Fig. 157.) If, for instance,
an anterior root be divided and three weeks later the animal be killed and sections made
of the corresponding segment of the cord and stained with toluidine blue or methylene
blue, a striking difference will be observed between the cells of the anterior horn of
the two sides of the cord. On the side of the lesion the nucleus of the cells will be
somewhat swollen, and may be displaced towards the periphery of the cell. The Nissl
granules are no longer distinct, but the whole cell is diffusely stained blue. In some
r;isrs this change may go on to complete atrophy of the cell and consequent degenera-
tion of the whole of its axon. Generally however the cell gradually recovers, so that
six months after the lesion no difference will be observable between the cells on the
two sides of the cord. This method must be used with some caution as a means of
tracing out the connections of any given neurons in the central nervous system, since
it has been shown by Warrington that somewhat similar changes may be produced
in the anterior horn-cells by division of the posterior roots, thus cutting off those im-
pulses by which their activity is normally excited. Here we have a lesion applied to
one neuron causing a histological change in the cell body of another neuron which
is next in the chain of the nervous arc.
The structure of the cord is closely connected with and determines its two-
fold function, namely, as a series of reflex centres for the different segments
of the body, and as a means of communication between the trunk and limbs
and the higher parts of the central nervous system. An examination of the
relative area of the white matter at different levels of the cord shows a
steady increase from the lower to the upper end. The increase is not how-
ever proportional to the number of fibres which enter or leave the cord in the
various spinal nerve roots. Of these fibres therefore a certain proportion are
destined to serve merely the local segmental reflexes, while others are con-
tinued directly upwards to the brain or are connected with cells which them-
selves send their axons up to the brain (cells of the columns). All the motor
fibres in the nerve roots arise from cells in the spinal cord near the point of
origin of the root. Any direct influence of the brain on the motor mechan-
isms of the body is therefore effected through the intermediation of the
segmental neural mechanisms of the grey matter of the cord. We will
consider the function and related structure of the cord in these two aspects :
first, as a reflex centre, and secondly, as a conductor of impulses to the
higher parts of the central nervous system.
■21
SECTION VII
THE SPINAL CORD AS A REFLEX CENTRE
In the evolution of the cord the primitive segmental arrangement has been
especially interfered with by the development of the four limbs. Since
the reactions of the limbs transcend in importance and complexity those of
the rest of the body, a great enlargement of the cord has occurred in the region
of the nerve roots which supply the limbs. Each limb must be considered
as produced by the fusion of a number of body segments, in which the
morphological segmental arrangement has entirely given place to a physio-
logical one. Thus no single muscle of the limbs is innervated from one
nerve root, every muscle being formed from elements belonging to several
segments and innervated from several nerve roots. The segmental arrange-
ment of the cord is hidden moreover by the increasing complexity of the spinal
reflexes and the consequent involvement of many segments in even the
simplest reactions. As we shall see later, practically no reflex can be
evoked, even by stimulation of one nerve fibre or nerve root in any of the
vertebrata, which does not involve in its response elements belonging to many
segments.
Since the reactions, which can be carried out by any part of the nervous
system, depend on the neurons of which the part is composed, it is necessary,
before treating of the reactions of the spinal animal, to consider the ' way in '
to and the ' way out ' of the centre, as well as the connections between the
entering and issuing paths. (Each segment of the cord gives off a pair of
nerve roots, subdivided into an anterior and a posterior root (Fig. 158). In
mammals it is easy to show that the posterior root is exclusively afferent in
function. Section of the root, either distal or proximal to the ganglion, pro-
duces no paralysis of any description. It may cause diminished sensation in
the area, supplied by it, andif two or three adjacent posterior roots be divided,
complete ana?sthesia results in the central part of the skin area supplied from
these roots. (.^Stimulation of the central end of a divided posterior rcot
evokes in a conscious animal signs of pain. In an animal possessing only
spinal cord and bulb, reflex effects are produced, i.e. movements of skeletal
muscles as well as effects on visceral muscles, such as constriction of blood-
vessels, relaxation of intestinal muscle, and so on. ' On the other hand,
section of an anterior root causes paralysis of muscles or parts of muscles.
Sestion of all the anterior roots going to a limb will produce complete
motor paralysis of the limb. Stimulation of the central end of a divided
322
THE SPINAL CORD AS A REFLEX CENTRE
323
anterior root has no effect. Stimulation of the peripheral end evokes con-
traction of muscles, and if the root experimented on be in the upper dorsal
region of the cord, certain visceral effects, e.g. dilatation of the pupil or
augmentation of the heart beat, may result.
To this general law, the law of Bell and Magendie; which affirms the purely afferent
function of the posterior roots and the purely efferent function of the anterior roots,
certain exceptions must be noted. In the first place, in the lower vertebrata the
separation of afferent from efferent fibres seems to be not so complete as in the higher
vertebrates. Thus in the chick Oajal and others have described fibres given off as
axons from the cells of the grey matter and leaving the cord by the posterior root.
The function of these fibres is unknown. In the frog Steinach lias stated that visceral
Flo. 158. Figures (from Yeo) to illustrate the degree and direction of degenera-
tion as a result of section of the spinal roots.
I, division of whole nerve below ganglion. IT, division of anterior root.
Ill, division of posterior root above ganglion. IV, division of posterior root above
and below ganglion.
effects may ensue on stimulation of the lower posterior roots. This statement is
controverted by Horton-Smith. who however has noticed contractions of fibres of
voluntary muscles as the result of stimulating these roots.
In a class by themselves we must place the vasodilator effects observed by Strieker,
Dastre and Morat, and Bayliss to follow excitation of the peripheral ends of the posterior
roots. Bayliss has shown that the fibres, through which the vasodilatation is produced,
must have their cell-station in the posterior root ganglia. It seems therefore that
the same fibres provide for carrying both afferent impulses from skin to cord, and vaso-
dilator impulses from the cord to the vessels of the skin. Bayliss has designated the
impulses which effect the vasodilatation as antidromic, since they are opposed in direc-
tion to the normal impulses of the nerve fibre. Of the same nature are the curious
trophic impulses which extend along the posterior roots and which must come into play
when eruptions of erythema or herpes occur as the result of inflammation or haemorrhages
in the substance of the posterior root ganglia. Both these phenomena are at present
but imperfectly understood ; and their anomalous character is only intensified by the
further fact elicited by Bayliss, viz. that it is possible, by stimulation of afferent nerves,
to excite reflexly vasodilatation through the intermediation of the posterior roots.
Unless this reflex dilatation is simply an example of an ' axon reflex ' (v. p. 275) it
would furnish an exception to the otherwise universal law of forward direction^in the
mammalian nervous system.
A third exception to the law of Bell and Magendie is only apparent. It is sometimes
found that excitation of the peripheral end of a divided anterior root gives rise to mani-
festations of pain or to reflex movement. This has been shown by Schiff to be due
to the presence, in the sheaths of the anterior roots, of fine fibres derived from the
posterior roots and taking a recurrent course to end probably in the membranes of the
cord. This recurrent sensibility is at once abolished by section of two or three adjacent
posterior roots.
524
PHYSIOLOGY
THE WAY IN
We may now consider the possible ways open to a nerve impulse entering
the cord. Each posterior root on entering the cord divides into two bundles.
The smaller bundle passes t<> the outer side of the tip of the posterior horn
where its fibres bifurcate (Fig. 159), giving
rise to fibres which pass up and down the
cords in a. small longitudinal band of fibres
known as Lissauer's tract. The fibres run
only a short distance before turning into the
grey matter, and terminate in arborisations
round the cells of the substantia gelatinosa
in the head of the posterior horn. By far
the greater number of the posterior root-
fibres pass to the inner side of the posterior
horn into Burdach's or the postero-external
column. Here they also divide into two
main branches, one running up and the
other down in the white matter. The
descending branch passes through two or
three segments before turning into the grey
matter of the posterior horn of a lower
segment. Of the ascending branches, some
end at different levels of the cord, but a cer-
tain proportion of the fibres from every
root traverse the whole length of the cord
in the posterior columns to terminate in the
posterior column nuclei (nuclei gracilis and
cuneatus) in the medulla oblongata. As we
proceed up the cord the entering posterior
root-fibres displace the long fibres of those
below towards the middle line, so that in a
section through the cord in the upper cervical
region the posterior median column, or
column of Goll, is made up almost exclu-
sively of fibres from the hind limb, while
the postero-external column consists of fibres
from the fore limb.
Besides these distant connections, every
entering nerve fibre makes connection with
all parts of the grey matter in and about its level of entrance by means
of collaterals (Fig. 160). Five groups of these collateral branches can be
distinguished, i.t.,
(1) Fibres which arborise round cells in the posterior horn of the same
side.
(2) Fibres which pass through the dorsal grey commissure to the grey
matter of the opposite side of the cord,
FlO. 159. Longitudinal section
of spinal cord of chick, showing
bifurcation of dorsal root-
fibres, and the passage of their
collaterals into the grey matter.
Three cells of the dorsal horn
are also seen sending their
axons into the dorsal columns.
(Cajal.)
THE SPINAL CORD AS A REFLEX CENTRE
325
(3) Fibres terminating round the median group of cells of the anterior
horn.
(4) Fibres which end in a rich basket-work round the cells of Clarke's
column.
(5) The sensori-motor bundle, which passes forwards through the
grey matter to end round the cells in the anterior horn of the same side
of the cord.
Each entering posterior root fibre,
of its entrance, gives but few to
higher segments of the cord before
it terminates in the posterior column
nuclei. Sherrington suggests that
the cells of Clarke's column receive
fibres mainly from the ascending
branches of the nerve roots from the
posterior linib, a corresponding sta-
tion for the nerve fibres of the ante-
rior limb being represented by the
cells of the nucleus cuneatus.
That several different systems of
fibres are included in these roots is
shown by the different periods at
which they acquire their myelin
^sheath. Among the earliest to ac-
quire a sheath are the fibres which
end in the posterior horn and those
which pass to the anterior horn, wliile
the long fibres in the dorsal columns
do not become medullated until much
later in foetal life. Since the nerve
fibres of the central nervous system
do not become functional until they
have acquired a medullary sheath,
we must conclude that the reflex
responses affecting the segment in
which the fibres enter are developed
earlier than those which involve
also the activity of the cerebellum
and medulla.
besides these collaterals in the neighbourhood
M«|V gj
Fig. 160. Chief collaterals of dorsal column
fibres from new-bom mouse. (Cajax.)
a, intermediate nucleus ; b, anterior (ven-
tral) cornu ; c, dorsal or posterior cornu ;
c. substance of Rolando.
The primitive segmental character of the central nervous system is
retained in its pure form only in the segmentation of the dorsal spinal root
ganglia. Each of these ganglia or afferent roots consists of the fibres from
the sense-organs in a segmental area of the body surface as well as from
the muscular and visceral apparatus in the same segment. Section of one
dorsal posterior nerve root will cause a diminution of sensibility over a
band-like area corresponding to the distribution of the fibres of the root,
though to produce a complete insensibility the two adjacent nerve roots must
be divided, in consequence of the overlap of fibres at the periphery. In the
limbs the segmental distribution of the sensory fibres is distinguished with
more difficulty. Each limb must be regarded as made up from a series of
32 (i
PHYSIOLOGY
fused segments, from five to seven in number. The accompanying diagram
(Fig. 162) from Sherrington shows the manner in which the skin fields of
FlO. 161. Transverse section of spinal cord, showing collaterals terminating in a
rich arborisation round the cells of Clarke's column (a, b), as well as others
passing to the anterior cornua, and through the commissures. (Cajal.)
these segments are combined to make up the total skin area in the hind limb
of the monkey.
dorsal or uercO-oU rneditfi Uii£- of trunk'
LetieL jf !Ae omUUi
THE SPINAL CORD AS A REFLEX CENTRE
327
THE WAY OUT
Primitively the motor nerves also represent fibres passing from a col-
lection of ganglion-cells to the muscles of the corresponding bod)' segment.
In the dorsal region this segmental arrangement of motor nerve fibres is
still traceable in the adult anirr.al. In all other parts the morphological
has become subservient to a physiological arrangement. Every muscle of
the limbs contains elements from several segments, and is innervated there-
fore from several anterior spinal roots. Hence it follows that stimulation
of one anterior root produces no definite movement of a group of muscles,
but partial contraction of a number of muscles which do not normally con-
tract simultaneously. Thus stimulation of a sensory nerve may evoke
either flexion or extension of a limb, but not both simultaneously. Stimula-
tion of the motor roots will cause simultaneous contraction of both flexor and
extensor muscles. It is this subordination of morphological to physiological
arrangement in the limbs -which has necessitated the formation of limb
plexuses. The nerve root is a mor-
phological collection of fibres ; the
nerve issuing from a limb plexus
and passing to a group of muscles is
a physiological collection. When it
is stimulated it evokes a contrac-
tion of a group of muscles which
are normally synergic, i.e. co-
operate in various movements
The fibres passing to the skeleta
muscles are large, about 14 ^ to 19 p
in diameter, and their axis cylinder;
represent the axons of large nerve
cells in the anterior horn. In the
dorsal region of the cord in man,
from the second dorsal to the second
lumbar nerve roots, the anterior
loots contain, besides these coarse
fibres, a number of fine fibres about CIS ^ to 3'6 ft in diameter (Fig.
163). These fine fibres were shown by Gaskell to leave the nerve shortly
after the junction of the two roots, to pass as a white ram/us communiccms
to the sympathetic. Excitation of the white rami evokes various visceral
effects, such as dilatation of the pupils, augmentation of the heart,
contraction of blood-vessels, inhibition of the gut, erection of hairs, &c.
Gaskell pointed out that the outflow of these fine fibres coincided with
the existence of a prominent lateral horn in the grey matter, and sug-
gested that cells of the lateral horn might be regarded as the origin of the
visceral nerve fibres. This suggestion has been confirmed by Anderson,
who has shown that section of the white rami communicantes brings about an
alteration in the cells of the lateral horn as a result of retrograde degeneration.
<5§S^
Fio. 163. Section across the second thoracic
ventral nerve root of the dog (stained with
osmic acid) to show varying sizes of the con-
stituent fibres. (Gaskell.)
328
PHYSIOLOGY
CENTRAL PATHS OF SPINAL REFLEXES
The impulse entering the cord is thus able to affect immediately a number
of systems of neurons, namely, cells in the anterior horn, in the posterior
horn, in Clarke's column, in the substantia gelatinosa, in the lateral column of
the same side of the cord, and the corresponding groups of cells on the oppo-
site side of the cord either directly by crossing collaterals or indirectly through
III -T
ILL
V.S.
Fig. 164. Cross-sections of spinal cord of a dog, showing the descending nerve-
tracts originating in the first three thoracic segments (method of ' successive
degeneration'). The eighth cervical segment had been excised and 568 days
later a cross-cut was made at level of the tliird thoracic nerve. The extent of the
lesion is shown in the first figure (III. T). The other sections show the degenera-
tions as revealed tliree weeks later by Marchi's method. (Sherrington.)
cells which send their axons across the middle line. Through the ascending
and descending fibres of the posterior columns it can also set into action the
reflex mechanisms of adjacent segments of the cord. In addition to this
direct spread of afferent impulses up and down the cord there is an anatomical
basis for a co-ordination between the grey matter of different levels. This
co-ordination is effected through the intermediation of the internuncial or
intra-spinal fibres which pass up and down the cord from segment to segment.
The course of the descending fibres may be studied by carrying out a total tran-
section of the spinal cord at the sixth cervical vertebra, and six months later, when all
the fibres degenerating as a result of the section have disappeared, carrying out a further
transection or hemisection a few segments below the first transection. If the animal
be killed two or three weeks after the second operation it will be found that a number
of fibres in the white matter are degenerated below the second section (Fig. 164). These
fibres therefore must be derived from cells of the grey matter situated between the
levels of the first and second sections, and the}- can be traced down the cord through a
THE SPINAL CORD AS A REFLEX CENTRE ' 329
large number of segments. Analogous methods may be used for tracing the course of
the ascending intra-spinal fibres.
These intra-spinal fibres occur in the following situations :
(1) In the lateral columns immediately outside the grey matter, in the bay between
the anterior and posterior horns.
(2) Close to the grey matter in the anterior basis bundle.
(3) In the posterior columns, united with the descending branches of the entering
posterior roots in the comma tract, and also in the immediate periphery of the cord and
abutting on the posterior fissure in the septomarginal tract.
(4) Mingled with the fibres of the pyramidal tract.
All these tracts are mixed, i.e. contain both ascending and descending fibres. As a
rule, the longer the course of a fibre the more peripherally does it lie in the cord. The
shortest of the fibres may only unite segment to segment, while the longest fibres may
run through the greater part of the cord.
THE SPINAL ANIMAL
An animal possessing only a spinal cord contains a reflex neural apparatus
which can be excited to activity by impulses of various qualities and from any
part of the skin. Thus the afferent impulse may correspond to what in
ourselves we call tactile and be provoked by mechanical stimulation, or may
result from changes of temperature and correspond to those producing
sensations of heat and cold. Strong stimuli of any kind may give rise also to
afferent impulses which in the intact animal would have the quality of pain.
Since these stimidi are such as to produce injury if continued, they may be
named, when applied to the spinal animal, pathic or nocuous. The spatial
distribution of the stimulus will determine the situation and number of nerve
fibres set into action, so that there will be a great variation in the distribution
of the excited neurons of the central grey matter according to the quality,
distribution, and intensity of the stimulus. The efferent part of the reflex
is provided for by the connection of the anterior cornual cells to the whole
skeletal musculature of the body, as well as by the distribution of the axons
of the lateral horn-cells to the sympathetic system and through this to. the
viscera. On the other hand, if the spinal cord be separated from the medulla
oblongata and higher parts of the brain, it is deprived of all connection with
the most highly elaborated sense-organs of smell, sight, hearing, and equili-
bration, and also of the important afferent and efferent impulses which pass
between brain and viscera through the vagus nerves. In studying the
reaction of the isolated spinal cord we are studying a nervous system cut off
from its most complex components, but at the same tune deprived of the
initiation and guidance which it must normally be continually receiving from
the higher sense-organs through the brain. A study of the spinal animal
will therefore be instructive as a study of the mammalian nervous system in
its simplest possible aspect. It will in all cases be the study of an incom-
plete and maimed system, the incompleteness becoming more evident
as we ascend the scale of animals in our experimentation, owing to the
increasing subordination of the lower to the higher centres, and of the
immediate reflexes to the educated reactions of the anterior part of the
brain.
330 PHYSIOLOGY
SPINAL SHOCK
If the spinal cord of the frog be divided just below the medulla, for some
minutes after the section all four limbs are perfectly flaccid, and it is impos-
sible to evoke any reaction by the application of the strongest stimuli.
If the animal be left to itself for half an hour there is a gradual return of
reflex tone ; the animal draws up its legs and assumes a position not far
removed from that of the normal frog, the head being lower than under
normal conditions. We may say that the phenomena of shock in the frog
last only a short time. With increasing complexity of the nervous system
the phenomena of shock become more lasting, so that among laboratory
animals it is in the monkey that spinal shock is most apparent. It is in-
teresting to note, as pointed out by Sherrington, that shock appears to take
effect only in the aboral direction. Thus, even in the monkey, section
through the lower cervical region, though causing profound paralysis of the
lower limbs and part of the trunk, apparently has no influence at all on
the reactions of the nervous system above the section. ' The animal imme-
diately after the section will contentedly direct its gaze to sights seen through
the window or, if the section has been below the brachial region, may
amuse itself by catching flies on the pane. This is the more remarkable since
the profound depression of the nerve-centres below the point of section
extends also to the blood-vessels and viscera, so that there is a great fall of
blood pressure and diminished production with increased loss of heat. The
sphincters are flaccid or patulous, the skeletal muscles are toneless, and no
reaction is evoked by the strongest stimulus to the skin or to a sensory
nerve.'
Much discussion has arisen as to the duration of shock. Goltz and others
Imagined that the phenomena of shock may persist for months or even years.
According to Sherrington, in the higher animals the phenomena of shock are
complicated by the onset of an ' isolation dystrophy ' which may occur
before the condition of shock has entirely disappeared. In order therefore to
examine the capabilities of the isolated spinal cord at their best, a time must
be chosenrwhen the sum of shock and isolation dystrophy together is at its
minimum.
The occurrence of shock after complete transection of the cord in the
cervical region cannot be ascribed to the fall of blood pressure which ensues
as a result of the severance of the efferent vaso-motor tracts from the
vaso-motor centre in the medulla. The centres above as well as those below
the transection are equally exposed to the effects of the lowered blood pres-
sure, but it is oidy those below the section which show signs of shock. Nor
can it be regarded as operative shock due to the severity of the lesion ; such
an operative shock would be effective in either direction, and we do not
find that the method of transection, whether by tearing across the cord or
cutting it with a minimum disturbance, alters appreciably the amount of
shock displayed by the segment of the cord situated below the lesion. On
the other hand, if in a dog, which has undergone transection of the cord in the
THE SPINAL CORD AS A REFLEX CENTRE 331
lower cervical region and has been allowed sufficient time to recover from the
shock, a second transection be carried out two or three segments below the
site of the first operation, the influence of the second section is hardly notice-
able on the lower segment of the cord. Apparently then the chief factor in
determining shock in all those centres situated aborally of the lesion is the
cutting off of the impulses which are continually streaming down from the
higher centres and from the great sense-organs connected with the anterior
portions of the nervous system. With every rise in the animal scale the im-
pressions received by the special senses take an increasing part in the deter-
mining of all the reactions of the body, so that we might expect the effect of
cutting off the impulses from the higher centres to be greater, the higher in the
scale of life is the animal on which the experiment is carried out.
The state of profound shock produced in the spinal cord by the operation
passes off gradually. The blood pressure, which may have fallen to 40 or
50 mm. Hg., rises within two or three days to its normal height, i.e. 80 to
I 1(1 mm. Hg. The sphincter muscles of the anus gradually recover their
tone, and within a short time the reflex evacuation of the bladder and rectum
may occur as in a normal animal. The skeletal muscles recover their tone
within a few days, and after a short time co-ordinated movements can be
brought about in the trunk and limbs by appropriate stimulation of sensory
surfaces. At first the reactions thus produced are feeble and the reflex is
rapidly fatigued. Of these reflexes those excited by nocuous or painful
stimuli are the first to make their appearance ; a little later are seen those
due to stimuli affecting the tactile organs in the skin, or the sense-organs of
deep sensibility situated round the bones and joints and excited by deep
pressure or changes in posture of the limbs.
In a dog which has undergone complete cervical transection two or three
months previously, the tone of the muscles is somewhat increased. Although
the dog is unable to walk, if it be raised and given a little push forward, so
as to stretch the extensor muscles of its hind limbs, it may take two or three
steps forward before its legs collapse. Although the locomotor apparatus
is present, the nexus is lacking which determines the regulation of these move-
ments through the organs of static sense, so that the spinal movements are
insufficient to maintain the animal in such a position that a line drawn verti-
cally from its centre of gravity shall fall between its points of support. On
the other hand, swimming movements may be carried out regularly. The
frog deprived of its brain can swim like a normal animal, but in consequence
of the depression of its head tends to swim ever deeper in the water. If a
' spinal ' dog be held up by the fore lhnbs, the hind limbs nearly always enter
into alternating movements of flexion and extension (' mark time ' move-
ments), the two limbs acting alternately as in normal progression. The
stimuli in this case seem to be started by the stretching of the skin and other
structures at the front of the thighs. In such animals three reflexes,
amongst others, can be excited almost invariably, viz. :
(1) Scratch reflex. Gentle stimulation, mechanical or electrical, of any
point over a saddle-shaped area on the dorsum behind the shoulders (Fig.
332
PHYSIOLOGY
THE SIMPLE REFLEX
105) causes rhythmic movements of flexion and extension of the hind limb of
the same side, the effect of which would be to scratch away the irritant
object. These movements are repeated at the rate of about four per second.
(2) Flexor reflex. Nocuous stimuli, such as the prick of a needle applied
to any part of the foot, causes flexion of the leg and thigh, often accompanied
by extension of the op-
posite hind limb.
(3) Extensor or ' stej>-
ping ' reflex. Gentle pres-
sure applied to the plan-
tar surface of the hind
foot, especially if the
limb is somewhat flexed,
causes a movement of
extension of the limb,
accompanied sometimes
by a flexion of the oppo-
site hind limb.
In such an animal the
carrying out of the vis-
ceral reflexes may be very
efficient. The blood pres-
sure has attained its
normal height and may
be altered reflexly in very
much the same way as in
Fig. 165. A. The receptive field, whence the scratch a normal animal, although
reflex of the left hind limb can be evoked. , , , i,
_ _. . , , , „ the medullary vaso-motor
B. Diagram of spinal arcs involved. L, afferent path
from left foot ; B. afferent path from right foot ; bo, b/3, centre Can no longer be
receptive paths from hairs on ' scratch area ' ; fc, final concerned Thus in the
common path (motor neuron) ; pa, pS, proprio-spinal neu- .. " . , ,»„. •
rons. (Sherrington.) diagram (Fig. Ib6) is re-
presented the effect on the
blood pressure of exciting the central end of the digital nerve in a spinal
dog. The pressure rises from 90 to 208- mm. Hg. — a pressor effect as
great as any which can be obtained in an animal still possessing all the con-
nections of the vascular system with the vaso-motor centre. The height
of the rise shows that as regards the influence on the blood pressure the
spinal cord must be acting as a whole. No effect on the blood-vessels confined
to the segment, or segments, adjacent to that of the nerve stimulated would
suffice to cause a rise of more than a few mm. Hg.
The reflex apparatus for other visceral functions seems to be equally
perfect. The urinary bladder, when sufficient urine 'is accumulated, con-'
tracts forcibly, the contraction being accompanied by relaxation of the
sphincter and followed by rhythmic contractions of the urethral muscles ;
accumulation of faeces in the rectum leads to their normal evacuation. With
a little assistance impregnation may be effected in or by such a maimed
THE SPINAL COED AS A EEFLEX CENTEE 333
animal, and in the female may result in normal parturition which goes on to
full term. Pregnane}- is accompanied by hypertrophy of the mammary
glands and is followed by secretion of milk, so that the young may be suckled
Fig. 166. Blood pressure tracing from a spinal dog. The signal indicates the
time during which the afferent nerve was stimulated. (Sherrington.)
as in a normal animal. Similar phenomena have been observed in the human
subject.
Such an animal furnishes us with an opportunity of analysing the factors
which are involved in the maintenance of muscle tone, as well as in the carry-
ing out of the simplest reflexes involving contractions of the skeletal muscles.
MUSCULAR TONE
Every muscle in the body is in a condition of slightly continued contrac-
tion which keeps it tense, so that when it contracts in response to a stimulus
there is, so to speak, no ' slack ' to be taken up before the muscle begins to
pull on its attachments. This tone is seen in the retraction undergone by
muscles or tendons when they are divided in the living animal.
If a frog possessing only spinal cord be hung up by its jaw, the limbs will
be observed to occupy a position which is short of complete extension. The
tone of the muscles which is concerned in the maintenance of this attitude is
at once abolished by the destruction of the spinal cord. It may be abolished
on one side by section either of the anterior roots going to the muscles, or of
the posterior roots coming from the muscles (Fig. 167). In the intact
animal muscle tone is diminished by disease and may be abolished during
profound anaesthesia, as it is indeed in the condition of shock.
Much light has been thrown on the factors which determine muscular
tone by a study of the ' tendon phenomena ' of which the knee-jerk is the
most familiar example. If the leg is allowed to hang loosely in a position
of slight flexion at hip and knee and the patellar tendon be struck, the
extensor muscles of the thigh contract and raise the leg. This phenomenon
is known as the knee-jerk. Similar ' tendon reflexes ' can be obtained in
334
I'llYSloLOCY
other muscles, such as the fcendo Achillis, the triceps, and the extensor
muscles of the wrist, but with not so great ease as is the rase with the knee.
The knee-jerk is not altered by rendering the tendon anaesthetic by section
of all its nerves. The essential feature is a slight passive increase of the
tension to which the muscle is already subjected. Mere tension of the
muscle is not however the only factor. The tone which is reflexly
maintained in the muscle is necessary for this response to direct stimulation
In take place. The knee-jerk is therefore of special im-
portance as an index to the tonic condition of the
muscles concerned, being brisk and easily elicited when ~
1 j the tonus is pronounced, and slight or absent when the
\ j y tone ill the muscle is depressed.
The tone of the muscles, as well as the consequent
tendon phenomena, is dependent on the integrity of
the reflex arc governing the muscles in question. It
has been shown by Sherrington that the afferent part
of the arc is represented by the afferent nerves from the
muscle itself, and that these nerves receive their sense
impressions from the special nerve-endings characteristic
of muscle — the ' muscle-spindles." Even in the purely
i Muscular nerves a large proportion of the fibres are
afferent in function and, after section of the appro-
priate posterior roots distal to the ganglia, as many as
10 per cent, of the fibres going to a muscle may be
found degenerated. Though most of these have the
muscle-spindles as their destination, a certain number
pass to the tendon and aponeuroses connected with the
muscle, where they end in the end-organs known as the
organs of Golgi and the organs of Ruffini. After sec-
tion of the motor nerves the muscle fibres degenerate,
Fig. L67. Hind part, w Jth the exception of the modified fibres which, enclosed
hung up ma |iy The in a connected tissue sheath, are concerned in the forma-
jaw. The posterior f[ on f the muscle-spindles. Muscle tone and tendon
roots of the nerves , ,, r , , ,. , , , , • ,■
to the left hind phenomena may therefore be abolished by lesions ot
limb have been afferent nerves, which leave a considerable part of
(Bechterew.) the cutaneous sensibility of the limb intact. In man
the spinal reflex mechanism connected with the knee-
jerk is situated in the third and fourth lumbar segments. The jerk may be
abolished by section of the third and fourth posterior nerve-roots, although
tu render the whole hind limb anaesthetic it would be necessary to divide all
the roots from the second lumbar to the fourth sacral inclusive.
The extremely short period which elapses between the moment of striking
the tendon and the contraction of the muscle, which was found by Gotch
to be only about "005 second, has been thought to prove that the tendon
reflex must be due to direct stimulation of the muscle and could not be
of the nature of a true reflex. It was therefore suggested that the func-
THE SPINAL CORD AS A REFLEX CENTRE 335
tic hi of the reflex arc was to keep the muscle in a state of wakefulness,
ready to respond to the slightest local stimulation.. No one has however
succeeded in imitating, by a slight continuous stimulation of the motor
nerve or otherwise, this reputed action of the reflex arc, and recent re-
searches by Snyder and by Jolly indicate that, in spite of the rapidity of
the response, the knee-jerk may nevertheless ho a true reflex action, and
in fact the most rapid reflex known.
Jolly, using the string galvanometer, has taken the current of action in the vastus
interims muscle as an index of the commencing contraction of this muscle in the knee-
jerk. He has also by the same method, by leading off the afferent and efferent nerves
respectively, measured the lost time in the sense-organs and in the motor end-plates
of flic muscle. In the spinal cord lie obtained the following electrical latencies in one
case :
Latency of knee-jerk ..... 5-3l the
animal as a whole. Since the nerve path involved in any reaction includes a
number of synapses, each of which may be influenced from other parts of the
body in a positive or negative direction, an absolute uniformity of response
cannot be predicated for any one reaction. There will be changes in the
facility with which it is evoked and changes in its extent, and these will
become the more operative the greater the complexity of the arc, and the
larger the number of other impulses to which it may be subject. The
fatality of response is therefore shown only at its best in the very simplest
of reflexes, or the most lowly organised nervous systems.
The purposive character of the reflexes obtained from the spinal frog has some-
times led writers, especially in pre-Darwinian days, to endow the spinal cord with a
guiding intelligence. At, the present time we recognise that every reaction of a living
being must be purposive, in the sense of being adapted to the preservation of the species,
if the latter is to survive in the struggle for existence. The question as to whether
we are justified in predicating the existence of even a germ of consciousness or volition
in the spinal animal must be decided in the negative. " Associative memory would
seem to be a postulate for the very existence of perception. Where even simplest
ideas are not, there cannot be consciousness. Animal movements that are appropriate
not only for an immediate but also for a remote end indicate associative memory.
THE MECHANISM OF CO-ORDINATED MOVEMENTS 345
The approach of a dug in answer to the falling of its name, the return of an animal
when hungry to the place where it has been wont to receive food, such movements
may be taken as indicative of consciousness since they indicate the working of associative
memory. Examined by this criterion all purely spinal reactions fail to evince features
of consciousness " (Sherrington).
THE PART PL*¥ED BY AFFERENT IMPRESSIONS IN THE CO-
ORDINATION OF MUSCULAR MOVEMENTS. Every reflex act is initiated
in the first place by some form of sensory stimulus. In the carrying out of
the muscular contractions and the resultant movements of the limbs, other
impulses are set up in the structures which subserve deep sensibility, in-
cluding those of muscles. These secondary afferent impulses in their turn
affect the excitability and the activity of the motor neurons, and are im-
portant whether the movements be aroused by immediate sensory stimula-
tion of the surface of the body, or through the higher parts of the brain,
as in volitional movements.
Their significance is shown by the marked disorders of movement pro-
duced in a limb by section of some or all of its afferent nerves. Thus if
all the posterior roots supplying one hind limb of the frog be divided, the
posture of the desensitised limb is abnormal, whether the frog be suspended
or be hi a sitting posture. Such a frog generally swims with the desensitised
limb in permanent extension. The complete absence of muscular tone under
these circumstances has already been mentioned. When a contraction of
the quadriceps extensor is induced by a single shock applied to the intact
motor nerve, the curve obtained shows a relaxation line much slower and
more prolonged than when the cut nerve is similarly excited. In the latter
case, or when the posterior roots alone are divided, the lever at the end of re-
laxation dips below the base line with an inertia fling, which is never present
while the nerve is intact. The contraction of the muscle, when its afferent
path is intact, seems to develop reflexly in the muscle itself a condition of
tone which damps the inertia swing of the contraction. In the dog, after
section of the afferent nerves of one hind limb, this limb is not at first used
for walking ; it is kept more or less flexed at hip and knee, and later, when
it is employed in walking, it is lifted too high with each step. After division
of the afferent fibres of both limbs these appear as if they were affected
with motor paralysis. At first, during walking, the fore limbs simply drag
the hind limbs after them, though later, as the hind limbs are drawn along,
they make alternate movements and may ultimately afford a certain amount
of support to the body.
Still more striking effects are observed in complete apaesthesia of the fore
limb in monkey or man. The limb is permanently paralysed ; it is never used
in climbing or in the taking of food. That the peripheral motor mechanism
is intact is shown by the fact that stimulation of the appropriate area of the
cerebral cortex in such animals elicits at once a perfectly normal movement
of the hand or limb. It seems however impossible for the cortex to initiate
Hi 1 1 movements in the absence of all afferent impulses arriving from the limb.
Similar paralysis was observed by Chas. Bell in the upper lip of the ass after
346 PHYSIOLOGY
section of the corresponding branches of both lift h nerves, and was interpreted
by him as indicating a possible motor function for these nerves.
In these phenomena of sensory paralysis we are dealing with the effects
produced by the deprivation of two distinct classes of afferent impressions,
viz. those from the skin and those from the deep structures and muscles.
The phenomena due to these two factors may be studied separately. If in the
monkey all the afferent brachial roots except the last cervical, which supplies
cutaneous sensations to the whole hand, be divided, the monkey uses the
arm and hand both in climbing and in taking food. A marked ataxy of the
movement is however observed. Whereas the normal monkey, in taking
grains of rice out of the observer's hand, exhibits perfect precision of move-
ment so that he rarely touches the hand on which the grains are lying.
the monkey with only cutaneous sensibility remaining grasps clumsily with
the whole hand, and the arm sways as it is put out, often missing the object
aimed at altogether. Cutaneous insensibility of the hind limb causes very
little disturbance of locomotion, the alternate movements ot which seem to be
started by the stretching of the structures at the front of the thigh. On the
other hand, a patient affected with such a loss may be the subject of ' static-
ataxy,' i.e. he is unable to stand with his feet together and his eyes shut.
The afferent impressions from the skin of the feet appear therefore to be
necessary for the maintenance of static equilibrium.
In the carrying out of co-ordinated movements, such as those of loco-
motion, the impressions from the muscles play a more important part.
Division of the afferent nerves from the muscles gives rise to a condition of
tonelessness, and the passive mobility of the joints is greater than usual, so
that the hip with the limb extended at the knee may be flexed to an abnor-
mal extent. The effect of this loss of tone is more apparent in the case
of certain muscles. The disturbance of co-ordination resulting from the
cutting off of afferent muscular impressions is well seen in cases of tabes
dorsalis, or locomotor ataxy, in man, and to a slighter extent in cases of
peripheral neuritis affecting chiefly the sensory nerves of rauscles. The
ataxic gait of such patient is characteristic. There is no loss of power in
the muscles, but there is loss of control. The patient is unaware of the
position of his limbs and has to guide his walk by visual impressions ; even
then the movements are inco-ordinated. The contraction of every muscle
is exaggerated, so that in walking the leg is first raised too high and then is
brought down on to the ground with a stamp. As thedisease progresses the
loss of control becomes more and more pronounced, so that attempts to walk
simply give rise to a profusion of disordered movements, the legs being thrown
in all directions with the patient's efforts, but with no effective result. The
centres are no longer informed of the degree to which each muscle is con-
tracted, and the impressions are wanting which should cut short the con-
traction of a muscle when it has attained its optimum, and which should
inhibit the antagonists during the contraction and induce activity of the
antagonists in successive alternation to those of the other muscles. In such
a patient therefore walking finally becomes impossible and, with well-
THE MECHANISM OF CO-ORDINATED MOVEMENTS 347
nourished muscles and a motor path which is intact, he is condemned to pass
the rest of his days in bed.
THE EFFECT OF POISONS ON THE SPINAL CORD
The reflex functions of the spinal cord may be abolished by the same
drugs, such as ether, chloral, &c, which abolish conductivity in a nerve
fibre. The central effect of these drugs is obtained with much smaller con-
ARM '-'-
BODY
prosthotonic
NECK .
turning
NECK
retraction
Fia. 173. Diagram by Sherrington to show influence of tetanus toxin on the
response to excitation of the motor area of the cortex in the monkey.
A, normal animal. B, after poisoning with tetanus. F and / = flexion of leg
and arm respectively. E and e signify extension. < signifies opening of mouth ;
= signifies closing of mouth.
centrations than is the case with the peripheral nerves. Hence their value
as general anaesthetics.
More interesting from the point of view of the physiologist is the action
of such a drug as strychnine, or the somewhat similar action of the toxin
formed by the tetanus bacillus. If a small dose of strychnine be injected
into a spinal frog, after a short period of heightened irritability the slightest
stimulus applied to the surface will cause spasms, which may affect every
348 PHYSIOLOGY
muscle in the body. Pinching the foot, instead of causing it to be drawn up
now causes the lens, arms and back to be rigidly extended. The extension
is not a co-ordinated act, but is associated with strong contraction of the
flexi >rs, the final position of the Limbs being determined by the preponderating
strength of the extensor muscles. The real meaning of this condition is seen
if, in a spinal mammal, the extensor muscles be connected with a lever and
the flexor muscles cut. < >n exciting the flexor reflex by pricking the foot,
there is instantaneous relaxation of the extensor muscles. A small dose of
strychnine is now given, insufficient to cause general convulsions. It is now
found that on pricking the foot the extensor muscles respond, not with
inhibition, but with a contraction. Strychnine acts by abolishing the
inhibitory side of every co-ordinated act and converting the process of
inhibition into one of excitation. Co-ordination therefore becomes an im-
possibility-, and stimulation of any spot excites contractions not only of the
appropriate muscles but also of the antagonists of these muscles, the direction
of the resulting movement being determined simply by the relative strength
of the two sets of muscles.
The same effect is produced by tetanus toxin and, since the action of this
toxin may be confined in its early stages to one limb, it is possible to show
the abolition of the inhibitor side of the reflexes in this one limb while the
limb of the other side reacts normally to the stimulus. The same abolition of
inhibition is found whether the response be excited by stimulation of the
skin or by voluntary excitation from the cortex of the brain. Thus in the
monkey, on stimulating the- cortex, opening of the mouth may be excited
from all the spots marked " <^ " in the diagram, closure being obtained only
from those spots marked " = " (Fig. 173). Under the influence of the
tetanus toxin excitation of every one of the spots, whether " <^ " or " =,"
causes closure of the jaw. It is impossible for a patient under these circum-
stances to open his mouth, because every willed impulse for opening in-
nervates at the same time the stronger masseter muscles and effectively
closes the mouth.
SECTION IX
TROPHIC FUNCTIONS OF THE CORD
The reflexes which are excited by painful or nocuous stimuli must be
regarded as prepotent in that their inhibitory efiect on other reflexes is
more marked than that produced by any other quality of stimulus. In the
struggle for existence the reaction to nocuous stimuli must predominate over
those due to any other kind, since it is essential for the survival of the animal
that the stimulus should be removed or avoided, so that the animal should
escape from its injurious effects.
It is natural therefore that after complete section of the afferent nerves
from any part of the surface of the body there should be a tendency to
trophic disturbances, such as the formation of ulcers. &c. Such ulceration is
lie; jiiently observed in patients suffering from spinal disease. After section
of the first division of the fifth nerve ulceration of the cornea is often produced.
These effects are however merely due to the absence of the normal protective
reactions of the part, and can be prevented by scrupulous cleanliness and
protection of the apsBsthetic part from all possible injuries. There are other
trophic effects caused by nerve lesions which cannot be ascribed to the mere
absence of protective reflexes. Thus inflammation of the. posterior root
ganglia often sets up herpes roster, or ' shingles,' in the region of cutaneous
distribution of the corresponding sensory nerve. Changes in the skin ( ' gL issy
skin ') nails and hair are often seen after irritative injuries of nerves to the
part. Section of a motor nerve causes rapid changes in the skeletal muscles
supplied, which become smaller and after months or years may disappear
altogether, beinj; replaced by connective tissue. The changes in the excita-
bility of the muscles produced under these circumstances have already been
described.
It seems that the nutrition of a tissue is determined by its activity, and
this in turn is under the control of some nerve path. Section of the nerve
path, by cutting away the impulses which normally maintain the activity of
the part, must at the same time seriously affect its nutrition. Thus the
muscles which, though striated, are not so immediately under the control
of the central nervous system, such as the sphincter ani. do not undergo
degeneration after section of their nerves, or after extirpation of the lower
part of the spinal cord.
On the other hand, it is only during post-fcetal life that the activity of
the skeletal muscles is determined by the motor nerves of the cord. Thus
349
350 PHYSIOLOGY
they may be developed normally even in the complete absence of a central
nervous system. Whether we are justified in assuming the existence of
trophic nerves exercising an influence on the nutrition of the part they supply,
apart from any influence on its other functions, the experimental evidence
before us is not sufficient to decide ; nor can we as yet give a physiological
analysis of the changes in nutrition which may be brought about in hysterical
patients under the influence of eihotion.
SECTION X
THE SPINAL CORD AS A CONDUCTOR
The nervous system is built up of chains of neurons which subserve reactions
of varying complexity. The complexity increases with the interference of
the higher parts of the brain in the reactions and becomes therefore more
and more marked as we ascend the animal scale. Whatever the course taken
by the impulses in the central nervous system they must all finally make use
of the motor common path, represented by the anterior spinal roots and by
the motor roots of the cranial nerves.
The co-operation in any co-ordinated movement of widely separated
portions of the central nervous system necessitates the existence of long
paths, i.e. the axons of certain nerve cells must extend through a considerable
distance in the central nervous system before they arrive at the next relay
in the chain of which they form part. During this course the axons run in
the white matter of the central nervous system and are surrounded by
medullary sheaths. The white matter of the cord consists almost exclusively
of medullated nerve fibres running for the most part longitudinally. These
are of various sizes, some of the smaller fibres being collaterals, which have
been given off from the larger ones and which will shortly turn into the grey
matter. In section they resemble closely the fibres of an ordinary peripheral
nerve, but differ from these in that they have no primitive sheath or neuri-
lemma. Each consists of an axis cylinder surrounded by a thick sheath of
myelin, the whole embedded in a tube formed by the neuroglia.
Of these fibres part belong to the spinal cord, the proprio-spinal or
interimiicial fibres, which we have studied previously. The greater number
serve to establish connection between the grey matter of the cord or the
afferent roots entering the cord and the different levels of the brain, and these
fibres may carry impulses either up towards the brain or down towards the
spinal cord ; they may be ascending or afferent, so far as the brain is con-
cerned, or descending and efferent. No fibre takes an isolated course on its
way through the cord ; practically every one sends off fine branches or
collaterals, which run into the grey matter at various levels, there making
connection or having synapses with the local reflex mechanisms contained in
each segment.
On inspection the white matter is seen to be divided by* the anterior
and posterior fissures of the cord into two symmetrical halves, and the
nerve i -uots divide each half into anterior or ventral, lateral, and posterior
351
352 PHYSIOLOGY
or dorsal columns. On account of the scattered distribution of the anterior
mot fibres over a considerable area of the surface of the cord, the division
between the anterior and the lateral columns is ill defined, and the whole
region is often called as the antero-lateral column. In the cervical and
upper dorsal region of the cord, slight grooves' on the surface of the cord
indicate a division of the anterior column into the antero-median and antero-
lateral columns, and of the posterior column into the postero-median and
postero-lateral columns. These two posterior columns are often designated
as the columns of Goll and Burdach. In order to determine the origin,
course, and destination of the fibres which make up these white columns, we
must have recourse to the indirect methods of development and of degenera-
tion which were described on p. 319. By these means we may divide
the white matter into ascending and descending tracts. An ' ascending '
tract means, not that the direction of conduction of the impulse is necessarily
in the upward direction, i.e. from spinal cord to brain, but that the nerve cell
which gives off the fibres sends its axons towards the brain, while a descending
fibre in the cord is the axon of a nerve-cell situated in the upper part of the
cord or in some part of the brain. If the assumption which we have made
as to the normal direction of conduction in axons and dendrites be correct,
an ascending fibre will also conduct impulses in an ascending direction.
After section of the cord, say in the mid-dorsal region, transverse sections
of the cervical and lumbar regions of the cord, taken at the appropriate
period after the lesion has been inflicted, show patches of degenerated fibres
in the white matter. The fibres which are degenerated above the section
represent the ascending tracts, whereas those which degenerate below the
section, i.e. in the lumbar region, are the descending tracts of the cord (cp.
Figs. 174 and 175).
In this way the following tracts have been distinguished :
A. DESCENDING TRACTS
(1) PYRAMIDAL TRACTS. If the spinal cord be divided in the upper cervical
region, degeneration of two distinct tracts on each side, in the anterior and postero-lateral
columns, is produced. These are the anterior or direct and the crossed pyramidal
tracts. The fibres composing these tracts are derived from large nerve-cells in the
motor area of the cerebral cortex, and therefore degenerate if the motor area of the cortex
is destroyed. The pyramidal tracts are derived from the cerebral cortex of the opposite
side, having crossed the middle line at the lower level of the medulla oblongata in the
pyramidal decussation. The anterior pyramids represent a certain number of fibres
which have not crossed with the others, but continue the course of medullary pyramids
for a time, crossing gradually by the anterior commissure on their way down the cord,
so that as a rule they come to an end in the mid-dorsal region, all the fibres having
passed into the lateral columns of the opposite side. A few fibres of the pyramids on
their way from the cerebral cortex pass into the lateral columns of the same side ; these
are the uncrossed pyramidal'Iibres. The greater number of the fibres however finally
reach the crossed pyramidal tracts, in which they can be traced as far as the lower end
of the cord. They end iu the spinal cord by turning into the grey matter where they
break up into a fine bunch of fibrils in close connection with the motor cells of the
anterior horn or, according to Schafer, with the cells of the posterior horn.
THE SPINAL CORD AS A CONDUCTOR
353
On their way down the cord they give off fine side branches or collaterals, which
run into the grey matter, thus establishing connections between one cortical cell and the
anterior cornual cells of several different segments of the spinal cord. These fibres
carry voluntary motor impulses from the cerebral cortex to the reflex motor mechan-
isms of the cord. Their destruction by disease, or otherwise, causes the abolition
of voluntary control over the muscles, without however interfering with the reflex
motor functions of the cord which.
as a ma iter of fact, are increased in ^-- ^ -^ ^e*zzz^xrr& >
cases where these tracts have under-
gone degeneration.
(2) RUBROSPINAL OR PRE-
PYRAMIDAL TRACT (also called
Monakow's Bundle). This is a fairly
compact group of fibres which degene-
rate downwards after section of the
cord. It is situated, in cross-section,
ventral to the pyramidal tracts. Its
fibres can be traced up to the cells in
the red nucleus, a mass of grey matter
in the mid-brain lying ventrally to
the nucleus of the third nerve. Thev
are probably chiefly concerned with Fl0 " 17 f: Diagram (/r^ SonAFER) showmg the
ascending (right side) ana the descendmg (left
carrying motor impulses involving
maintenance of posture, and are the
main efferent channels of the cere-
bellum — red nucleus co-ordinating
mechanism .
side) tracts in the spinal cord.
1, crossed pyramidal ; 2, direct pyramidal ;
3j antero-lateral descendmg ; 3a, spino-olivarv
descending (bundle of Helweg) ; 4, pre-pyramidal
(rubro-spinal) ; 5, comma ; 6, postero-mesial ;
7, postero-lateral ; 8, Lissauer's tract ; 9, dorsal
(3) VESTIBULOSPINAL TRACT, (ascending) cerebellar; 10, antero-lateral ascend-
This consists of scattered fibres in the ing ; * m > septo-marginal ; spl, dorsal root zone ;
antero-lateral column, which degene- ■» anterior horn-cells ; i, intennedio-lateral horn;
e p, cells of posterior horn : a. (. larkes column,
rate m the downward direction. Tbey The fa e dots represent the situation of the
were formerly supposed to be derived ' internuncial ' or ' endogenous ' fibres of the spinal
from the cerebellum of the same side, e°rd.
but it has been shown that they are
in all probability derived from Deiters' nucleus in the inedulla— an important trans-
mitting station between the cerebellum and cord.
(4) OLIVOSPINAL AND THALAMICO-SPINAL TRACTS (Bundle of Helweg).
This tract is also situated in the antero-lateral column, opposite the head of the anterior
horn. It consists mainly of fibres which pass from the thalamus (the fore brain) through
the inferior olive of the medulla downwards in the cord as far as the -lower cervical
region.
(5) COMMA TRACT. This tract lies in the posterior columns at the junction of
the postero-median and postero-lateral portions. It consists for the most part of the
descending branches of the afferent dorsal nerve roots. These divide as they enter
the cord, and their descending branches pass down for two or three segments in the
comma tract before turning into the grey matter. The tract, however, contains fibres
of other origin, some of which begin and end in the spinal cord itself.
(6) TRACT OF MARIE. This, also in the anterior column, contains both descend-
ing and ascending fibres and is largely a continuation of the posterior longitudinal bundle,
the connections of which we shall have to study later on. A small tract of fibres, which
degenerate in the descending direction, is also found in the posterior part of the cord
adjoining the posterior longitudinal fissure.
(7) SEPTOMARGINAL BUNDLE. This is largely proprio-spinal, but may
contain fibres coming from the mid-brain.
23
354 PHYSIOLOGY
B. ASCENDING TRACTS
These may be divided according as they are situated in the posterior, the lateral,
or the anterior columns.
(a) THE POSTERIOR COLUMNS. Almost the whole of the fibres making
iij > these columns are exogenous, being axons of cells in the posterior cool ganglia.
They can be divided into long, medium, and short fibres, all of which, on their way up,
give off collaterals, which pass into the grey matter and ramify round nerve cells, especi-
ally in the posterior horns (cp. Fig. 160). The longest lilacs pass to the upper end of
the cord, where they end in the posterior column nuclei, the nucleus gracilis and the
nucleus cuneatus of the medulla. These fibres remain entirely on the side of the cord
on which they have entered. As they pass up they are displaced towards the middle
line l>v each incoming and higher placed root. Thus in the cervical region, and indeed
from the fifth dorsal segment upwards, two columns can be distinguished in the postci ior
part of the cord, viz. the postero-median and postero-lateral columns, the division
between which is indicated by a small groove on the surface. The postero-median
column contains from within outwards the fibres from the sacral region, those from the
lumbar region, and those from the inferior dorsal region. The postero-lateral column, or
column of Burdach, contains mesially the four upper dorsal mot fibres and more laterally
the fibres from the cervical nerves.
{!>) THE LATERAL COLUMNS. In these columns are found the two cerebellar
tracts, as well as scattered fibres passing to the fore- and mid-brain.
(1) The Direct or Dorsal Cerebellar Tract arises from the cells of Clarke's
column on its own side. It consists of large fibres, which pass through the grey matter
to the lateral columns of the same side, and ascend in the cord immediately ventral to
the incoming posterior root fibres, and external to the crossed pyramidal tract. In
the medulla they are joined by a bundle of fibres from the opposite inferior olive and
pass with the restiform body into the cerebellum, where they terminate in the superior
vermis of this organ.
(2) The Ventral or Anterior Cerebellar Trait, often called the tract of Gowers,
arises in cells scattered through the grey matter, chiefly of the posterior horn of the oppo-
site side, though a few fibres are derived from cells of the same side. The tract consists
of fine fibres which pass upwards in the peripheral margin of the lateral column, extend-
ing from the direct cerebellar tract behind to the level of the anterior roots in front : it
passes upwards through the cord, the medulla, and the pons, then turns round to
enter the cerebellum through the superior cerebellar peduncle, ending chiefly in the
ventral portion of the superior vermis.
(i3) THE SpINO-THALAMIC AND SPINO-TECTAL TRACTS. These fibres form a scattered
bundle lying internally to the anterior cerebellar tract, and are practically part of Gowers'
tract. They may be traced through the cord, medulla, and pons, and end partly in the
anterior corpora quadrigemina of both sides, but to a greater extent in the optic
thalamus of the same side.
(c) ANTERIOR COLUMNS. A number of scattered fibres pass up the anterior
columns, mingled with the descending fibres of the tract of Marie in the angleof the
anterior fissure. Others pass up partly to end in the olivary body, partly to run on
with the mesial fillet towards the thalamic region.
The white matter of the cord can thus be regarded as made up of short
and of long tracts, which maintain direct connection between the following
parts of the central nervous system :
(1) Different levels of the cord itself by means of the proprio-spinal
fibres.
(2) Hind-brain and spinal cord, by the anterior and posterior cerebellar
tracts, the posterior columns, and thc'spino-olivarv fibres among the ascend-
THE SPINAL CORD AS A CONDUCTOR
355
Fig. I To. Diagram of sections of the spinal cord of the monkey showing the position of
degenerated tracts of nerve fibres alter specific Lesions of the cord itself, the afferent
nerve roots, anil of tlie motor region of flu- cerebral cortex. (Sch \fkk.) (The degenera-
tions are shown h\ the method of Marchi.) The left side of the cord is at the reader's
left hand.
I. Degenerations resulting from extirpation of the motor area of the cortex of the
I'll , erebral hemisphere.
II. Degenerations produced by section of the posterior longitudinal bundles in the
upper part of the medulla oblongata.
HI and IV. Result of section of posterior loots of tin first, second, and third lumbar
m-vves on the right side. Section III is from tin jegmen1 of cord between the last
thoracic and first lumbar roots : section IV from the same cord in the cervical region.
V to VIII. Degenerations resulting from (right) semi-section of the cord in the
upper thoracic region. V is taken a short distance above the level of section ; VI
higher up the cord (cervical region); VII a little below the level of section; VIII
lumbar* region.
356 PHYSIOLOGY
iag tracts, and the vestibulospinal and olivospinal among the descending
tracts.
(3) The mid-brain and cord connections are represented by the spino-
tectal tracts in the lateral columns as a direct ascending path, and by the
rubro-spinal tract which furnishes a direct efferent connection between
mid-brain and cord.
(■i) The fore-brain, viz. the thalamus, receives the spino-thalamic fibres
which, though scattered, are of considerable importance. They run chiefly in
the lateral and anterior columns. Its efferent fibres cannot be traced below
the lower cervical region.
(5) The cerebral cortex, the master tissue of the body, receives no fibres
directly from the cord or periphery of the body, but by the pyramidal tracts
is able to influence directly the activities of the motor mechanisms at every
level of the cord. These fibres, so far as is knowr, exist only in mammals,
and show a great increase in relative extent when traced from lower to higher
types. While in the rabbit the pyramidal tract is hardly perceptible, in the
monkey it is the best marked of all the tracts, and in man is still, more highly
developed. This relative increase, which is probably associated with the
shunting of more and more of the reactions of the body from the region of
the unconditioned reflex to that of the educatable reaction, is shown not
merely by the tract occupying a larger proportion of the transverse area
of the cord, but by its fibres being more densely set within that area.
THE PATHS OF IMPULSES IN THE CORD
The greater part of the white matter is thus concerned in transmitting
impulses to nerve cells in the brain, and from the brain towards the cord.
The complex reactions determined by these impulses are in many cases as
unconscious and automatic as those we have studied in the spinal cord, even
though they may involve the activity of the cerebral cortex itself. Others
however influence consciousness, so that their afferent side appears in con-
sciousness as sensations of various qualities, and their efferent side as the
result of volition, i.e. as willed or emotional movements.
The posterior spinal (sensory) roots at their entrance into the cord divide
into two bundles. The smaller of the two, situated more laterally and
consisting of fine fibres, enters opposite the tip of the posterior horn and turns
up at once in Lissauer's tract, a bundle of fine longitudinal fibres close to the
periphery of the cord. The fibres seem to pass into and end in the substance
of Rolando. The larger median bundle of coarse fibres passes into the pos-
tero-external column. Here each fibre divides into a descending and an
ascending branch, the former running in the comma tract, the latter in the
posterior columns up as far as the gracile and cuneate nuclei of the medulla.
Both of these branches give off collaterals in the whole of their course, most
numerous near the point of entry of the nerve. These collaterals may be
divided into four sets according to their destination :
(1) Fibres ending round cells of anterior horn on same side or crossing by
posterior commissure to grey matter on other side.
THE SPINAL CORD AS A CONDUCTOR 357
(2) Fibres ending in grey matter of posterior horns.
(3) Fibres ending round cells of Clarke's column.
(4) Fibres to lateral horn.
Since the motor nerves arise from the anterior horn-cells, the first set,
the ' sensori-motor ' collaterals, represents the shortest possible spinal reflex
path. The second group may also represent a spinal reflex path with two
relays of cells, and therefore greater choice of response and longer reaction
time The third set puts into action the cerebellar tracts which arise from
the cells of Clarke's column, and therefore calls into play a much more com-
plicated mechanism, the limits of whose action it would be difficult to define.
The collaterals to the lateral horn probably represent the afferent tracts of
the various visceral and vaso-motor reflexes which we shall study later.
We find no special tracts devoted to those impulses which affect con-
sciousness as sensations. All tracts going towards the cerebral hemispheres
are interrupted by cell relays, in the medulla, cerebellum, or optic thalamus,
and must serve as afferent channels for unconscious as well as for conscious
reactions. The quality of an afferent impulse can be defined only by its
origin, or by its effect on consciousness, and much discussion has arisen
as to the exact path of the various cutaneous and muscular sensations in
the cord.
It is evident that an impulse might travel to the cortex by way of the two
cerebellar tracts through the cerebellum, or by way of the posterior columns
through the intermediation of the bulbar nuclei, or by the spino-thalamic
fibres, or by a series of relays from one segment of the cord to another
through grey and white matter alternately. It is supposed that all of the
ascending tracts may convey afferent impulses from the posterior spinal
roots to the brain, although evidence as to the part taken by each tract is
very conflicting. The following account represents the views which may
be regarded as the most probable (Page May) (Fig. 176) : Pain impulses,
on entering the cord by the posterior roots, cross to the other side at once,
and then pass up, chiefly in the antero-lateral column, by the spino-thalamic
til >ies as far as the optic thalamus. Sensations of heat and cold take a
very similar course. Hence they are generally affected by lesions of the
cord in the same way as pain sensations. Impulses of touch and pressure,
after entering the cord, pass up in the posterior column of the same side for
four or five segments, then cross gradually and pass up in the opposite anterior
column. Impulses serving muscular sensibility, including the impulses
from joints and tendons, take two courses. Those which do not reach
consciousness and are involved in the involuntary guidance of muscular
movements, run up chiefly in the anterior and posterior cerebellar tracts
of the same side. Those which furnish the material for conscious sensations
and give information as to the position of the limbs, &c, are entirely homo-
lateral, and travel up in the posterior columns of the same side of the cord.
All impulses which reach the brain cross finally to the optic thalamus and
thence to the cerebral cortex of the opposite side.
358
PHYSIOLOGY
5- §
THE SPINAL COED AS A CONDUCTOK 359
Hemisection of the cord on one side, as was first pointed out by Brown
Sequard, causes the following symptoms:
1) Paralysis of the voluntary motor conductors on the same side.
(2) A paralysis also of the vaso-motor conductors on the same side and,
asa i onsequence, a greater afflux of blood and a higher temperature. There
may be some degree of hyperesthesia on this side.
1 3) There is anaesthesia affecting all kinds of sensibility, excepting the
muscular sense, in the opposite side to that of the lesion, owing to the fact
thai the conductors of sensitive impressions from the trunk and limbs
decussate in the spinal cord ; so that an injury in the cervical region of that
organ in the right side, for instance, alters or destroys the conductors from
the left side of the body.
it) There is some degree of anaesthesia also on the side of the lesion, in
a very limited zone, above the hyperaesthetic parts, and indicating the level
of the lesion in the cord. This anaesthesia is due to the fact that the con-
ductors of sensory impressions, reaching the cord through the posterior roots,
at t he level or a little below the seat of the alteration, have to pass through
the altered part to reach the other side of the cord
The only direct unbroken cortico-spinal fibres are those contained in the
pyramidal tracts. Motor impulses, which start from the cerebral cortex on
one side, pass down that side till they reach the lower part of the medulla.
Here the greater number of the fibres crossover in the pyramidal decussation
to run down in the crossed pyramidal tract on the other side of the cord."
The few fibres which do not cross over in the pyramidal decussation are
continued as the direct or anterior pyramidal tract. These however also
cross to the other side in their passage down the cord before becoming con-
;ted with the anterior coniual cells. Hemisection therefore of the spinal
cord in the dorsal region will produce paralysis of voluntary movement and
loss of or impaired muscular sensation in the parts supplied by the nerves
on the same side below the lesion.
\ great part of the white matter of the cord is concerned then in main-
taining connection between the brain and higher parts of the nervous system
and the periphery, through the intermediation of the cells of the grey matter
of the cord. Corresponding to this function we find a gradual increase in
the number of fibres in the white matter as we ascend from the sacral part
of the cord to the medulla, the white matter being continually reinforced as
it ascends the cord by fibres establishing connection with the ganglion-cells
forming the nuclei of the nerve roots.
Vaso-motor impulses to the limbs travel down the lateral columns of the
tin' same side.
THE BRAIN
SECTION XI
THE STRUCTURE OF THE BRAIN STEM
The physiology of the brain falls naturally into two main divisions; namely,
that of the brain stem, including the medulla, the pons. Sylvian iter, corpora
quadrigemina and third ventricle, and that of the cerebral hemispheres. It
is usual, in treating of the structure of the brain stem, to consider it as
a prolongation forwards of the spinal cord and as consisting, like this, of a
central tube of grey matter surrounded by a tube of white matter. Like the
spinal cord, the brain stem may be regarded as originating primitively by
the fusion of a series of ganglia presiding over the local reactions of their
respective somites. The modifications in this segmental arrangement, which
have occurred in the course of evolution, have been so profound that little
trace of the primitive segmental arrangement is to be observed. At the
fore end of the body have been developed the organs of special sense, which
are the most important in determining the reactions of the animal in response
to present or approaching changes in its environment. Indeed the whole
course of evolution is conditioned by the development of the brain stem in the
first place, and of its outgrowth, the cerebral hemispheres, in the second.
Hence we cannot expect to find in the brain stem the regularity of arrange-
ment of grey and white matter that we have studied in the cord. The typical
division of the grey matter into cornua becomes altogether lost. While some
nerves take their origin from or terminate in the central tube of grey matter,
in other cases the collections of nerve cells and fibres forming the nuclei
of the cranial nerves have become more or less separated from the central
axis. Moreover the central grey matter is by itself quite inadequate to deal
with the flood of afferent impressions entering the central nervous system
through the organs of special sense, or to co-ordinate these with one another
or with those arriving from the skin and lower part of the body. Masses
of grey matter, which have no representative in the cord, make their appear-
ance, and may be regarded as additional sorting stations or fields of conjunc-
tion for the afferent and efferent impulses which determine the nervous
activities of the animal.
The general features of the structure of the brain will be best understood by reference
to the mode of development of this part of the central nervous system. At the front
end of the body, the primitive neural tube, formed by the invagination and growing over
360
THE STRUCTURE OF THE BRAIN STEM
361
Fig. 177. Diagram of the
cerebral vesicles of the
brain of a chick at the
second day. (Cadiat.)
1, 2, 3, cerebral vesi-
cles ; 0, optic vesicles.
of the epiblast, is somewhat enlarged and is marked off by two constrictions into the three
primitive cerebral vesicles, which are named respectively the fore-, the mid-, and the
hind-brain, or the prosencephalon, the mesencephalon, and the rhombencephalon (Fig.
177). At their first formation the walls of these vesicles are composed of simple epithe-
lial cells, and show no trace of nervous structm'e. A little later the cells fprming tin-
walls present a differentiation into neuroblasts and spongio-
blasts, the former developing into nerve cells, while the
latter form the neuroglial supporting tissues of the brain and
probably also furnish the cells of the sheath of Schwann to
the outgrowing cranial nerves. In some places the wall of
the vesicles remains undifferentiated : no nervous tissues
develop in it, and it forms a layer of epithelium known as
ependyma. By the varying growth of nervous tissue in
different parts of the wall, the typical structure of the adult
brain is brought about (Fig. 178). Thus in the hind-brain.
or rhombencephalon, the roof of the neural canal posteriorly
fails to develop, so that in the adult brain there is merely
a layer of epithelium covering the expanded central canal,
here known as the fourth ventricle. Tins back part of the
hind-brain is often called the myelencephalon, the anterior
portion being the metencephalon. The Moor of the mye-
lencephalon undergoes considerable thickening and forms
the future medulla oblongata. In the metencephalon, ner-
vous tissue is developed all round the canal, the floor of the
canal forming the pons Varolii, while the cerebellum is developed by an outgrowth
of the dorsal wall. In the region of the constriction between- the hind- and mid-brain
known as the isthmus, the roof or dorsal wall forms the superior cerebellar peduncles
at the side, and between them a thin layer of nervous matter known as the valve of
Vieussens, or superioi medullary velum. The cavity of the third vesicle corresponds
in the adult brain in whal is known as the fourth ventricle.
The mesencephalon, or second
i'S?.*, '"" cerebral vesicle, takes a relatively
small part in the formation of the
adult human brain, though very con-
spicuous in manj' of the lower types
of brain. The whole of its wall is
transformed into nervous tissue t he
roof or dorsal wall forming the cor-
pora quadrigemina, while the two
crura cerebri are developed in its
ventral wall. The cavity of the
second cerebral vesicle is retained as
a narrow canal known as the aque
duct of Sylvius, and connects the
fourth ventricle with the third ven-
tricle.
Very soon after its first appearance
the first cerebral vesicle is modified
by the formation of lateral expansions, known as the . ,ptic vesicles, which later on are con-
stricted off from the central part of the ca vity so as to be connected with this by two short
tubular- passages, the optic stalks. From the optic vessels are ultimately developed the
retinae of the eyes. By the development of nerve cells in the optic cup the ganglion-
cell layer of the retinaj is produced, and from these cells fibres grow back along the
optic stalk and make connection with the grey matter developed in the lateral wall of
the fore-brain and with the adjacent parts of the mid-brain, viz. the superior corpora
Fig. 178. Longitudinal section through brain of
chick of ten days. (After Mihalkovicz.)
oil, olfactory lobes ; h, cerebral hemisphere ;
U\ lateral ventricle ; pin, pineal gland ; bg, cor-
pora bigemina ; chl. cerebellum ; oc, optic com-
missure : pit, pituitary body; po, pons Varolii;
mo, medulla oblongata : »*, i- 1 . third and fourth
ventricles.
362
PHYSIOLOGY
quadrigemina. The Large masses of nervous tissue developed in the lateral walls of the
fore-brain are the optic thalami, which represent the head ganglia of the brain stem.
The front portion of the first cerebral vesicle expands in a forward and downward
direction, and from the upper and lateral aspects of the outgrowth thus formed the
cerebral hemispheres are produced as two hollow pouches. The original hack part of
the fore-brain is sometimes spoken of as the diencephalon, while the anterior part
of the cerebral hemisphere growing from it, is the telencephalon. The floor or ventral
l.uminu truiiualis
Optic recess
< tptie nerve
< '[I n i iiNiinissurt'
Hypophysis
ebellun
^ Medulla oblongata
entricle
' Superior medullary velum
/Corpora quadrigemina
Suprapineal rer
Pineal bodj
Cerebral aqueduct '
Fig. 179. Median section of an adult human brain. (J. Symington.)
wall of the fore-brain undergoes moderate thickening to form the nervous structures
which occupy the ' interpeduncular space ' at the base of the brain, viz. the posterior
perforated spot, the corpora mammillaria and the tuber cinereum. The roof of the
first cerebral vesicle remains thin and in its primitive epithelial condition, like the roof
of the back part of the fourth ventricle.
In the course of development the cerebral hemispheres become larger than the
whole of the rest of the brain put together, growing backwards over the latter as far
as the middle of the cerebellum (Fig. 179). Their dorsal and lateral walls become much
THE STRUCTURE OF THE BRAIN STEM 363
Fig. ISO. Diagrammatic view of the brain in different classes of vertebrates.
(G ISKEIA.)
i B, cerebellum j ft. pituitary body ; pn, pineal body : C.STR, corpus striatum
ghr, right ganglion habenulse ; i, olfactory ; n, optic nerves.
:;c,l
PHYSIOLOGY
thickened and consist of white mattei internally and grey matter externally. The part
oi the hemisphere which lies over the first cerebral vesicle is undifferentiated and remains
as a simple epithelial layer. This becomes closely applied to the similar layer forming
the roof of the third ventricle, from whieli il is separated only by a process of the pia
mater carrying numerous blood-vessels (the velum inter pesitum). In the adult brain the
eavities of the cerebral hemispheres are known as the lateral ventricles, the remains
ol the first cerebral vesicle receiving the name of the third ventricle. The lower and outer
part of the hemispheres, i.e. the part whieli is first formed, becomes much thickened and
forms the corpus striatum, which is closely applied to the front and outer part of the
optic thalamus. In the corpus striatum two masses of grey matter are developed,
namely, the nucleus caudatus and the nucleus lenticularis. A layer of nerve fibres ascends
from the brain stem to be distributed throughout the whole of the cerebral hemispheres.
This forms a sort of capsule to the optic thalamus, lying between this body and the corpus
striatum behind, but in front piercing the corpus striatum between its two nuclei. It
is called the internal capsule.
The development of the different parts of the brain stem from the three cerebral
vesicles and their gradual subordination and overshadowing in the course of development
by the cerebral hemispheres is well shown if we compare the brain of a fish with that of a
reptile and again with that of a mammal (Fig. 180). Man's position in the scale of
animal life is determined not by increasing complexity of the structures forming his
brain stem, but by the gradual subordination of these to the latest formed cerebral
hemispheres, and by the enormous growth of his capacity to adapt himself to a varying
environment consequent on the increase in size of his cerebral hemispheres.
THE HIND-BRAIN
It will be convenient to trace first the modifications undergone by the
axial part of the nervous system in the brain" and then to deal with the
new masses of grey mutter which have no homologies in the spinal cord, as
Fig. 181. Section through the lower border of the medulla oblongata, at the
pyramidal decussation. (Bechtekew.)
fla, anterior fissure ; d, decussation of the pyramids ; 1", anterior columns ;
C'd. anterior cornu ; cc, central canal ; »S'. lateral columns ; fr, formatio reti-
cularis ; ce, neck, and m
the lower limb, end in arborisations round the cells of the nucleus gracilis,
while those of the postero-extemal column, or column of Burdach. of which
the majority is formed by fibres from the upper limbs, terminate in the
366
l'rlYSiOLOfJY
grey matter of the nucleus cuneatus. The cells of these two masses of
grey matter of course give off axons, which can carry on the impulses
brought to them by the fibres of the posterior columns. These axons speedily
leave the dorsal aspect of the medulla, bending round, as the arcuate fibres,
to the deeper parts of its structure. Thus nothing is left to take the place
of the posterior columns on the posterior aspect of the cord. With the dis-
appearance of these columns and the development of the pyramids we get a
practical obliteration of the anterior fissure and a displacement of the central
canal towards the dorsal surface. A little higher up (Fig. 183) the canal
opens out altogether, forming the fourth ventricle, covered on its dorsal
surface only by a thin layer of ependyma. a simple epithelium representing
s «&.
Posterior longitudinal fascicul
~i'l>-T. t nti:i <,'■!. it ui"~:i Kolandi,
■*|.in;il root, ot tilth nerve
— Nucleus amoiguus
erebello-olivary fibres
sal acci -my olivary nucleus
tor superficial arcuate fibres
! accessory olivary nucleus
Inferior olivary nucleu 5
Fig. 1s:j. Transvers
section thrum
medulla.
Pyramid
uate nucleus
Anterior superficial arcuate fibres
h the middle of the olivary region of the human
(< luKNINGHAM.)
all that is left of the dorsal wall of the primitive cerebral vesicle. The
appearance of the section is now modified by two structures. In the first
place, a new mass of grey matter, consisting of a thin layer shaped like a
flask with its orifice directed inwards, is developed in the lateral part of the
medulla, between the pyramids in front and the tubercle of Rolando behind.
This is the olivary body, and has on its inner and dorsal sides two little grey
masses which are the accessory olivary bodies. The other feature is the new
relay of sensory fibres which start from the dorsal nuclei, the nuclei gracilis
and cuneatus. These fibres run outwards and forwards from the nuclei
THE STRUCTURE OF THE BRAIN STEM
367
riulit round the medulla. Some fibres pass into the restiform body of the
same side. A larger number, forming the superficial arcuate fibres, pass
superficially to the olive to join the restiform body of the opposite side,
while others, the deep arcuate fibres, pass deeply to the olives, and crossing
in the median raphe turn upwards in the broken mass of grey and white
matter which lies between the olives and the superficial grey matter of the
-.-C 01. Fibres
Subdfl.-Bol:-
FlG. 184. Diagram to show the sources of the fibres making up the restiform body.
Ar.N, arcuate nucleus ; Ar fibres, arcuate fibres ; Pyr, pyramid ; C.Sp.
Tract, direct cerebellar tract; C.01 fibres, cerebello-olivary fibres; (Pl.B,
posterioi longitudinal bundle : f >X. nucleus of Deiters ; NB, nucleus of Bech-
t'-n w ; I'o.X, roof nuclei; Vest. N, vestibular nerve.
fourth ventricle. This decussation, which is known as the 'decussation
of the fillet ' or the sensory decussation, takes place immediately above the
level of the decussation of the pyramids. In its upward course it forms a
conspicuous strand of fibres, lying close to the mesial plane and separated
from its follow of the opposite side simply by the median raphe. To this
collection of fibres is given the name of the fiUei or lemniscus. It is perhaps
368 PHYSIOLOGY
the most important of the afferent tracts of the brain stem, receiving
as it does continuations of the posterior columns of the cord as well as
contributions from the various sensory cranial nerves. It may be traced
forwards as far as the thalamus and subthalamic region, where its fibres
terminate. The region corresponding to the anterior column of the spinal
cord is thus invaded in the medulla by two great longitudinal tracts of
fibres namely, the pyramids and the tracts of the fillet. The region corre-
sponding to the anterior basis bundle, i.e. that part of the anterior columns
occupied chiefly by intra-spinal fibres, is thus pushed further backwards and
finally comes to lie immediately beneath the grey matter of the floor of the
fourth ventricle. Immediately dorsally to the fillet is to be seen another
well-marked bundle of longitudinal fibres, known as the posterior longi-
tudinal bundle. These fibres, which serve to connect the nuclei of many of
the cranial nerves, can be regarded as analogous to the constituent fibres of
the anterior basis bundle in the cord, and can in fact be traced into this part
of the anterior columns in the first and second cervical segments of the cord.
The fourth ventricle is covered in by the cerebellum, which is attached
to the axial part of the brain by three peduncles, the inferior peduncles
or restiform bodies, the lateral peduncles, which form the great mass of
transverse fibres known as the pons Varolii, and the superior peduncles,
which run forward to the posterior corpora quadrigemina. The restiform
bodies can be regarded as the direct continuation forwards of the lateral
columns of the cord, minus the pyramidal tracts, the chief remaining tract
therefore being the posterior or direct cerebellar tract. In the region
of the dorsal nuclei however, it receives accession of fibres from the gracile
and cuneate nuclei of the same side and, through the superficial arcuate
fibres, from the nuclei of the opposite side, and thus passes as a thick white
bundle into the cerebellum. Among these arcuate fibres are also a number
derived from the olivary body of the opposite side, known as the cerebello-
olivary fibres. On its way it is joined by a smaller bundle, the ' internal
restiform body,' which conveys fibres from the vestibular division of the
eighth nerve and also serves to connect Deiters' nucleus with the cerebellum.
The restiform body is thus made up of the following fibres (Fig. 184) :
(1) The direct or posterior cerebellar tract, derived from the cells of
Clarke's column on the same side of the cord.
(2) The posterior superficial arcuate fibres, derived from the gracile and
cuneate nuclei of the same side.
(3) The anterior superficial arcuate fibres, from the gracile and cuneate
nuclei of the opposite side.
(4) The cerebello-olivary fibres.
(5) The vestibulocerebellar fibres.
A section through the pons shows the fourth ventricle widely dilated,
with a floor formed of grey matter as in the medulla. The chief difference
in the appearance of the section is due to the great masses of transverse
fibres which pass into the pons by the lateral peduncles of the cerebellum,
cross by the median raphe, and turn either upwards or downwards on the
THE STRUCTURE OF THE BRAIN STEM
369
opposite side or end in connection with the nerve cells which are scattered
throughout the white fibres. The pyramids can still be seen as thick longi-
tudinal bundles on each side in the midst of the transverse fibres. They are
considerably larger than in the medulla and become larger as we trace them
up towards the mid-brain, owing to the presence of a number of fibies
which are derived from the cortex cerebri and end in the grey matter of the
Supr. ccr. peduncle
Valu of Yi. Transverse, ection I ugh middle of pons Varolii (if orang on level of
nuclei of fifth nerve. (Ct/nsdigham.)
pons. The tract of the fillet lies on each side of the middle line dorsally to
the transverse fibres. A little to the outside of the fillet is seen a special
mass of grey matter, known as the superior olive. The nervous mass lying
behind the transverse fibres of the pons, between them and the grey matter
of the floor of the fourth ventrit le, is known as the formatio reticularis. It
is divided into a lateral and mesial part by the fibres of the hypoglossal
nerve. In the lateral portions there is a considerable quantity of grey
matter, which can be regarded as continuous with the grey matter of the
lateral horns of the cord. The ' lateral nucleus ' is simply a condensed part
of this grey matter, lying between the olive and the gelatinous substance of
Rolando. The mesial part of the formatio reticularis is almost free of nerve
cells. The reticular appearance of this part of the pons is due to the inter-
24
370
PHYSIOLOGY
section of fibres which run longitudinally and transversely. The transverse
fibres are a continuation of the deep arcuate fibres. The longitudinal fibres
in the miter part of the formatio reticularis are the representatives of the
lateral columns of the cord after the removal of the direct cerebellar and the
crossed pyramidal tracts. They include therefore the anterolateral ascend-
ing tract (tract of Gowers) and a number of other fibres corresponding to the
lateral basis bundle in the cord. In the mesial part of the formatio retiou-
4th ventriele
Mesenc. root of 5th n. • — . t^'^S
Postr. long, bundle
Form, reticularis
Nucleus of lateral fillet
Valve of Vieussens
Floor of 4th ventricle
s. Supr. cerebellar
peduncle
ing de-
cussation of supr.
3§gffl cerebellar pcd.
Mesial fillet
Bf' Pyramids
Fig. 186. Section across upper part of pons Varolii of the orang. (Cunningham.)
laris the longitudinal tracts are the tract of the fillet and the posterior longi-
tudinal bundle on each side of the middle line. In the upper part of the pons
Varolii a well-marked collection of transverse fibres are to be seen lying
dorsally to the tracts of the fillet. This collection is called the corpus
trapezoides and is made up of ascending fibres derived from the nuclei of the
cochlear nerve, the auditory part of the eighth nerve.
A little further forward a section will escape the cerebellum altogether,
being bounded ventrally by the upper or anterior part of the pons and
dorsally by a thin mass of grey matter, the valve of Vieussens (Fig. 186).
On each side of the valve of Vieussens may be seen the superior peduncles of
the cerebellum. As these peduncles are traced upwards they sink gradually
deeper into the pons until they lie on the outer side of the tegmental region
or formatio reticularis. They are made up of fibres which run from the
dentate nucleus of grey matter in the cerebellum to the mid-brain, where
they decussate below the Sylvian iter and end in the red nucleus and in the
thalamus of the opposite side. They also contain the continuation upwards
of the antero-lateral ascending tract which, passing up in the superior
peduncles, bends dorsally round the fourth nerve and then, turning back-
wards, ends in the superior vermis of the cerebellum. In a section through
THE STRUCTURE OF THE BRAIN STEM
371
the upper part of the pons, the division into the formatio reticularis or
tegmentum and the part made up of transverse and longitudinal fibres, the
pedal portion, is well marked (v. Fig. 186). The fourth ventricle has now
become constricted to a narrow canal triangular in section and closed above
by the valve of Vieussens. It is surrounded, especially on its ventral side,
by grey matter containing the cells of origin of the fourth nerve. In the
' Inf. corpus quadri
. Mesenc. root of 5th n.
Nucleus of 4th nerve
UPostr. long, bundle
>\ Mesial fillet
Grey matter 1
Aqueduct of Sylvius_ __/\
Raphe
Pupr. cer. pi duncle.
Substantia nier;
Fio. 187. Transverse section through human mid-brain, on level of the inferior
corpora quadrigemina. (Cunningham.)
tegmental portion we may distinguish on each Side the superior cerebellar
peduncle. Outside the longitudinal fibres of this peduncle are a number
of transverse fibres derived from the corpus trapezoides seen in the previous
section. To these fibres is given the name of the ' lateral fillet.' They are
on their way to end in the roof of the mid-brain in the posterior corpora
quadrigemina. The posterior longitudinal bundle lies near the middle line,
immediately under the grey matter of the floor of the fourth ventricle, while
the longitudinal fibres of the fillet, now called the mesial fillet, form a distinct
mass in the ventral portion of the formatio reticularis. The pedal portion
contains the longitudinal fibres of the pyramids, now much increased in
amount, cut up into bundles by transverse fibres derived from the middle
peduncles of the cerebellum.
The cerebellum, which covers in the fore part of the fourth ventricle,
will have to be described in greater detail later on. At present it will suffice
to say that it consists of a middle and two lateral lobes. The surface of the
;$72
PHYSIOLOGY
middle lobe turned towards the fourth ventricle is known as the inferior
vermis, the dorsal surface forming the superior vermis. Each vermis and
each lateral lobe is subdivided into a number of smaller lobes. The intimate
structure of all parts of the cerebellum is however very uniform. It consists
of a mass of white matter internally, covered by a layer of grey matter, the
extent of grey matter being largely increased by the formation of numerous
parallel and more or less curved grooves or sulci which give the whole organ
a laminate appearance. In the mass of white matter, which forms the
Transverse section through human mid-brain at the level of the superior
corpus quadrigeminum. (Cunningham.)
core of each lateral hemisphere, is an isolated nucleus of grey matter known
as the corf as dentatum. In the white matter of the middle lobe is another
mass of grey matter known as the roof nucleus or nucleus fastigii. Be-
tween the nucleus fastigii and the nucleus dentatum are two other nuclei,
the nucleus globosus and the nucleus emboliformis.
THE MID-BRAIN
A little further forward the fourth ventricle comes to an end, and the
section passes through the mid-brain (Fig. 187), the cavity of the second
cerebral vesicle being represented by the narrow Sylvian aqueduct, bounded
dorsally by the corpora quadrigemina and ventrally by the crura, the stalks
of the brain. The crura are divided by an irregular mass of grey matter, the
substantia nigra, into two parts. The ventral portion is known as the pes or
THE STRUCTURE OF THE BRAIN STEM 373
orusta. It is composed almost entirely of longitudinal white fibres, among
which is the continuation forwards of the pyramids of the medulla. The
pyramids however form only about two-fifths of the total mass of white
fibres, the rest consisting of fibres which run from the different parts of the
cerebral cortex, especially from the frontal and temporal lobes, to end in the
formatio reticularis of the pons, probably in relation with the grey matter in
this situation and with the endings of the transverse fibres derived from the
cerebellum and forming the middle peduncles of the cerebellum. The dorsal
part, the tegmentum, is a direct prolongation forwards of the formatio reticu-
laris of the medulla and pons, and like this contains much scattered grey
matter. On a level with the inferior corpora quadrigemina a number of
decussating fibres are to be seen in the tegmentum, which are derived from
the superior cerebellar peduncles. Their decussation is complete at the level
of the upper border of the inferior corpora quadrigemina. Here each
peduncle turns upwards, and a large proportion of its fibres end in the red
nucleus (Fig. 188), a mass of grey matter forming a conspicuous feature of
sections through the anterior part of the mid-brain. Many of the fibres pass
round the red nucleus, forming a sort of capsule over it, to the ventral
I in it of the optic thalamus, in which they probably end. It is possible that a
certain proportion pass through the optic thalamus and run straight to the
cerebral cortex of the Rolandic area. The lateral fillet has disappeared from
the region of the tegmentum and passed into the inferior corpora quadri-
gemina. The mesial fillet forms a flat band lying to the outer side of the red
nucleus and comes into close relation with a ganglion of the fore-brain, known
as the internal geniculate body. The roof of the mid-brain is formed by the
corpora quadrigemina. The inferior corpora quadrigemina are composed of
central grey matter encapsulated by white matter, derived chiefly from
the lateral fillet. The superior corpora quadrigemina are composed of several
layers of grey matter traversed by nerve fibres, derived partly from the
fillet, partly from the optic tract, and partly from the occipital lobe of the
cerebral hemisphere.
THE FORE-BRAIN
In the fore-brain the most important feature is the optic thalami, the
two head ganglionic masses of the brain stem (Fig. 189). In this region
the central neural canal, which in the mid-brain forms the Sylvian iter,
widens out to the third ventricle, in the lateral walls of w T hich are developed
the two optic thalami. It is a narrow cleft, rapidly increasing in depth from
behind forwards. As w T e trace sections forwards we see that the two crura
cerebri diverge from one another. The floor of the third ventricle is thus left
thin. It is formed from behind forwards by a thin layer of grey matter witn
numerous vessels, the locus perforates posticus, two small eminences, he
corpora mammillaria, and in front of these another lamina of grey matter
known as the tuber cinereum. In front of the tuber cinereum is the infun-
dibulum, which leads to the posterior lobe of the pituitary body. In front
of the infundibuluin the optic chiasnia is closely attached to the lowest part
of the anterior wall of the ventricle. The front wall is formed by a thin layer
374
PHYSIOLOGY
of nervous matter, the lamina emerea, at the upper border of which, project-
ing slightly into the ventricle, is a strand of white fibres connecting the an-
terior parts of the two optic thalami and known as the anterior commissure.
The roof of the third ventricle is formed entirely of epithelium, the ependyma,
Corpus callosum
Lateral ventricle
Nucleus caudatus
Internal capsule
Thalamus
Nucleus lcntiforniis
Anterior commissure
Collicuhis superior
Inferior brachium
Colliculus Inferior
4 th
Trigonum Iemniscl
5th nerve /
Brachium conjunctivum
Pons.
8th nerve
Rrstifonn body
9th nerve
lOth nerve
Vl2th nerve
Fig. 189. Right lateral aspect of brain stern, with a part of the cerebrum.
(J. Symington.)
along the upper surface of which is the layer of pia mater, the velum inter-
position. The roof is invaginated into the cavity by two delicate vascular
fringes, the choroid plexuses. At the back part of the roof is attached the
stalk of the pineal body, and behind this stalk, between the anterior parts
of the anterior corpora quadrigemina, is a small space known as the trigomnn
habenulw, which contains a well-marked collection of nerve cells known as the
ganglion habemdw. The lateral walls are formed entirely by the optic
thalami. The upper surface of the optic thalamus looks into the lateral
ventricle of the cerebral hemispheres, from which it is separated by the
velum interpositum and by the ependyma, the epithelium completing the
inferior wall of the lateral ventricle in this region. It consists of three
THE STRUCTURE OF THE BRAIN STEM
375
masses of grey matter- — the anterior nucleus, the lateral nucleus (the largest
of the three), and the mesial nucleus. Its outer surface is in contact with the
layer of nerve fibres formed by the crusta of each crus cerebri as it diverges
from its fellow to pass up into the cerebral hemispheres. Into this layer,
' the internal capsule,' fibres proceed from all parts of the thalamus to pass
to the cerebral cortex. The anterior extremity of the thalamus, known as the
anterior tubercle, forms a marked projection into the lateral ventricle. In
front of this, the foramen of Monro leads from the third ventricle into the
lateral ventricle. This foramen is bounded anteriorly by a strand of fibres,
known as the ' anterior pillar of the fornix,' which lies just behind the anterior
Fig. 190, Transverse section through upper part of mid-brain.
Th, thalamus ; brs, brachium superior ; cqs, anterior (or superior) corpus
quadrigeminum ; cgi, cge, internal and external geniculate bodies ; /, fillet ; «, aque-
duct ; pi, posterior longitudinal bundle ; r, raphe ; III, third nerve ; nlll, its
nucleus ; Ipp, posterior perforated space ; sn, substantia nigra ; cr, crusta ; II,
optic tract ; H, medullary centre of the hemisphere ; nc, nucleus caudatus ; st,
stria terminahs.
commissure and forms a conspicuous feature in the anterior part of the
lateral wall of the third ventricle. It passes in the wall down to the corpus
mammillare. From the corpus mammillare a well-marked bundle of fibres
passes up into the optic thalamus to end round the large cells in the anterior
nucleus of the thalamus. The posterior extremity of the thalamus forms
a definite prominence, the pulvinar. To the outer and back part of the
pulvinar two bodies are developed, known as the geniculate bodies. These
may be regarded as special outgrowths of the grey matter of the optic
thalamus, one of which, the external geniculate body, is in close connection
with the fibres from the optic tracts, while the other, the internal geni-
culate body, receives fibres from the lateral fillet ultimately derived from
the organ of hearing. In a section through the fore part of the mid-brain
(Fig. 190) these two bodies may be seen lying to the outer side of the anterior
corpora quadrigemina, so that the fore-brain, to a certain extent, enfolds the
anterior part of the mid-brain. Below the thalamus at its back part is the
37G
PHYSIOLOGY
prolongation forwards of the tegmentum of the crus. This is often spoken
of as the subthalamic region. The red nucleus is a conspicuous object in
sections through the back part of this region, but gradually diminishes as we
proceed forwards, and disappears before the level of the corpora mammillaria
is reached. The mesial fillet, which in the mid-brain lies on the lateral and
dorsal aspect of the red nucleus, is prolonged upwards together with fibres
from the superior cerebellar peduncle into the ventral part of the thalamus,
where probably all of the fibres end in connection .with the thalamic cells.
The substantia nigra gradually disappears. Before it has disappeared we
may see on its outer side a special collection of grey matter called the nucleus
of Luys or the corpus suithalamicum. In addition to the anterior and
posterior commissures already described as connecting the two optic thalami
at the front and back of the third ventricle, the two sides are connected about
the middle of the cavity by the middle or soft commissure. The optic
thalamus is often described together with the corpus striatum as forming
the basal ganglia. The corpus striatum is however genetically, and
probably functionally, part of the cerebral hemispheres, and its connections
will therefore be best dealt with when describing the latter bodies.
THE AXIAL GREY MATTER
In the spinal cord we could distinguish between the anterior grey matter
giving origin to the motor nerves, the posterior grey matter serving as an end
Cross-section of medulla showing
(Cunningham.)
XII.
[HYPOGLOSSAL]
nuclei of nerves X and xn.
station for a number of the sensory posterior root fibres, and a lateral horn,
less well marked, probably giving origin to the visceral system of nerves.
As the central canal widens out to form the fourth ventricle, the relative
THE STRUCTURE OF THE BRAIN STEM
377
position of these various parts becomes altered, the anterior grey matter
being now neatest the median line, while the posterior grey matter lies more
laterally. Part of the lateral grey matter seems to lie deeper than the rest,
from which it is separated by the tangle of fibres and cells known as the
formatio reticularis. All the cranial nerves from the third to the twelfth
arise or end in the axial grey matter, or in close proximity to it. So great
however is the complexity of this part of the nervous system, and so in-
volved are the genetic relations of the various nerves, that it is difficult or
Fig. 192. Diagram showing the brain connections of the vagus, glosso-pharyngeal,
auditory, facial, abducent, and trigeminal nerves. (Cunningham after Ober-
steiner..)
impossible in many cases to state definitely the spinal analogies of these
nerves.
The cranial nuclei (of origin or termination) may be roughly classed as
follows :
(1) Motor Somatic Nuclei « These consist of an almost continuous column
of multipolar cells. Iving close to the middle line on each side in the floor of
the fourth ventricle, the Sylvian iter, and the back part of the third ventricle.
From below upwards these groups of cells give origin to the fibres of :
378
PHYSIOLOGY
(a) The hypoglossal nerve.
(b) The sixth nerve.
(c) The fourth nerve.
(d) The third or oculo-motor nerve.
(2) Splanchnic Sensory Nuclei. Immediately outside the column of
motor cells is a column of grey matter which receives the terminations of
the afferent fibres belonging to the ninth, tenth, and eleventh nerves, and
is sometimes called the vago-glossopharyngeal-accessory nucleus. This grey
Fig. 193. Plan of the course and connections of the fibres forming the cochlear
root of the auditory nerve. (Schafer.)
r, restiform body ; V, descending root of the fifth nerve ; tub.ac, tuberculum
acusticum ; n.acc, accessory nucleus ; s.o, superior olive ; n.tr, nucleus of trape-
zium ; n. VI, nucleus of sixth nerve ; VI, issuing root-fibre of sixth nerve.
matter of course does not give rise to the fibres of these nerves which, like
other sensory nerves, are axons of ganglion-cells lying outside the central
nervous system.
(3) Splanchnic Motor Nuclei. These lie more deeply at some distance
from the middle line, and include the nucleus ambiguus for the efferent fibres
of the vaso-glossopharyngeal, the nucleus of the seventh or facial nerve
(originally splanchnic or branchial, now typically somatic), and the motor
nucleus of the fifth nerve with its prolongation into the mid-brain.
(4) Sensory Somatic Nuclei. The chief representative of this group
is the great sensory root of the fifth nerve. The fibres of this nerve arise
from the Gasserian ganglion, pierce the fibres of the pons Varolii, and run
to the dorso-lateral part of the pons, where they divide into ascending and
descending fibres. These fibres form a cap to the substantia gelatinosa,
the descending branches, which are longer, being conspicuous in sections of
the medulla as low down as the first or second cervical nerve. This nerve
gives common sensation to practically the whole of the head.
It is doubtful in what group we should place the fibres of the eighth
nerve. This nerve really consists of two parts very different in function,
the cochlear or auditory nerve, and the vestibular or labyrinthine nerve.
THE STRUCTURE OF THE BRAIN STEM
379
The- fibres of each are derived from ganglion-cells in the internal ear, pass to
the medulla at its widest part and then, dividing into two, terminate in
masses of grey matter situated at the extreme lateral part of the floor of the
fourth ventricle.
The branches of the cochlear nerve (Fig. 193) make connection with two
collections of cells, the dorsal nucleus, apparently embedded in the fibres of
the root itself, and the accessory nucleus, a little triangular mass of grey
matter situated in the angle between the cochlear and vestibular nerves.
TO HEMISPHERE
FIBRES OF
VESTIBULAR
ROO~
NERVE
ENDINGS
IN MACUL/E
& AMPULL/E
p.l.i
Fig. 194. Plan of the course and connections of the fibres forming the vestibular
root of the auditory nerve. (Schafer.)
r, restiform body ; v, descending root of fifth nerve ; p. cells of principal nucleus
of vestibular root ; d, fibres of descending vestibular root ; nil, a cell of the descend-
ing vestibular nucleus ; d, cells of nucleus of Deiters ; B, cells of nucleus of Bech-
terew; nt, cells of nucleus tecti (fastigii) of the cerebellum ; plb, fibres of posterior
longitudinal bundle. No attempt has been made in this diagram to represent the
actual positions of the several nuclei. Thus a large part of Deiters' nucleus lies
dorsal to and in the immediate vicinity of the restiform body.
From these miclei fibres are given off which take two courses. Some, follow-
ing the previous course of the cochlear nerve, pass across the, surface of the
fourth ventricle as the strim medullares or stria acousticce, and then bending
inwards pass into the tegmentum of the opposite side. Others pass deeply
and form a mass of transverse fibres in the ventral part of the tegmentum, the
corpus trapezoides or trapedum. After making connections with the superior
olivary body and a special nucleus, they join the superficial set of fibres, and
run up in the tegmentum to the inferior corpora quadrigemina, forming the
■lateral fillet.
The vestibular nerve (Fig. 194) also has two nuclei of termination, the
median nucleus with small cells, and the lateral or Deiters' nucleus with large
cells. Some fibres pass also to the nucleus of Bechtereiv, which is in close
relation with the roof nuclei of the cerebellum. The descending fibres end
chiefly in the median nucleus, while the ascending fibres end in Deiters'
380
PHYSIOLOGY
nucleus. From the latter a distinct band of fibres passes up to the cere-
bellum, forming the median division of the restiform body, while other fibres
run across to the tegmentum of the opposite side, where they take part in the
formation of the posterior longitudinal bundle.
In a section through the fourth ventricle through the middle of the pons,
a group of large cells is seen in the position
occupied by the nucleus of the hypoglossal
below. These cells give rise to the fibres of
the sixth nerve. Another group is seen lying
laterally and more deeply, evidently belong-
ing to the lateral horn system. This is the
nucleus of the seventh or facial nerve, the
fibres id which pass dorsallyand anteriorly,
looping round the sixth nerve-nucleus, before
issuing as the root of the seventh nerve.
In the upper part of the pons we find the
lit ih nerve (Fig. 195) with its two roots.
The fibres of the sensory root derived from
the cells of the Gasserian ganglion bifurcate.
The upper divisions, which are short, end in
a mass of grey matter at the lateral part of
the formatio reticularis, the so-called sensory
root, while the descending divisions form a
long strand of white fibres passing down as
far as the second cervical nerve and lying
over the substantia gelatmosa of Rolando,
around the small cells of which the fibres
finally terminate. The motor fibres arise
partly from the motor nucleus, a mass of
Fig. j 95. Diagram showing ceu- ce U s l ymg internally to the sensory nucleus,
tral connections ot fifth, nerve. " . . . .
(Cajal.) and belonging probably to the lateral horn
a, Gasserian ganglion ; b, acces- sys t em . A large number are derived from
sory motor nucleus ; c, main motor J °
nucleus ;D, facial nucleus; b, nucleus along column of cells, which stretches
of hypoglossal; f, sensory nucleus of f onvar( j f rom the nucleus as far as the level
fifth nerve; a, cerebral tract (fillet) . ...
of fifth nerve. of the anterior corpora quadrigemina.
These fibres are known as the descending
motor root of the fifth nerve.
In the region of the mid-brain, besides the root of the fifth nerve just
mentioned, we find only the motor nuclei of the third and fourth nerves,
which are situated near the median line in the ventral part of the central grey
matter, corresponding in situation to the sixth and twelfth nerves lower
down.
INTERMEDIATE GREY MATTER OF THE CEREBRAL AXIS
The masses of grey matter which are found throughout this region may
be regarded as extra shunting stations (or association centres for various
THE STRUCTURE OF THE BRAIN STEM 381
systems of nuclei and conducting paths), which have arisen in consequence
of tlie great complexity of reaction required of the nerve mechanisms in
connection with the organs of special sense. We must confine ourselves
here to little more than the enumeration of the chief masses, though we
shall have occasion to refer to some in more detail when dealing with the
co-ordinating mechanisms of the cerebral axis. From below upwards we
may enumerate the following grey masses :
In the medulla is the large olivary body, with the accessory olive lying on
its inner side. Each olive sends fibres across the middle line to the opposite
cerebellar hemisphere, and must be regarded as connected with this body
in its functions, since atrophy or removal of one side of the cerebellum is
followed by atrophy of the opposite olive.
In the pons w T e find a similar but smaller body, the superior olive, in the
neighbourhood of the nucleus of the seventh nerve. The superior olive is
closely connected with the co-ordination of visual and auditory impressions
with the eye movements.
Deiters' nucleus, which occurs in the same region, although described as
one of the nuclei of the eighth nerve, might equally well be included in this
class owing to its manifold connections with both afferent and efferent
mechanisms.
In close connection with Deiters' nucleus are a number of grey masses
in the cerebellum, the roof nuclei in the roof of the fourth v.entricle.
In the mid-brain we must mention the superficial grey matter covering
the corpora quadrigemina.
On the ventral side of the Sylvian iter are the various masses of grey
matter in the crura, the red nucleus, a large mass in the tegmentum just below
the. oculo-motor nucleus, and the substantia nigra, which divides each crus
into two parts, the dorsal tegmentum and the ventral pes or crusta.
Finally at the fore part of the cerebral axis we come to the great ganglionic
mass already described, the optic thalamus and the geniculate bodies. The
geniculate bodies may be regarded as outgrowths of the optic thalamus
which have developed in connection with the terminations of the auditory and
the optic nerve fibres. The optic thalamus is connected by fibres with all
parts of the cortex and represents the termination of the whole tegmental
system, so that in many ways it may be regarded as a sort of foreman of the
central nervous system, controlling the activities of the lower level centres
and bringing all parts of this system in relation with the supreme cerebral
cortex.
THE CHIEF LONG PATHS IN THE BRAIN STEM
In dealing with the spinal cord we were able to treat it as one organ,
very largely on account of the uniformity of the afferent and efferent
mechanisms connected with its various segments. Every afferent impulse
arriving at the cord has many possible paths open to it, on account of the
branching of the nerve fibres as they enter ttie cord and the connection of
these branches with different neurons of varying destination. The exact
382 PHYSIOLOGY
path taken by any given impulse under any given set of circumstances
is determined by the varying resistance at the synapses which intervene
between the terminations of the afferent fibres conveying the impulse
and the next relay of neurons. These resistances in their turn are altered
by the process of facilitation and inhibition, which may be due to con-
temporaneous or previous events. A conspicuous example of these con-
ditions is afforded by the phenomena of simultaneous and successive spinal
induction.
The uniformity of afferent and efferent mechanisms disappears when we
include the brain stem with the spinal cord. The main efferent channel
of impulses is still through the spinal cord, since here are found the efferent
mechanisms for all the skeletal muscles of the trunk and limbs, the chief
servants of the central nervous system in the daily events of life. Other
efferent channels are added, which acquire special importance with the
growth of the upper brain or cerebral hemispheres. These mechanisms
include those for the movements of the eye muscles, those concerned in facial
expression, and those responsible for the movements of the mouth in mastica-
tion and deglutition, and in man, in speech. Important visceral efferent
fibres are also contained in the vago-glossopharyngeal nerves, which leave
the brain stem at its hindmost part in the region of the medulla oblongata,
and influence the condition of the heart and the alimentary canal with
its accessory organs. On the other hand, the afferent mechanisms of the brain
stem far transcend in importance, i.e. in their influence on the reactions of
the animal, those of the spinal cord. Among these afferent mechanisms are
those which we have spoken of as ' projicient ' sense organs or organs of
foresight, the impulses from which must predominate over all reactions
determined by the immediate environment of the animal. Into the medulla
oblongata are poured the impulses from the greater part of the alimentary
canal and from the heart (the chief factor in the circulation) and the lungs.
At the junction of the medulla and pons is the great eighth nerve, really con-
sisting of two, one of which, the cochlear nerve, carries impulses from the
projicient sense-organ of hearing, while the other, the vestibular nerve, has
its terminations in the labyrinth, the sense-organ of equilibration. To the
impressions received from this organ all the complex co-ordinating motor
mechanisms of the spinal cord have to be subordinated, in order that they
may co-operate in the maintenance of the equilibrium of the body as a whole.
Into the pons enters the fifth nerve, carrying sensory impressions from the
whole of the head, while in the mid- and fore-brain we find the endings of
the optic tracts derived from the eyes and carrying visual impressions. From
the front of the fore-brain are produced the olfactory lobes.
At each segment or level in the brain stem the afferent fibres from these
various sense-organs enter and join afferent tracts, carrying impulses on from
the spinal cord — impulses originally derived from the muscles and skin of
the trunk and limbs. At each level there may be an immediate ' reflection '
back to the cord, so that the spinal afferent impressions may co-operate
with the cranial afferent impressions in the production, through the spinal
THE STRUCTURE OF THE BRAIN STEM
383
cord, of reactions affecting the viscera or the skeletal muscles. On the
other hand, both kinds of afferent impressions may pass on up the brain stem
to involve higher centres and, mingling with impulses from other afferent
nerves or from the projicient sense-organs, may result at some higher level
in an efferent discharge, which may include reactions not represented in the
cord, or reactions of far greater complexity than are possible in the purel)
spinal animal.
In consequence of the endless complex intermingling of afferent im-
pulses, any diagrammatic representation of tracts is apt to be misleading,
unless it be remembered that at each break or synapse in the chain of neurons
there are numerous possibilities of branching discharge, and that in our
diagrams we can only give the course of such impulses as, by the frequency
of repetition in the average life of the animal, have involved the grouping
of a large number of nerve paths of similar function into tracts. The con-
stituent elements of these tracts will present similar destinations and possi-
bilities of interruption, i.e. of reactions involving
the motor mechanisms at the different levels in
the brain stem. It is thus much more difficult in
the brain stem than in the spinal cord to describe
a ' way in ' and a ' way out.' In a chain consist-
ing, say, of six neurons, a, b, c, d, e, / (Fig. 196),
though a is certainly afferent and/ efferent, it
must always be more or less a question of words
whether we regard neurons c and d as
afferent or efferent in character. It is
usual in our classifications to be
guided chiefly by the direction of such
impulses in relation to the cerebral
hemispheres. All tracts going up to
the cerebral hemispheres may be
involved more or less in the production
nervous matter of these hemispheres as are
scions sensation. In the same way there is a possibility that the
chains of neurons which carry impulses in a descending direction may be
involved in the production of voluntary movement. It is therefore usual
to classify these two sets of tracts as ascending and descending, or as afferent
and efferent. If we adopt such a classification it must be with a distinct
reservation that tracts which apparently are going downwards may play
a greater part in the determination of sensation than in the determination
of movement, and that there may, and indeed must, be a reverberation of
impulses through these ascending and descending tracts, so that it must
be difficult to dissociate the various elements in the extremely complex neural
events which are involved, say, in the simplest kind of conscious sensation.
As we trace out the evolution of the brain we find an ever-increasing
subordination of the lower to the higher centres, so that in man himself
many reactions which in the lower animals are carried out by the spinal
of
such changes in
associated with
the
384 PHYSIOLOGY
cord alone, involve the educated co-operation of the cerebral hemispheres.
With this increased control there is a corresponding increase in the develop-
ment of long paths. In the brain of a fish, for instance, the cerebral hemi-
spheres are connected only with the fore-brain ; a little higher in the scale
there are connections between the hemispheres and the mid-brain as well.
The chief long tracts are those which run between the thalamus,the mid-brain
or the hind-brain, and the spinal cord. With the huge development of the
cerebral hemispheres in man there is also development of long paths, the
pyramidal tracts, from the hemispheres down to all the motor mechanisms
of the cord, and of tracts which connect all parts of the cortex with the grey
matter of the pons and indirectly with the cerebellum. The tracts which in
the lower animals were of supreme importance in determining subordination
of lower to higher centres, of immediate reactions to those determined by the
organs of foresight, dwindle therefore in importance. Those tracts, such a s
the thalamo-spinal, tecto-spinal, vestibulo-spinal, which form the main mass
of the white matter of the brain stem in lower types of vertebrates, become
reduced to a few scattered fibres in the brain of man and are insignificant
as compared with the great cerebro-bulbar and cerebro-spinal tracts.
ASCENDING TRACTS
The Tracts of the Fillet. The fibres which enter the spinal cord
by the posterior roots pass into the posterior columns and along these to
the dorsal column nuclei, the nucleus gracilis and the nucleus cuneatus,
where they end by arborisations among the cells composing these nuclei.
From these nuclei the axons of the cells pass in various directions, the chief
mass of them forming the deep arcuate fibres. These emerge from the inner
side of the nuclei and pass through the raphe to the other side of the medulla
where they join the spino-thalamic fibres and form the definite collection
of longitudinal fibres, lying dorsallv to the pyramids, which is known
as the main tract of the fillet or, often, the mesial fillet. As these fibres
traverse the pons they are joined at the outer side by a number of bundles
which are derived from the central continuation of fibres connected with
those derived from the cochlear nerve. This part is known as the lateral
fillet. The cells of the accessory and lateral nuclei of the cochlear nerve
send their axons by the trapezium to the superior olivary nucleus and
other small masses of grey matter on the other side. In these nuclei the
fibres for the most part terminate, but a fresh relay of neurons carries
on the impulses and forms the main part of the lateral fillet. These pass
up, getting more dorsal as they ascend, and finally terminate in the inferior
corpora quadrigemina. The mesial fillet, which we can regard as a con-
tinuation of certain spinal tracts upwards, is reinforced throughout the
whole extent of the medulla and pons by fibres originating from the masses
of grey matter in which the sensory cranial nerves terminate. Certain
of these fibres may form a distinct tract in the formatio reticularis, known
as the central or thalamic tract of the cranial nerves. Another similar
tract in the formatio reticularis is derived from the central terminations
TIIK STRUCTURE OF THE BRAIN STEM
385
(crbusCoJIosum ,__
Thalamo-CorfKjl FibrfS
Rtd Nucleus ,
Substantia Nipr&
Peduncle -
Ctrtbellum - '~~~~a
\ Muscular Tons
Pyramid
Dttp Arcuift Fibres
Dorsal Column (dirtcD
lUnst of pcufion
\ inovtmenf,
Spinal Ganglion
Spirr&l Nerve _
Sbmo-Ctrebtllar
Tracfs \\
/Co-ordination %t\ \^
TRACT5.
r l0. 197 Diagram of ascending tracts between the spinal cord and brain (Gordon
ll"i mi>). with the probable path oi sensory impulses.
25
386
PHYSIOLOGY
of the fifth nerve, and is known as the trigemino-thalaniic tract. All
these fibres pass up in the tegmentum of the mid-brain and finally end, partly
in the grey matter of the subthalamic region and parti}- in the grey matter of
the thalamus itself. To the thalamus are also continued a few fibres from the
lateral fillet. By this means the head ganglion of the fore-brain is in a posi-
tion to receive, so to speak, samples of the afferent impressions derived from
every sense-organ of the body.
The Visual Taths. Two classes of afferent impressions which arrive at
the optic thalamus are probably of
equal importance to all the other
afferent impressions taken together.
These are impulses derived from
the organs of vision and of smell.
The greater part of the fibres com-
posing the optic nerves arise as
axons of the ganglion-cells of the
retinae. Passing backwards, the
nerves of the two sides join in the
optic chiasma, which is dosely
attached to the floor of the third
ventricle. After joining in the
chiasma the optic nerves are ap-
parently continued round the crura
cerebri as the optic tracts. These
pass round on each side and can be
seen to make coimection with the
back part of the thalamus, the
external geniculate body, and the
superior corpus quadrigeininum.
Part of the tract, which is some-
times called the mesial root, passes
into the internal geniculate body.
This part of the tract has probably
nothing to do with vision and
forms a commissure running in
the optic chiasma connecting the internal geniculate bodies of the two
sides. The course of the optic fibres is shown in the diagram (Fig. 198). In
man and in some other mammals, e.g. dog, monkey, the nerve fibres decussate
incompletely in the chiasma. The uncrossed bundle is derived from the
outer half of the retina of the same side, whereas the crossed bundle is derived
from the mesial half of the retina on the other side. The right optic nerve
thus carries all the impulses originating in the right eye. The right optic
tract carries all the impulses originating from stimuli occurring in the left
field of vision. It must be remembered that vision in man is binocular, both
retinas being concerned in the perception of each field of vision. The external
and internal geniculate bodies may be regarded as extensions of the optic
Fig. 198. Diagram-
matic representa-
tion of the optic
tracts and their
connections.
(Cunningham.)
THE STRUCTURE OF THE BRAIN STEM 387
thalamus, the former in special relation with the organ of vision, the latter
with the organ of hearing.
The olfactory bulb is also connected by tracts with the thalamic region,
probably through the column of the fornix and the bundle of Vicq d'Azyr.
Since however the chief connections of the olfactory lobe are with the
more primitive portions of the cerebral hemispheres, the olfactory tracts
will be more conveniently treated of in connection with the latter.
The Cerebellar Paths. We have already traced out the course of
spinal fibres which terminate in the cerebellum. They may be shortly
summarised as follows :
(1) The posterior or direct cerebellar tract, originating in Clarke's
column of cells of same side, passing up in the lateral columns and by
the restiform body into the superior vermis of the middle robe of the
cerebellum.
(2) The anterior cerebellar tract or tract of Gowers, originating in the grey
matter of both sides of the cord and passing in the lateral columns through
the lateral part of the medulla and pons, and finally attaining the superior
vermis through the superior cerebellar peduncles.
(3) The posterior columns, ending chiefly in the homolateral posterior
column nuclei. From these nuclei, though the great mass of fibres passes
into the fillet, a certain number from the nuclei of both sides join the resti-
form body to pass into the middle lobe of the cerebellum.
In the medulla these afferent tracts of the cerebellum are joined by the
following sets of fibres :
1. The olivo-cerebellar.
"2. The vestibulocerebellar.
3. A few fibres from the chief sensory nuclei, including those of the vago
glossopharyngeal nerves.
All these fibres terminate in the cortex, chiefly of the middle ldbe. From
the cortex of this lobe fibres pass to the central and roof nuclei of the cere-
bellum, namely, the nucleus dentatus, the nucleus emboliformis, the nucleus
tastigii, and the nucleus giobosus. The efferent tracts of the cerebellum
start from these central nuclei, no fibres which originate in the cortex of the
cerebellum apparently leaving the precincts of this organ. Some of these
efferent fibres of the cerebellum will be better described with the descending
tracts of the brain stem. Of those which take an ascending direction, the
great bulk are contained in the superior cerebellar peduncles. These origin-
ate for the most part in the dentate nucleus and the nuclei emboliformis and
giobosus. As the superior peduncles run forwards they sink below the
posterior corpora quadrigemina, and in the tegmentum, below the Sylvian
iter, decussate with the tract of the opposite side to pass to the red nucleus.
In the red nucleus many of the fibres end some however passing through the
nucleus together with fibres derived from the cells of the red nucleus itself
to end in the thalamus and in the grey matter of the subthalamic resion.
388
PHYSIOLOGY
Optic
Tha.lj>mus|~
Infernal 1
CApsulej-
Lenficutarl ''
Nucleus J
Substantia Ni(Sr& !ji\
RubroSpin*! Iract
Outers Nucleus — i
L^- - CUusfrui
-Red Nucleus
Pyramidal Tract-
Wsfibulo Spinal Tract s
>cssed Pyramidal Tract
Dentate Nucleus
^ Inferior Olive
Direct Pyraniulal Tract
D€SC6MDING~h£RV/£
TRACTS.
Fig. 199. Schema of course taken by chief descending tracts of brain stem. (Cordon
Holmes.) The tract in red. to the right of the rubro-spinal tract, includes the pi sterioX
longitudinal bundle, together with the fibres of the thalamo-spinal and tecto-spinal
tracts.
THE STRUCTURE OF THE BRAIN STEM 389
DESCENDING TRACTS
The chief descending tracts having their origin in the brain stem are the
rubro-spina] bundle or bundle of Monakow, the complex system of fibres
known as the posterior longitudinal bundle, and the vestibulo-spinal fibres
from the upper part of the medulla.
(1) The rubrospinal fibres originate in the red nucleus. They cross
the median line and run down, at first in the tegmentum and later in the
lateral column of the medulla oblongata and cord. In their passage they
communicate with the various motor nuclei of the cranial nerves. They
can be traced to all segments of the cord, where they terminate in connection
with the anterior horn-cells.
(2) The posterior longitudinal bundle. This bundle is to be seen in
ajl sections through the brain stem below the level of the oculo-motor nucleus.
It consists of fibres, some of which pass upwards, while others pass down-
wards. Most of the fibres take origin in the cells of Deiters' nucleus and of
the reticular formation of the pons, medulla, and mid-brain, as well as from
certain cells in the sensory nucleus of the fifth nerve. The fibres traced
upwards can be seen to send collaterals to end in the various parts of the
nuclei of the third, fourth, and sixth nerves.. Lower down it becomes con-
tinuous with the anterior basis bundle of the spinal cord and merges in the
mternuncial fibres which serve to connect the various levels of the cord.
Some of the fibres, which are descending, are derived from a small nucleus,
the so-called nucleus of the posterior longitudinal bundle, which is found in
the grey matter at the side of the posterior part of the third ventricle. This
bundle also receives fibres from the superior olivary body. It is one of the
earliest to undergo myelination in the foetus (cp. also Fig. 205, p. 407).
(3) The vestibulo-spinal tract takes origin for the most part in the
cells of Deiters' nucleus. The fibres pass down in the anterior part of the
spinal cord and terminate in the anterior horns. They are sometimes known
as the antero-lateral descending tract. It is probably through this tract
that the cerebellum is able to affect indirectly the activity of the motor
mechanisms of the cord.
Two other descending tracts which are important in the lower vertebrates
arc insignificant in man. These are the thalamo-spinal tract, consisting of
descending fibres derived from the optic thalamus, and the tecto-spinal tract,
containing fibres derived from the roof of the mid-brain. In the mid- and
hind-brain these fibres run in the tegmentum. In the cord they are found
in the anterior columns. The olivo-spinal tract, which is supposed to
on-mate in the olivary body, forms a small tract in the cervical region near
the surface, opposite the lateral angle of the anterior horn.
SECTION XII
THE FUNCTIONS OF THE BRAIN STEM
The brain stem may be taken to include all those parts lying between the
cerebral hemispheres and the spinal cord, from the optic thalamus in front
to the medulla oblongata behind. The brain may be divided into the follow-
ing parts from before back :
(1) Thalamencephalon, including the corpus striatum, the cerebral
hemispheres and rhinencephalon, or olfactory lobes.
(2) Diencephalon, i.e. the fore-brain, especially the optic thalamus.
(3) Mesencephalon, or mid-brain, including the quadrigemina, the iter of
Sylvius, and the crura cerebri.
(4) Metencephalon, composed of the pons Varolii, the upper part of the
fourth ventricle, and cerebellum.
(5) Mvelencephalon, or bulb, consisting of the medulla oblongata.
We may get some idea of the part played by these different regions of
the brain in deter minin g the reactions of the individual as a whole by
examining the behaviour of the animals in whom all the rest of the brain
in front of the part in question has been removed. If however we take
into account the numberless connections existing between the different levels
in the central nervous system, the interdependence between the different
portions, and the subordination, especially in the higher animals, of the
functions of the lower to those of the higher levels, we must acknowledge
that such experiments can give us but an imperfect idea of the possibilities
of each level when in connection with all other portions of the nervous sy~t.-n;.
THE FUNCTIONS OF THE MEDULLA OBLONGATA
OR MYELENCEPHALON
The possibilities of any given nervous centre are determined by the
afferent impressions which enter it, and by the connections made by the
nerves carrying these impulses with the motor tracts within the centre. The
bulb receives afferent impressions of ' taste ' from the tongue through the
nervus intermedins, from the alimentary canal as low as the ileocolic sphinc-
ter, from the lungs, the heart, and the larger blood-vessels, i.e. from the most
important of the viscera of the body, by the fibres of the vagoglossopharyn-
geal nerves. Its only skeleto-motor centre is that for the muscles of the
tongue (the hypoglossal). It sends also to the viscera efferent fibres, which
arise from cells in the nucleus ambiguus. These fibres carry motor impulses
390
THE FUNCTIONS OF THE BRAIN STEM 391
to the muscles of the larynx and bronchi and to the oesophagus stomach
and intestines, secretory fibres to the stomach and inhibitory fibres to the
heart.
At the upper border of the bulb enter also the fibres of the eighth nerve,
carrying important impressions from the organ of hearing and the organ of
static sense. These will be in all probability divided or injured in isolating
the bulb from the higher portions of the brain. While in connection with the
upper portions of the brain, the bulb receives also afferent impressions
from the skin of the face, and the mucous membrane of the nose and mouth
through the descending branches of the root of the fifth nerve, which pass
down superficially to the tubercle of Rolando. When in connection with the
cord, the medulla receives afferent impressions from the whole surface of the
body and from all the muscles and joints through the posterior column
nuclei.
The bulbo-spinal animal, i.e. one in whom a section has been carried out
at the upper boundary of the medulla, differs from the spinal animal chiefly
in the maintenance of the nexus between the visceral functions and the
skeleto-motor functions of the body. After removal of all the brain in
front of the bulb, the animal still continues to breathe regularly and auto-
matically. The blood pressure and the pulse rate remain normal, and all
three mechanisms, respiration, pulse rate, blood pressure, may be affected
reflexlv bv appropriate stimuli, or may be altered in consequence of central
.stimulation of the medulla.
In addition to the reflex mechanisms of locomotion, which are evident
in the spinal animal, the bulbo-spinal animal shows a greater degree of
solidarity in its responses. It is easier to evoke movement of all four limbs.
In the frog, if the eighth nerve has been left intact, there is a certain power
of equilibration left, and the animal when laid on its back tries to right itself
and usually succeeds.
It is in this portion of the central nervous system that have been located
the great majority of the so-called centres. By a statement, that the centre
nf such-and-such movement or function is situated in the medulla, we mean
merely that the integrity of the medulla, or certain parts of it, is essential for
the carrying out of the function. Every function, for instance, in which
impulses passing up the vagus nerves are involved, is necessarily dependent
on the integrity of these nerves and their central connections, and, since these
are situated in the medulla, the centres for these functions are also located
in this region. From a broad standpoint the medulla or bulb may be looked
upon as a ganglion, or a collection of ganglia, whose main office is to guard and
preside over the working of the mechanisms at the anterior opening of the
body ; by means of which food is seized, tasted, taken into the alimentary
canal, and finally digested. The respiratory apparatus belongs to the same
system and is innervated through the same nerve channels. Hence the
various events in alimentation, such as deglutition, vomiting, mastication,
or in the allied respiratory functions, such as phonation, coughing, and
respiration itself, are endowed with centres in this part of the brain. In
392 PHYSIOLOGY
connection with the termination of the vagus nerves of this pari "I the brain
is the location here of the chief vaso-motor centre, i.e. in a region which is
in close proximity to the endings of the chief afferent nerves from the heart
and larger blood-vessels and to the nucleus of the efferent controlling nerve
to the heart.
THE METENCEPHALON (PONS VAROLII AND CEREBELLUM)
Destruction of the brain at the front of the fourth ventricle and just
behind the posterior quadrigemina will leave the animal with a central
nervous system, which is in connection by efferent nerves with the whole
musculature of the body (with the exception of certain eye muscles) and
which receives impressions through the spinal cord from the whole surface
of the trunk and limbs, and through the fifth nerve from the face and head,
and also the higher specialised impressions from the organ of hearing and
the organ of static sense. The impressions from the two great projieient
senses of smell and sight would be wanting.
Such an animal presents considerable advance in the complexity of its
reactions above one possessing only spinal cord and bulb. The frog, for
instance, after such an operation, can still walk, spring, and swim : when
placed on a turntable it reacts to passive rotation by turning its head in the
opposite direction. On stroking its back it croaks. If the cerebellum be
also removed, the animal becomes spontaneouslyactive and crawls about until
it is blocked by some obstacle. In this condition there is great activity of the
swallowing reflex. Anything which touches the mouth is snapped at. If
placed on its back the frog at once rights itself.
In the mammal a similar increase of reflex activity is observed though the
power of progression is not retained.
THE MESENCEPHALON OR MID-BRAIN
A section in front of the anterior corpora quadrigemina would leave
the animal with the nervous system receiving all normal sensory impressions.
with the exception of the olfactory, and with efferent paths to all the muscles
of the body, including those of the eye. In the mammal such an operation
brings about a condition known as ' decerebrate rigidity.' Though respira-
tory movements continue normally, the whole musculature is in a cataleptic-
condition, the elbows and knees being extended and resisting passive flexion ;
the tail is stiff and straight, the neck and head retracted, i This condition
seems to depend on an over-activity of the reflex toni&functions of the lower
centres.V/That it is reflex is shown by the fact tha|_the rigidity is at once
abolished in a limb on dividing the appropriate posterior roots^J The
position of the limbs may be also modified by sensory stimuli. A similar
condition of increased tonus is observed in the frog.
The apparatus for emotional expression is still intact though somewhat
modified, and an impression which would give rise to pain in the intact
animal may cause vocalisation in an animal in whom the brain above the
mesencephalon has been destroyed.
THE FUNCTIONS OF THE BRAIN STEM 393
THE BRAIN STEM AS A WHOLE (INCLUDING THE THALAM-
ENCEPHALIC, OR OPTIC THALAMI)
The introduction of the head ganglia of the brain stem, viz. the optic
t ha la mi. completes in the lower animals at all events the apparatus for im-
mediate response to stimulus. The powers of such an apparatus may be
studied by examining the behaviour of an animal in whom the cerebral
hemispheres have been destroyed. The result of this operation varies
according to the type of animal chosen, though all types present certain
common features. When a frog's cerebral hemispheres have been excised, a
casual observer would not at first notice anything abnormal about the animal.
It sits up in its usual position, and on stimulation may be made to jump
away, guiding itself by sight, so that it avoids any obstacles in its path.
Movements of swallowing and breathing are normally carried out. The
animal thrown on to its back, immediately turns over again. If put into
water, it swims about until it comes to a floating piece of wood or any support
when it crawls out of the water and sits still. If it be placed on a board and
the board be inclined, it begins to crawl slowly up it, and by gradually in-
creasing the inclination may be made to crawl up one side and down the
other. But a striking difference between it and a normal frog is the almost
entire absence of spontaneous motion — that is to say, motion not reflexly
provoked by changes immediately taking place in its environment. All
psychical phenomena seem to be absent. It feels no hunger and shows no
fear, and will suffer a fly to crawl over its nose without snapping at it. " In
a word, it is an extremely complex machine, whose actions, so far as they go,
tend to self-preservation ; but still a machine in this sense, that it seems to
contain no incalculable element. By applying the right sensory stimulus
to it, we are almost as certain of getting a fixed response as an organist is
when he pulls out a certain stop."
According to Schrader and Steiner, if care be taken not to injure the
optic thalami, spontaneous movements may be occasionally observed after
removal of the cerebral hemispheres. On the approach of winter such a
frog has been observed to bury itself in order to hibernate, and with spring to
resume activity and to feed itself by catching insects. The behaviour of
such decerebrate animals depends on the part taken in the initiation of
movement and adapted reactions by stimuli entering through the higher
sense-organs. Thus an ordinary bony fish after ablation of the cerebral
hemispheres maintains its normal equilibrium in water. It is continually
swimming about, stopping only when it reaches the side of the vessel or when
worn out by fatigue. Here again, if the thalami and optic lobes be intact,
the fish has been observed to show very little difference from a normal
animal and to possess the power of distinguishing edible from non-edible
material. On the other hand, in the elasmobranch fishes, which depend
mainly upon their olfactory apparatus as a guide to movement, the removal
of the cerebral hemispheres with the olfactory lobes, or of the latter alone,
394 PHYSIOLOGY
produces complete immobility and absence of spontaneous movement,
even though the optic thalami and optic lobes may be intact.
In the. bird the cerebral hemispheres may be removed with ease. A
decerebrate pigeon, if its optic lobes be intact, walks about avoiding all
obstacles, and may even fly a short distance. In the dark, i.e. in the absence
of visual impressions, it remains perfectly still. The bird however is unable
to recognise food, or enemies, or individuals of the opposite sex ; it shows
no fear and responds to stimuli like the brainless frog described above.
Goltz has succeeded in the dog in removing the whole of the cerebral
hemispheres in three operations. The dog was kept alive for eighteen
months after the final operation. It was able to walk in normal fashion
and spent the greater part of the day in walking up and down its cage.
At night it would sleep and then required a loud sound to awaken it. It
reacted to stimuli in a normal fashion, shutting its eyes when exposed to a
strong light, shaking its ears in response to a loud sound. On pinching its
skin it attempted to get away, snarling or turning round and biting clumsily
at the experimenter's hand. It had no power to recognise food and had to be
fed by placing food in its mouth, though, if this food were mixed with a
bitter substance such as quinine, it was at once rejected. The dog never
showed recognition of the persons that fed it, nor any signs of pleasure or
fear. Removal of the hemispheres had thus produced loss of all understand-
ing and memory. There was no sign of conscious intelligence, and all the
actions of the animal must be regarded as reflex responses to immediate
excitation.
With the development of the cerebral hemispheres in the higher mammals
there is a considerable shifting of motor reactions from those which are
immediate and ' fatal ' or inevitable to those which are edueatable. The
cerebral hemispheres in man take a large part in the determining of even
the common reactions of everyday life. Ablation of the hemispheres
therefore, or even part of the hemispheres, in the ape and man gives rise
to much more lasting symptoms than is the case in the animals we have just
studied. These defects we shall have to consider more fully later. The
results however obtained on the lower animals, from the dog downwards,
show that the brain stem, from the head ganglion of the optic thalamus back
to the medulla, with the spinal cord, represents a complex mechanism which
can be played upon by impulses received through all the sensory apparatus
of the body, and is able to adjust the motor and visceral reactions to the
immediate environment of the animal.
Certain of these immediate reactions are susceptible of further physiologi-
cal analysis. We have seen that the spinal cord contains the co-ordinated
mechanism for the movement of the limbs. We may now discuss how the
movements of the limbs are co-ordinated with thosa of the trunk and head in
the maintenance of the unstable position of the animal in standing and in
locomotion. For this purpose there has been developed the great mass of
nerve matter in the roof of the metencephalon, viz. the cerebellum.
SECTION XIII
THE FUNCTIONS OF THE CEREBELLUM
The carrying out of co-ordinated movements is associated with and regu-
ated by afferent impressions which can be divided into two main groups.
In the first group may be placed those due to the changes in the environ-
ment of the animal, working on sensory structures or ' receptors,' of varying-
qualitative sensibility, in the surface of the body. These receptors may be
excited by the mechanical stimuli of pressure, by changes of temperature,
or by nocuous or harmful impressions, such as would, in the presence of
consciousness, give rise to pain. At the fore end of the body we have in
addition the special receptor organs excited by waves of light or of sound.
The action of any of these impressions, if of sufficient intensity, is to evoke
an appropriate reflex movement, such as the flexor reflex in response to
nocuous stimulus applied to the foot, or the stepping, or extensor, reflex
excited by steady pressure on the sole of the foot.
The integrity of the nerve paths carrying these afferent impressions and
of the motor paths to the muscles is not however sufficient. A secondar} T
set of afferent impulses is essential in order to i>,uide and regulate the extent
of the resultant discharge. These secondary afferent impulses start in the
deep tissues, viz. the muscles, joints, and ligaments, which are provided with
special sense-organs capable of being stimulated by the mechanical changes
of tension or pressure set up by the movements themselves. The importance
of these impressions for the carrying out of muscular movements is shown
by the ataxia which is the result of injury to the corresponding afferent
nerves. Degeneration of the nerves to muscles, or section of the afferent
roots, causes marked ataxia of the movements of the limb, whereas no such
result follows section of all the cutaneous nerves supplying the surface of the
limb with sensibility. To this system of afferent nerves Sherrington has
given the name of the ' proprioceptive ' system, since it is excited, not directly
by changes in the environment, but by alteration in the animal itself. It is
responsible for reactions differing in many respects from those which are the
immediate result of stimulation of the other system, the ' exteroceptive.'
which is distributed over the surface of the body. Since it is excited by
the movement of the muscles themselves, i.e. by the first result of the reaction
to external stimulus, it Serves as a governing mechanism to regulate the
extent of each motor discharge. Its excitation not only prevents over-action
of the muscles, but may evoke a compensatory reflex in an opposite direction
to the reflex immediately excited from the skin. A marked feature of this
395
396 PHYSIOLOGY
system is its tendency to continued 01 tonic activity. The steady slight con-
traction, or ' tone,' which is observable in most skeletal muscles, is inde-
pendent of the surface sensibility and depends entirely on the proprioceptive
system of the muscles and their accessory structures.
In the decerebrate animal the rigidity of a limb disappears at once after
section of its afferent roots, though it is unaltered by division of the main
skin nerves. This tonus does not affect all muscles to an equal degree.
In every limb there is a predominance of tonus in certain muscles, so that
the result on the whole limb is an attitude br posture which is typical
of the limb or the animal. Thus the spinal frog takes up an attitude which
is very different from that which would be impressed on it by gravity
in the absence of muscular activity. If one of its hind limbs be extended
gently, it soon draws it up to reproduce the same crouching position. The
posture of the limb is therefore a result of afferent impressions continually
ascending its proprioceptive nerves and exciting a tonic activity which
predominates in certain definite muscles. This posture, as carried out by
the spinal cord, is a segmental response. It determines the relation of the
limb to the trunk, and to a less extent of the four limbs to one another. It is
not concerned with the relation of the animal as a whole to its environment,
and only to a slight extent with the maintenance of equilibrium in the
presence of the continually acting force of gravity.
In the evolution of the nervous system there has been a continual
subordination of the hinder parts to the head end, in consequence of the
development at this end of the all-important distance receptors, the impulses
from which take a predominating part in determining the reactions of
the body as a whole. In fact the subordination of one part of the central
nervous system to another is in direct relation to the importance of the
afferent impulses arriving at each portion of the system. Thus the vaso-
motor centres segmentally distributed throughout the spinal cord are
subject to the vaso-motor centre in the medulla, which is developed at the
point of entry of the vagus nerves, i.e. the chief afferent nerves from the heart
and large blood-vessels. The collections of grey matter presiding over the
segmental reactions of the intercostal muscles are entirely subordinated to
the grey matter in the medulla around the entry of the vagus fibres from
the lungs.
This subordination of the hinder to the anterior sense-organs is paralleled
in the case of the proprioceptive system. Entering the hind-brain at the
upper border of the medulla is the eighth nerve, composed of two parts which
differ widely in functions, viz. the cochlear division and the vestibular
division. The former is entirely concerned with the reception of sound
waves, and is therefore the auditory nerve. The vestibular nerve, which is
distributed to the rest of the membranous labyrinth, must be assigned to the
proprioceptive system. The labyrinth is practically a double organ. The
primitive auditory sac arises as a simple involution of the surface. In the
course of development the front part is modified to form the canal of the
cochlea, which is set apart entirely for the reception of sound. From the
THE FUNCTIONS OF THE CEREBELLUM
397
back part there are formed two sacs — the saccule and utricle — and the three
semicircular canals. The saccule and the utricle, which receive each a large
branch of the vestibular nerve, represent the otolith organ, which is found
in almost all classes of animals. The crayfish, for instance, at the base
of its antenna 1 presents a small sac lined with hairs and richly supplied
with nerves. In this sac a small calcareous particle rests on the hairs.
It is evident that the incidence of the pressure of the small stone or otolith
on the bail's will vary according to the position of the animal (Fig. 200),
so that any change in the position of the head will be attended by altera-
A
a be
I'm:. 200. Diagram of an otolith organ, I" show how alterations
in its position will cause the weight of the otolith [ot.) to press on
different sense cells, and therefore to affect different nerve fibres.
tion in the nerve fibres which have been stimulated by the pressure of
the otolith, and therefore in the nature of the impulses flowing to the central
nervous system. The importance of these impulses in regulating the loco-
motion and the maintenance of the equilibrium of the animal is well shown
if the otolith be replaced by a small fragment of iron. Under normal
circumstances the iron particle will act quite as well as an otolith. If
however a powerful magnet be brought in the neighbourhood of the animal,
the pressure of the particle will not be determined simply by gravity and
therefore by the position of the animal, so that there will be a discordance
between the impulses arriving from the otolith organ and those arising from
the sense-organs of the body, and marked disorders of equilibrium are the
result.
In the saccule and utricle the vestibular nerve ends in similar otolith
organs known as the maculae acousticse. These are small elevations
covered with long hairs and supplied with nerves. One or two calcareous
secretions or otoliths are embedded in the hairs, so that any change in position
will cause a corresponding change in the nerve fibres which are being excited
by the weighl i if the otoliths. The semicircular canals, which lie in the three
planes of space, are also provided with end organs, somewhat similar in
structure to the maculae acousticse, but devoid of otoliths. The end organs
are excited by mass movements of the fluid endolympli, which arc set
up by rotation of the head.
Since the nervous apparatus of the labyrinth is excited not by changes
in the environment, from which it is carefully shielded, but by changes in the
398 PHYSIOLOGY
animal itself, we are justified in assigning it to the proprioceptive system, of
which indeed it represents the most important receptor, .rust as the pro-
prioceptive nerves of a limb are responsible for the tonus of tin' limb muscles.
so. as Ewald has shown, each labyrinth is responsible to a considerable degree
for the tonus of the corresponding side of the body. Extirpation of one
labyrinth causes a lasting loss of tone in the muscles of the same side. A
further functional resemblance lies in the part played by the labyrinth in the
determination of posture. The resultant effect of the impulses arising in it
is to maintain a reflex posture of the head and eyes, so that the optic axes in
a position of rest are directed towards the horizon. Stimulation of the
labyrinth causes therefore movements of the eyes which may or may not be
associated with correlated movements of the head.
As in the case of the other sense-organs of the anterior end of the body,
the reflexes excited from the labyrinth dominate over those evoked by pro-
prioceptive impulses from the hinder portions of the body. At the entry
of its nerve into the brain stem, a mass of grey matter is developed which
must be regarded as the head ganglion of the proprioceptive system, and
the chief co-ordinating organ of all the reflex systems which determine
posture of the limbs and of the whole animal, and therefore the maintenance
of equilibrium both at rest and during locomotion. This organ is the
cerebellum, associated with the grey matter in the upper part of the fourth
ventricle at the point of entry of the vestibular nerves. The cerebellum
commences in early foetal life as a small elevation in the dorsal wall of the
neural tube, where the eighth nerve enters. Simple in structure and small
in extent in most of the fishes and amphibia, it grows in extent with increasing
complexity of the animal's motor reactions, and attains its greatest develop-
ment in the mammalia. In this class the cerebellum, like the cerebrum, is
most highly developed in man and the higher apes. It is generally described
in man as consisting of a middle lobe, composed of the. superior and inferior
vermis, with two lateral hemispheres, and these are subdivided by anatomists
according to the situation of the chief sulci. From the physiological point
of view the structure of the organ is relatively simple, as is shown by the
uniformity of its structure throughout all parts. It may be considered as
formed of two main structures, viz. the cortex and the central or roof ganglia.
The surface of the cerebellum is increased by being thrown into folds or laminae,
so that a section of this organ has a tree-like appearance. A section through a lamina
shows three distinct zones : an outer molecular layer presenting a granular appearance
with a few nuclei ; internal to this a granule layer composed of many nuclei of nerve
cells ; and most deeply a central core of white matter. Between the molecular and
granular layers are situated the cells of Purkinje, large flask -shaped cells each with one
apical dendrite, distinguished above all other dendrites of the central nervous system
by the richness of its branching, and with one axon, which leaves the base of the cell
and passes down into the central white matter, giving off collaterals in its course.
In preparations made by Golgi's method we are able to distinguish the various elements
composing these layers and their relations. The molecular layer, besides neuroglia-
cells and the brandling dendrites of the cells of Purkinje, contains certain star-shaped
cells (a Fig. 201), which give off an axon running parallel with the surface in the
molecular layer. From this axon branches dip down towards the cells of Purkinje.
THK Fl'XCTIOXS OF TIIK < KREBKLLUM
399
where they end in a rich basket-work of fibres around the body and beginning of the
axon of these cells. The nuclear or granular layer presents two kinds of cells. The
most numerous is a small cell with a few short dendrites, each of which terminates
in a claw-shaped arborisation, and a single lung axon, which passes straight up into
the molecular layer, where it bifurcates. The two branches run parallel with the
surface in a direction at right angles to the plane of expansion of the dendrites of
Purkinje's cells, apparently resting against the serial inns on the edges of these processes.
The second kind of cell in the granular layer is the so-called- Golgi's cell — a large cell
Central
white
matter.
Fig. 201. Schema of constituent elements of cerebellum. (Modified from Boh.u
and Davidoff. ) On the left is a section of the cortex as it appears when
stained by ordinary methods. The middle portion represents diagrammaticallv
a section at right angles to the lamina", while to the right of the dotted line the
section is taken in the same plane as the lamina?.
a, star-shaped cells of molecular layer ; b, b, cells of Purkinje ; c, ' Golgi cell ' ;
d, small cells of nuclear layer ; e, ' tendril fibre ' ; f, • moss fibre ' ; g, axon of cell
of Purkinje.
with many dendrites and an axon which terminates by frequent branches in the neigh-
bouring grey matter.
The fibres making up the white matter are of three kinds — two afferent and one
efferent. The moss fibres, so called from the curious thickenings they present in the
nuclear layer, pass up into the grey matter and terminate by frequent branches in
this layer. The tendril fibres, also afferent, end in a rich arborisation which surrounds
the distal part of the bodies and the bases of the dendrites of the cells of Purkinje.
Tin' efferent fibres are represented by the axons of the cells of Purkinje, which acquire
a medullary sheath and run down into the white matter.
This slight sketch of the anatomy gives us a conception of the extreme complexity
of choice presented to nervous impulses traversing the cerebellar cortex. Thus a
discharge along an axon of the cell of Purkinje may be excited (1) by an impulse ascend
nag the tendril fibres; or (2) by one ascending the moss fibres through the grannie
nil-, and then passing by their bifurcating axon i" the dendrites of the cells of Pur-
kinje; or (3) by the star-shaped cells of the molecular layer and their basket-work
round the body of Purkinje's cells.
400 PHYSIOLOGY
The roof ga nuclei fastigii near the middle line, the nuclei em-
boliformes situated just dorsal to these, and the nuclei dentati. large crenated capsules
of grey matter lying in the middle of each lateral lobe. 'II
matter of the central nuclei are large and multipolar, resembling those found in the
nuclei of motor nerves.
The cerebellum receives fibres from all the receptor apparatus of the body which
can be classed in the proprioceptive system. The greater number of these fibres
ran directly to the cortex, especially of the vermis, and there is no evidence of the
passage of any efferent fibres from the cortex directly to the motor apparatus of the
cord.
The connections of the cerebellum are established by means of its three peduncles,
and may be classified a* follows:
AFFERENT TRACTS. Inferior Peduncle. By this peduncle afferent fibres
pass to the superior vermis:
1 Prom Clarke's column of the same side by the posterior cerebellar tract.
_' From the dorsal column nuclei, viz. the nucleus gracilis and nucleus cuneatus
of each side, so that connection is established in this way with the prolongations of the
posterior sensory roots which run into the posterior columns of the cord.
(3) Bv the internal restiform body from the vestibular division of the eighth nerve,
part of the fibres passing through, and perhaps making connections with, Deiters'
nucleus.
(4) A strong band of fibres passes from the inferior olivary body into the opposite
cerebellar hemisphere. Atrophy of one side of the cerebellum induces a corresponding
atrophy in the opposite olivary body.
Middle Peduncle. The broad mass of fibres making up these peduncles is partly
afferent and partly efferent. Many fibres originate in the cells in the formatio reticu-
laris of the pons, cross the middle line, and pass up into the lateral cerebellar hemi-
sphere of the opposite side. F:l from the cerebellum to the pons to end
round cells in the same region. By this means' connection is established between the
cerebellar hemispheres and the corticopontine fibres which pass by the crura cerebri
between the pons and the frontal and temporal portions of the cerebral cortex of the
- ••■ side. On account of this connection there is a close association between the
development of each cerebellar hemisphere and the contralateral cerebral hemisphere.
Atrophy of one half of the cerebrum brings about atrophy of the opposite hemisphere of
the cerebellum.
The Superior Peduncle. By this path fibres from the superior corpora quadri-
gemima, i.e. from the terminations of the optic nerve, pass into the cortical grey matter
of the cerebellum (Fig. 202
EFFERENT TRAClS. The cerebellar cortex must be regarded as a receiving
rather than as a discharging station. Stimulation of it has little effect uuless strong
currents are employed, and a motor response is obtained more easily the deeper the
electrodes are sunk below the grey matter. The fibres which form the axons of the
cells of Purkinje pass partly towards the pons by the middle peduncle, largely, how-
ever, towards the roof nuclei, where they terminate. These nuclei form the efferent
stations of the cerebellum. From them fibres pass in various directions. A large
bundle leaves the dentate nucleus, runs into the superior peduncle, or brachium,
and passing deeply across to the tegmentum of the opposite side, traverses the red
nucleus to end in the subthalamic region of the opposite side of the brain. A certain
number of fibres, chiefly derived from the central nuclei, such as the nucleus fastigii,
i ward to the corpora quadrigemina chiefly on the same side. From the cerebellum
itself no direct tract runs into the spinal cord. The nuclei of Dieters and of Bechterew
(the paraeerebellar nuclei), which are connected with the ending- oi the vestibular
nerve, are. however, closely associated with the roof nuclei, and give rise to descending
fibres which pass into the antero-lateral region of the cord as the vestibulospinal
tract.
THE FUNCTIONS OF THE CEREBELLUM
401
The cerebellum is a receiving station, not only for impulses which arise in
the skin and eyes, i.e. on the surface of the body, but especially for those
which have been defined as proprioceptive, and originate either in the muscles
and tendons or in the labyrinth. Activity of this apparatus is roused as a rule
by the movement of the organism itself, and is only a secondary result of the
environmental stimulation which provoked the original movement. By its
efferent tracts starting in the roof- and paracerebellar nuclei, the cerebellum
is -able In affect the musculature of the same side <>{ the body by a direct
influence on the anterior horns, it also enters to a much greater extent into
relation with the opposite cerebral hemi-
spheres, so that it is in a position to
controloi modify the actiyityof these,
whether exerted on their sensor) - or on
their motor sides.
STIMULATION OF THE CEREBEL-
LUM. It was first shown by Ferrier
that movements of the same side of
the body can be excited by stimulation
either of the cerebellar hemispheres or
of the superior vermis. These results
have been confirmed by subsequent
observers, and point to each half of the
cerebellum being connected functionally
with the skeletal muscular apparatus of
the corresponding side of the body.
The cortex cerebelli is not excited
with ease. To evoke movements much
stronger stimuli are necessary than
e.g. for the excitation of the motor area
of the cerebral cortex. This again
is in accordance with what we should
expect from the anatomy of the organ,
knowing as we do that the cortex is an Fig. 202. Diagram of afferent and efferent
end-station for a number of afferent tracts of cerebellum
(After v. Gehuchten.)
paths, but has no direct efferent paths ot, optic thalamus; en, red nucleus;
from it to the lower motor mechanisms PCT V P^or cerebellar tract; ACT. anterior
cerebellar tract ; v. fifth nerve,
of the cord. On the other hand, move-
ments are excited by minimal stimuli from the intrinsic nuclei of the
cerebellum.
As a result of his experiments Horslev concluded that the cortex
cerebelli must be regarded as an afferent receptive centre from which axons
pass 1.. lb.' ventrally placed efferent nuclei, viz. the nuclei dentati. fastigii,
emboliformes, as well as Deiters' nuclei. Whereas excitation of the roof nuclei
produces more especially movements of the eyes and head, the paracere-
bellar (e.g. Deiters' nucleus) are responsible more especially for the move-
ments of the trunk and limbs. The movements of the body which are thus
26
402
1'IIYSIOUHiY
C.R.V-
evoked arc those concerned in maintaining equilibrium and are involved in
every alteration in the position of the body.
EFFECTS OF ABLATION OF THE CEREBELLUM. Complete unilateral
extirpation of the cerebellum, after the irritative effects of the lesion itself
lia vi> passed away, brings about a condition of the animal characterised by :
(1) Slight loss of power on the same side of the body.
(2) Considerable loss of tone on the same side.
(3) Tremors or rhythmical
SupA/ermis movements of the muscles on
the. same side accompanying
any willed movements.
These three symptoms are
denoted by Luciani as asthenia,
atonia, and astasia. At first
the animal is quite unable to
stand, and lies on the side of
the lesion with neck and trunk
curved in the same direction ;
when it attempts to stand it
always falls to the same side.
After two or three weeks the
power to stand is regained,
though when it attempts to
walk the hindquarters drag
and tremors accompany every
effort. The animal endeavours
to correct the tendency to fall
towards the side of the lesion
by an exaggerated abduction
of the limbs to that side, and
is always ready to take ad-
en. restiform body ; en, roof nuclei ; SF, sagittal vantage of the Support of a
iibres from cortex to roof nuclei; cvt, cerebello- , „n . „„„i.i„ ;+ i„ ™„:„i„4„ it-
vestibular tract ; Dx, Deitcrs' nucleus; III. vr, wall to enable it to maintain its
nuclei of third and sixth nerves; plf. posterior equilibrium. Swimming is much
longitudinal bundle; viii, vestibular division of better carried out than walking
eighth nerve ; sc, semicircular canals ; vst, vesti- Detter Carried OUT. man walking.
bulo-spinal fibres. the contact of the water with the
skin furnishing guidance to the
spinal mechanism which is lacking when the animal attempts to walk.
When the whole cerebellum is removed the animal is unable to walk,
sometimes for months. After a time it gradually learns to walk, but this is
carried out by an alteration of the method of progression. The disorders of
locomotion are quite distinct from the spinal ataxia observed after interfer-
ence with the afferent tracts from the muscles. The difficulty now is that
each diagonal movement of the limbs in progression tends to throw the
centre of gravity to one side or other of the basis of support, and it is the
mechanism for maintaining the right position of the centre of gravity, i.e. the
THE FUNCTIONS OF THE CEREBELLUM 403
posture of the body as a whole in relation to its environment, which is at
fault. The animal, in the case of the dog, therefore attempts to correct the
tendency to fall to one side or other at each step by making its basis of
support as wide as possible, and gradually acquires a peculiar gait, consisting
of a series of springs, in which the two fore limbs and two hind limbs act
together, the diagonal movements of the fore limbs being practically
abandoned. That the compensation, which is slowly acquired after extirpa-
tion of the cerebellum, is of cerebral origin is shown by the fact that subse-
quent removal of the cerebral hemispheres, or even of the motor areas of
the hemispheres, at once abolishes the power of movement which has been
reacquired ; and after the motor areas are destroyed on both sides, the loss
of power of progression is permanent.
These experiments show that the cerebellum, in Sherrington's words,
must be regarded as the head ganglion of the proprioceptive system, acting
as a centre where arrive the afferent impulses from the cord, the fifth nerve
and especially from the labyrinth. It influences, through the superior
peduncle, the cerebral cortex and furnishes the subconscious basis for the
guidance of the motor functions of the latter organ. Through its connections
with the nuclei of the bulb and the efferent tracts arising therefrom, it aug-
ments the tonic activity of all the muscles of the body, especially of those
concerned in the maintenance of posture, an effect which is especially
marked in the absence of the cerebral hemispheres and is responsible for
the condition known as decerebrate rigidity. As a centre of conjunction
for the afferent impressions from the muscles and those from the laby-
rinth, it co-ordinates the segmental reflexes, which determine the relative
posture of each limb, with those originating in the labyrinth and determining
the position of the head. Thus the whole mechanism provides for a mainten-
ance of equilibrium of the body as a whole, and for the proper balancing
of the reflex movements of the different limbs with those of the trunk
during all the changes in the position of the centre of gravity attending
locomotion.
The view here put forward really includes the various descriptions of the functions
of the cerebellum which have been given by different authorities. Thus Luciani
describes the cerebellum as an organ which by unconscious processes exerts a continual
reinforcing action on the activity of all the spinal centres. Munk ascribes to the
cerebellum the function of maintaining bodily equilibrium. Lewandowsky regards the
cerebellum as the central organ of the muscular senses. Hughlings Jackson expressed
many years ago an important characteristic of the cerebellum when he wrote that the
cerebellum is the centre for continuous movements, and the cerebrum for changing
movements. All these descriptions come under Sherrington's conception of the
cerebellum as head ganglion of the proprioceptive system.
DESTRUCTIVE LESIONS OF THE CEREBELLUM IN MAN
The general results of the lesions of the cerebellum in man are broadly similar to
those described for animals. As in these, the effects of unilateral lesions are always
limited to the same side of the body.
One invariable result is diminished tone of the muscles on the same side of the body.
This does not necessarily involve diminution or absence of the tendon reflexes ; in fact,
lol PHYSI0L0G1
there may I"- some exaggeration of these reflexes accompanying the diminished tone.
The loss of ("lie is easily perceived on lifting up the leg and letting it drop, hi
on taking the fore arm and shaking the hand. The knee-jerk in these circumstances
differs from the normal jerk in the absence of the tonic contraction which ordinarily
follows and continues the short sharp contraction; the leg thus falls after the jerk,
in-lead of being held up for a short time by the continued contraction of the quadriceps
muscle.
Associated with this atonia is a loss of voluntary power — asthenia « bich is generally
mi ire marked in the arm than in the leg. The initiation and the execution of voluntary
movements are slower than normal, and the end of the movement is delayed, so thai
there is a tendency to over-action of the muscles. Sustained effort is difficult, the con-
tractions becoming intermittent, or giving place to coarse tremor- so-called astasia.
There may lie defective maintenance of equilibrium in walking, so that a staggering gait
is produced, closely resembling that of a drunken man. There is a tendency to fall or
deviate to the injured side, hut this defect is not nearly so marked as in the case of the
dog, already described.
Even when the cerebellar gait is not marked, there is always some ataxy of the arm
or hand muscles ; the usual co-operative antagonism of opposing muscles is faulty,
and these may contract together instead of alternately, or the wrong muscles may be
used. When, for instance, the man tries to approximate one finger to the thumb, In-
tends to move all the others.
Speech is often slurred, drawling, or ' scanning ' in character, and the difficulty ex-
perienced by the man in articulation frequently gives rise to explosive utterance.
The head is generally inclined towards the injured side and rotated to the opposite
side. Abnormal position of the eyes is always a prominent symptom. Both eyes
are deviated to the opposite side, and there is nystagmus owing to the difficulty
experienced in moving the eyes towards the side, of the lesion. When a patient w ith a
lesion on the right side attempts to look towards the right, the eyes move slowly towards
the right and then drop back rapidly towards their position of rest, to be slowly moved
up again towards the right. The movements are similar to those which may be seen
in any person looking out of the window of a rapidly moving train.
There is no loss of sensation or of muscular sensibility.
SECTION XIV
VISUAL REFLEXES
Foremost among the afferent impulses determining the reactions of higher
animals are those arising in the eyes. Each retina, or rather the two
retinae acting together as a single organ, can
be regarded as a sensory surface, every point
of which corresponds to a point, or series
of points, lying in a given direction outside
the body. Each optic nerve contains about
half a million nerve fibres, i.e. as many as
enter the cord by the posterior roots from
the whole of the body. The two optic nerves
coming from the retinas meet together in the
floor of the fore-brain and form the chiasrna.
At the chiasrna a decussation of fibres takes
place which, in animals such as the rabbit
with no fusion of the fields of the two eyes.
is practically complete. In man only those
fibres which arise in the mesial half of each
retina cross the mesial plane ; these, together
with the uncrossed fibres from the temporal
half of the other retina, form the optic tract
of the opposite side (Fig. 20:>). The optic tract
passes backwards across the eras cerebri and
finally divides in the roof of the mid- and
fore-brain into three branches, which end in
the grey matter of the anterior corpora quad-
rigemina and in the external geniculate body
and the pulvinar of the optic thalamus.
Running in the optic tract are also fibres
which are simply commissural ; these form
the mesial root of the optic tract. They cross
in the optic chiasrna and serve to connect the
two internal geniculate bodies. In addition
to the afferent fibres from the retina to the brain the optic tract contains
a certain number of efferent fibres which pass out and end in the retinae
It is evident from these connections thai whereas section oi one optic
405
Fig. 203. Diagram to show con-
nections of optic tracts. (After
Sherrington.)
L, left, and R, right retina; OD,
optic decussation (chiasrna) ; OpT,
optic tract; NC, nucleus caudatus :
I X. lenticular nucleus ; Th. optic
thalamus ; G, external geniculate
hody ; At,', anterior corpus cruadri-
geminum ; P, pulvinar : OpR, opi ic
radiations running to OC, the occi-
pital cortex : Illn. nucleus of third
nerve in floor of Sylvian aqueduct ;
IV, fourth ventricle.
406
PHYSIOLOGY
nerve, say the right, will only cause loss of vision in the right eye, section
of the right optic tract will divide the fibres coming from the right halves of
both retinae. This portion of the retina in each eye is stimulated in the
normal position of the eyes by rays of light coming from the objects lying to
i lie lei t ( il the field of vision. Section of the right ojotic tract therefore causes
blindness to all objects to the left of the median line, left hemianofia.
Section of both ojjtic tracts of course causes complete blindness.
Every movement of the head involves compensatory movements of the
eyes, and conversely, in any change in the environment of the animal which
demands its attention, there is
a movement of the eyes so as to
turn the gaze on to the origin of
the disturbance as an antecedent
to any body movement. In the
absence of normal regulative im-
pulses from the skin or from the
semicircular canals, the afferent
impressions from the eyes may
serve for the maintenance of
fairly well co-ordinated move-
ments—a compensation which is
rendered possible by the power
of the cerebral cortex to learn
new reactions by experience.
The centres for the eye move-
ments are contained in the grey
matter in the floor of the back
part of the third ventricle and of
Diagram to show origin of the different the iter of Sylvius. Here We find
the nucleus of the third or
oculo-motor nerve. The oculo-
motor nucleus consists of several divisions, viz. a lateral part containing
large motor cells, a superficial median nucleus with small cells, and a
deeper median nucleus with large cells. By localised stimulation it has been
found possible to differentiate the functions of the various parts of the
nucleus (Fig. 204). Stimulation of the back part of the third ventricle causes
contraction of the ciliary muscles, and of the part immediately behind this
contraction of the pupil. On stimulating the floor of the iter from before
backwards, we obtain contractions in order of the rectus internus, the rectus
superior, the levator palpebra? superioris, the rectus inferior, and the inferior
oblique muscle. On stimulating more laterally, or exciting the corpora
quadrigemina, dilatation of the pupil is obtained.
It seems probable that the optic thalamus and the closely related external
geniculate body are mainly concerned with the reception of visual impulses
and their forwarding to the cerebral cortex. On the other hand, the anterior
or superior corrjora quadrigemina are mainly concerned with the co-ordination
fibres of the third and fourth nervea from the
oculo-motor nuclei.
VISUAL REFLEXES
407
of visual impressions and visual movements with the movements of every
part of the body, and especially with the complex mechanism we have already
studied in connection with the labyrinth and cerebellum. Stimulation of the
corpora quadrigemina therefore evokes movements of the eyes and of the
head ; extirpation of this part, even when bilateral, though it may inter-
fere with co-ordination, does not necessarily involve loss of sight.
The multifarious intercourse which is continually taking place between
Vlll.Vest.n
(tJ Jy j* \Anf- 'basis bun die
Fig. 205. Diagram of connections of posterior longitudinal bundle.
Ant.C.Quad, anterior corpus quadrigeminum ; oc.m.n, oculo-motor nucleus ;
IV.n, nucleus of fourth nerve ; Vl.n, nucleus of sixth nerve ; D.N, Deiters' nucleus ;
S.O, superior olive ; VIII. Veat.n, vestibular nerve ; p.l.b, posterior longitudinal
bundle ; 1st c.n, first cervical nerve.
the eye centres and those for the movements of the body, and between
afferent impressions from the eyes and those from the semicircular canals and
the proprioceptive system generally, is effected to a large extent through the
intermediation of the posterior longitudinal bundle, which extends through-
out the whole length of the mid-brain and the hind-brain, and in the spinal
408 ' PHYSIOLOGY
cord becomes continuous with the anterior basis bundle of the anterior
columns. Receiving fibres above through the anterior commissure from
the optic thalamus and from the superior corpora quadiigemina 3 it is
associated in its course with the three motor nuclei that give origin to the
nerves supplying the muscles of the eyeball, viz. the third, fourth, and sixth
nerves. Fibres enter the posterior longitudinal bundle Erom the auditory
system and from the superior olive, and connections are also established
between this bundle and the facial nucleus, and the nucleus of Deiters,
representing the central station of impulses from the labyrinth. The general
connections of the bundle art 1 shown in Fig. 205.
SECTION XV
SUMMARY OF THE CONNECTIONS AND FUNCTIONS
OF THE CRANIAL NERVES
Crdnial nerves. The cranial nerves are generally reckoned as twelve in
number : 1st, olfactory ; 2nd, optic ; 3rd, oculo-motor ; 4th, or trochlear :
5th, or trigeminus ; 6th.; 7th, or facial ; 8th, auditory ; 9th, glossopharyn-
geal ; 10th, vagus or pneumogastric ; 11th, spinal accessory ; 12th, hypo-
glossal.
Of these the first two stand on a different footing from the rest which,
like the spinal nerves, are outgrowths of nerve fibres from the central tube
of grey matter surrounding the neural canal or from ganglia corresponding
to the spinal posterior root ganglion.
The olfactory bulb and the retinas, from which the majority of the
fibres forming the olfactory tract and the optic nerve respectively take their
origin, are analogous rather to lobes of the brain than to peripheral sense-
organs. Thus in the retina there are three relays of neurons through which
the visual impulse must pass before it arrives at the optic nerve. The
olfactory tract and optic nerve are thus comparable with the association or
commissural nines connecting different parts of the central nervous system.
The connections of these sensory fibres have already been fully dealt with, and
i lie structure of the peripheral sense-organ will be treated of under the physi-
ology of the special senses. Among the cranial nerves proper we may
therefore reckon the third to the twelfth.
The third or oculo-motor arises from an elongated nucleus which ex-
tends on either side from the back part of the third ventricle along
almost the whole length of the ventral part of the aqueduct of
Sylvius close to the middle line (Fig. 204). The anterior part is com-
posed of small cells which give origin to the fibres innervating the intrinsic
muscles of the eye, namely, the ciliary muscle and the sphincter pupillae.
The rest of the nucleus is made up of large multipolar cells, arranged in
groups, and gives origin to the fibres passing to most of the extrinsic muscles
of the eye. The fibres of the third nerve pass through the tegmentum to
emerge at the inner margin of the crusta of the same side. The fibres from
the posterior large-celled nucleus supply the following muscles ; levator
palpebrarum, superior rectus, inferior rectus, internal rectus, ami inferior
oblique.
Stimulation of the trunk of the third nerve causi thi eyeball to look
409
410 PHYSIOLOGY
upwards and inwards, wit li conl i action of the pupil and spasm of accommo-
dation.
Thegtiucleus of the fourth nerve is situated, just behind that for the third,
in the floor of the Sylvian aqueduct, on a level with the inferior corpora
quadrigemina. The fibres run from here down towards the pons, then turn
sharply backwards to pass into the valve of Vieussens, which they cross hori-
zontally, decussating with the nerve of the opposite side. The superficial
origin is therefore from the valve of Vieussens. This nerve supplies the
superior oblique muscle of the eyeball. Its stimulation causes the eyeball to
look downwards and outwards.
The sixth nerve, the motor nerve for the external rectus muscle of the
eyeball, arises from a group of large multipolar cells lying on each side of
the middle line in the floor of the fourth ventricle. The fibres of the
nerve pass directly outwards to emerge from the anterior ventral surface
of the medulla between the pyramids and the olivary eminence, at the
lower border of the pons. Stimulation of this nerve causes the eyeball
to look directly outwards. All these three oculo-motor nuclei receive
collaterals from the fibres forming the posterior longitudinal bundle, many
of which are axons of cells in Deiters' nucleus. It is by this means that the
contractions of the muscles moving the eyeball are co-ordinated. Sherring-
ton has shown that, although the third, fourth, and sixth nerves arise directly
from the brain stem and have no ganglion on their course, they are really
mixed afferent-efferent nerves. Their afferent fibres, which must arise
from the cells in the central nervous system itself, run to the receptor nerve
endings with which all the extrinsic eye muscles are richly provided. They
are exclusively proprioceptive, and supply no organs outside the muscles
innervated by the motor fibres. The occurrence of afferent fibres in these
nerves explains the fact previously observed by Sherrington that, after total
desensitisation of the eyeball by means of cocaine, or by section of the first
division of the fifth nerve, the ocular movements are carried out with as
much precision as in the normal animal. As we have seen, such precision
of movement requires the co-operation of afferent impressions from the
muscle, and the only possible channels for these impressions are the pro-
prioceptive sense-organs and the afferents of the third, fourth, and sixth
nerve pairs themselves.
The fifth nerve, or trigeminus, resembles a spinal nerve in that it has a
motor as well as a sensory root. The motor root is much the smaller of the
two. The fibres of the sensory root take their origin in the cells of the
Gasserian ganglion, which is in all respects similar to the ganglion of a
posterior spinal nerve root. The sensory root represents the somatic
afferent part of all the motor cranial nerves from the third to the hypoglossal
and has a correspondingly wide field of termination in the brain stem. The
afferent fibres of the fifth nerve, as they enter the pons, bifurcate, like a spinal
afferent nerve, into ascending and descending branches. The ascending
branches are short and pass to an upper sensory nucleus, situated below the
lateral part of the fourth ventricle in the upper part of the pons. The
CONNECTIONS AND FUNCTIONS OF CRANIAL NERVES -11 I
descending branches, which are much longer, are collected into one or more
bundles which pass downwards in the lateral part of the reticular formation,
accompanied by the downward extension of the sensory nucleus known as the
substantia gelatinosa. The descending root can be traced down in the
upper part of the cervical cord, its fibres in this region forming a cap to the
gelatinous substance of Rolando. From the cells of the sensory nucleus
fibres pass towards the median raphe, crossing to the other side to take part
in the formation of the tract of the fillet (the trigemino-thalamic tract). The
efferent fibres forming the motor root arise from two nuclei. The chief motor
nucleus consists of large pigmented multipolar cells situated just below the
surface of the lateral margin of the fourth ventricle at the upper part of
the pons. The accessory or mesencephalic nucleus is composed of large
unipolar cells, situated in the central grey matter along the lateral aspect of
the anterior end of the fourth ventricle, and in a corresponding position in
mid-brain as far as the upper border of the inferior corpora quadrigemina.
The fifth nerve is the motor nerve for the muscles of mastication, and for
the tensor tympani and tensor palati muscles. It is the sensory nerve for the
whole of the face (including eyeball, mouth, and nose). It also contains
dilator fibres to blood-vessels derived from the chorda tympani, and is
said to have trophic, functions. The latter conclusion is from the fact
that section of the fifth nerve in the skull is followed by ulceration and
sloughing of the cornea, and finally by destructive changes involving the
whole eyeball. Since however these results may be prevented by carefully
shielding the eye from all dust and deleterious influences, it is probable that
the ulceration is merely a secondary consequence of the anaesthesia. The
cornea being anaesthetic, foreign objects that fall on its surface are allowed
to remain there, and so, give rise to injurious changes and ulceration.
The fifth is also said to be the nerve of taste for the anterior third of the
tongue, but it is probable that the taste fibres which run in the fifth arc
derived from the glossopharyngeal or from the nervus intermedius.
The eighth nerve and its connections have been discussed already on
several occasions. We may here briefly summarise what has already been
stated. In describing the eighth nerve it is necessary to consider separatelv
its two divisions, the dorsal or cochlear division and the ventral or vestibular
nerve. The fibres of the cochlear nerve originate in the bipolar cells of the
spiral ganglion of the cochlea. They carry impulses from the auditory end-
organ. On entering the medulla they bifurcate into ascending and descend-
ing branches which terminate in two nuclei, the ascending branches in the
ventral nucleus, the descending branches in the dorsal nucleus. The ventral
or accessory nucleus lies between the cochlear and vestibular divisions ven-
trally to the restiform body. The dorsal nucleus, often called the acoustic
tubercle, forms a rounded projection on the lateral and dorsal aspects of the
restiform body. From these two nuclei new relays of fibres start, pass to the
other side, by crossing the median raphe (where they form the trapezium) to
run up in the lateral fillet of the opposite side. From the ventral nucleus
the fibres pass directly to the opposite side, forming the greater part of the
412 PHYSIOLOGY
trapezium, ma id Ti g conned ion on their way with the nucleus of the trapezium
and with the superior olive. From the dorsal nucleus most of the axons pass
dorsally, forming the stria? acousticse at the middle of the floor of the fourth
ventricle. On arriving at the middle line they dip down and join the fibres
of the trapezium of the opposite side. The further course of these fibres
up to the internal geniculate body, the posterior corpora quadrigemina, and
1 he auditory radiations of the cerebral cortex, have been described on p. 378.
The ventral division of the eighth nerve, or vestibular nerve, originates
in the bipolar cells of the vestibular ganglion or ganglion of Scarpa. These
cells, like those of the spiral ganglion, retain the primitive bipolar character.
The fibres divide into ascending and descending branches which become
connected with two nuclei. The dorsal or vestibular nucleus, or principal
nucleus, which receives the ascending fibres, is a mass of grey matter lying
laterally of the vago-glosso-pharyngeal nucleus and corresponding to the
lateral triangular area, the trigonuni acoustici, which is seen on the surface
of the fourth ventricle outside the ala cinerea. The descending vestibular
nucleus, receiving the descending branches of the vestibular nerve, lies
below but continuous with the principal nucleus. The fibres of the vestibular
nucleus send also collaterals to the nucleus of Deiters and the nucleus of
Bechterew, two accumulations of large multipolar cells lying ventrally and
internally to the vestibular nucleus, both nuclei being in close relation to the
roof nuclei of the cerebellum. Many fibres of the vestibular nerve pass
apparently through these various nuclei on the inner side of the restiform
body into the cerebellum, where they make connection with the roof nucleus
or nucleus fastigii. By the nuclei of Deiters and Bechterew the vestibular
nerve is connected through the dorsal longitudinal bundle and the descending
vestibulo-spinal tract with the motor nuclei of the cranial and spinal nerves.
The use of the vestibular nerve is entirely connected with the function
of equilibrium. It is probably not concerned in conveying auditory im-
pressions, all its nerve fibres being derived ultimately from the nerve-endings
in the saccule and utricle and semicircular canals.
The seventh cranial nerve or facial nerve emerges from the brain at the
inferior margin of the pons, lateral to the point of exit of the sixth nerve.
It is almost entirely a motor nerve, but carries also some sensory blues
for taste and general sensibility which it receives from the nervus intermedins
of Wrisberg. The motor nucleus of the seventh nerve lies in the reticular
formation, dorsally to the superior olive, at some depth below the floor
of the fourth ventricle. From this nucleus the fibres first pass inwards
and dorsally towards the floor of the ventricle, where they collect to form
a bundle which runs upwards in the grey matter for a short distance and then
turns sharply in a ventro-lateral direction to emerge on the lateral aspect of
the pons. The fibres from the motor nucleus supply the muscles of the face.
the scalp, and the ear. Secretory fibres also run in the chorda tympani,
which is a branch of the facial. These are probably derived, like the
sensory fibres, from the nerve of Wrisberg. The sensory fibres of the
nerve of Wrisberg originate in the nerve cells of the geniculate ganglion, and
CONNECTIONS AND FUNCTIONS OF CRANIAL NERVES 413
passing inwards with the main root of the facial, divide into ascending and
descending branches and end in the upper part of the column of grey matter
which receives also the sensory fibres of the ninth and tenth cranial nerves.
The ninth and tenth cranial nerves arise by a series of bundles of nerve
fibres from the side of the medulla. Both the ninth and tenth are mixed
visceral sensory and motor nerves. The sensory nucleus is a column of
grey matter lying laterally to the hypoglossal nucleus just below the promin-
ence on the floor of the fourth
ventricle known as the ala
cinerea. The descending fibres
of these nerves form a well-
marked bundle of white fibres
known as the fasciculus soli-
tarius, or sometimes, from its
supposed connection with the &\
regulation of respiration, the
'respiratory bundle of Gierke.'
It may be traced down as far
as the uppermost part of the
cervical cord, its fibres losing
themselves on their way down
among the cells of the enclos-
ing grey matter. The efferent
fibres of the ninth and tenth
nerves are derived partly from
the dorsal nucleus of the vagus
and accessory nerves lying ex-
ternallv to the nucleus of the
twelfth nerve, and partly
from the nucleus ambiguus,
a mass of grey matter lying deeper in the medulla (Fig. 206).
The ninth or glossopharyngeal nerve supplies motor fibres to the muscles
of the pharynx and the base of the tongue, and secretory fibres to the parotid
gland. The sensory fibres convey impulses from the tongue, the mouth, and
pharynx, the fibres originating outside the central nervous system in the
ganglion cells of the ganglion petrosum and the ganglion superius. It also
contains inhibitory fibres to the respiratory centre.
The tenth nerve, vagus or pneumogastric, is joined by the accessory part
of the spinal accessory, so that the two nerves may be considered together.
It has both afferent and efferent functions :
Efferent functions :
Motor to levator palati and three constrictors of pharynx.
Motor to muscles of larynx.
Inhibitory to heart.
.Motor to muscular walls of oesophagus, stomach, and small intestine.
Motor to unstriated muscle in walls of bronchi and bronchioles.
Fig.
Plan
tenth ami
I the origin of tin
I uiUth nerves.
pyr, pyramid; nXII. nucleus of hypoglossal;
XII. hypoglossal nerve ; il/iX, XI. dorsal nucleus of
vagus and accessory; n.amb, nucleus ambiguus;
ft, fasciculus solitarius (descending root of vagus and
glossopharyngeal) ; fun, its nucleus ; A", crossing
motor fibre of vagus ; r/, cell in ganglion of vagus
giving origin to a sensory fibre ; d V, descending root
of fifth ; cr. corpus restiforme ; o, olivary nucleus.
•114 PHYSIOLOGY
Secretory to glands of stomach and to pancreas.
Afferent functions :
Regulate respiration. Stimulation of central end may quicken
respiration and promote inspiration, or may inhibit inspiration.
Stimulation of central end of superior laryngeal branch causes
stoppage of inspiration, expiration, cough.
Depressor and pressor (from heart to vaso-motor centre).
Reflex inhibition of heart.
Its afferent, fibres arise from cells in the ganglia on the trunk of thf>
vagus, namely, the jugular ganglion and the ganglion triinci vagi. The
spinal accessory nerve arises partly in connection with the vagus, partly by
a series of roots from the lateral region of the spinal cord as low as the sixth
cervical segment. The spinal portion of the nerve is purely motor and
supplies fibres to the sterno-mastoid and trapezius muscles.
The twelfth or hypoglossal nerve arises from a collection of large multi-
polar cells in the floor of the fourth ventricle at its lower end close to the
middle line. The nerve-trunk issues from the ventral part of the medulla
in the groove between the anterior pyramid and the olivary body. The
hypoglossal is purely motor in function, supplying the muscles of the tongue,
the extrinsic muscles of the larynx, as well as those moving the hyoid bone.
Since the integrity of the nuclei of the cranial nerves is a necessary con-
dition for the carrying out of various reflex acts in which those nerves are
involved, the grey matter of the fourth ventricle and aqueduct is often
spoken of as if it were cut up into a series of centres distinct for every act.
The chief of these are the respiratory and the vaso-motor centres. Other
centres that may be enumerated are :
Centres for movements of intrinsic and extrinsic ocular muscles.
Cardiac inhibition.
Mastication, deglutition.
Sucking.
Convulsive (connected with respiratory).
Vomiting.
Diabetic (connected with vaso-motor).
Salivary.
Centres of phonation and articulation.
We shall have to consider the action of these centres more fully in treating
of the several functions of the body. It must be remembered however
that, when a dozen or more centres are enumerated as being situated in the
fourth ventricle, it is not meant that we can anatomically distinguish a group
of cells for each act or group of actions named. When we say that a part of
the nervous system is a- centre for any action, we merely mean that this part
forms a necessary link, or meeting of the ways, in the complicated directing of
nerve impulses that takes place in every co-ordinated act.
THE CEREBRAL HEMISPHERES
SECTION XVI
GENERAL STRUCTURAL ARRANGEMENTS OF
THE CEREBRUM
The cerebral hemispheres form the most important part of the brain. It is
bo the development of this part that is due the rise in type in vertebrates.
In development they are formed as two diverticula from the front part of an
outgrowth of the first cerebral vesicle. In the lowest vertebrates these
outgrowths are connected entirely with the olfactory sense organs, and we
may regard the olfactory
part of the brain as a fun-
damental part on which
has been built up all the
rest of the cerebral hemi-
spheres. In a cartilaginous
fish the whole of the upper ,^) ! \ '/ // . j
brain is connected with HiV A- *
the organ of smell, and I. ... ¥ ,
consists of a thickening
ill the floor of the Out- Fig. 207. Section through cerebral cortex of the frog.
growth from the fore-brain. (After Edi ™ er ->
The roof of the outgrowth is formed of simple epithelium. With the
development of the visual sensations in the bony fishes there is still very
little corresponding growth of the fore-brain, most of the fibres from the
optic nerves going to the roof of the mid-brain (the optic lobes). The
beginning of the cerebral hemispheres is associated with the development
of nervous tissue in the roof of the prosencephalon. At its first appear-
ance this higher brain material still receives chiefly olfactory impressions.
But the structure of the cerebral cortex thus laid down differs from that
of the centres forming the brain stem or the olfactory lobe itself in that
it provides for a very rich association of impulses between all its parts.
The fibres entering the cortex break up into a fine meshwork of fibres
which run tangentially to the surface and come in contact with innumer-
able dendrites of nerve cells situated at some little distance below the
surface (Fig. 207). We have here the first germ of an apparatus in which
the nerve paths can be determined by education, i.e. in consequence of
inhibitions by pain, rather than by the limits set by Hereby- T" *'"'
amphibian brain, and still more in the brain of the reptile, the cerebral
415
in
PHYSIOLOGY
cortex extends over the whole of the roof of the cerebral hemispheres,
though even here a very large proportion of it is devoted to the association
of olfactory impulses. The importance of these olfactory association fibres
is well shown in the figure (Fig. 208) of a diagrammatic section through a
lizard's brain. Above the reptiles there is a divergence in the course of
development. The wider reactive powers of birds are based chiefly on an
enormous development of the corpus striatum, whereas in mammals the
corpus striatum remains relatively small and the chief development occurs
in the roof of the cerebral hemispheres, the so-called pallium or mantle.
With the increased entry of fibres from the optic thalamus into the cerebral
hemispheres, carrying impulses from the eyes. ears, and all the other sense
organs of the body, the olfactory part of the brain diminishes in importance,
FlG. 208. Schematic section through brain of lizard showing the chief
nerve tracts. (After Kdinger.)
and in the higher mammals and man is altogether overshadowed by the newly
formed structures of the pallium. On this account those parts of the
cerebral hemispheres in special connection with the olfactory sense organs
are often spoken of as the archif allium, in distinction to all the rest of
the more newly formed brain substance, known as the neopallium.
In man the cerebral hemispheres form a great ovoid mass exceeding
in size all the rest of the brain put together. The two hemispheres are
separated by a deep fissure, the great longitudinal fissure. Before and
behind, this fissure extends to the base of the cerebrum, but in the middle the
two hemispheres are connected by a mass of transverse fibres known as the
corpus callosum. On the outer side each cerebral hemisphere presents a
deep cleft, the Sylvian fissure. The whole surface of the brain is thrown
by fissures (or sulci) into convolutions, by which means a very large increase
of the surface grey matter is obtained. By these fissures the brain surface
is divided into lobes. The general arrangement is shown in Figs. 209 and 210.
The chief lobes are the frontal, the parietal, the occipital, the temporal, the
insular, the limbic, and the olfactory. On the inner side, from before
backwards, we have the marginal, the paracentral, the pre-cuneus, the
cuneus ; and in close proximity to the corpus callosum, the cingulum or
STRUCTURAL ARRANGEMENTS OF CEREBRUM 417
S.precentral.s inferior 5f , recentratlS supei
S-fr'ontatiS Inferior
S. frontalis superior
7. frontalis medius
S.centralis (Rolandi)
, S. postcentrals inferior
5. post '■centralis intermedius
postcentrals superior
ntrapariefafis
Ramus
anthorizontalis
Ramus ant ascendens
S. diagonal is
Ramus post, of Sylu
S occipitalis lateralis
S.occipitaiis transuersu
Fig. 209. Lefl cerebral hemisphere of mmi. lateral aspect. (Symington.
Sprecenfralis mesiahs
S.centralis (Roland/)
■Pars marainalis s.cinduli
Spanetalis superior
S. pane to -occipitalis
5 cm fuh
Scorporis catlosi
S.subpanetalts
>.cotianratis
5. temporalis infer/oj-
Fasc/'a denfata
!' '■ - 210. Lefl cerebral hemisphere of num. from tKe mesial aspect. (Symj
27
418
PHYSIOLOGY
supra-callosal convolution above, and the liippocampal convolution and the
uncus below. The chief fissures separating these are the Sylvian fissure, the
Midbrain
Cerebellum
Eye I'
-■- Occipital cortex
radiate Midbrau
Fig. 211. Diagrams from Monakow, showing the evolution of the neopallium,
and the gradual shifting of the visual sensory tracts from the mid-brain to the fore-
brain, and thence to the Occipital cortex.
A, a bony fish. B, brain of a lizard. C, brain of a mammal (cat).
central sulcus or fissure of Rolando, the parieto-occipital fissure, the cal-
carine fissure, the collateral fissure, and the calloso-marginal fissure. Each
of the main lobes (or gyri) mentioned above is further subdivided by smaller
STRUCTURAL ARRANGEMENTS OF CEREBRUM
419
fissures. The extent of these secondary fissures varies from brain to brain,
the higher types of brain being richer in convolutions than those of the more
primitive races.
The gradual evolution of the cerebral cortex, and the concomitant shifting
of the chief afferent impulses, arising in the projicient sense organs, from the
lower ganglia to the higher educatable cortex, is well shown in the diagrams
from Moankow (Fig. 211, p. 418). In the lower fishes practically all the
reactions to visual impressions are carried out by the optic lobes. In the
higher types the reflexes through
these lobes become subordinated, first
to the more complex organ of the
optic thalamus (where representatives
from all the afferent tracts of the body
assemble), and later to the still more
complex occipital cortex, when the
reactions are determined not only by
inherited nerve paths but also by
the various blocks and facilitations
imprinted on the nerve paths by
the experience of the individual
himself.
The original cavities of the hemispheres
form the lateral ventricles, each of which,
in the adult brain, is prolonged into the main
divisions of the hemispheres as the anterior
horn, the posterior horn, and the inferior
horn. Each lateral ventricle is roofed over by
the corpus callosum and the adjoining white
matter of the hemispheres. On opening the
ventricle we see on its floor the body of the
fornix, a flattened tract of white matter with
longitudinal fibres, which in front bifurcates FlG 2 12. Horizontal section through the
into two cylindrical bundles which pass verti- optic thalamus and corpus striatum, the
cally downwards in front of the foramen of 'basal ganglia.' (Natural size.) (Quahj.)
Monro into the mesial part of the subthala- vl, lateral ventricle, its anterior cornu :
mic tegmentum. Internal to the fornix is a <*■ cor P" s ^Uosum ; si. septum tacidnm:
6 . . , ,, , . , af. anterior pillars of the fornix ; r3, third
layer of pia mater, including the choroid ventric i e . t h, thalamus opticus ; nt, stria
plexus. On removing this the third ventricle medullaris : nc, nucleus caudatus. and
is opened, so that in this region the wall of nl, nucleus lenticularis of the corpus stria-
the cerebral hemispheres, like the roof of tum : ie > mt ^ m . al f W^ ' '• lts "$V*
r . genu ; nc, tail of the nucleus caudatus
the third ventricle, is limited to a simple appeai . ing ^ the descending cornu of the
layer of ependyma. At the margin of the lateral ventricle ; <•'. claustrum ; /, island
choroid plexus can be seen a part of the supe- of Reil.
rior surface of the optic thalamus, separated
however from the cavity of the ventricle by a layer of ependyma. Outside
and in front of the optic thalamus are the masses of nervous material con-
stituting the corpus striatum. These present two nuclei of grey matter, known
as the nucleus caudatus and the nucleus lenticularis (Fig. 212). The crusta
of the crura cerebri as it ascends to the cerebral hemispheres passes behind between
the optic thalamus and the corpus striatum, and in front between the nucleus lenticu-
420 PHYSIOLOGY
laris and nucleus caudatus of the corpus striatum. Outside the corpus striatum we find
another mass of white fibres, known as (he external capsule, and this is separated from
the white matter of the cortex cerebri by a thin layer of grey matter known as the clans-
t rum. In a horizontal section through the brain, the part of the internal capsule
which pierces the corpus striatum forms an angle with the posterior pari separating the
optic thalamus from the lenticular nucleus. The part where the two limlis come in
contact is known as the genu of the internal capsule (Kig. 212).
THE OLFACTORY APPARATUS OF THE BRAIN
In mini the olfactory sense is luit feebly developed, and the parts of the
brain connected therewith are inconspicuous in comparison with those en-
gaged in the reception of impressions from the other two main projicienl
sense organs, namely, sight and hearing. On this account it is not easy to
make out the connections of the olfactory lobe proper, the rhmencepkalon,
with the primitive part of the cortex, the arcJiipaUium, subserving the olfac-
tory sense and probably the allied sensations derived from the mouth cavity.
The wide connections of the olfactory sense organs with the different parts
of the brain in the lower vertebrate are shown in the diagrammatic figure of
the brain of a reptile (Fig. 208, p. 416).
It is interesting to note that the olfactory nerve fibres are derived from cells situated
actually on the surface of the body. These are bilateral, spindle-shaped cells, lying
in the olfactory mucous membrane at the upper part of the nasal cavity. The peri-
pheral process is short and passes towards the surface, while the deep process passes
as a non-medullated nerve fibre through the cribriform plate of the ethmoid to sink
nito the olfactory bulb. The bulb, in man. is a greyish enlargement at the anterior'
end of the olfactory tract. In sections stained by (iolgi's method of impregnation it
may be seen that the olfactory fibres terminate in an arborisation in close connection
with a thick end arborisation derived from a dendrite of a large nerve cell, known as
a mitral cell. The synapses between these two sets of fibres are prominent objects
in a section through the olfactory bulb and form the 'olfactory glomeruli ' (Fig. 213).
The axons of the mitral cells pass back in the olfactory tracts. Each olfactory tract-
divides posteriorly into two roots, the mesial root which curves inwards behind Broca's
area and passes into the end of the callosal gyrus, and the lateral root which runs back-
wards and over the outer part of the anterior perforated spot. Its fibres pass into the
uncinate extremity of the liippocampal gyrus. The small triangular field of grey
matter between the diverging roots of the olfactory tract is known as the olfactory
tubercle. The primitive rhineneephalon includes in the adult human brain the olfactory
bulb and tract, together with the anterior perforated space, the anterior part of the unci-
nate gyrus, the subcallosal gyrus, the septum lucidum. and the liippocampal convolution.
The two sides of the rhineneephalon are united by fibres passing through the anterior
commissure. Other tracts subserving this apparatus include the habenula passing
from the fornix to the ganglion of the habenula. the fasciculus retroflexus passing from
this to the interpeduncular ganglion, and the corpus mammillare which is connected
with the column of the fornix on the one hand and through the bundle of Vieq d'Azyr
with the thalamus on the other.
THE CHIEF TRACTS OF THE CEREBRAL HEMISPHERES
We may divide the tracts of the upper brain or cerebral hemispheres into
three classes :
I, Tracts connecting the 'brain with lower levels of the central nervous
system.
STRUCTURAL ARRANGEMENTS OF CEREBRUM
421
II. Tracts connecting different parts of the cortex of one hemisphere
and serving as a means of association between these different parts.
III. Tracts (commissural) connecting the two cerebral hemispheres
together.
I. THE PROJECTION FIBRES
These are the fibres which connect the cerebral cortex with the different
lower levels of the central nervous system. They form a great part of the
Fig. l'I:'.. Schema of oourse of olfactory impulses. (Ramon y Cajal.)
A, olfactory mucous membrane; B, olfactory glomeruli; C, mitral cells;
e. granule cells ; D, olfactory tract ; L, centrifugal fibres.
fibres of the corona radiata and are condensed at the base of the brain into
the broad band of fibres known as the internal capsule. A few of the fibres
of the projection system may gain the cortex through the lenticular nucleus
and by the external capsule. The projection fibres may be divided into
two groups according as they conduct impulses to or away from the cere) ira 1
cortex : the afferent or corticipetal, and the efferent or corticifugal.
A. AFFERENT TRACTS OF THE CEREBRUM.
( I ) The thalamo-cortical. From all parts of the optic thalamus fibres
arise as axons of the cells of its grey matter and, streaming out from its outer
and under surfaces, pass to every part of the cortex. Although there is no
division of them into distinct groups as they leave the thalamus, fchej are
often described as constituting a frontal, a parietal, an occipital, and a vent ra I
stalk. The front fibres pass through the anterior limb of the internal capsule
to reach the cortex of the frontal lobe, many of the fibres however termina-
ting in the caudate and lenticular nuclei. The parietal fibres issuing from
the lateral surface of the thalamus pass through the internal capsule to be
distributed chiefly to the parietal lobe. The occipital fibres issue from
the outer part of the pulvinar and the external geniculate body and constitute
the so-called ' optic radiation,' passing outwards and backwards to be
distributed to the cortex <>f the occipital lobe. The ventral fibres pass
downwards and outwards below the lenticular nucleus and end partly in the
422
PHYSIOLOGY
latter nucleus and partly in the cortex of the temporal lobe and of the insula
or island of Reil.
(2) The fillet system of fibres. This great mass of ascending fibres
has been already described (cp. Fig. 197) as gathering up the impulses from
the different sensory nerves of the cerebro-spinal system and terminating
in the thalamus and subthalamic region.
(3) The superior cere-
bellar pedunclk. These
fibres, from the central
ganglia of the cerebellum,
terminate for the most part
in the thalamus and sub-
thalamic region. It is pos-
sible that some of them may
pass through the hinder end
of the internal capsule, with-
out interruption in the thal-
amus, to end in the Rolandic
area.
(4) The optic radiation.
These diverging fibres in the
back part of the corona-
radiata are mixed up with
fibres which are partly corti-
cifugal. The corticipetal
fibres arise in the pulvinar
and the external geniculate
body and end in the occipital
cortex.
(5) The auditory radia-
tion. These fibres consist of
the axons of cells situated in
the internal geniculate body.
They pass through the posterior limb of the internal capsule under the
lenticular nucleus to end in the temporal lobe.
Pig. l>I4.
<- UOBL
Schema of projection fibrea of cortex.
(Cunningham.)
B. THE EFFERENT PROJECTION FIBRES.
( 1 ) The pyramidal tract. This is composed of fibres which arise from
the large Betz cells in the ascending frontal convolution, the ' motor area.'
They pass through the corona radiata into the internal capsule, where they
occupy the genu and the anterior two-thirds of the posterior limb. Hence
they pass into the crusta, where they occupy the middle two-fifths of this
structure, and are continued as the pyramids of the pons and medulla to
the upper part of the spinal cord, where most of them decussate to the other
side to form the crossed pyramidal tracts. Some of the fibres do not cross
STRUCTURAL ARRANGEMENTS OF CEREBRUM
423
at the pyramidal decussation, but are continued down in the same position
in the anterior columns of the spinal cord of the same side, forming the direct
or anterior pyramidal tracts. These fibres cross for the most part lower down
in the cord, so that the direct pyramidal tract is not seen below the cervical
region. The pyramidal tracts are not found in lower vertebrates, and make
their first appearance in the mammalia. Their development corresponds
with the gradual increase in the direct interference of the cerebral cortex
in the reactions of the organism as a
whole and is an index to the gradual
shifting of these reactions from the
inevitable to the educated reflex. The
fibres of the pyramidal tract end at
various levels of the spinal cord and
can be traced to the lower end of the
sacral region. According to Schafer
they end in the posterior cornua, so
that their action is to set going a reac-
tion which could otherwise be elicited
by stimulation of the afferent fibres
entering by the posterior root at the
level of the cord where they end.
(2) The fronto-pontine fibres.
These arise from cells in the cortex of
the frontal lobe, and pass down in the
anterior limb of the internal capsule
to gain the mesial part of the crusta of
the Crus cerebri. The fibres end in
the grey matter of the formatio reti-
cularis of the pons, the nucleus pontis.
(3) The temporopontine fibres.
These arise from the two upper
temporal convolutions, especially from that area which is associated with
hearing. They pass inwards under the lenticular nucleus through the hinder
limb of the internal capsule to gain the outer part of the crusta. In this
situation this tract passes down into the pons, where it ends in the nucleus
pontis.
As part of these projection fibres we Ought probably to reckon the fibres
which take origin or end in the corpus striatum. The afferent fibres of this
body are derived chiefly from the thalamus, forming the thalamo-striate
fibres. Other fibres arise in the nuclei of the corpus striatum and pass down
in the dorsal portion of the crusta to end for the most part in the pons, the
strio-pontine fibres.
The relative position of these various fibres in the internal capsule
and in the crusta is shown in the accompanving diagrams (Figs. 215 and
216).
The fronto-pontine and temporo-pontine fibres, which end in the nucleus
Fig. 215. Diagrammatic representation
of the internal capsule, as seen in hori-
zontal section. (Cunningham.)
424
PHYSIOLOGY
pontis, come there in relationship with thcfibres Eorming the middle peduncles
of the cerebellum and derived chiefly from the lateral lobes of the cerebellum.
These fibres may therefore be regarded as the efferent side of the greal
cerebro-cerebellar connections of which the afferent side is represented
by the fibres — efferent so far us concerns the
cerebellum- -which pass from the cerebellar
cortex to the dentate nucleus and thence by
a fresh relay in the superior cerebellar
peduncles to the red nucleus, optic thalamus,
and cortex of the opposite side. The devel-
opment of these fibres, as of the lateral
lobes of the cerebellum, is largely proportional
to the growth of the cerebral hemispheres. In
cases where there has been congenital atrophy
of one cerebral hemisphere, the crusta of the.
same side and the lateral lobe of the cerebellum
of the opposite side also fail to develop.
Fig. 21(i. Transverse section
through mid-brain t<> show
position of fillet and pyramid.
AQ, anterior corpus quadri-
geminum ; dV, descending roof
of fifth nerve ;F,fillet (I, lateral,
and m, mesial fillet) ; Pyr. pyra-
mid ; Fr. fibres from frontal lobe
to pons ; TO, fibres from tem-
poral and occipital lobes to
pons ; Ne, fibres from nucleus
caudatus to pons ; ITT, mot of
third nerve ; 8, .Sylvian iter ;
Rn. red nucleus.
II. ASSOCIATION FIBRES
These tidies serve to unite different portions
of the cortex of the same hemisphere ami may
be classified into short and long association
fibres. The short association fibres pass round
the bottom of the sulci in U-shaped loops
connecting adjacent convolutions. These fibres are some of the
latest to acquire a medullary sheath and probably first become functional
Fio. 217. Chief association bundles of the cerebral hemispheres. (Ccnningh \m.)
A. Outer aspect of hemisphere. B. Inner aspect of hemisphere.
as associated activity between the various portions of the cortex is gradually
acquired by education.
The long association fibres may be divided into five groups as follows :
(a) The uncinate fasciculus passes from the orbital convolutions of the frontal lobe
to the front part of the temporal lobe round the stem of the Sylvian fissure (Fig. 217).
STRUCTURAL ARRANGEMENTS OF CEREBRUM
425
(t) The (-ingnluai is closely associated with those parts of the cerebral cortex known
together as the limbic lobe. In front it originates in the neighbourhood of the anterior
perforated space, passes round the genu of the corpus callosum, and then is carried
backwards over the upper surface of this body to its hinder end, where it turns round
and is distributed to the hippocanipal gyrus and to the temporal lobe.
(c) The longitudinal superior fasciculus lies in the base of the frontal and parietal
lobes, and passing from before backwards connects the frontal occipital, and temporal
parts of tlic cerebral cortex.
(d) The longitudinal inferior fasciculus runs along the whole length of the occipital
.mil temporal lobes, being situated behind on the outer aspect of the optic radiation.
(e) The occipito-frontal fasciculus lies on the inner aspect of the corona radiata in
intimate relation to the caudate nucleus, and projects out over the upper and outer
aspect of the lateral ventricle immediately outside the ependyma.
III. THE COMMISSURAL FIBRES
These are arranged in three groups :
(a) The corpus callosum forms a great mass of while fibres passing trans-
\'i ely in both directions between the two hemispheres, [ts fibres are
Flo. 218. Schematic section through cerebral hemispheres, to show chief classes
of nerve tracts. (After Ram6n y Cajal.)
a, corpus callosum ; B, anterior commissure ; c, pyramidal tract ; a, cell
giving off projection fibre ; '). cell giving off commissural fibre ; c, cell with a son
forming association fibres.
derived from every part of the cerebral cortex with the exception of the
olfactory bulb and the hind and fore parts of the temporal lobe. As the
fibres cross the middle line they become gradually scattered, so that tiny
tend to connect wholly dissimilar parts of the cortex of opposite hemispheres.
Each callosal fibre arises in one hemisphere and ends by fine arborisations in
the opposite hemisphere. It may represent either the axon of one oi the
cortical cells or a collateral from a fibre of association or a collateral from a
projection fibre (Fig. 218).
(6) The anterior commissure is situated in the anterior wall of the third
ventricle in front of the two pillars of the fornix. It connects together the
two olfactory lobes and portions of the opposite temporal lobes. In lower
vertebrates it is almost entirely olfactory in function, but in man the olfad ory
426 PHYSIOLOGY
fibres form only a small proportion of the total number making up the
bundle.
(c) The psalterium or hippocampal commissure is a thin lamina formed
of transverse fibres filling up the small triangular space on the under surface
of the hinder part of the corpus callosum formed by the divergence of the
posterior pillars of the fornix. Like the anterior commissure, the hippo-
campal commissure is closely associated with the sense of smell. Its fibres
arise from the pyramidal cells in the cornu ammonis or hippocampus and pass
for the greater part to the cornu ammonis of the opposite side.
MINUTE STRUCTURE OF THE CEREBRAL CORTEX
The cortex of the cerebral hemispheres consists of a layer of grey matter
covering a central mass of white fibres. With the growth in size of the
brain, which accompanies the development of increased intelligence and
powers of adaptation, the necessary increase in cortex is rendered possible by
the folding of the surface into convolutions and fissures. The chief of these
convolutions have already been indicated in the sketch of the anatomy of the
brain (Fig. 209).
On section the grey matter is seen to consist of many layers of nerve
cells embedded in neuroglia and nerve fibres, both medullated and non-
medullated. The nerve cells vary in size and shape : one kind of cell is
however typical of this part of the central nervous system. This is the
pyramidal cell (Fig. 219), a cone-shaped or pear-shaped cell with one large
apical dendrite which runs towards the surface and breaks up in the most
superficial layer into a number of branches. Dendrites are also given off from
the sides and lower angles of the cell. The axon, which arises from the axon
hillock in the middle of the base of the cell, passes downwards into the white
matter, giving off collaterals in its course. Some of these axons pass by the
corona radiata into the internal capsule and into the crura cerebri, including
those which form the pyramidal tracts ; others, or their collaterals, may pass
into the adjacent regions of the cortex, or across by the corpus callosum into
the opposite hemisphere.
Although varying in structure at different parts, it is generally possible
to distinguish four or five layers in the cortex.
(1) The most superficial layer, known as the outer fibre lamina, or
'molecular layer, contains very few cells. It is composed generally of the den-
drites of cells from the deeper layers. It contains a few cells which are
spindle-shaped and are provided with several processes running parallel
to the surface. These are sometimes called association cells. It is probable
that afferent fibres, entering the cortex, pass up towards the surface and end
for a large part in this molecular layer.
(2) Below this is a layer of pyramidal cells, the outer cell lamina, which
is divided by some observers, e.g. Campbell, into three, viz. :
(a) The small pyramidal cells.
(b) Medium-sized pyramidal cells.
(c) Internal layer of large pyramidal cells.
STRUCTURAL ARRANGEMENTS OF CEREBRUM
127
(3) Below the pyramidal layer we find a stratum of small cells, most of
which are stellate in form. This is known as the stellate or granule layer,
or middle cell lamina.
(4) Internal to the granule layer is the inner fibre lamina. In the
motor cortex and in certain other parts of the brain this contains large
solitary cells, which in the motor area receive the name of the cells of Betz.
(5) Most internal of all, lying next to the white matter, is the poly-
l'lo. 219. Schematic representation of the neuro-hbrillar apparatus of a cortical
pyramidal cell. (After Cajal.)
o, axon ; dh, dendrites.
morphous layer or inner cell lamina, composed of many types of cells, among
which spindle-shaped cells predominate. Other cells are also found resem-
bling pyramidal cells of the more superficial layer, but directed in the reverse
direction, so that their axons take a course towards the surface. These
are the cells of Martinotti. We also find Golgi cells with a freely branching
axon, which terminates in the adjacent grey matter.
128
PHYSIOLOGY
If sections of the cortex be stained by some method such as Weigert's,
which displays medullated nerve fibres, sheaves of radial fibres may be
seen running from the white centre towards the surface and giving of! a rich
Fig. 220. Diagrammatic section of cerebral cortex. (From Barker after Starr,
Strong, and Leamtng.)
I, molecular layer with a, bipolar cell ; II, liyer of small pyramidal cells ;
III, layer of large pyramidal cells ; IV, polymorphous layer ; V, white matter.
meshwork of fibres to the intervening portions of the grey matter. In
addition, bands of tangential fibres are seen running parallel to the surface
in certain situations, viz. :
STRUCTURAL ARRANGEMENTS OF CEREBRUM
429
(a) A layer of very fine fibres just under the surface of the cortex. This
layer is especially marked in the hippocampal convolution and is but slightly
developed in other regions of the cortex.
(b) A layer between the molecular layer and the layer of pyramidal
cells, known as the mi/cr live <>j Bailh rger.
ill Molecular or mil
Hlnv lamina.
Il-.'tl mm.
a, Tangential laye
Fig. 221. Motor leg
(c) Internal to the granule layer is another zone of fibres, the inner
1 1 in' nj Baillarger, giving its name to the inner fibre lamina.
[(I) In the part of the occipital cortex, distinguished as the visuo-sensory
area, which receives fibres of the optic radiations, a special layer of tangential
fibres is observed running through the middle of the granular layer and
dividing it into two parts. This is known as the line of Gennari (Fig. 222).
A careful study of the histology of the different parts of the cortex in
man enables us to distinguish certain types of structure characteristic of
various regions of the grey matter. In attempting by such means an
histological localisation of functions we have to take into account :
(a) The thickness of the cortex.
430
PHYSIOLOGY
(b) The relative thickness of the various layers.
(c) The character of the cells found in the various layers.
(d) The •arrangement and degree of development of the systems of
medullated fibres, both radial and transverse.
The possibilities in such a method are at once apparent if, as in Figs. 221,
222 and 223, we compare the structure of the cortex from, e.g. the pre-central
T7* itex:, or
win 1 her, as seems more likely, it is the
endings of the afferent nerves to the
cortex which are really excited by the
stimulus, wo cannot at present deter
mine.
When we compare different animals, such as the dog, monkey, and man,
we find there is a much finer differentiation of movements evoked by stimula-
tion of the cortex in the higher than in the lower type. Whereas in the dog
the excitable areas shade into one another, in the higher ape and man the
areas are much more circumscribed and are often separated from adjoining
areas by an inexcitable zone. The localisation of motor functions in the
cortex of the chimpanzee is indicated in the accompanying diagrams by
Sherrington (Figs. 227, 228). It will be seen that the motor cortex is limited,
on the convex side of the brain, to the precentral convolution, or ascending
frontal convolution, situated immediately in front of the 'fissure of Rolando.
On the inner aspect of the hemispheres only the corresponding part of this
convolution gives motor responses on excitation. We may say broadly that,
FlG. "220. Tracings to show latent periods
of movements obtained by stimulating r
A, grey matter ; B, underlying white matter
of cortex. Time-marking = T ,'„- sec.
(V. Franck.)
436
PHYSIOLOGY
from above downwards, by stimulation of the precentral convolution we gel
movements of the leg, arm, and face ; though, as is shown in the diagram,
within those larger areas smaller areas can be distinguished for definite
co-ordinated movements of the different parts of the body.
Anus &i
Ear- ■■ /
Eyelid, --'Closure
Nose ° f j av/ Opening
of jaw Vocal
cords Mastication
Fig. 22s.
Sulcus centralis
Sulc precentr mary
Sulc.calcarin
C.S S. del.
FlG. 227, outer surface ; Fig. 228. inner surface of brain of chimpanzee, showing
movements obtained by excitation of the motor areas. (Sherrington.)
NATURE OF MOVEMENTS EXCITED. The movements obtained by
excitation of these areas resemble in every respect the co-ordinated move-
ments observed during the normal willed or spontaneous activity of the
animal. Like the movements evoked by stimulation of a sensory surface
FUNCTIONS OF THE CEREBRAL HEMISPHERES 437
they involve the reciprocal innervation of antagonistic muscles. Never
do we find simultaneous contractions of antagonists, even where two
opposing centres are excited simultaneously ; one reaction is prepotent, as
is the case with cutaneous excitation, and this reaction is attended and
brought about by ordered contraction of certain muscles accompanied by
an ordered relaxation of their antagonists. Thus the movement of opening
t he jaw, which can be excited from a fairly large area of the cortex, involves
a relaxation of the normal tone of the masseter muscle. Flexion of the leg
demands relaxation of the extensor muscles. As in the case of the spinal
reflexes, this relaxation or inhibition can be abolished under the action of
strychnine or the toxin of tetanus. After administration of either of these
it is impossible to evoke inhibition of any muscle. Excitation of the cortical
centre for the movements of the jaw causes contraction of both closers and
openers of the jaw, i.e. a strife in which the stronger masseter muscles
predominate, so that the jaw is firmly closed.
The part played by muscular relaxation in the response to cortical
stimulation is also well seen in the case of the eye muscles. Stimulation of the
centre for eye movements on the convex surface of the frontal lobes on the
right side causes ' conjugate deviation ' of both eyes to the left. This move-
ment involves contraction of the right internal rectus and left external rectus
and a simultaneous inhibition of the tone of the right external rectus and left
internal rectus. If all the muscles of the right eye be divided except the
external rectus, this eye looks permanently towards the right side, i.e. a right
external st rabismus or squint is produced. On now exciting the right cortex
both eyes move to the left, although the right internal rectus is divided. The
movement of the right eye stops at the middle fine, and is brought about
simjilv by a relaxation of the tone of the right external rectus muscle
(Sherrington).
This movement of both eyes on stimulation of one side of the brain shows
that the function of each hemisphere is not entirely unilateral with regard
to the muscles of the body. As a rule the response to excitation of the motor
area for limbs is strictly unilateral. In the case of those movements how-
ever which arc normally carried out by co-operation of the muscles of the
two sides, such as the movements of the trunk, neck, and eyes, stimulation of
I he motor area in one hemisphere evokes a movement involving the muscles
of both sides of the body, i.e. the cortical representation is one of movement
rather than one of muscles. Where an action is carried out by similar con-
tractions of corresponding muscles on the two sides, the movement itself
is bilaterally represented in the cortex. Types of such reactions are found
in closure of the mouth, contractions of the abdominal muscles, erection or
flexion of the trunk. It seems that under such circumstances there is a free
communication between the lower motor centres of the two sides, since the
I'ilatcrality of the response is not altered by extirpation of the cortex of
the hemisphere opposite to that which is being stimulated.
CORTICAL EPILEPSY. When electrical excitation of any strength
over the minimum effective stimulation is applied to the motor area of the
438
PHYSIOLoiiV
cortex, the movements evoked tend to persist for a short time beyond the
duration of the stimulus. On still further increasing the strength of the
current, the contraction spreads to adjoining muscles, and finally may
affect all parts of the body, giving rise to the phenomenon known as an
epileptic convulsion. The same effect may often be caused by weak stimuli,
if the irritability of the cortex be raised in consequence of repeated previous
stimulation. A typical fit consists of two parts. The first effect of t lie stimu-
lation is a strong tonic contraction; this outlasts the stimulus for some
time, and then gives way to a series of clonic contractions, repeated at first at
intervals of from six to ten per second, but gradually getting slower as the
tit dies away. The tracing of such a contraction is given in Fig. 229.
Fig. 229. Tracing of muscular contractions durum an epileptic convulsion aroused
by strong stimulation of the motor area. (HOBSLEY and Schafer.)
The main phenomena of a fit, due to irritation of any portion of the
motor area, were described by Hughlings Jackson in L864, even before the
experimental proof of cortical localisation had been brought forward by
Fritsch and Hitzig. A similar condition may occur in the human subject
as a result of irritative lesions of this part of the cortex, such as that due to
t he presence of a tumour or a spicule of bone pressing on the brain. Jackson
showed that in this condition the convulsive movements follow a certain order
or ' march.' Thus if the thumb area be the seat of stimulation, the fit
begins by a contraction of the thumb muscles, then spreads to the muscles
of the hand, fore-arm and shoulder of the same side, and then to the
face, trunk, and leg. If it begins in the toes the order would be up the leg and
down the arm. The same ' march ' is observed in artificial stimulation of
the motor area. If the convulsions are very strong they spread to the
leg of the opposite side and then to the whole body. The spread to the other
side of the body is not prevented by division of the corpus callosum, nor by
isolating the centres from one another, so that the sequence seems to be
maintained through the mediation of the sub-cortical centres. Complete
excision of the cortical centre for any given movement excludes this move-
ment from participation in the fit. In man this type of epilepsy is, in the
milder cases at any rate, generally unattended with loss of consciousness.
In animals epileptic convulsions can be excited by stimulation of any portion
of the cortex, though it is obtained by a weaker stimulus applied to the motor
cortex "than to any other part. Jacksonian epilepsy is often preceded l>y
a sensation of numbness or tingling, the ' aura,' in the part in which such
convulsions begin. In ordinary idiopathic epilepsy tactile or visual sensory
FUNCTIONS OF THE CEREBRAL HEMISPHERES 139
aura? may precede the attack ; but in this case loss of consciousness is always
a prominent symptom, even in the milder form of the disease. UniversaJ
epileptic convulsions can be excited in animals by the injection of absinthe
into a vein. During the convulsion there is a rise of blood pressure and a
quickening of the pulse ; the respiration is very often stopped during the tonic
pari of the spasm, so that the patient becomes livid. The universal con-
dition of excitation affects also the centres from which the secretory nerves
originate, so that there is an excessive flow of saliva which, in the idio-
pathic case, is responsible for the characteristic frothing at the mouth.
EFFECTS OF ABLATION OF THE MOTOR CENTRES
We have seen that a dog may preserve complete power of movement
after a total ablation of both cerebral hemispheres. We should not exped
therefore to find any lasting paralysis as a result of extirpation of portions
of the brain, such as the motor centres. Ablation of the motor areas in
these animals, during the first few weeks after the operation, gives rise to
considerable disorders of movement, the muscles on the side of the body
opposite to the lesion being markedly weaker than those on the same side.
These symptoms however gradually pass off, so that after a time not only
are both limbs employed in the ordinary automatic movements of progression,
hut t he animal can be taught new movements in the limb, the cortical centre
for which has been excised. We must conclude therefore that in the dog all
the movements, including those which are voluntary and conscious, can be
carried out in the absence of the motor centres, although destruction of these
centres may impair the accuracy with which some of the finer movements are
regulated.
In the monkey (Macacus) the effect of ablation is more marked, corre-
sponding to the greater degree of localisation in these animals. If the whole
of the motor area on the external surface of the brain be excised, e.g. on the
right side, there will be almost complete paralysis of the left arm and the left
side of the lace, and weakness of the muscles of the left leg. The animal
will continue to use the leg in walking and in climbing. If the lesion extends
to the medial side of the hemisphere, paralysis of the leg is more marked, and
the muscles of the left side of the trunk are also affected. Many of these
symptoms disappear in the course of time. In a monkey, in which Goltz had
destroyed the greater part of the left side of the cerebral hemispheres, it was
found that the right arm and hand could be still employed alone for such
purposes as taking food, although the movements were much more awkward
than those of the left hand.
Still less complete is the recovery from lesions of the motor area in man.
We possess now a considerable number of typical histories of cases in which
part of the motor cortex has been destroyed by disease or by operation, and
the seat of the lesion verified by post-mortem examination. In all these
e ises t here ha s l n a loss of voluntary movement corresponding in disl ribvj
lion to the seat of the lesion and proportionate in its severity to the extent
of the lesion. On the other hand, equally extensive lesions outside the
110 PHYSIOLOGY
ascending frontal convolution have been shown to have no eff eel on voluntary
movements. The loss of movemenl is chiefly confined to those which we
regard as volitional. Although, for instance, the arm may be paralysed, it
can be still raised in association with a movement involving the other arm.
A certain degree of recovery from the immediate effects of the lesion may be
observed, but tin- recovery is never complete.
The difference in the reaction of various animals to lesions of the motor
cortex is connected with the gradual shifting of functions from the sphere
of fatal necessary read ions to the sphere of educatable adaptations (i.e. from
the lower centres to the cerebral cortex), which is a characteristic of the evolu-
tions of the higher type of nervous system, and is a concomitant of the in-
creased adaptability which distinguishes man from all the lower animals, in
I he animal \\ it bout hemisphere the motor mechanisms for all the movements
of the body are present and can be set into action from any point on the
sensory surface of the body. The first effect of adding the cerebral hemi-
spheres to this mechanism is to increase the range of reactions, to modify
them or to inhibit them, by diverting the stream of nervous impulses into
channels which have to a large extent been laid down in the cortex by the
past experience of the individual. In the frog and bird we notice an auto-
maticity and a 'conscious' adaptation of movements to purpose, although
the hemispheres have no direct connection with the motor centres of the
cord, and present no areas which we can designate as motor. In the dog,
although a portion of the brain is in direct connection with the spinal motor
centres, and can therefore initiate movements without making use of the
mid-brain motor machinery, these movements play only a small part in the
motor life of the animal, and the removal of the corresponding centres takes
away but little of the conscious functions of the animal. In man the enor-
mous power of acquisition of new movements is rendered possible by the
shifting of one motor function after another to the sphere of influence of the
cerebral hemispheres. Almost every act of life in man has become one
involving co-operation of the cerebral cortex. For many years after birth
man is helpless and far inferior, as a reactive organism, to animals much
lower in the scale. Even the lower motor functions, such as those of loco-
motion or defence, have to be painfully learnt, and this learning implies the
laving down of paths (Bahnung) in the cortex. On this account the sub-
cortical centres in man are no longer complete. Acting in every instance
of life as a subordinate or adjunct to the cerebral hemispheres, they are unable
to carry out even the simpler motor reactions of the body after removal
of those portions of the hemispheres especially engaged in the control of
voluntary movement. The motor defect therefore which is brought about
in man, as a result of destruction of one or more of the motor centres, is to a
large extent permanent.
If the lesion in man be strictly limited to the motor areas in the ascending
frontal convolution, it is impossible to detect any loss of sensation in the
affected parts of the body. On the other hand, some loss of sensation is
often found where the paralysis is widespread and occasioned by extensive
FUNCTIONS OF THE CEREBRAL HEMISPHERES 441
lesion in the neighbourhood of the Rolandic area. Moreover, even in localised
lesions in man, an epileptic fit may be preceded by a sensory aura in the part
which is the starting-point of the convulsive movements. Much discussion
has taken place as to the exact significance to be assigned to these slight
sensory phenomena. By some observers, e.g. .Munk, it has been thought
that the motor centres were the end-stations of the fibres subserving muscular
sensations, and that the movements resulting from their stimulation were
due 1<> the revival of such sensations. Bastian insisted on the important
pari played in voluntary actions by afferent impressions, and these centres
have sometimes been spoken of as ' kinsesthetic ' or sensori-motor. The
discussion has however now resolved itself practically into one of terms.
There is no doubt that, when the lesion is strictly localised in the motor aTea,
paralysis may be present without any loss of sensation whatsoever. The
paralysis therefore cannot be classed with the sensori-motor paralysis dis-
tinguished earlier as the result of division of sensory roots. On the other
hand, when we say that this part of the brain represents a 'centre fur
voluntary movements,' we do not mean that the volitional motor impulses
arise de novo from the pyramidal cells in its grey matter. Every neuron in
the nervous system is part of an arc, and it is generally difficult to label any
given neuron as definitely sensory or motor. In a reaction involving a chain
of neurons we can assign the name of motor to that neuron which sends
its axon to the muscle, and of sensory or afferent to that neuron which
receives the impulses at the periphery of the body. Where in the chain we
are to draw the dividing line and to say " these neurons are sensory and those
motor," it is difficult to decide. The motor areas in the cortex give origin to
the long fibres of the pyramidal tract, which passes right through the central
nervous system to the segmental centres of the cord. We know that the
integrity of these tracts is essential for the carrying out of voluntary move-
ment. It is therefore convenient to speak of them as motor or efferent
tracts, and their origin as motor centres; although these tracts have the
same relation to the motor cells of the spinal segment as have the afferenl
fibres from the posterior roots by which similar movements may be evoked.
On the other hand, the activity of the pyramidal cells of the cortex,
like those of the motor cells of the spinal cord, is determined by the arrival
at them of afferent impressions. In the absence of these afferent impressions
no spontaneous discharge of motor impulses takes place. Thus in the spinal
frog we have seen that complete inactivity is brought about by section of
all the posterior roots. In the same way paralysis of the arm is induced
by section of all its posterior roots, although it can be shown that the motor
cortex is still excitable, and that the application of an induced current to the
motor centres of the arm evokes a movement as easily as in the normal
animal. The motor cells in the cortical motor centres are normally played
upon and aroused by impressions arriving a t them from all other parts ol the
brain and nervous system, and determined originally by impressions falling
on tin' surface of the body.
442 PHYSIOLOGY
THE FUNCTIONS OF THE CORPUS STRIATUM
The mass of grey matter known aw the corpus striatum, which consists
of the nucleus lenticularis and the nucleus caudatus, is the basal part of the
outgrowth from which each cerebral hemisphere is formed and in the lowest
vertebrata represents almost the whole of the telencephalon. For many
years the corpus striatum was classed with the optic thalamus as the ' basal
ganglia,' and these two ganglia were regarded as relay stations between the
cerebral cortex ami the lower parts of the central nervous system. This view
u as correct so far as concerns the optic thalamus, in which end all the afferent
tracts and from which afferent impressions are carried on by fresh relays of
fibres to the cortex. In the higher mammals the motor cortex has a direct
connection with the motor nuclei of the bulb and spinal cord through
the pyramidal tracts, which are not interrupted anywhere on their course.
On destroying 1 be corpora striata. degenerated fibres are found running to the
optic thalamus, to the red nucleus, and from the latter to the posterior
longitudinal bundle. On the other hand the corpus striatum receives fibres
from the olfactory tracts and from the optic thalamus. These connections
would tend to show that the corpus striatum serves in no way as an inter-
mediary between the cortex and the lower parts of the central nervous
system, but is an independent mass of grey matter, receiving impulses from
the same source as the cortex and sending impulses which may join in the
stream of impressions which play upon the lower motor mechanisms of the
bulb and cord.
Isolated excitation of the caudate and lenticular nuclei has no visible
effect, provided the current is not so strong as to spread to the adjoining
pyramidal fibres in the internal capsule. A study of the evolution of the
central nervous system in different classes of animals points to a diminishing
importance of these bodies in the normal life of the animal. In the carti-
laginous fishes it probably serves to a greater or less degree the same functions
in the determination of educated reflexes as the cerebral hemispheres in
mammals. In birds the corpus striatum attains its greatest relative develop-
ment, the increased powers of adaptation in these animals being
apparently procured by development of the corpus striatum instead of the
pallium or cerebral hemispheres as is the case in mammals. In the
monkey Kinnear Wilson found no definite results to follow destruction of
the grey matter in these bodies. The animals were however allowed to
survive the operation of destruction only three weeks, and the same observer
has pointed out that destruction of the corpora striata in man may give rise
to a morbid condition, characterised by tremor in the execution of willed
movements and increased tonicity of the muscles. He therefore ascribes
to these bodies, or rather to the sensori-motor mechanism which has its chief
meeting-place in their nuclei of grey matter, a steadying effect on the motor
system, and places this system by the side of the other systems which we
have already studied, namely, the vestibular, the cerebellar, and the
pyramidal systems.
FUNCTIONS OF THE CEREBRAL HEMISPHERES 443
According to Meyer and Barbour, the anterior part of the corpus striatum
plays an important part in the regulation of body temperature. In the
experiments a metal tube, closed at one end, was introduced through
the brain so as to lie in or on the corpus striatum. Through this tube water
at any temperature could be passed. It was found that cooling the water
gave rise to shivering and increased heat production in the body with a rise
of body temperature, while warming the water had the reverse effect. They
are therefore inclined to regard this part of the nervous system as representing
the chief thermo-taxic mechanism of the body.
THE LOCALISATION OF SENSORY FUNCTIONS IN THE CORTEX
It was pointed out by Ferrier that movements might be obtained on
electrical excitation of regions of the cortex cerebri other than those we have
described as motor. Thus excitation of the superior temporal convolution
on the right side causes the animal to turn its head and eyes to the left and to
prick tin its ears. In the same way stimulation of the right occipital lobe
causes movement of both eyes and head to the left side. These portions
ol tin- brain cannot be regarded as having a direct relationship to the motor
mechanisms involved in the above movements, since their ablation leads to
no defect of movement but does, in many cases, lead to defect of sensation.
Thus excision of the right occipital lobe in the monkey, though leaving the
eye movements intact, causes a loss of power to discern objects lying to the
left of the middle hue. The obvious explanation therefore of the movements
obtained on excitation of this portion of the cortex is that they are due to
the revival or arousing of sensory impressions, that these portions of the
cortex represent the cortical receiving-stations for the impulses from
definite sense-organs, and that the movements obtained are simply those
which are normally associated with a corresponding sensory excitation.
This conclusion is borne out by the fact that to excite movement it requires
a greater strength of stimulus when applied to the sensory areas than is
necessary if t In- stimulus be applied to the Rolandic area. Moreover Si haier
lias shown that the latent period which intervenes between the stimulus and
the resulting movement is considerably longer when the stimulus is applied
to the sensory centre than when it is applied to the motor centre, suggesting
that more neurons are interpolated between the point of stimulus and the
discharging motor neuron in the first case than in the latter. Thus in one
experiment the latent period between the stimulus and the resulting move-
ment of the eyes amounted to 0'2 sec. when the frontal lobes were stimulated
and 0"4 sec. when the occipital lobes were stimulated. Finally the anatomi-
cal investigation of the course of the fibres in the white matter of the cerebral
hemispheres points to a concentration of sensory fibres from different sense-
organs towards certain regions of the cortex. The diagrams (Fig. 230
and 231) show those portions of the brain to which the endings of i he sensory
tracts of the central nervous system are directed.
From the purely anatomical standpoint we may designate as ' sensory
areas ' of the coitex :
414
PHYSIOLOGY
(1) An area including Lot li cent ral convolutions, i.e. the ascending frontal
and the ascending parietal, and spreading forward into the frontal lobes.
(2) An area occupying the hinder portion of tin' occipital lobe and the
greater pari of its inner surface
Auditory area
Fig. 230. Outer side of right cerebral hemisphere, according to Flechsig. The
dotted surface indicates the regions where I lie majority of the afferent (sensory)
fibres end.
(.')) Aii area occupying flip superior temporal convolution and extending
well into the fissure of Sylvius.
(4) An area on the 'inner side of the hemisphere, occupying the hippo-
' Tactile i
Olfactory area
Fig. 231. Inner surface of the same hemisphere. (Fi-echsio.)
campal gyrus and the margin of the gyrus fornicatus close to the corpus
callosum.
Let us see how far experimental evidence bears out this localisation.
FUNCTIONS OF THE CEREBRAL HEMISPHERES 445
TACTILE AND MOTOR SENSIBILITY
A lesion limited to the ascending frontal convolution may produce
paralysis of definite movements or groups of muscles without any detectable
interference with sensation. When however in man a widespread injury,
involving both the Rolandic area and the adjacent portions of the brain,
occurs as the result of some morbid condition, such as blockage of the middle
cerebral artery, the resulting hemiplegia is almost always associated with a
greater or lesser degree of hemiancBsthesia. We are therefore justified in
locating tactile and muscular sens-
ibility somewhere in the region of L£FT RE ,, NA right retina
the central convolutions, and it is
probable that, while it may in-
clude the motor area, its chief
representation is to be found in
the post-central gyrus, i.e. the
ascending parietal convolution.
The sensory aura which pre-
cedes an attack of Jacksonian
epilepsy points to the motor area
itself having some degree of sen-
sory functions, and it has been
observed that faradisation of the
central run volution in man may
produce tingling sensations in the
part of the body which is the
'it the muscular contractions
induced by stimulation. No pain
is however felt as a result of the
stimulation. The impulses which
subserve cutaneous and muscular
sensibility travel up to the brain in
the mesial fillet. This tract comes
to an end in the- ventro-lateral
portion of the thalamus and the
subthalamic region. The new relays of fibres, which carry on impulses to
the cortex, arise in the thalamus and pass through the hinder limb of the
internal capsule to be distributed to the central convolutions. Their area
of distribution is however much wider than the area of origin of the pyra-
midal fibres. We may therefore conclude that tactile and muscular sensi-
bility are chiefly subserved by the central convolutions, including the motor
area, but are especially dependent on the integrity of the post-central gyrus.
Flechsig has shown that fibres from the thalamus, which may probabbj b<
regarded as continuations of the fillet system, arc also distributed to other
portions of the cortex, i.e. the temporal, the frontal, and the occipital lobes.
It is therefore not surprising that the hemianaesthesia produced by lesions
in the central convolutions is rarely or never complete.
Jc o£7
Fig. 232. Diagram showing the probable
relations between the parts <>f the retinas
and the visual area "I I he coi tex. (Schafer.)
in; PHYSIOLOGY
The term ' tactile and motor sensibility ' is very inadequate as describing
the complex afferent impressions which proceed from all parts of the body
to the brain. They may perhaps be better grouped under the term ' somatic
impressions,' and include three main classes, viz. :
Exteroceptive . . From the surface of the body
Enteroceptive . . From the viscera
Proprioceptive . . From the muscles and joints, aroused by
changes occurring within the organism
itself.
Of these, the exteroceptive are the most important in giving information
as lo the external world, and predominate among those impressions which
reach and affect consciousness. The enteroceptive under normal conditions
very rarely rise to the conscious level. The proprioceptive impressions are
also for the most part unconscious, yet those, which do reach consciousness,
play a great part, in conjunction with the exteroceptive, in forming the
basis of our schema of the material world.
We find — as Head has shown — a constant regrouping of somatic impres-
sions as we trace them from their origin, at or near the surface of the body,
through the spinal cord and nerve tracts to the cerebral cortex. At the
periphery these impressions are divided into superficial and deep sensations,
and the former again into the epicritic, which determine localisation, dis-
crimination and the finer gradations of pressure, heat, and cold, and the proio-
/niiliir, comprising pain, the coarser degrees of heat and cold, and tactile
sense with defective localisation.
When these various impulses reach the cord, they are regrouped, so-
that the pain, heat and cold, and tactile sensations are collected each in a
separate bundle, with no distinction between the coarser kinds of tactile
sense and the finer qualities involved in discrimination and localisation.
This grouping' persists as far as the thalamus, and even beyond the thalamus
a similar grouping is observed in the sub-cortical white matter through
which the tracts run from the thalamus to the sensory cortex. Lesions at
any part of these paths may therefore affect one or more of these qualities
of sensation separately. .
On arrival at the cortex cerebri all these different kinds of sensation are
poured into the grey matter to form the basis of the schema of the external
world and the relations thereto of the individual. The cortical type of loss
of sensation differs therefore profoundly from the loss produced by a lesion in
any other part of the sensory tracts. It may occur as the result of lesions
of. the pre- and post-central convolutions, of the internal part of the superior
parietal lobule and of the angular gyri. The chief feature of this cortical
loss of sensation is a defect, not in one or other of the different sensations
which have been described, but in the appreciation of the meaning of these
sensations, i.e. the loss appears to be rather psychical than physiological.
Thus, it is not a question of recognition of touch, pain, heat and cold, but of
certain discriminating faculties which can be classed as : — (a) recognition of
FUNCTIONS OF THE CEREBRAL HEMISPHERES 117
spacial relations, (b) appreciation of intensity of stimuli, and (c) apprecia-
tion of similarity and difference in external objects which are brought into
contact \Vith the surface of the body.
It is not surprising therefore that in such cases the answers of the patient,
when his sensibility is tested, seem to be confused, and it is this confusion
of judgment which is more apparent than definite loss of sensibility. With
regard to sensory localisation, it should be noted that the functions rather
than the anatomical relations of any one part of the body, are represented
on the cortex ; hence, as in the motor functions of the brain, those portions,
such as the hand, which are endowed with the highest powers of discrimina-
bive sensibility, are most extensively represented, and next in order comes
tin 1 sole (if the foot. Thus, after a cortical lesion, sensibility of the hand and
loot may he dist ui'bed without there being any alteration in that of the elbow,
shoulder or knee.
VISUAL IMPRESSIONS
Bach optic t pact, carrying impulses arising as a result of events occurring
in the opposite field of vision, ends in the pulvinar of the optic thalamus, the
external geniculate body, and the superior corpora quadrigemina. The last
named is apparently not concerned in vision, but represents a centre for
the co-ordination of visual impressions with those from other regions of the
body in influencing bodily movements. From the pulvinar and external
geniculate body arises a shsaf of fibres, which pass through the extreme binder
end of the posterior limb of the internal capsule and diverge in the centrum
ovale to hi' distributed to the occipital lobes, being here known as the optic
radiations. The anatomical connexion of the occipital lobes with vision
is confirmed by evidence derived from experiment. .Movements of the
e\ es result from stimulation of almost any part of this lobe. If the upper
surface of the right occipital lobe be stimulated, both eyes move downwards
and towards the left. Excitation of the posterior part causes movement
ol i he eyes up and to the left ; while between these two parts there is an
intermediate zone, most marked on the mesial surface, stimulation of which
evokes a purely lateral deviation of the eyes to the left. It is therefore con-
cluded not only that there is representation of visual impressions in the
occipital lobes, but that there is a certain amount of localisation within the
visual area itself, as is represented in the diagram (Fig. 232).
These conclusions are fully borne out by the results of ablation. While
extirpation of the whole occipital lobe on one side in animals causes crossed
in iniauopia. i.e. has the same effect as division of the corresponding optic
tract, extirpation of these lobes on both sides causes complete blindness.
It seems that the fovea centralis — the region of distinct vision — is bilaterally
represented, so that central vision is usually retained in both eyes after
destruction of one occipital lobe (Fig. 233).
The area connected with vision seems to be smaller in man than in the
ape, and in the ape than in the dog. Thus in man complete blindness has
been observed as the result of localised bilateral lesions of the internal sur-
IIS
PHYSIOLOGY
faces df 1 1 ccipital lobes, and we find the same relative limitation of area
as we proceed from lower to higher forms in the case of il tiler sensory
areas of the cortex.
THE AUDITORY AREA
Anatomical study indicates a connexion of auditory sensations with the
superior temporal lobe. The impulses, started by the arrival of sound waves
at the ear,travel by the cochlear nerve to the medulla, From the I wo audi-
tory nuclei a well-marked set of fibres passes across to the opposite side in
the corpustrapezoid.es, then turns up into the tegmentum of the opposite side
to form the tract known as the lateral fillet. The fibres of this tract end
Fig. 233. Perimeter charts from right and left eye, showing the limitation of the field of
vision (right hemianopia) produced by a lesion of the" left occipital cortex. (Bechterew.)
partly in the inferior corpora quadrigemina, partly in the internal geniculate
body. From the latter, fibres pass into the internal capsule, and thence as
' auditory radiations ' directly to the superior temporal convolution.
In the monkey stimulation of the upper two-thirds of this lobe of the
brain causes pricking of the opposite ear, dilatation of the pupils, and rotation
of the head and eyes to the opposite side. It was stated by Ferrier that
ablation of the superior temporal convolution causes deafness, but Schafer
found that, even after extirpation of the superior temporal convolutions of
both sides, monkeys showed signs of hearing quite distinctly, and of under-
s1 anding the nature of the sounds heard. One must conclude therefore that
the function of auditory perception is not entirely confined' to the temporal
lobe, though its focal point may be located in the superior temporal eon-
volution, especially in that part which is seated within the fissure of Sylvius.
This conclusion is strengthened by the results of clinical evidence in man, in
whom cerebral lesions, which have produced disturbances of auditory per-
ception, are found almost invariably to be closely associated with the superior
temporal convolution.
FUNCTIONS OF THE CEREBRAL HEMISPHERES 119
SMELL AND TASTE
The course of the fibres from the olfactory lobe may be used to throw
light upon the localisation of olfactory sensation in the cerebral cortex.
There is a great divergence between different animals in the degree 1" which
the olfactory sense, is developed, and with this divergence we find corre-
sponding variations in the development of certain portions of the brain.
In those species with highly developed olfactory sense the following parts
of the brain show special growth:
(I) The olfactory lobe, including the olfactory bulb, and the olfactory
tract.
(•_') The posterior part and the inferior surface of the frontal lobe.
(v$) The hippocampal gyrus and the dentate convolution.
(4) A convolution termed the gyrus supracallosus and forming that pari
of the gyrus fornicatus closely encircling the corpus callosum.
(")) The anterior commissure.
The olfactory lobe is connected almost exclusively with the cerebral
hemispheres of the same side. Ferrier found that electrical excitation of
the hippocampal region causes contortion of the lip and nostril on the same
sidi i.e. a reaction such as that actually induced in these animals by applica-
tion of an irritative, or pungent odour direct to the nostril. Ablation ex-
periments have not yielded very definite evidence on the question oflocalisa-
tion of t!n> olfactory sense. So widespread are the connexions of the olfac-
tory tract throughout the brain that it would be extremely difficult, if not
impossible, to extirpate all those parts which receive fibres from this tract.
C i- usual to regard the sens.' of taste as associated with that of smell, but
hereagain experimenl and clinical evidence have yielded very little that i^
definite.
GENERAL CHARACTERISTICS OF CORTICAL MOTOR FUNCTIONS
The motor phenomena, which may be observed as the result of artificial
excitation of the motor and senspry areas in the cortex, constitute a very
small fraction of the activities which must be associated with the cerebral
hemispheres. An animal with its cerebral hemispheres intact differs
markedly from a decerebrate animal in the variety of combined movements
which it may exhibit, either spontaneously or in response to external stimuli.
When however we excite the motor areas directly, we obtain movements
which are practically identical with those which we may elicit from a bulbo-
spinal animal by appropriate peripheral stimulation. The movements thus
excited from the skin may be looked upon as variations from tin- tonic
postural activity of the musculature of the body. We have seen that From
i he end-organs subserving deep and muscular sensibility (the proprioceptive
system), as well as from the labyrinth, impulses are continually arising
which travel up to the spinal cord. bulb, cerebellum, and mid-brain, mid
excite a tonic activity of these centres. The normal attitude of the animal
depends on the tonus thereby produced in certain muscles. .Muscular lone
is indeed a qualitv specially found in certain groups of muscles. If the cere-
29
150
PHYSIOLOGY
bra! hemispheres be removed, as l>v a section through the crura cerebri
or in front of the mid-brain, this postural tonus is increased and the animal
enters into the condition of ' decerebrate rigidity.' Destruction of one laby-
rinth diminishes the tone on the same side of the body ; section of all the
afferent nerves from a limb abolishes the tone in that limb, so that its post hit
thereafter depends entirely on gravity.
The movements which are excited in such animals by cutaneous stimula-
tion involve as a necessary factor inhibition of the postural tone as well as
co-operative inhibition of the an-
tagonistic muscles. In the same
way excitation of the motor area of
the cortex lias as its most essential
feature an inhibitory action on the
postural tonus in addition to its exci-
tatory action on the muscles con-
cerned in the movement. A cer-
tain antagonism is evident between
the total action of the cerebral hemi-
spheres and that of the propriocep-
tive part of the central nervous sys-
tem. Whereas in the decerebrate
animal there is increased tonus in
the masseters, in the neck muscles.
the muscles of the trunk, and the
extensor muscles of the limbs, stim-
ulation of the cortex produces
opening of the mouth, flexion of the
fore limb or of the hind limb, more
easily than any other movements.
That an essential part of this action
is inhibitory is shown by the effects
of exciting the motor area of the cor-
tex after exhibition of strychnine or
during the local action of tetanus
toxin. Whereas in the normal animal
closure of the jaw and extension of
the fore limb are obtainable
only from one or two points on the
surface of the brain, after the injection has taken place, every part of
the jaw area gives closing of the jaw, every part of the arm area gives
extension of the lirub (op. Fig. 173).
Since the predominant influence of the motor cortex is therefore inhibitory
of the stronger muscles of the body, as well as of the tonus, which is con-
tinually and reflexly maintained, it is not surprising that excision of both
hemispheres should give rise to decerebrate rigidity, or that destruction
or division of the chief direct tracts from the cortex to the motor spinal
Fig. 234. Diagram (from Mott after Mon-
akow) to show the interaction of the
different levels in the central nervous
system in the production of co-ordinated
' volitional ' movements.
s, sensory neuron ; B, bulb ; Tir, thala-
mus ; MA, motor area ; i>, pyramidal fibre ;
C, cerebello-pontine nuclei ; vs, vesti-
bular neuron (Deiters' nucleus).
FUNCTIONS OF THE CEREBRAL HEMISPHERES 451
mechanisms, viz. the pyramidal tracts, should determine increased tonus and
rigidity of the limbs — the so-called ' spastic ' condition observed in cere-
bral paralyses.
Two separable systems of motor innervation appear thus to control two
sets of musculature. One system exhibits the transient phases of heightened
reaction which constitute reflex movements ; the other maintains that steady
tonic response which supplies the muscular tension necessary to attitude.
Hughlings Jackson long ago called attention to this contrast between the
two systems. He pointed out that while the cerebrum innervates the muscles
in the order of their action from the most voluntary movements (the limbs)
to the most automatic (trunk), the cerebellum, or, as we should say now,
the whole proprioceptive system, innervates them in the opposite order.
The cerebellum therefore he regarded as the centre for continuous move-
ments and the cerebrum for changing movements. The increased tone of the
paralysed muscles, observable after hemiplegia, he ascribed to unbalanced
cerebellar influence. While there is no doubt that the cerebellum must play,
and does play, a considerable part in the production of decerebrate rigidity
and of the spastic condition of hemiplegia, it is not the only element
involved ; nor is it essential, since decerebrate rigidity may continue after
extirpation of the cerebellum and an exaggerated knee-jerk may result from
section of the spinal cord in the lower cervical region.
HIGHER ASSOCIATIVE FUNCTIONS OF THE CORTEX
Tin' simple and uncomplicated nature of the movements elicited on
cortical stimulation shows that we cannot regard these motor centres as
responsible for the whole, or even the greater part, of the motor functions of
the cortex. They are in fact simply the starting-point for the motor impulses
which run down the long pyramidal tracts, but which result from the
activities of the cerebral hemispheres as a whole. In the lower mammals
they do not even represent the only starting-point, as is shown by the almost
perfect recovery of volitional motor power in a dog deprived of its motor
cortex. The distinguishing feature of the response of an animal possessing
cerebral hemispheres is that it is not determined solely and exclusively
by the nature and position of the peripheral stimulation, but involves
elements connected with the past experiences of the animal, and including
therefore the results of previous stimulation of many of the sense-organs,
either directly, or indirectly as a result of reflex movements. The animal's
reactivity is determined by its past history, and this modifying influence on
the brain must involve parts connected with all its sense-organs. In any con-
scious motor act we may say therefore that the brain functions as a whole, or
nearly as a whole.
In endeavouring to arrive at some idea of the neural processes concerned
in voUtional movements, i.e. movements of the intact animal, we are dealing
with events which in ourselves come within the sphere of consciouMH sss,
so that some assistance is derived by appealing to our own mental experiences.
Especially is this necessary in the case of the sensations. It might 1 e
152 PHYSIOLOGY
imagined thai a simple sensation would ensue as the result "I local stimula-
tion, say of the visual centre on one side. Our knowledge of the properties
of the systems of neurons composing the cenl ral nervous system would teach
us that no excitatory process could remain confined to one portion of the
brain, bu1 must diverge in many directions. It is true thai excision ol the
occipital lobes on one side causes blindness to objects in the opposite half
of the field of vision. This is however merely a result of localisation of the
end of visual fibres, and the same effect can be brought about by division of
the right optic tract, or damage to the right half of both retina'.
On the other hand, an appeal to our own experience shows that no
sensation can be regarded as simple, i.e. as following merely stimulation of
visual fibres or visual centres. Thus the sensation of a luminous point
has connected with it not only luminosity but also colour and intensity.
Moreover the apparent position of the luminous point comes into conscious-
ness at the same tiine as the consciousness of the luminosity itself, and this
location of the stimulation involves muscular impressions from the eyeballs
and an association between certain points on the retina and certain corre-
sponding muscular movements of the eye muscles, of the head and neck, and
even of the body and arm — movements which would be necessary to bring
the image of the spot on to the fovea centralis and to approach the whole
body to the site of the stimulating object.
As the visual sensation becomes more complex, the associated sensations
and experiences which it evokes become more numerous. Thus the image
of a chair falling on the retina excites a long train of nervous processes. At
once we become aware not only of a visual impulse but of an object which
possesses colour, extension, or size in three dimensions, solidity, hardness,
distance or position in space, etc. These qualities are founded on past ex-
periences — visual, muscular, and tactile. Moreover we are at once aware
of the uses of the chair, and of its name both spoken and written, a mental
activity connoting revival of higher visual and auditory sensations. The
higher in the scale of intelligence, the greater is the development of the
cerebral hemispheres and the more extensive are the associations arising in
connexion with any single sense impression.
Besides the portions of the brain which send out the motor paths and
which receive the endings of the sensory paths, there may be whole regions
taken up by the interconnecting neurons which subserve the association of
the activities of all parts of the cerebral hemispheres, and the higher the
animal is in the scale of intelligence the larger must be the relative amount
of brain substance set apart for these functions of association. This is very
evident if we compare the brain of three animals, such as the dog. the ape.
and man. Although as we ascend to man there is an absolute increase in the
amount of brain substance involved — say in the motor areas or in the sensory
areas — the increase is very small as compared with that in those portions
of the brain which give no response on stimulation, and in man these
' silent ' parts of the brain form the greater part of the cerebral cortex.
Although every phase of cerebral activity, every conscious event, involves
FUNCTIONS OF THE CEREBRAL HEMISPHERES 453
co-operation of a large number of distant portions of the brain substance, in
most of them there will be some seat of sense impressions which will be
predominant, and a train of ideas may be specially visual, or auditory, or
tactile. It is therefore not surprising that, in the immediate neighbourhood
of the cortical areas which receive the endings of the sensory tracts associa-
t n m areas are developed which may be labelled according to the sense-organ
with which they are most nearly in relation. Thus we' may speak of the
visual-sensory and the visual association, or psychic area, the auditory-
sensory and the auditory-psychic, and so on. The limits of these areas are
indicated in Fig. 224. p. 431.
Conditioned reflexes. Until recently, our study of the processes of association
and therewith all tin- higher functions of the cerebral hemispheres was chiefly carried
nut in man, and in most cases by the introspective method. Even when carried out
on other men. it was chiefly by using speech as an index to the introspective experi-
ences of those who were being investigated. During the last fewyears a method has
been introduced by Pawlow for investigating the higher cerebral functions by an
objective method which is capable of very wide application. When a hungry
animal is shown food, we say that 'its month waters,' i.e. there is a secretion of
saliva ; and if the animal be provided with a salivary fistula the extent of the emotion
of appetite may be gauged in ee. of saliva flowing from the fistula. It is found in
such an animal that a flow of saliva may be excited, not only by the sight or adminis-
tration of food, but also by any other event which has become associated, as the result
of experience, with the taking of food. We may use this method in order to deter-
mine the sensitiveness of the animal's perception of pure tones. Thus if we wish to
know whether the animal can recognize the difference between middle C and middle
i "Z-. as produced by tuning-forks, we can for some days or weeks allow him to hear both
i hese sounds frequently but always follow' up one of them, say C, by giving him a piece
of meat. After a time it is found that not onlj^ can he distinguish between the two
sounds, but that he has a memory of the absolute pitch, so that whenever the note
middle (' is sounded or any note differing from it by not more thanSd.v. per second,
there is a How of saliva from the fistula, whereas the note C;is heard without producing
any response. Such an acquired reaction is designated by Pawlow, a 'conditioned
reflex ' and the method has been applied by him to study the association between the
most widely different impressions and the condition which we can regard as appetite
and which is associated psychically with the idea of food.
THE FUNCTION OF SPEECH
The acts of a conscious individual, i.e.one possessing cerebral hemispheres,
are determined by Ins experience. The wider the range of past sense
impressions which can be called up and taken into the chain of processes
involved in any reaction — the more, that is to say, the individual weighs hi.s
acts in the light of past experience — the more fitted will these acts be to his
maintenance amid the ever-changing stresses of the environment. In this
guiding of behaviour by experience man, as well as the higher mammals, may
profit also from accumulated racial experience. The increased complexity
of the neural processes concerned in every reaction of the body, anil the
excessive ' lost time ' brought about by the intercalation of one neuron after
another in the chain of the excitatory process, would finally counteract the
advantages derived from the growth in complexity of the brain, were it not
I.'.l PHYSIOLOGY
that, as a result of education or training, short cuts are laid down, by means
of which reactions adapted to the maintenance of the individual can be carried
out immediately, without thought and without correlated calling up of
numberless sense impressions. Education in fact consists in laying down
these ' short cuts ' which, as habits, are the basis of the behaviour of the
animal. The more complex the central mechanism and the wider the range
of environmental change to which adaptation is necessary, the longer must be
the time involved in this process of road-making within the cerebral hemi-
spheres. The behaviour of man is therefore a product of many years'
training, during which time he is in a state of subjection and unfit, from
the absence of habit, to maintain himself as a unit in the human com-
munity. The neural short cuts of habit are however of advantage to the
individual only in dealing with those events which are of everyday occur-
rence. Every novel circumstance must involve a revival of past sense
impressions and a calling up of activities of the most diverse portions
of the brain in order to arrive at the safest or most advantageous mode
of action adapted to the circumstances. Here again the complexity of
the process would, by the very delay involved, put a stop to a further
rise in intellectual, i.e. associative, capacities, were it not for the invention
of Speech.
In speech we have a symbolism which acts as an economy of thought or of
cerebral activities. An object, such as a table, with its associated properties
of colour, consistence, spatial extension, and resistance, with the connoted
acts associated with its use, can now be evoked as a word, involving com-
paratively simple auditory and motor processes, which itself may be em-
ployed as a unit of thought and brought into connexion with other words,
each of which in the same way is the symbol for a whole series of sensory and
motor processes. The training of the cultivated man consists in a constant
extension of the range of this symbolism, and the acquisition of words
including wider and wider groups of neural processes, so that finally we arrive
at those short verbal collections which, as the so-called natural laics, sum-
marize the experience not only of the individual but such as is common to the
whole race of mankind. All science may in fact be regarded as an extension
of the process of representation of neural experience in symbolic shorthand,
which in the child begins with the utterance of such a simple word as
' mamma,' and from which speech has arisen. A study of the nervous
mechanisms involved in speech is therefore of interest in its relations to t V e
development of the intelligence, and heljis us to realize more completely the
conditions which determine the activity and functioning of the cerebral
hemispheres. Much light is thrown upon this mechanism by the study of
disorders in man grouped together under the name Aphasia.
It has been usual to divide the disorders of speech known as aphasia into
various groups, as follows :
(1) Motor aphasia, or aphasia of Broca. In this condition, which was de-
scribed fully by Broca and referred by him to a lesion of the third left frontal
convoluti Hi, the patient is unable to speak, although he understands what is
FUNCTIONS OF THE CEREBRAL HEMISPHERES 155
said to him and lias been stated to suffer from no impairment of his intelli-
gence.
(2) Sensory aphasia, or aphasia of Wernicke. This condition was con-
nected by Wernicke with the existence of lesions in a fairly -wide area, known
as the area of Wernicke, which involves the supramarginal and angular gyri
and the hinder portions of the first and second temporo-sphenoidal convo-
lutions. In these cases there may be limited power of speech, but there
is serious impairment of the intelligence and especially of the power of
appreciation of spoken words, so that the patient does not understand what
is said to him. This condition may or may not be attended with alexia, loss
of power to read. Any impairment of the motor processes of speech which
is present is due rather to the inability of the patient to appreciate what
he himself is saying, so that there is here a species of sensory paralysis
in the higher sphere of neural processes.
(3) Anarthria. This is a condition in which there is marked impairment
of the motor powers of expression, although intelligence and appreciation of
speech, both spoken and written, may be unaltered. This condition is
generally associated with lesion of the white matter of the external capsule
as it passes round the lenticular nucleus.
There are however considerable difficulties in the acceptation of this
traditional classification. Microscopic examination of Broca's convolution
shows a type of cortex entirely different from that part, viz. the psycho-
motor area of the ascending frontal convolution, which is concerned with
the higher cerebral processes resulting in movement. Its structure is in fact
identical with that described by Campbell as the ' intermediate precentral
area ' and regarded as characteristic of the association areas. Moreover it is
difficult to comprehend how a function such as speech, with its enormously
complex mechanism, could be limited to so small a portion of the brain as
Broca's convolution. The neural basis of language must in fact be co-
extensive with the sensory centres (the projection spheres) and with the
whole region of lower association. AVe might indeed speak of auditory and
visual word-centres as located in the visuo-psvehie and auditory psychic
i-entres. There is probably however no word, still less a collection of words,
expressing an idea, which does not involve the activity of practically all parts
of the cerebral cortex. As Bolton* points out, " a word, such as ' mouse,' at
once sets in effect processes of association which puss to every projection
sphere with the solitary exception of the gustatory, and even this may be
aroused in a person who has eaten a fried mouse in the hope of thereby
recovering from an attack of whooping-cough."
A careful examination of an extensive series of cases by Marie has shown,
in fact, that Broca's aphasia does not exist as a result of lesions of Broca's
convolution. This part of the brain may be destri >yed without anj 7 disorder
of speech. The cases described by Broca of motor aphasia are really cases of
sensory aphasia from lesion of Wernicke's area, combined with anarthria due
to subcortical injury of the fibres of the external capsule. The statement
* In his admirable article in Hill's "Further Advances in Physiology."
156
piivsioi.ocv
that there is no loss of intelligence in these cases of so-called motor aphasia
does not bear invesfigation. Although as patients they may comport
themselves reasonably, as soon as they have to performany duties which
have been learnt by them in connexion with their ordinary avocations
they show their deficiency. They are incapable of transacting ordinary busi-
(i)
(2)
W
(5)
Pig. 2:{."j. Types of lesions giving rise to deficient intellectual power, [n amentia,
the deficiency is due to failure of development; in dementia, to atrophy of
the cells (especially small pyramidal) previously present in the cortex. (Mott.)
ness. at any rate to the extent to which they were before the lesion. The
amount of impairment of intelligence will vary in different cases according
to the extent of the lesion. Thus softening affecting the occipital lobe
may, with hemianopia, cause ' word-blindness' or alexia, a loss of power
of appreciating the meaning of written words. In most individuals, and
certainly in the uneducated, this power may he cut out altogether without
interfering considerably with the mental powers. On the other hand,
from babyhood upwards we have learnt the meaning of words and their
FUNCTIONS OF THE CEREBRAL HEMISPHERES 457
grouping by auditory impressions. If the whole of the auditory associa-
tions be destroyed by an extensive lesion in the first and second temporal
convolutions, the resulting loss of word appreciation, sensory aphasia, will
be attended with great diminution of mental powers. It must be remem-
bered that the area of Wernicke is not a sensory centre, but a centre of
association between the various sense-impressions, especially I hose of
hearing and sight. It may therefore be spoken of as an intellectual centre.
Pure muter aphasia of course exists, but is always anarthria and is due to a
lesion in the lenticular zone. i.e. in the lenticular nucleus and its neighbour-
hood, in the anterior part and the genu of the internal capsule, and possibly
in the external capsule.
It is important to make a distinction between loss of sanity and loss
of intellectual powers. The essential factor of sensory aphasia is the exist-
ence of intellectual impairment, though in his behaviour the patient may
appear perfectly uormal. On the other hand, in insanity there may he
perfect retention of the intellectual processes, which depend on the proper
working ol' the lower association centres. The personality of the individual,
and therefore anally his behaviour, involves a further association on a higher
plane of these intellectual processes and therefore control in accordance with
the relation, past, present, or future, of the individual to his environment.
The prefrontal region is in all probability the seat of this highest plane of
association. Insanity always involves alteration of personality and depends
on failure of development or on disintegration processes (subevolution or
dissolution of this region) (Fig. 235). In monkeys and cats Franz has found
that destruction of the frontal lobes causes a loss of recently formed habits.
He concludes from his experiments that the frontal lobes are the means by
which we are able to learn and to form habits, i.e. to regulate our behaviour
in accordance with the needs of our position in society.
THE TIME RELATIONS OF CENTRAL NEURAL REACTIONS
In the spinal animal a stimulus of any particular quality and localisation
always evokes an appropriate reaction. A certain period of time necessarily
elapses between the moment at which the stimulus is applied and the moment
at which the resulting reaction takes place. This interval is spoken of as
the simple reaction time, and in the spinal animal is entirely independent
of consciousness. .Many reactions, even in the intact animal, are also, as we
may say, involuntary and are not modified perceptibly by our consciousness
of their occurrence: such reflexes as the withdrawal of the hand when it
conies 111 contact with a hot surface, the shutting of the eyelid when the con
junctiva is touched, the drawing up of the leg when the sole of the foot is
tickled. Not only are these carried ou1 in the absence of voluntary impulses,
but in many cases it is almost, if not quite, impossible to check the reaction
by any etiorl of the will.
When the leg is drawn up in response to a painful or nocuous stimulus
applied to the foot, a certain amount of time is involved in each of the
following links in the chain of processes which determine the reaction ;
158
I'JIYSIOLOCY
(1) The conversion in the peripheral sense organ of the mechanical
stimulus into a nerve process.
(2) The passage of a nerve impulse up the nerve from the end organ to the
spinal cord.
(3) The passage of the impulse across two or more synapses in the grey
matter of the cord.
(4) The passage of the impulse down the motor nerve fibres From the
spinal curd to the muscles.
Fia. 236. Arrangement of apparatus for determination of reaction time.
(Alcock and Ellison.)
r, coil; E, exciting electrodes ; F, tuning-fork ; a, b, keys ; s, t, electro-
magnetic signals ; D, drum.
(5) The processes occurring in the end organs of the muscle.
(6) The latent period in the muscle fibre itself.
With a weak stimulus No. I is impossible to measure. With a strong
stimulus it may he so short as to be practically negligible. (2), (4), (5)
and (6) represent quantities for the measurement of which we have all the
necessary data.
In any given reflex therefore we may add these periods together and
subtract them from the total reaction time ; we thus get a ' reduced re-
action time,' which represents the time involved in the passage of the impulse
through the central nervous system, and in the conversion of an afferent
impulse into an aggregate of co-ordinated motor impulse's. It is found
that the reduced reaction time accounts for the greater part of the total
reaction time. Since we have no reason to assume that the rate of passage of
an impulse through the intra-spinal course of a nerve fibre differs appreciably
from the rate at which it is conducted by the same nerve fibre outside the
FUNCTIONS OF THE CEREBRAL HEMISPHERES 159
cord, the extra delay which occurs in the passage of the impulse through the
cord must take place either in the nerve cells themselves, or in the synapses,
through which the impulse passes from one neuron to the next in the chain of
reflex elements.
The rate of passage of an impulse through the nerve cell can be deter-
mined only in one part of the body, viz. in the posterior spinal root ganglia,
since only in these is it possible to detect the moment of passage of an im-
pulse across a given section of a nerve fibre on both sides of the ganglion cell
in which the nerve fibres arise. Experiments on this jjoint have been made
by Steinach and by Moore. In each case the time occupied in the passage
of the impulse through the ganglion was not appreciably longer than if the
impulse had passed through a corresponding stretch of uninterrupted nerve
fibre. We are therefore justified in concluding that the relatively great
delay in the passage of an impulse through the central nervous system has
its seat in the synapses across which the impulse has to pass. This con-
clusion is in accordance with our experience on the latent period of muscle,
the greater part of which is due to changes occurring in the nerve endings,
i.e. in the synapses between motor nerve and muscle. The greater the
number of synapses involved in any given reaction, i.e. the greater the coin
plexily of the reaction, the longer will be the period which elapses between
the moment of application of the stimulus and the moment at which the
response takes place. Especially is this the case when the complex mesh-
work of neurons of the cerebral hemispheres is involved, or when the occur-
rence of the reaction is associated with the conscious processes of sensation
and volition. In the latter case the determination of the reaction time has
the added interest that it gives information as to the time relations of the
psychical processes which are the representation in consciousness of the
physiological changes occurring in the neurons of the central nervous
system.
Many methods an- employed fur the measuring of the reaction linn- oi conscious
processes. In most methods the application of the stimulus is arranged mi as in close
the circuit of a currenf which flows through an electro magnel ai tivath e a [ever which
writes nil a rapidlj moving blackened surface 1 . The reaction of the individual who
is flu- subject of experiment is arranged si. that tin- resulting movement activates a
key by which the same current is opened. We thus obtain a tracing on flic blackened
surface showing the moment of application of tin- stimulus and the moment at « hich the
reaction takes place. Thus, if tin- reaction tune for an auditory stimulus is to he
determined, flu- electric current is arranged so as to pass through:
(1) A spring contact key which can be pressed so as to make a noise.
(2) An electric signal writing on a rapidly moving surfai e.
(3) A second key which the subject will release as sunn as he hears the imise of
the first key and so break the current.
The recording surface may he a drum, a pendulum myograph, or a spring myograph,
such as the 'shooter' of du Bois-Reymond. If the sensory impression is to be from
the skin, the current may be made to pass through the primary coil of an inductorium
and wires be taken from the second coil to some part of the surface of the skin. In
this ease the signal may be started by opening the circuit, and the subject of the experi-
ment will respond by closing the circuit by means of a spring key directly be feels
MO PHYSIOLOGY
tin- shook caused by the break of the primary circuit. If the reaction period is to be
determined for sight, a white piece of paper may be placed on an electro-magnet in the
primary circuil and the person will respond directly lie- sees this move. Many other
instruments have been devised for the same purpose.
The average reaction limes obtained with the different senses arc as
follows:
Electrical
Sighl Hearing. Stimulation of Skin.
0-186 to 0-222 see. 0-115 to 0-182 see. 0-117 to 0-201 see.
The t w ci figures given for each ease are the extremes obtained in different
series of observations.
The times vary according to the condition of the person that is the subject
of the experiment. They are lengthened by fatigue; they are shortened
up to a certain point by continued practice. Within limits also they are
shortened by increase of the strength of the stimulus.
DILEMMA. When the subject has to make a deliberate choice between
the parts of the body stimulated, the reaction time is considerably Longer.
To show this, the wires from the secondary coil are connected by a switch
to two pairs of electrodes which are applied, one to the right and one to the
left half of the body. It is agreed beforehand that the subject shall react
only to stimulation, say, of the right side. The switch is removed from
the observation of the subject and the stimulus is applied irregularly t e
side or to the other. It is found that the additional neural processes
involved in determining whether the stimulus is on the right side, and there-
fore should be followed up as agreed, adds considerably to the length of the
reaction time (on an average -006 sec). It is possible to complicate the
dilemma to almost any extent. Thus the experiment may be so arranged
that either a red or a white disc appears and the subject lias to react with
the right hand to the red disc and with the left hand to the white disc. In
such an experiment the reaction time was found to be be 0-131 sec. longer than
the simple reaction time. A still more complex process would be involved
in the experiment in which a word was spoken, and the subject had to speak
some other word which had some association with the word which formed the
stimulus, e.g. horse — mammal : paper pen, &c In such an experiment
the reaction time was found to be as long as 0-7 to IKS sec.
We see that the recording of the time of occurrence of any physical event
can. occur only after a certain lost time, which represents the observer's
reaction time for the stimulus in question. This applies however only
to movements carried out in response to single stimuli or to stimuli repeated
at irregular intervals. When the stimuli are rhythmic the lost time applies
only to the first one or two of the stimuli. The observer or subject is
conscious of the interval elapsing between the physical event and his react ion.
and anticipates the later stimuli so that his reaction becomes synchronous
with the stimulus. This synchronism of stimulus and reaction characterises
all rhythmic movements, such as dancing or the playing of an orchestra in
time with tin' beat of the conductor's baton.
SECTION Will
THE NUTRITIVE AND VASCULAR ARRANGEMENT
OF THE CENTRAL NERVOUS SYSTEM
The brain and spinal cord arc enclosed within three membranes or meninges,
named from without inwards, the dura mater, the arachnoid membrane]
and the pia mater. The dura mater consists of a strong fibrous membrane,
smooth and lined with endothelial cells on its inner surface. In the head
its outer surface is closely attached to the bones forming the cranium, of
which it represents the periosteum. Strong fibrous partitions are sent from
the dura mater into the cavity of the cranium to support the chief parts
of the brain. One of these, the falx cerebri, supports the two cerebral hemi-
spheres ; a second, the tentorium cerebelli, forms a horizontal division between
the cerebral hemispheres and the cerebrum; and a smaller one. the falx
cerebelli, passes ,i short distance inwards between the cerebellar hemispheres.
In the spinal canal the bones have their own periosteum, and the dura mater,
which is closely attached round the margins of the magnus, forms a loose
sheath round the spinal cord, being slung up in the vertebral canal by the
tubular prolongations which it sends along each nerve root to form the outer
sheath of the nerve. The dura mater in the cranium may be separated
with greater or less difficulty into two layers, and between these two layers
are found the venous sinuses, which receive the whole of the blood returned
from the brain. These venous sinuses are angular clefts, the chief of which
lie along the attached margin of the falx cerebri and the tentorium cerebelli.
Most of the blood leaves the skull by the internal jugular veins. In the
spinal cord the place of these venous sinuses is taken by a plexus of thin-
walled veins, imbedded in fat, lying on the outside of the dura. Under tin 1
dura mater we find the subdural space, which is rather potential than actual.
It can be regarded as a large lymph space and any contents are drained
off into the lymph spaces of the nerve roots and adjoining tissues.
The arachnoid is a delicate transparent membrane which covers I he whole
of the brain and spinal cord. Superficially it presents a layer of
endothelial cells which bound the subdural space. On its deep surface it is
connected with the pia mater by fine fibres. It bridges over the inequalities
in the surface of the brain so that in various localities a space is left which is
filled with cerebro-spinal fluid and is known as the subarachnoid space.
In certain situations it sends prolongations into the fissures of the brain.
Thus a marked expansion passes by the transverse fissure between the
cerebral hemispheres and the third ventricle, sending prolongations into the
461
162 PHYSIOLOGY
lateral ventricles. This layer of connective tissue is covered on one surface
by the ependyma of the ventricles, on the other surface by the ependyma
forming the roof of the third ventricle. It carries a rich plexus of blood
vessels known as the choroid plexus, and the ependyma covering the vascular
fringes which dip into the cerebral ventricles consist of clear columnar or
cubical cells, often spoken of as the epithelium of the choroid plexus.
Similar vascular fringes are found in the roof of the fourth ventricle.
The pia mater is a layer of connective tissue which serves to carry the
blood-supply to the whole surface of the brain. It is closely applied to the
surface and follows all the irregularities of the latter, dipping down into the
various fissures and crevices on the brain. In the spinal canal the pia mater
sends out a series of processes on each side of the spinal cord, the ligamentum
denticulatum, the outer extremities of which are attached to the dura
mater and serve to sling the spinal cord in its dural sheath.
The brain is richly supplied with blood. Its chief supply is derived from
the two carotids and the two vertebral arteries. The vertebrals unite on
the lower surface of the bulb to form the basilar artery, which divides again
at the anterior extremity of the pons varolii into two branches which unite
with the two carotid arteries to form the circle of Willis, so that the pressure
in this arterial circle can be maintained indifferently by any three out of the
four arteries by which it is supplied. From these vessels three main arteries,
the anterior, middle and posterior cerebral, pass up to supply the correspond-
ing regions of the outer surface of the brain, while the inner parts of the
brain, e.g. the corpus striatum, optic thalamus, &c, are supplied from
arteries arising from the circle of Willis and passing straight into the sub-
stance of the brain. The connection between the vascular supply of the
different parts of the brain is slight and effected only by the capillaries ;
hence obstruction of any one vessel, such as the middle cerebral, perma-
nently cuts off the blood supply to the greater part of the area supplied 'by
it and the result is death and softening of the brain substance. The arteries
supplying the surface of the brain divide up into arterioles and capillaries
within the pia mater, and the capillaries run into the brain substance sur-
rounded by a so-called lymphatic sheath, which apparently communicates
with the subarachnoid space.
In certain cases of disease these perivascular sheaths may be found to
contain leucocytes often filled with products of disintegration of the nervous
tissues.
THE CEREBRO-SPINAL FLUID
The subarachnoid space contains a thin transparent colourless fluid,
known as the cerebro-spinal fluid. In composition this fluid resembles
blood plasma minus its protein constituents. It contains a mere trace of
coagulable proteins but it has the same molecular concentration as the blood
plasnia and its salts are identical with those of the blood plasma. It also
contains other diffusible constituents of blood plasma, e.g. small traces of
sugar and of urea. It may be collected by introducing a cannula through the
THE CENTRAL NERVOl JS SYSTEM 463
atlanto-occipital membrane into the ample subarachnoid space lying over
the fourth ventricle. Another method is to introduce a glass cannula through
a slit in the sheath of a nerve root up into the subarachnoid cavity of the
spinal canal. In man it may be obtained in small quantifies for examination
by introducing a hollow needle directly into the spinal canal in the lumbar
region between the laminae of the vertebrae. On introducing a cannula
into the subarachnoid space, the fluid may spurt out, showing that it is under
a, certain pressure (about 100 mm. H 2 0). After the first rush the fluid begins
to drop away, at first rapidly, but more slowly with lapse of time. If
the fluid be allowed to drain off for some hours, signs of interference with the
functions of the central nervous system are evinced. The cerebrospinal
fluid appears to be formed chiefly in the neighbourhood of the choroid plexus.
Although its composition would suggest that it was merely a transudation
from the blood, the amount formed does not seem to run parallel with the
pressure in the capillaries of the brain. Moreover, it has been shown by
Dixon and Halliburton that a considerable increase in the flow of cerebro-
spinal fluid may be brought about by injecting an extract of the choroid
plexus itself. It has therefore been concluded that this fluid is really a
secretion by the modified ependyma cells covering the fringes of the choroid
plexus.
Although the method of formation of i\iv cerebro-spinal fluid is still not
clear, there is no question that its removal from the subarachnoid space is
brought about by simple physical factors. The subarachnoid space com-
municates with the ventricles by means of openings in the roof of the fourth
ventricle. The pressure of the fluid is ordinarily about equal to the pressure
in the venous sinuses of the cranium. If salt solution be injected into t lie
subarachnoid space, it escapes with extreme ease, and it is found that its
channel of escape is into the veins and especially into the venous sinuses of
the dura mater. Its removal by these sinuses is facilitated by the existence
of peculiar structures, known as the Pacchionian bodies. Each of these
bodies is a bulbous protrusion of the arachnoid membrane into a blood
sinus. It remains connected with the arachnoid by a narrow pedicle,
through which a continuation of the sub-arachnoid space is prolonged into
the interior of the sinus. It is therefore a little sac of arachnoid membrane
separated from the blood stream only by an invagination of the endothelium
linin g the sinus. Filtration of the cerebro-spinal fluid will occur into the
venous sinuses whenever (he pressure of the fluid rises above that ol the
blood in the sinus. The fluid can also escape, but with greater difficulty,
along the sheaths of the spinal nerve roots, by which it will pass into the
lymphatics outside the spinal canal.
THE NUTRITION OF THE BRAIN
The grey matter of the brain is very richly supplied with blood
vessels. Any interference with the blood flow through the brain rapidly
checks the functions of the central nervous system in consequence of
Kil PHYSIOLOGY
deprivation of oxygen. Although so susceptible to slighl deprivation
(il oxygenil doesnotseem thai the brain tissues have a verj rapid gaseous
metabolism ; thai is. they need oxygen supply at high tension bu1 do
mil deprive the blood ol any very large amount of the oxygen which il con-
tains. Nor does it seem probable thai the brain requires a large supply
of I I material. It must be remembered thai in all parts of the brain
a peri-vascular lymphatic intervenes between the capillary and the brain
tissue. Since these 'lymphatics' communicate with the subarachnoid
space, they must contain a fluid which differs little if at all from the compo-
sition of the cerebrospinal fluid obtained from the subarachnoid space. 'I tie
iniiiieiit fluid of the brain is therefore practically salt solution with a trace
of sugar and possibly minute traces of amino acids.
Our study of the events which accompany the propagation of a nervous
impulse down a nerve fibre has prepared us for the conclusion that very little
energy is involved in ordinary nerve activity. It is true that extreme fatigue
causes changes in the Nissl granules of the nerve cells and is therefore asso-
ciated with the using up of some material constituent. But even though
material changes in the nerve cells and in the synapses may be larger in
amount than those in nerve fibres, they arc probably not to be compared
in extent wit h those taking place in a cunt railing muscle or in an active liver
THE CEREBRAL CIRCULATION
In all higher animals the brain is enclosed in a rigid ca- e formed by the
bony cranium. In the child, before the crania! vault is fully ossified, pari
of this vault consists of membrane, known as the anterior fontanelle. It
is easy to see that the fontanelle pulsates with each beart-beal as well
as with rise of venous pressure, such as that produced during strong expira-
tory efforts. -When ossification is complete, such alterations in the volume
of the cranial i ontents are impossible. And vet the pressure in the arteries
within the cranium must be still pulsatile, the rise of pressure a1 each heart-
beat must make the arteries expand, hut room for this expansion has to
be found by contraction of some other part of the cranial contents. We
find that each arterial beat is associated with a corresponding expulsion
of some of the contents of the veins and a contraction of these vessels. If,
lor instance, a cannula be introduced through the occipital bom' into the
torcular Herophili, the venou blood is -ecu to pulsate and to be pressed ou1
with each beat of the heart. II there is a rise of arterial pressure, although
the arteries may expand somewhat at the expense of the veins, there can be
no dilatation of the whole organ. The only effect of the rise oi pressure
will be to cause an increased pressure fall in the cranial vascular system, and
therefore augmented velocity of flow through the system. A prolonged rise
of pressure may cause a certain amount of dilatation of the vessels, but only
at the. expense of the cerebrospinal fluid. Since this is only small in amount,
any expansion of the brain due to vascular causes must be very limited.
BRAIN PRESSURE. II bv means of a trephine an opening be made into
THE CENTKAL NERVOUS SYSTEM 465
the cranial vault, the brain bulges into the opening. By screwing a tube
covered with a membrane into the trephine opening, we can find the pressure
necessary to force the brain back to its previous position. This is known
as the brain pressure, and is approximately equal, as might be expected, to the
cerebro-spinal pressure and to the pressure in the venous sinuses. It is
closely dependent on the latter. Forced expiratory efforts, such as may
occur in the convulsions of strychnine poisoning, may raise the pressure from
30 to 50 mm. Hg. In the vertical position in man, the pressure may be
slightly negative in consequence of the tendency of the venous blood to run
downwards towards the heart.
REGULATION OF THE BLOOD SUPPLY TO THE BRAIN
Xo satisfactory evidence has been brought forward of the existence of
vaso-motor nerves controlling the calibre of the cerebral blood vessels. Nor
indeed are such nerves necessary. The brain, as the master tissue of the
body, controls through the medullary centres the circulation through all
other parts of the body. It is therefore able to regulate the blood supply
through its arteries by allowing less or more blood to pass through other parts
of the body. For the exercise of its normal functions it requires a certain
blood supply, which again will depend simply on the pressure in the carotid
arteries and circle of Willis. If this pressure fails, the functions of the
brain are affected and loss of consciousness rapidly ensues. This is what
occurs when a person who is weak from long illness faints on suddenly getting
up from bed. In the normal individual the change in the circulation with
alteration of bodily position, which would be produced by the action of
gravity, is at once counteracted through the vaso-motor system. The
(splanchnic area is contracted or dilated according to the necessities of the case,
but the pressure in the carotid and the circulation of the brain remains unal-
tered. Even when the heart in consequence of disease is scarcely able to carry
on the circulation, the arterial pressure undergoes little or no alteration.
Any other tissue of the body, even the heart itself, may suffer, but the brain
at all costs must receive its proper supply of blood.
30
SECTION XIX
THE VISCERAL OR AUTONOMIC NERVOUS SYSTEM
In the medulla oblongata it is easy to differentiate the central grey matter
connected with the peripheral nerves into two categories, viz. splanchnic
and somatic. Each of these two sets of nerves jrossesses both afferent and
efferent fibres. Gaskell has suggested that the same arrangement would hold
for any typical segmental nerve, which would therefore have four roots, viz.
two somatic — the motor and sensory roots distributed to the skin and
skeletal muscles — and two splanchnic roots, also motor and sensory, and
composed of small fibres distributed to the viscera or structures which are
visceral in origin (e.g. developed from the branchial arches). In the medulla
the somatic efferent fibres, such as the sixth and twelfth nerves, arise from the
column of large cells lying in the floor of the fourth ventricle close to the
middle line. The splanchnic fibres, e.g. those of the facial and vagoglosso-
pharyngeal nerves, arise from a column of cells — the nucleus ambiguus and
facial nucleus, lying more laterally and deeper, below the surface of the
ventricle. The motor root of the fifth would also belong to the same system.
In the spinal cord the visceral fibres arise in the cells of the lateral horn. i.e.
from a situation corresponding to the splanchnic motor nuclei of the pons
and medulla. Whereas however the splanchnic afferent nerves, such as the
glossopharyngeal, and perhaps the sensory nucleus of the fifth, form a well-
marked splanchnic system of nuclei in the medulla, in the cord the afferent
fibres from the viscera pass in with the other afferent somatic fibres, and their
immediate connections in the cord are as yet unknown.
The autonomic system of nerves include, the sympathetic system
(properly so called) and some of the cranial and sacral nerves. The sym-
pathetic system (Fig. 237; is composed of a chain of ganglia lying each side
of the vertebral column, there being as a rule one ganglion to each spinal
nerve root. In the cervical region these ganglia are condensed into two,
the superior and inferior cervical ganglia, united by the cervical sympa-
thetic trunk ; and the upper three or four thoracic ganglia on each side are
condensed to form the ' stellate ' ganglion. At the bottom of the chain
there is only one coccygeal ganglion for the coccygeal vertebrae.
In the abdomen is a second system of ganglia, in special connection
with the abdominal viscera, lying in front of the aorta and surrounding the
origins of the large arteries to the alimentary canal. These are the semi-
lunar or solar ganglia, the superior mesenteric and the inferior mesenteric
ganglia.
466
THE AUTONOMIC NERVOUS SYSTEM
467
Sup cerv. g .-
inf cerv.g.^
> Head & Neck
Abdominal
Viscera
Hypogastric n ' ppJvmcn
Fig. 237. Diagrammatic representation of the distribution of the sympathetic system.
The black lines represent the medullated pre-ganglionic fibres, such as those making
up the white rami communicantes, while the post-ganglionic fibres are printed in red.
On the extreme right of the figure is indicated the general distribution of the white rami
arising from the several nerve roots, while the double brackets point to the nerve
roots making up the limb plexuses. H, heart : s. stomach ; i. small intestine ; c, colon ;
B. bladder.
468 PHYSIOLOGY
In the organs themselves we find a third system of ganglion cells, cither
scattered or collected to form small ganglia. These isolated ganglion cells
as a rule have no connection with the fibres of the sympathetic system, but,
as we shall see later, lie on the course of the impulses descending by other
nerves of the autonomic system, e.g. the vagus or the pelvic visceral nerves.
The three systems of ganglia have been distinguished as the lateral, collateral,
and terminal ganglia.
Fig. 238. Diagram of spinal segment with its nerve
roots, somatic and visceral. (G. D. Thane.;
(The visceral roots are represented in red.)
The ganglia of the sympathetic chain are connected with all the spinal
nerves, just after they have given off their posterior divisions, by means of the
rami communicantes. These rami communicantes are of two kinds : white
rami consisting of small medullated fibres, and grey rami composed almost
exclusively of non-medullated nerves. It has been shown by Gaskell that
the white rami are formed by fibres which have their origin in the spinal cord
and perhaps in the posterior root ganglia ; whereas the grey rami represent
fibres which, arising in the sympathetic ganglia, run back to join the spinal
nerves. The visceral outflow represented by the white rami is limited to a
distinct region of the cord, viz. from the first thoracic to the third or fourth
lumbar nerve roots ; whereas the grey rami pass from the sympathetic
to all the spinal nerve roots. It is found by experiment that stimulation of a
limited number of white rami produces all the effects that can be evoked by
stimulation of the grey rami, showing that the impulses leaving the cord pass
upwards and downwards in the sympathetic system and are broken some-
where in their course, being transferred to a fresh relay which, by means of
non-medullated nerves, carries them on to their destination.
Finally, in certain organs of the body are to be found sheets of nerve
structures, including both ganglion cells and fibres, which must be regarded
as local nerve centres, capable of carrying out co-ordinated acts in response
to stimuli, independently of the central nervous system. It seems probable
that these systems are to be regarded as analogous rather to the diffuse neuro-
fibrillar system of an animal, such as the medusa, than to the synaptic ner-
vous structures characteristic of the central nervous system of vertebrates.
THE AUTONOMIC NERVOUS SYSTEM
469
In the latter the direction and effect of any impulses are determined by the
synapses intervening between various systems of neurons and allowing the
passage of the impulse only in one direction. This law of forward direction
has not been proved to hold good for the primitive nerve systems ; an
impulse apparently spreads equally well in either direction. As a type of this
peripheral diffuse nerve system may be cited the Auerbaeh/s and Meissner's
plexuses in the wall of alimentary canal. How far we are to regard the
nerve nets in other viscera, such as the heart and the bladder, as conforming
to this type is still a moot point, and will be discussed in dealing with the
origin of the heart beat.
Posc'root-,
Ant/ root
Made-up ' spinal nerve '
-Pre -ganglionic fibre
- -Symp. gangl
Post-gangliomc fibre
Fig. 230. Diagram (after LanoLET) to show the manner in which a spinal nerve is
completed by the. entry of a grey ramus, containing fibres derived from cells in
the sympathetic chain.
p.pr.d, posterior primary division. (The post -ganglionic fibres are represented red.)
The relationships of the white and grey rami are strikingly illustrated
in the case of the pilomotor systems of nerves. These in the cat arise from
the cord by the anterior roots from the fourth thoracic to the third lumbar
inclusive. Passing by the white rami to the sympathetic system, they
travel upwards and downwards and end by arborisations in the various
ganglia of the main chain. From the cells of each ganglion a fresh relay i ti
fibres starts, which runs as a bundle of non-medullated nerves (the grey
ramus) to the corresponding spinal nerve, with which it is distributed to
its peripheral destination. Each grey ramus causes erection of the hairs
above one vertebra, whereas stimulation of one white ramus causes erection
over three or four vertebrae, showing a distribution of the fibres of the white
ramus to the cells in several successive ganglia.
These pilomotor fibres in the cat have the following distribution :
( 1 ) For the head and upper part of the neck the fibres arise by the fourth
170 PHYSIOLOGY
to the seventh thoracic anterior roots, and have their cell stations in the
superior cervical ganglion. They travel as small medulla ted nerve fibres
from the white rami up the sympathetic chain, through the stellate ganglion
and ansa Vieussenii and up the cervical sympathetic.
(2) The next set of nerve fibres have their cell station in the stellate
ganglion. The white rami arise from the fifth to the eighth thoracic nerves,
while the grey rami pass to the nerve roots from the third cervical nerve
to the fourth thoracic nerve.
(3) The remaining nerves, supplying all the rest of the body and tail, arise
by the white rami from the seventh thoracic to the third or fourth lumbar
nerve, and are distributed as grey rami to all the spinal nerves below
the fourth thoracic.
We thus see that, in speaking of the functions of a spinal nerve root, we
must clearly distinguish whether we mean the root as it arises from the
spinal cord, in which case its visceral functions will include those of its white
ramus, or whether we mean the made-up or complete spinal nerve after it has
received its grey ramus (Fig. 239). In the latter case the visceral functions
of the root will be more restricted than in the former case, and will have a
different distribution. In stimulating the nerve roots in the spinal canal
it is sometimes possible, by weak stimuli, to display the functions of the
corresponding white ramus, and then by increasing the stimidus to get
superadded the effects due to the excitation of the grey ramus in the made-up
nerve, in consequence of the spread of current.
" When, for example, the eleventh thoracic anterior roots are stimulated in the
spinal canal with weak shocks, a fairly long strip of hairs in the lumbar region will
be erected, the maximum movement of the hairs being near the middle of the strip.
This marks the area of distribution of the pilomotor nerves given by the eleventh thoracic
nerve to the sympathetic. If then the strength of the shock be increased to a certain
point, the hairs in the long strip will of course be erected as before, but in addition
there will be energetic erection of hairs in a short strip a little distance above the long
strip, and separated from it by a quiescent region. This short strip is the same as that
affected by stimulating the grey ramus or the dorsal cutaneous branch of the eleventh
thoracic nerve. It marks the area of distribution of the pilomotor fibres received
by the spinal nerve from the sympathetic." (Langley.)
We may now indicate briefly the main course and functions of the fibres
of the sympathetic system.
(1) The head and neck are supplied by fibres leaving the spinal cord
by the first five dorsal nerves (chiefly by the second and third). They all
have their cell station in the superior cervical ganglion. They convey :
Vaso-constrictor impulses to the blood vessels.
Dilator fibres to the pupil.
Secretory fibres to the salivary glands and sweat glands.
Vaso-dilator fibres to the lower lip and pharynx (?).
(2) The thoracic viscera (heart and lungs) are supplied by the same five
nerve roots. The cell station of these fibres is however situated in the
stellate ganglion. They convey :
Accelerator or augmentor impulses to the heart.
THE AUTONOMIC NERVOUS SYSTEM
471
(3) The abdominal viscera receive fibres from the lower six dorsal nerves
and the tipper three or four lumbar. Most of these fibres run through the
sympathetic chain without making any connection with the ganglia, and
have their cell stations in the collateral ganglia of the solar plexus, the semi-
lunar and superior mesenteric ganglia. On their way to these ganglia t hex-
form the greater and lesser splanchnic nerves. Their functions are :
Vaso-constrictor for stomach and small intestine, kidney, and spleen.
Probably vaso-dilator for the same viscera.
Inhibitory for both muscular coats of stomach and small intestine.
Motor for ileocolic sphincter.
(1) The pelvic viscera are supplied by the lower dorsal and upper three
or four lumbar nerve roots. These fibres also pass by the main chain to
4 * Spinal cord
Sympathetic chain
- - Soiar ganqlian
Fig. 24H. Figure (after Lw.i ey) to show the probable mode of connection
of the fibres i 10 lb. in order to produce ;i distinct difference
in sensation. In the latter case we should not be able to appreciate any
difference until we had added a pound, i.e. one-tenth of the whole stimulus
to the weight. We can distinguish between 10 oz. and 11 oz., or between
10 lb. and 11 lb., but not between 10 lb. and 10 lb. 1 oz.
Several methods have been proposed for testing the limits of the applica-
bility of this law. Of these the most important are :
(1) The method of minimal difference.
(2) The method of average error.
In the first method we find by trial how much a given stimulus must be
increased in order to evoke an appreciable increase of sensation, and this
determination is made for a number of stimuli of different intensity. In
the second method it is sought to find a strength of stimulus which is just
equal to another stimulus of given intensity. It will be found that errors
will be made on both sides, and the average error is taken as representing
the minimum difference, which is just sufficient to cause a distinct difference
of sensation.
In all sense organs Weber's law is applicable only between limits which
vary with each sense organ, and it does not hold either for very weak or for
very strong stimuli. Within these limits the ratio which an increase of
stimulus must bear to the whole stimulus in order to produce an increase of
sensation may be given approximately as follows for the different sense
organs :
When weights are placed on corresponding points of two sides of the
body, e.q. on the two hands, we can appreciate differences of about one-
third ; if the contrast be successive, i.e. if the weights be placed on the same
spot in succession, we can appreciate differences between one-fourteenth
and one-thirtieth. The range over which this amount of accuracy is attained
extends from 50 to 1000 grammes. In judging of weights with the help of
Fig. 242. Diagram to show relationship between stimulus and sensation.
movement (the method one ordinarily adopts) the limit of accuracy is about
one-twentieth ; for sounds the appreciation of difference amounts to about
one-ninth, The organ which is most susceptible to slight changes of intensity
THE SENSE ORGANS 485
is the eye ; by this organ we can appreciate differences of one one-hundredth
to one one-hundred-and-sixty-seventh in the total illumination.
FECHNER'S LAW gives the result of an attempt to state Weber's law
in mathematical terms. It states that the sensation varies as the natural
logarithm of the stimulus. This relationship is shown diagrammatical]} - in
Fig. 242.
In view of the fact however that Weber's law holds good only between certain
limits, not much practical value can be attached to such a mathematical expression.
Moreover Pechner's calculation is based on the unprovable and unjustifiable assump-
tion that, within the limits of applicability of Weber's law, the smallest appreciable
increase in sensation is always the same, i.e. that the increased sensation which is evoked
by the addition of 6 grammes to a weight of 100 grammes is identical with the increased
sensation called forth by adding 60 grammes to an initial weight of 1000 grammes.
Such an assumption does not, as a matter of fact, agree with our own experience ; and
it is probably premature here, as in many other departments of biology, to attempt
to include the complex of variable phenomena presented by animal functions within
the Procrustean bed of a mathematical formula.
PART II
VISION
By H. Hartridge.
Section 1. — Properties of light, colour, and the spectrum
2. — Orbital cavity and its contents .
3. — Eyeball, its histology. Pupil reflex
4. Nutrition and protection of the eyeball
5. — Optical media of eye, and accommodation .
6. — ( Iptical properties and defects of the eye
7. — Retina, its- histology and physiology .
8. — Response to light and colour
9, — Subjective phenomena of vision .
10.- Defects of vision, and their detection .
] 1 . — Duplex theory and hypotheses of colour vision
12. — Binocular and stereoscopic vision
PAGES
48U
4fl3
500
514
'519
529
540
555
563
577
5s3
588
SECTION I
PHYSICAL PROPERTIES OF LIGHT
Light is a form of energy, and consists of electro-magnetic waves which travel with
greal velocity through the ether. Since we receive light from the stars, we conclude
that the ether permeates the whole of space. We know also from electrical experi-
ments that the. ether also permeates matter. Wo might expect therefore that light
would freely pass through matter, or in other words that all matter would be trans-
|i.i n-nt. This is not the case however, because most forms of matter have the property
of absorbing light energy ; and therefore the jiroperty of transparency is relatively
rare.
LIGHT IS A FORM OF WAVE MOTION. Because of this, one of its char-
acteristic properties is amplitude. But since this depends on the amount of light
energy present, it is equivalent to what is known as intensity. The other characteristic
property of wave motion is wavelength. In the case of ordinary light it is found by
experiment that a whole gamut of waves varying greatly in length is present. Those
falling between certain limits are able to stimulate the eye, and are therefore called
visual rays. These limits are slightly less than 8000 Angstrom units* for the longer
limit and 4000 A.U. for the shorter. Rays whose wavelength falls outside these limits
are invisible to the eye, and are called infra-red rays when they are too long, and
ultra-violet when they are too short. Since the infra-red rays are able to stimulate
the sensory end organs of the skin, which respond to heat, they are also called heat
rays ; while the ultra-violet rays from their ability to perform certain chemical re-
actions, and notably those used in photography, are called actinic rays. There is
however no sharp line of demarcation between the three groups, which the use of
these terms might be thought to imply.
THE SPECTRUM. It is possible by suitable apparatus to cause the constituent
rays in a beam of light to arrange themselves according to their wavelength. When
thus arranged they are said to form a spectrum. The apparatus is therefore called
a spectroscope. The visible lays thus arranged are seen as a coloured band which has
* An Angstrom unit = one ten-millionth of a millimeter.
486
PHYSICAL PROPERTIES OF LIGHT 487
the following appearance. Visibility usually begins at about 8000-7800 A.U., the
rays of longest wavelength being red. As the wavelength becomes shorter the colour
gradually changes to orange, the transition being at 6500 A.U. nearly. From orange
the colour changes to yellow, at 6000 A.U. nearly. From yellow to green at 5500 A.U.,
to blue-green at 5000 A.U., to blue at 4500 A.U., and to violet at 4000 A.U. The
violet extends to 3800 A.U., where visibility ceases. The spectrum exhibits therefore
a gradual change of colour with wavelength. Above the red is the invisible region
ocoupied by the infra-red or heat rays, and below the violet (he invisible ultra-violet
or actinic rays, as explained above.
Tlie colours of tin" spectrum have important properties which form the foundation
of the science of colour mixture. If the spectrum produced from white light is caused
tn fold up again, it is found that white light is reformed. But white light is produced
if certain pairs of colours only are caused to combine in the correct proportion. Thus
red (0562 A.U.) and blue-green (4921 A.U.) when mixed correctly form white light,
so also do yellow (5636 A.U.) and violet (4330 A.U.). Such pairs are called comple-
ments y colours. But sir.ee there is in the spectrum a gradual transition from one
colour to the next, so there are between red and yellow an infinite number of rays
of different wavelength, each of which has its complementary colour, between blue-
green and violet. If therefore from white light we remove one of a pair of complemen-
tary colours the other member of the pair will be left unneutralised, and the light there
fore becomes tinted with its colour. Green rays do not possess a complementary in
the spectrum ; but it is found by experiment that, by combining red ami violet to form
purple, the required colour may be produced. If we include purple with the spectral
colours, we can imagine these colours to form a closed ring. Each colour will then have
its complementary opposite to it.
THE SPECTRUM COLOURS have another important property, for if red and
yellow are caused to combine, they are found to produce orange, the intermediate colour.
If red and green arc mixed, then again the intermediate colour, yellow, may be produced.
It is found that by vary ing tin- intensities of the two components, it is possible to produce
orange, or yellow-green, or in fact any other intermediate colour at will. Careful
experiment slums that the intermediate colour thus formed is no mere approximation
but an exact match. If red and green are thus able to combine to form the intermediate
colour, while led and blue green an complementaries producing white by their mixture,
the question arises as to the elicit produced by mixing red with a colour intermediate
between green and blue green. Experiment shows that a range of colours is produced
containing an amount of white light, which varies with the intensities and wavelengths
i't (he combining colours. Colours diluted with white light are spoken of as unsaturated.
In order that the colours produced by a mixture of red and green rays shall be fully
saturated, and thus be able to match the colours of the spectrum exactly, the green
must not be shorter in wavelength than 5400 A.U. Similar phenomena are to be found
at the oilier end of the spectrum ; green and violet, when mixed in various proportions,
form colours which match the intermediate spectral colours. With red, green and violet,
it is therefore possible to match the whole spectrum. But since red and violet, when
mixed, form the intermediate purples, with the three coloured rays it is possible to
imitate the whole range of colours. Now the purple formed from red and violet is, as we
have seen, the complementary colour to green ; by means of these three colours it is
thus possible to produce white light. It should therefore be possible to match
an unsaturated colour as easily as a saturated one. Experiment, shows thai such is
l he case. The third property beside colour and saturation, is intensity, which depends
on the amplitude of the waves. The intensity of the mixture formed by red, green
and violet, can therefore be readily adjusted by varying the intensity of each of the
three component rays. We may summarise the above facts by stating that by varying
the intensities of the red, green and violet rays it is possible to match every shade and
colour. This statement has been put to the test by Maxwell, Abney and ol her observers,
and has been found to hold good in all cases but one, spectral blue being slightly more
488 PHYSIOLOGY
saturated than the mixture of green and violet. In describing the complementary
pairs of colours, we have mentioned that if the spectral colours are placed in a closed
ring, complementary pairs are found to be opposite to one another. If now the
three fundamental colours are placed at equal intervals round the ring, we may
regard white as occupying the centre, because it is equidistant from the three fundamen-
tals, and at the same time lies on the diameter between the various colours and their
complementaries. If the other spectral colours are arranged in position relatively
to the three fundamentals, they form a figure that in shape resembles a triangle more
closely than it does a ring. This is due to the facts already mentioned (1) with regard
to flic exact matching of the spectral colours between red and green, by mixtures of
those two fundamental colours : (2) with regard to the approximate matching of the
region between green and violet by the mixtures of those colours, and (3) with regard to
the exact matching of mauves and purples by mixtures of red and violet. The colour
triangle which is shown in figure 243 therefore has a purely experimental basis, and
lias no association whatever with theories of vision.
sooo
BLUB GRCEM
KED saoo
Fig. 243. Colour triangle.
The black hue shows the shape of the curve along which the different rays of
the spectrum fall for white to occupy the central position.
THE OPTICAL PROPERTIES OF MATTER
Since matter is permeated by the ether, we should expect matter to be transparent
to light. We find however that all matter absorbs light to a greater or less extent;
even substances that are called transparent, like glass and water, absorb strongly when
in sufficient thickness. Beside substances which may be classed as transparent
or opaque, there is a large class of bodies which reflect light. When the body presents
a smooth surface to the fight rays, the reflected ray forms a compact bundle, and the
surface is therefore said to reflect light. If on the other hand the surface presented
to the light rays is rough, the light bundle is split up into a number of separate units
which scatter diffusely in every direction. Such a surface is therefore said to diffuse or
scatter light. If light is incident on matter, there are thus four different processes t ha t
may occur, viz. the light maybe partiallyabsorbed.it maybe partially transmitted,
it may In- partially reflected and lastly it may be partially scattered. In the great
majority of cases, all these processes take place to a certain extent, and are found to affect
the different parts of the spectrum differently. For example, while the colours of short
wavelength are absorbed, those of long wavelength may be almost completely reflected.
(A polished copper surface is found to have these properties.) Another example would
be a substance which while absorbing colours of long wavelength, scatters almost
PHYSICAL PROPERTIES OP LIGHT 489
completely all colours which belong to the other end of the spectrum. (Basic acetate
of copper, i.e. verdigris, has this property. ) Lastly t he case of a fluid may be, given which
absorbs colours in the middle of the spectrum, while it transmits freely those at the
ends. The light transmitted is therefore violet in colour, (as the appearance of a solution
of potassium permanganate or methyl violet shows.) Colour is thus due in every case
to some difference in the behaviour of the substance towards the various rays of the
spectrum. In order to complete the description of colour formation, two other methods
should be described by which colour may be produced, namely fluorescence and pJios-
phorescence. The former term is applied when a substance absorbs light of one colour,
and at the same time emits light of another. The latter is applied when a substance
emits light for an appreciable time after the exciting light stimulus has ceased.
LIGHT SOURCES fall into two classes, those which emit, radiant energy because
of the high temperature to which they have been raised, and those which are excited in
other ways. The light from the former class as a rule consists of rays of all wavelengths,
IK an the longest heat rays to the shortest ultra-violet. The light from the latter
class on the other hand, is frequently found to consist of rays corresponding to char-
acteristic regions of the spectrum. The mercury vapour lamp may be mentioned as
an example of the latter typo of light source, which has come into general use. If
the \ ir-i I >!< - spectra obtained from a few light sources of the first type are carefully
measured, it is found that although rays of all wavelength are present, there are con-
siderable variations in the intensities of the different rays. This causes variation not
only in the colour of the light as a whole, but also affects the colour of objects and the
case with which the eye can judge vol. airs. This variation in the distribution of intensity
in the spectrum is found to be accompanied by corresponding changes in the infra-
red ami ultra-violet. For equal visual intensity, as the temperature of the source is
increased, the greater is the amount of ultra-violet light and the less is the infra-red.
Moreover as the temperature is raised, the w hiter, and therefore the more like daylight,
does t In- light become. Measurements of the energy present in different parts of the
HEAT VISUAL ACTINIC
PlO. 244. Curves shewing relative energy and luminosity of different regions of
the spectrum.
spectrum show that much the greater part of the energy is present in the infra-red.
These heat rays play no useful part in vision, and may in fact do harm ; the greater
part of the energy is thus wasted, and for this reason the efficiency of this class of
light source is very low. Since raising the temperature of the light source causes the
light to approximate more closely to daylight and at the same time reduces the
relative amount of the infra-red rays, it effects considerable advantage because it
increases efficiency.
THE ENERGY IN THE SPECTRUM is present in greatest amount at the red
end, and least at the violet. In spite of this the part of the spectrum with the greatest
luminosity to the eye is the yellow. The values obtained by Abney are shown in
figure 244.
DIFFRACTION AND REFRACTION. Beside the properties of light that have
400 PHYSIOLOGY
been already considered, namely, the relationship between actinic, visual, and
heat rays, and the effects of colour mixture, there are others of importance
to vision. (1) The property of travelling in straight lines; (2) ' of suffering
refraction; (3) of causing chemical change. The first property can be easily demon-
strated by investigating shadow formation. But it should be noted that straight line
propagation is only approximate, for it can be shown that at the edge of a light ray
there may be considerable deviation. This effect is called diffraction, and will lie con
sidered in greater detail later. The second property, namely that of suffering refraction,
is found to take place whenever light travels from a. medium of one optical density
(refractive index) into that of another. Briefly, refract ion consists of a deviation of
the light rays towards the normal to the surface, when entering a denser medium, and
away from the normal on entering a lighter. Rays of long wavelength tend to keep
their original direction more than those of short wavelength. Red rays are therefore
less refracted than orange rays, and orange less than yellow, and so on according to
wavelength. It is in this way that the spectrum is formed in the special apparatus
for experiments on colour mixture referred to above. But the most important effect
of refraction, from the point of view of vision, is the formation of an image by a lens.
This action may be briefly explained by considering what will happen to a beam o!
light, when it encounters a mass of high optical density having a convex Bpherical
surface. Since the rays on entering are deviated towards the norma] to the surface,
it is clear that rays that have entered near the edge of the lens will he bent towards one
another, and will therefore approach as they travel through the lens substance, till
they ultimately meet at the loins u ith all the other rays that have entered the lens from
tin- same source as themselves. Hut if there he a number of different sources, then the
rays from each are found to form their own focus, af a position that may be determined
either by experiment or by the rules of geometry. The positions of the different foci
are found to bear the same relationship to one another as (hose of the original sources,
or iii other words an image is produced. This important subject will he found referred
to again in greater detail in section 5.
PHOTO-CHEMICAL CHANGE, which is the third property of light mentioned
above, is well illustrated by photography. The most important principle of light action
is that light, to cause chemical change, must, be absorbed (Draper's law). For example,
an ordinary photographic plate which is found to be opaque to blue violet and ultra
violet rays, and to be transparent to the rcsl of the visible spectrum, is therefore sensitive
to the former rays but inactive to the latter. Further by colouring the plate by a
dye which absorbs nil, yellow and green, it is possible lo make the plate react to these
rays. Draper's law is therefore obeyed. Chemical reactions caused by light are of
many types, but ma\ he divided into reversible and irreversible. The former type
of reaction occurs only so long as the light acts (the change from CO to oxyluemoglobin
may be given as an example), while the latter type remains in the final state that has
been reached (the changes in a photographic plate may be given as an example). There
is further another and more complicated type which, when once started by an incident
beam of light, goes on automatically with an evolution of energy until the reaction is
completed. These effects of light are probably of great importance in connection with
vision and will therefore receive further consideration later.
THE MECHANISM OF VISION
The organ of vision makes use of the properties of light which have been above de-
scribed, and we may briefly consider the form that such an organ would take. Tocom-
mence with, there must be some method of causing light to stimulate the end of a nerve.
I me possible scheme would be to connect the nerve to a modified taste bud, which had
been selected for its sensitiveness to the presence of a chemical substance called A. If
this substance A is formed when light acts on another substance B, so long as light is in-
cident A is being formed and the end "I thenerve is being stimulated. With cessation of
the light however B is reformed from A, and the stimulus to the nerve at once ceases. The
PHYSICAL PROPERTIES OF LIGHT 491
mechanism must now be further elaborated in order to permit of the separate apprecia-
tion of at least three different fundamental colours. Two courses are open to us :
we may either provide three chemical reactions instead of one, each of which responds
to light of one fundamental colour, and may assume that the end organ is able ac-
curately to determine the amount of each of the three breakdown products present; or
we may provide three times the original number of nerves and end organs and place
them behind colour niters, similar to those used in three-colour photography. Which-
ever method be adopted, we should rind we had added considerably to the complexity
of the sensitive apparatus. Such an apparatus by itself would form a very inefficient
organ of vision because it would record only the average quality of the light which fell
on it. Some additional mechanism is required by which the direction from which the
light rays come may be inferred. Probably the simplest method would be to place
each end organ at the bottom end of a narrow box, the top end of which is open while
the sides are covered w ith a black material in order to prevent reflections. By arranging
these boxes radially in relation to a common centre, the apparatus would be capable of
'localising the direction of a light source. (This is roughly the arrangement found in
the faceted eyes of insects.) (See Fig. 251a.) Although such a visual organ can
be astonishingly efficient (one need only mention the case of certain dragon-flies, in
which the faceted elements number 12,000 to 17,000), yet there can be no question that
the use of some sort of optical system which could produce a focussed image of external
objects en flic sensitive surface or retina would be better still. The employment for
this purpose of a mass of high refractive index with a spherical anterior surface at once
suggests itself. Certain complications are however introduced at the same time,
namely the necessity of changing the focus or accommodating for images at different
distances, and of automatically controlling this mechanism in order that no mental
effort may be required for focussing. In order that such an apparatus may be employed
with light of different intensity, it is necessary to be able to control the amount of light
allowed to reach the sensitive surface. This could be effected by introducing a senii-
opaque screen such as the nictating membrane of the bird; a better plan would be
h'iwe\ ei' to employ an opaque screen with an aperture of adjustable size in it, because, as
will be shown later, by this means we can reduce flu- effects of chromatic and other aber
rations. Since the rays which pass through the centre of the refracting body, or lens.
pass through undeviated and therefore with the least amount of aberration, the best
pi ice for the aperture would be immediately opposite the centre of the lens, and for
Bimilar reasoning its best shape is found to be circular. The diameter of this aperture
must be automatically adjustable, according to the intensity of the illumination falling
on the sensitive surface of the eye, in order that its action may be independent of mental
effort. We may now conveniently consider for a moment the utility of such an organ
of vision to its owner. In the first place he will be able to recognise the presence of
objects sending light of different intensity and colour into his organ of vision. Move-
ment on their put. relative to himself, will be at once perceived, because- of change
in the size and position of tin- area of the retina which is receiving stimulation. Owing
further to the way that their images either intercept, or are intercepted by, the images
of other objects near them, he will be able to infer their relative position in space,
and the distance at which they are placed from him. This estimate will however be
very vague, and therefore the judgment of size will be equally uncertain. In the second
place we must assume that the whole of the retina, which we have described, is equally
sensitive everywhere, and that further the image formed on it by the lens system is
equally sharp throughout. There will thus be a very complicated picture of external
objects presented to the consciousness of its owner, and it will be correspondingly difficult
for him to concentrate his attention on some particular pari of the visual field to the
partial exclusion of the rest. His organ of vision therefore requires two further improve
ments, one to increase the effioiency of the appreciation of distance, the other to
increase his power of concentration, The first might be obtained bygreatlj increasing
the ensithcness of the mechanism of accommodation, since thefocui i altered i ling
492 PHYSIOLOGY
to the distance at which an object is placed. Such a me1 hod would be found ineffective
except for relatively near objects however, because of the small change of focus which
is involved. A superior method would be to endow a particular part of the retina with
increased sensitiveness, next to provide two complete organs of vision instead of one,
both capable of rotation in all directions, and then to mount them as far apart as
possible, so that as they are turned relatively to one another, in order to view near or
distant objects, the amount of such relative deviation may be estimated and so a means
be provided of appreciating distance. But the provision of increased sensitiveness in a
particular part of the retina also tends to diminish the disturbing effects of the rest and
therefore improves at the same time the power of concentrating the attention on a
particular object. This in its turn greatly simplifies the task of producing the lens system,
which forms the image of external objects, since only a part of the image is required
to have the maximum sharpness, namely that corresponding to the most sensitive
region of the retina, this part being always used whenever an object of particular
interest is being examined. In order to employ a simple lens system to the greatest
advantage, that part of tin- image should be used which lies immediately in front of I lie
axis of the lens : for it is here that the best definition is found. The most sensitive part
of the retina should be placed therefore in this position. It remains to describe a further
improvement which may be effected in the perception of distance, when a pair of eyes
are used which move in co-ordination. Suppose, for example, that there are two objects
one more distant than the other, which appear to the right eye to lie in line. Then to
the left eye the more distant one will appear to lie to the left of the other. There is
thus a relative displacement of the two images of the objects, which will be found
to increase as the distance between the objects increases. If tl bjects do not appear
in line to either of the eyes, it will still be found that there is a constant difference between
the positions of the two images formed on the retinse. If there be a suitable mechan-
ism for estimating the amount of this displacement, there is at once provided a
very accurate method of judging distance. One form which this mechanism could take
will be considered later.
In the development of a hypothetical organ of vision, which has been traced above
from a simple and inefficient to an elaborate and. improved type, we have seen that each
modification had to be introduced in order to make use of the application of some well-
known physical property; not once has the impossibility of obtaining some obvious
beneficial feature to be faced. The eye as we find it in man is almost identical with
this organ which we have developed as it were from first principles. The eye therefore
provides an excellent example of the efficiency with which evolution has been controlled
by natural laws, and of the small extent to which the limitations of the materials avail-
able have prevented the introduction of desirable features.
SECTION II
EYE MOVEMENTS
ANATOMY OF THE ORBIT
The eyeball and its accessory structures lie in the bony orbital cavity,
Burrounded and padded by a mass of semiliquid fat. The cavity is pierced
by several apertures, through which pass various vessels and nerves. The
optic nerve enters through an aperture of its own, the optic foramen, together
with the ophthalmic artery. Most of the other nerves and vessels concerned
with vision pass through the sphenoidal fissure. These are the 3rd,
4th and 6th motor nerves which innervate the muscles controlling eye
movement, sensory branches of the upper division of the 5th nerve,
connected with the cornea, conjunctiva, lids, etc., and the ophthalmic
veins. In order to allow the eye free movement the surrounding structures
form with it a ball-and-socket joint. The joint cavity is formed by a pouch-
shaped structure called the capsule of Tenon. This pouch surrounds the
posterior four-fifths of the eyeball, in fact its folded margin touches the
ocular conjunctiva. The pouch is made of a tough smooth membrane, and
contains synovial fluid so as to allow the eye the greatest freedom
of movement. Since the six muscles which cause the eye movements arc
attached to the bony wall of the orbit behind and to the front portion of
the globe in front, it is clear that the tendons of the muscles must pierce
the capsule. This is done in a very admirable maimer, so as to allow free
movement and at the same time to prevent escape of synovial fluid. Moreover
the edges of the apertures, through which the tendons enter, form strong,
Imnds which are attached to the bony walls of the orbit. These bands act
as check ligaments, preventing excessive movement on the part of the
muscles. Tenon's capsule contains numerous smooth muscle fibres which
are innervated by sympathetic nerves from the cavernous plexus, via, the
ciliary (lenticular) ganglion and the long ciliary nerves. Stimulation of the
nerves described causes contraction of these muscle fibres, protrusion of the
eyes and rise of intraocular pressure. But the most important function of
these fibres is that by their tone they prevent the eye from being dragged
back into the socket by the contraction of the external muscles. One of the
explanations of the protrusion of the eyes in exophthalmic goitre is given
to he the stimulation of the sympathetic nerves in the neck by the local
pressure of the thyroid tumour, and it is said that removal of the superior
cervical ganglion relieves the condition.
With regard to the position of the centre of rotation of the eye it might
493
494
PHYSIOLOGY
be though! that, since the eye forms a ball and socket joint, 1 he centre of rota
tion would be at the geometrical centre of the eyeball. Careful measuremenl
shows that such is very nearly the case. The amount of rotation of the eyes
is considerable, being 1S8 degrees in a horizontal, and 80 degrees in a vertical
plane. If the sphericity of the globe of the eye is destroyed through disease.
myopia for example, then it- is found that rotation is impaired.
ANATOMY AND FUNCTION OF THE EXTERNAL MUSCLES OF
THE EYEBALL
The six external ocular muscles produce cotati if the eyeball ; four are
called recti and two oblique. The recti arise from a fibrous ring attached
to the margin of the optic foramen, and pass forward to meel the
eyeball at its equator, where they form tendons. These having passed
through Tenon's capsule are attached to the sclera about ti mm. behind the
corneal margin. From the positions they occupy they are called superior,
inferior, external and internal. When they contract they will cause upward,
downward, outward and inward rotation of the eyeball respectively.
In the case of the first two muscles there is a turning movement
inwards at the same time; this is due to the muscle attachment
round the optic foramen being on the inner side of the back of the orbit,
since the muscles can cause rotation only in the directions which their tendons
take. Tn addition to the above movements, and for the same reasons, there
is a very small amount of rotation of the eye about the visual (antero-posterior)
axis in the case of the superior and inferior recti, the directions in both cases
FR.ONT VIEW
Fig. 245. The anatomical position of the external muscles in respect to the eyeball.
being obvious from the directions of the pull of the muscles. Figures
245 and 246 show the above diagrammatically. The two oblique muscles,
the superior and inferior, are both smaller than the recti. The former arises
near the optic foramen, and passes forward to the upper and inner side of the
orbit, forming on its way a round tendon. It here passes through a narrow
fibrous ring, and then turns downwards and backwards under the superior
EYE MOVEMENTS 495
rectus and becomes attached to the eyeball. The inferior arises from the
nasal side of the orbit, just within its lower margin. It passes outwards
and backwards beneath the inferior oblique to become attached to the
eyeball nearly opposite to the attachment of the superior oblique. On con-
traction of the superior oblique the upper side of the eye is rotated towards
the nose ; at the same time the pupil is directed slightly downwards and out-
OBLIQUE
fir sent
(IV n)«J
shewing the directions in which the different external eye
inn iles i ■iili' the eyeball.
wards. The inferior oblique alsocauses rotation about the visual axes, but
in the opposite direction ; i1 at tin' same time produces upward and mil ward
movement of the pupil. The function of these two small muscles appears to
be to prevent the eyes from rotating about their visual axes, and in particular
to prevent the rotation inwards which is associated with the contraction
of the superior and inferior recti. For this purpose the superior rectus is
associated with the inferior oblique and vice versa. In this action theoblique
muscles appear to be very efficienl : for if the eye is first fatigued by looking
at a brilliant line ot light, e.g. a long straight electric lamp filament, and is
then directed upwards or downwards at a white surface, the after image thus
produced is always found to keep its vertical direction.
On tilting the head suddenly about a transverse axis, it is found that the
eyes rotate in the opposite direction, so that in fact the image formed on
the retina shall still keep in the same apparent meridian. This rotation
is called compensatory, and is largely effected by the oblique muscles.
CO-ORDINATED MOVEMENTS OF THE EYES
The notable feature of the eye movements is the close association which
exists between the muscles of the two eyes. For so perfectly has this mechan-
ism been developed that the eyes are able to glance rapidly from place to place
without there being any obvious doubling of the images. The eye movements
are therefore of such a kind that the image of an object conveys a single
impression to consciousness. But objects vary in the distance at which
they are placed and therefore, beside movements of the eyes in which the
visual axes remain parallel, there are also movements in which there is
a certain amount of convergence. In the latter case there is usually some
496
PHYSIOLOGY
associated accommodation of the lens for near objects, and at the same time
some contraction of the pupil. By experiments in which prisms are placed in
front of the eyes, thus calling for convergence or divergence without accommo-
dation, and by others in which lenses are placed there instead, thus requiring
accommodation without change in the angle between the axes, it can readily
be shown that the association between the functions of accommodation and
convergence is not very rigid. The co-ordinated deviations of the eyes appear
to be much more closely connected. Thus Donders found co-ordinated
deviations both in the newly born and in congenital blindness. This is
probably due to the close anatomical relationship which exists between the
nerve centres of the muscles on the two sides. This relationship may be
explained with the help of Figure 247, which shows roughly the relative
positions of the various nerve centres in the central part of the Sylvian
grey matter at the level of the quadrigeminal bodies.
PUPIL
ACCOMMODATION
LEVATOR. PALP
Fig. l'47. Diagram to shew relationships of different parts of oeulo-motor nuclei,
and tlie principle connections between them.
It will be seen that the third or oculo-motor nerve supjmes all the external
eye muscles except three, viz. : Tenon's capsule, which is supplied by the sym-
pathetic ; the superior oblique, which is supplied by the fourth or trochlear
nerve ; and the external rectus, which is supjjlied by the sixth or abducent
nerve. Further, while most of its nuclei supply muscles on the same side,
two are found to go to muscles on the opposite side, namely the internal and
inferior recti. Another eye muscle also has a crossed connection, namely
the superior oblique (4th nerve). Of the many bundles of association fibres
which connect these different nuclei, the following may be mentioned as
being of special importance: — (1) From the external rectus of one side
through the posterior longitudinal fasciculus to the internal rectus of the
other ; thus allowing conjugate deviation of the eyes. (2) Between the
nuclei of the pupil sphincter, of the mechanism for accommodation, and of the
EYE MOVEMENTS 497
internal rectus ; thus co-ordinating the adjustments required for near vision,
namely convergence, accommodation for near objects, and reduced pupil
diameter. (3) Between the superior recti muscles of the two eyes; thus
causing symmetrical upward deviation. (4) Between the inferior recti of
the two eyes for similar reasons. (5) Between the superior oblique of one
eye and the inferior oblique of the other ; thus permitting conjugate rotation
of the eyes.. (6) Between the superior rectus and the inferior oblique of
the same eye ; thus permitting the deviation caused by the one to be
corrected by the other. (7) Between the inferior rectus and the superior
oblique of the same eye for a similar reason. (8) Between the nucleus of
the superior rectus and that of the levator palpebral of the same eye. This
association permits simultaneous raising of the eyelid with the upward
deviation of the eyes, thus preventing any restriction of vision.
Besides these connections between the muscles producing like or associ-
ated action there are others equally important between the brain and these
centres, namely those which connect antagonistic muscles. Sherrington
showed that, as the muscle on one side of a limb contracts, its antagonist
at the same time relaxes, so as to allow the movement to take place smoothly
and without waste of energy. This is called 'reciprocal innervation.' The
eye muscles show the phenomenon very well. If the right frontal cortex
be stimulated, the eyes perform co-ordinate deviation to the left. If now all
the muscles of the right eye are divided except the external rectus, it is found
that this eye still moves in coordination as far as the middle line, through
the relaxation of the external rectus muscle.
The orbicularis palpebrarum is also supplied by the 3rd nerve, for in
lesions of its nucleus paralysis of this muscle is found. The fibres innervating
it probably travel all the way with the 7th nerve.
CAUSES AND DIAGNOSIS OF STRABISMUS
'Squint or strabismus may be caused by a number of conditions: (1) by congenita]
abnormality ; (2) by interference with the proper rotation of the eyeball ; (3) by injury to
one of the external eye muscles ; (4) by injury to or stimulation of one of the nerves sup-
plying these muscles ; (5) by the presence of certain errors of refraction. With regard to
nerve injury the following description may be given. Injury to the third nerve causes (a.)
drooping of the upper lid owing to paralysis of the levator palpebrse ; (ft) external
strabismus from paralysis of the upper, inner and lower recti and the unopposed action
of the external rectus; (c) rotation of the eye about its visual axis from paralysis of
tli.- superior oblique and therefore unopposed action of tin- inferior; (ii) dilatation ,,|
the pupil from paralysis of its sphincter and tin- unopposed action of the dilator fibres
which are innervated by the sympathetic; (e) loss of the power of accommodation
from paralysis of the ciliary muscle ; (/) exophthalmos or protrusion of the eye, caused
by the paralysis of so many of its muscles and the unopposed action of the smooth
muscle fibres in Tenon's capsule. Owing to the fact that for a considerable portion
of its course the 3rd nerve lies beside the 4th, 5th and 6th nerves, there is usually
also some associated symptoms of paralysis in the structures which these nerves supply.
Injury to the 4th nerve causes paralysis of the superior oblique, which shows itself
by defective movements in a downward and outward direction. Injury to the 6th
nerve causes internal strabismus owing to paralysis of the external rectus. This fre-
quently occurs when tumours, haemorrhage or injuries involve the base of the brain.
32
198 PHYSIOLOGY
Experimental st inm la.< i< >n <>f these nerves causes (lie ei inverse ell'eels In paralysis, whioh
therefore 'I" no! require specific description.
When strabismus due to the complete paralysis of one of the recti is present, there
is not as a rule any difficulty in ascertaining which muscle is ahVcted. When however
nne of the oblique muscles is paralysed or when the paralysis is only partial, there may
be some difficulty in diagnosing the exact condition. It is found however thai l hen
is a simple method by which the affected muscle may lie found. This depends on the
principle that, if t he eyes are rotated in that direct ion which requires complete contract ion
of the affected muscle, the strabismus will be found to get worse, owing to the
failure of that muscle being made, more pronounced ; if on the other hand the eyes are
turned in the. opposite direction, the injured muscle is relaxed and the strabismus
vanishes. The following example will slum the »a\ the method is used i a man com-
plains of double vision following an injury to the eyes ; by directing the gaze in different
direct inns it is found that the double vision increases in amount as the eyes are turned
to the right. The injured muscle must therefore be clearly a. dextro-rnfatnr, that is,
the external rectus of the right eye, or the internal rectus of the left. Fig. 248 will
&
L.INF.R,.
L.S.O. r.s.o:
DOWN
Fig. 24S. Showing the direction in which paralysis affecting the different eye
muscles produces diplopia and the relative positions occupied by the true
and false images (Hartridge). Black shows image of right eye. white shows
image of left eye. The false image is always the one placed furthest from the
centre. •
be found of assistance, because the arrows which show the directions in which the diplo-
pia increases, point to the names of the muscles the injury of which will set up the
condition which is found to exist. Experience shows that the injured eye is always
that, to which the more deviated image belongs, and this fact may be readily ascertained
by placing in front of the right eye a slip of coloured glass. If the coloured image is
found to be the one that is the more deviated, then it is the right eye that is involved
in the injury, and therefore in the case that we have been considering, the right external
rectus is the injured muscle. Conversely if the uncoloured image is found to be the
more deviated, then the injured muscle was the left internal rectus. In fact it is found
in every case that the injured muscle is the one which would give by its contraction
that, position to the more deviated image which it is actually found to occupy.
EYE MOVEMENTS 499
TREATMENT OF STRABISMUS. This consists either in the use of suitable
prismatic spectacles which will cause a recombination of the double images, or in
operative measures. In the latter, either the tendon of the paralysed muscle is shorl
rued, or that of its antagonist is lengthened, or better still a combination of both
methods of treatment. Lastly there is a type of strabismus which is found to accom-
pany the refractive errors which cause long and short sight. This type of strabismus,
which is called concomitant, is eliminated by correcting the refractive error. (This
important subject will be referred to again later on page 537.)
SECTION III
THE STRUCTURE OF THE EYEBALL
The eyeball is a sphere, about 20 mm. in diameter. It lies near the front
of the orbital cavity protected by the eyelids. The greater part of its
external surface is formed by a firm white membrane called the sclera. In
front this is replaced by a transparent structure called the cornea. This
hasa greater curvature than the rest of the eye, the radius of its surface being
about 8 mm. Attached to the eyeball behind and slightly to the inner
Fig. 249. Transverse section through equator of left eye seen from above.
side is the optic nerve, the function of which is to convey to the brain the light
impressions received by the eye. Attached to it also, about 6 mm. from the
corneal margin, are the tendons of four of the ocular muscles, as described
in Section II. The sclerotic is fined within by a highly vascidar and deeply
pigmented coat called the choroid. In front this coat has a circular aperture,
in relationship with which the choroid becomes modified into several impor-
tant structures, namely the iris, ciliary muscles and ciliary glands. Spread
500
THE STRUCTURE OF THE EYEBALL
£01
out within the hollow cup formed by the sclera and choroid is a soft delicate
membrane of nervous tissue, the retina, which is connected with the optic
nerve. The spherical cavity thus formed is entirely filled by three trans-
parent structures, the lens, the aqueous humour and the vitreous humour.
The lens is a biconvex body of higli refractive index, which is situated
symmetrically behind the opening in the iris, being held in place by the
suspensory ligaments. The aqueous is the fluid which fills the cavity in front
of the lens, while the semi-solid vitreous fills the cavity behind it. The eye
is therefore a solid orgaii having considerable rigidity.
DEVELOPMENT OF THE EYE. The period at which the development of (he
eye commences in the embryo follows rapidly after the invagination of the epiblast
to form the central nervous system, namely at about the first week in the human
foetus. It shows itself by a bulging outward of a pair of buds from the nervous layer
towards the sides of the head. During its advance each bud becomes folded on
itself to form a hollow cup which remains in connection with the central nervous
system through a hollow tube, the future optic nerve. As the optic cup approaches,
the epiblast becomes thickened, and this portion sinks inwards till it comes to lie in
the mouth of the optic cup. The epiblast now becomes folded over it, and the edges
coalesce, leaving the thickened mass as a nearly spherical body (the future crystalline
go" MOUTH
Piq. 250. Diagram to show the different stages in the development of the o.\e.
502 PHYSIOLOGY
lens) af the mouth of the optic cup. The two layers of the optic cup now become
contiguous, and the outer develops pigment, while the inner increases greatly in the
complexity of its structure to form the adult retina. Through a special cleft in the
optic cup (the choroidal cleft) enters a bud of mesoderm to form the vitreous body.
This carries with it blood vessels which form the central artery of the retina and those
which nourish the lens and iris during their development, namely the hyaloid artery
and its branches. These vessels are accompanied by corresponding veins. During
these changes tin- mesoblast surrounding the optic cup has condensed to form the highly
vascular choroid and outside it the dense and hard sclera. The latter becomes at the
same time transparent in front to form the cornea. Behind the cornea a cleft-like
aperture appears which develops into the anterior chamber, and thus separates the
cornea from the iris. The anterior chamber becomes lined by endothelium, and is filled
with fluid, the aqueous humour. The iris thus becomes composed of three layers : (1 ) the
posterior pigmented layer which is the continuation of the retina; (2) the iris tissue
propei developed from mesoderm, and containing the two muscle layers and elastic
tissue ; (3) the anterior layer of endothelial cells. The iris is thus at first a continuous
sheet of tissue, but its structure is thinner at the part corresponding with the pupil,
thus forming the pupillary membrane. This disappears shortly before birth. The
ocular muscles are formed from the mesoderm in a similar way to other muscles.
The lids form as two buds growing out from the epiblast; they advance till they
meet and then fuse together, to reopen again about the time of birth. The
nervous layer appears to take a very important part in tin- development of
the eye. and this is borne out by experiment ; for if the outgrowing optic cup be diverted
during its advance to the epiblast towards some other part of the embryo, it is found
that a normal organ of vision develops in this new and entirely abnormal situation.
COMPARATIVE ANATOMY OF THE EYE. The types of light-receiving
organ in the animal kingdom make an elaborate study because of the variety of
form that is met with. We may however effect an approximate classification,
The most primitive type of all light organs consists of a single pigmented spindle-
shaped cell such as is found in the epidermis of certain amphibia and coelenterata (see
Fig. 251 A). In cases where the creature is transparent, the end organs may be devel-
oped in connection with the nervous system. The functions of such organs may be
to inform their possessor if a part is exposed to light, and therefore also liable to be
noticed and attacked by passing enemies. In the next type of light organ, a number
of such cells are grouped together, often to form a hollow cup in the epidermis, as shown
at B. These cups retain their connection with the nervous system by means of an
oplie nerve. This type of organ (B) is found in Platyhelminthes and in the mollusc
Patella. In the next type (C) the cup becomes deeper and its mouth small, the epidermis
round it becoming deeply pigmented. This organ therefore functions like a pinhole
camera, allowing its possessor to observe a rough image of external objects ; it should
be noticed however that this image formation occurs at the expense of brightness.
This type ((') is found in most annelida and in the mollusc Nautilus. The next type
(D) is a modification of the last, in that the centre of the optic cup is filled w ith a spherical
highly retractile body. This permits a larger opening to be used for the admission of
light without at the same time causing too much confusion in the image. This is the
arrangement met with in the mollusc Helix and the arthropod Scorpio. In the next
type of light organ (E) the highly retractile lens becomes separated from contact with
the retina, and the space between is filled by liquid or a mass of transparent cells which
form a vitreous humour. This interval between the lens and retina allows the former
to produce a focussed image on the latter, so that for the first time we find an eye having
the property of defining external objects. This type of eye (E) is found in the
eoelenterate Charybdea and in the ocellus of insects. In the mollusc Sepia
the eye is further improved by possessing an adjustable iris. The eye of Pec ten
(F) has another interesting feature, namely that the optic nerve spreads out over, and
THE STRUCTURE OF THE EYEBALL
503
becomes connected with, the retina on the side nearest to the lens, an arrangement
similar to that found in vertebrates. The insect eye (G), which is also found in Crus-
tacea, is arranged on an entirely different plan. It may be regarded as being formed
by packing an exceedingly large number of elongated ocelli together, with their lenses
Fig. 251. Comparative anatomy of the eye.
(A) Single cell as in amphibia and coelenterata. (B) Mollusc Patella. (C)
Mollusc Nautilus. (D) Mollusc Helix. (E) Ccelenterate Charybdea and ocellus
of inserts. (K) Mollusc Pecten. (G) compound eye of insect.
anterior and their retinae posterior, to form a solid hemispherical body. If is this
formation from a number of separate elements which gives the eye of the insect its
faceted appearance. Exner and others have shown that the refracting media
of the separate elements cannot form a focusscd image on the sensitive end organ
which each contains, but that vision must consist of a mosaic, as Johannes Miiller had
suggested. It is said that such vision is well adapted to observing movement. The
eyes of vertebrates may be considered In be of the same type as that found in man, for
the differences that are met with chiefly concern detail, except as regards the mechan
ism used for accommodation.
504
PHYSIOLOGY
In nnm, as we shall see later, this is accomplished by adjusting the power of the lens.
In fish the eye, which is normally focussed for near objects, is caused to focus objects
at a distance by movement of the lens closer to the retina. This is brought about by
l In- contraction of a muscle called the retractor lentis (see Fig. 252a). In snakes the eye
,il ivsl is also far-sighted. II is accommodated for near vision by the contraction of a
circular ring of muscle which compresses the eye and makes tin- lens travel forward
(Fig. 252c). In birds (he eye at rest is long-sighted. The focussing of near objects is
obtained by increasing the curvature of the cornea. This is caused in the following
manner. Attached t>> the inside of the sclerotic, which forms a complete bony ring
round the eye, is a radially arranged muscle (Crampton's muscle). (See Fig. 252b.)
The other end of this muscle is attached to the corneo-scleral junction. Therefore when
the muscle contracts it draws the periphery of the cornea backwards. But this tends
to cause an increase in the intraocular tension, since the total volume of the eye
tends to be decreased. This increased tension causes a bulging of those external eye
structures which are most elastic, namely to a slight extent the sclerotic where it
Fio. 252. The methods of accommodation used in fish, birds and snakes.
does not contain bone, but to a much greater extent the front of the cornea, because
of its thinness and greater elasticity. The curvature and therefore the refracting power
of the cornea very greatly increase, thus causing light rays from near objects to be
focussed sharply on the retina. The increase in the distance of the cornea from the
retina still further assists this process. It should be noted that Crampton's muscle
contains voluntary fibres and is under the direct, control of the will. This probably
serves two purposes: it allows the bird to rapidly accommodate as it swoops towards
the ground, and at the same time it may assist the judgment of distance.
In describing the comparative anatomy of the visual organs it should be remem-
bered that the pineal gland is, in mammalia, the rudiment of one of a. pair of median eyes
or ocelli, which were functional in the vertebrate ancestors.
MINUTE ANATOMY OF THE EYE. The Cornea forms the trans-
parent anterior convex front of the eye. Its curvature has a radius of
nearly 8 mm. and a diameter of 11 mm. Its thickness is 1*1 mm.,
and is composed of the following live layers: (1) Stratified epithelium
continuous with that covering the conjunctiva. Superficially the cells
are nucleated square!?, deeply the}' are nucleated columnar cells, and
THE STRUCTURE OF THE EYEBALL
505
the layers between are a gradual transition from one type to the other.
(2) The anterior elastic lamina of Bowman. This is not true elastic
tissue, but a layer of modified substantia propria. (3) Substantia propria
which consists of a special type of fibrous connective tissue. The fibres
are arranged in parallel rows to form laminae, and the lamina? are built
one above the other, leaving cell spaces or lacunar between. The fibres of
each lamina are cemented together by an amorphous substance of nearly
the same optical density so that the lamina? form one homogeneous structure.
It is on this arrangement that the transparency of the cornea depends.
If an excised eye be squeezed so as to produce a high intraocular tension,
the cornea is seen to become partially opaque. This is caused by the
tension in the corneal fibres making them become doubly-refracting in a
similar manner to that set up by the contraction in a striated muscle fibre.
But owing to this double refraction the laminae of the cornea cease to
form one homogeneous structure, and therefore opacity is the result.
Within the lacunae are to be found
the corneal corpuscles, which are flat-
nucleated star-shaped cells. (4) The
posterior elastic lamina of Descemet.
This is a clear structureless membrane
which splits at its periphery into three
layers. The first enters the sclera, the
second gives attachment to the ciliary
muscle, while the third enters the iris
as the ligamentum pectinatum and
gives attachment to it ; the intervals
between its fibres are called the spaces
of Fontana. (5) A layer of endothe-
lium. This consists of a single layer of
flat nucleated cells which line the
spaces of Fontana and the anterior
surface of the iris.
The cornea is nourished during
health by a How through the cell spaces
of lymph which comes from the peri-
pheral vessels. During its development
ami when diseased it is supplied by
capillaries which run in from its edge.
Its sensory nerve supply is extremely
rich, but pain end organs alone appear
to be present.
Histologically the sensory nerve
filaments are found to ramify actually
in the surface layers of the stratified
epithelium, a condition not found, in
any other part of the body. This ar-
Nerve supply to the eyeball.
(After Fostee.)
l.g, lenticular ganglion with its three
roots, viz. : r.b, radix brevis or short
root; r.l, radix longus or lung root;
sym, sympathetic root; V. opth. oph-
thalmic division of V nerve j /// ocm,
oculo-niotor nerve ; 11, optic nerve ;
I.e. long ciliary nerves; s.r, short ciliary
nerves.
506 PHYSIOLOGY
rangement and the acute painresponse, which even t he smallest foreign body
can initiate, obviously has for its object the protection of this important
surface from injury. The pain impulses are conveyed to the brain either
via the perichoroidal nerve plexus and the long ciliary nerves to the nasal
branch of the 1st division of the 5th nerve, or from the plexus by the short
ciliary nerves to the ciliary ganglion, and from this through the radix
longa to the nasal nerve. In either case the nerves appeal to have I heir
ci'll station in the Gasserian ganglion.
THE SCLERA, which forms the tough shell of the eyeball, consists of
three layers : (]) a. thin layer of endothelium in contact with the capsule
of Tenon ; (2) numerous interlacing bundles of white fibrous connective
tissue ; (3) a layer of flat endothe'ial cells and a network of fine pigmented
connective tissue cells, forming the lamina fusca.
Beside the optic nerve the sclera is perforated by the short and long
ciliary nerves and by the ciliary arteries. The four venas vorticosae leave
it at the equator. At the corneo-scleral junction the two structures are
continuous. A space is left however which forms a ring round the cornea.
This is called the canal of Schlemm ; it communicates with the anterior
chamber through the spaces of Fontana and also with the scleral veins.
The presence of these canals renders the sclero-cornea weak and therefore
liable to be ruptured by violence.
THE CHOROID forms the vascular and pigmentary lining of the eye.
It intervenes'between the sclera and the retina. Histologically it consists
of three layers: (1) the lamina sirpra-choroidea, which is similar in its
structure to the lamina fusca of the sclera : (2) the lamina propria "which
consists of connective tissue, richly supplied with blood vessels, capillaries,
veins, and nerves : (3) the basilar membrane of Bruch. This is a thin
t ransparent structureless layer like that of Descemet in the cornea. A highly
reflecting surface, called the Tapetuni, is present in certain animals. This
is formed by a layer of iridescent cells in the lamina propria.
THE CILIARY | BODY connects the choroid to the iris. It consists
of three parts : (1) the ciliary muscle, the function of which is to cause
the accommodation 1 of the lens ; (2) the ciliary glands which secrete the
aqueous humour ; and (3) the orbiculus which is the part of the ciliary body
connecting it with the choroid. The ciliary bodies are covered by a thin
pigmented layer which is a continuation of the retina. This also covers
the posterior surface of the iris and ends there.
THE IRIS consists of three layers : (1) the endothelium continuous with
that on the posterior surface of the cornea : (2) the stroma of the iris, which
consists of connective tissue (especially elastic fibres), two thin sheets of
muscle, some pigment cells, vessels and nerves; (3) the pigmented layer
continuous with the retina.
It should be noted that the posterior elastic lamina of Descemet in the
cornea, after its division into three parts, forms by its posterior portion
the ligamentum pectinatum iridis, by which the iris gains attachment to
the sclero-corneal junction.
THE STRUCTURE OF THE EYEBALL
507
THE FUNCTIONS OF THE IRIS. The iris contains two layers of
unstriated muscle fibres, the anterior which is circularly arranged so that
by its contraction it acts as a sphincter, while the posterior is arranged
radially, stretching from the attachment of the iris to the rim of the pupil
so that by its contraction it causes the pupil to open. Because of the
numerous pigment cells which it contains the iris is opaque to
light. Contraction of the pupil thus causes the following
effects: (1) reduction in the amount of light entering the eye,
so that an image of less intensity is formed on the retina ; (2)
Cornea
Sinus venosus
Conjunctiva /£!$?>
Rstma
Fig. 2o4. Section through anterior part of eyeball to show relations of iris and
ciliary bodies to corneo-scleral junction and lens.
the use of the more central zones of the lens system only. The advantage
of this lies in the fact that, as will be described later, the more peripheral
zones suffer from errors of refraction to a much greater degree than do the
central ones: the contraction of the pupil therefore improves the definition
nl Hie image; (:i) an increase in the depth of focus of the eye, which is
of great value for near vision. The way t hat depth of focus is obtained will
be described later (see page 5'30).
CONTRACTION OF THE PUPIL occurs under the following cir-
cumstances :
(1) When light falls on the retina. This movement, which is known
as ' the light reflex,' is determined by a contraction of the sphincter pupillse,
together with a relaxation of the dilatator muscle. The contraction ensues
within a period of 004 to 0*05 sec. after the moment at which the light has
508 PHYSIOLOGY
access to the retina, and attains its maximum within O'l sec. In man as
well as in other animals which have binocular vision, and in which there
is a partial decussation of the fibres of the optic nerves in the optic chiasma,
the reflex is bilateral, i.e. light falling into one eye causes simultaneous
contraction of both pupils. In the higher animals this reaction of the
pupil to light demands the integrity of the nervous paths between the eye
and the brain ; but in many of the lower animals, e.g. in the frog and eel,
the reflex nervous mechanism is aided by a local sensibility of the iris to
light. In these animals the contraction of the pupil in response to illumi-
nation takes place even in the excised eye, and seems to be determined by
a direct stimulation of the pigmented contractile fibres of the sphincter
pupillae by means of the light.
The effect of light on the pupil varies considerably according to the
condition of adaptation of the eye. The dilatation of the pupil is maximal
when the eye has been in the dark for some time and may amount then
to 7"3 to 8 mm. In one experiment, on exposing the eye to a feeble light,
e.g. 1'6 candles at a moderate distance, the pupil diminished in size to 6'3
mm. ; with an illumination of 50 to 100 candles the size of the pupil was
37 mm., and with 500 to 1000 candles, 3 - 3 mm. This effect was obtained
by a rapid change in the illumination of the eye. When the change in
illumination is sufficiently slow no alteration of the pupil takes place, and
when the illumination, which has at first caused a maximal constriction
of the pupil, is continued the pupil gradually relaxes with the adaptation
of the retina to fight. This relaxation occurs within three or four minutes
after exposure to light has taken place. The same influence of adaptation
will be observed if two individuals are brought into a moderately lighted
room, one from bright daylight and the other from a dark room. The
pupils of the first will dilate widely, while those of the second will constrict
to their maximum extent. In each case the change will pass off regularly,
so that at the end of five or ten minutes there will be no difference observable
between the eyes of the two persons.
(2) When vision is directed to a near object the functions of accommoda-
tion of the lens and of convergence of the visual axes which result, are
associated with contraction of the pupil. The sharpness of vision is thereby
improved together with an increase in the depth of focus. Results are very
beneficial for the close examination of detail. Since it is possible by ex-
periment to cause accommodation without convergence and vice versa,
we may ascertain which function is the more closely associated with
the pupil mechanism. The evidence appears to be in favour of convergence.
(3) In sleep the pupils are always contracted. This behaviour may enable
us to distinguish feigned from real sleep. This contraction of the pupils,
in spite of the fact that no light is entering the eyes, has been held to be caused
by association with the upward and inward direction of the eye axes which
was said to be found in sleep. There now appears to be irrefutable evidence
that the eyes during sleep may occupy any position; another explanation
of the constricted pupils must therefore be found.
THE STRUCTUKE OF THE EYEBALL 509
(1) Contraction of the pupils is a marked effect of certain drugs such as
Morphia or its crude extract Opium ; other examples are Pilocarpine, Mus-
carine, Physostigmine and Cocaine. The parts of the pupillo-rnotor mechan-
ism on which these drugs act will be considered later (see page 513).
(5) Constricted pupils are also met with in excitable conditions of the
centra] nervous system, and therefore during the induction of
chloroform and other anaesthesia.
(<>) Small pupils which do not react to light are also met with in injuries
to the spinal cord which involve the cervical region. The explanation of
this will be given later (see page 511).
(7) Contracted pupils are found to accompany agon}-. This is probably
due to the powerful flow of efferent impulses which leave the brain in this
condition, affecting the 3rd nerve nucleus which controls the pupil.
(8) The pupil contracts when the aqueous is allowed to escape
from the anterior chamber. The cause of this is said to be the dilatation
of the vessels of the iris, owing to the fall of the surrounding pressure.
DILATATION OF THE PUPIL (1) Occurs on removal of alight stimulus
from the eyes. If the removal be complete the pupil remains dilated, but
if there be any light at all the pupil gradually contracts again as the eye
becomes dark adapted.
(2) Occurs on accommodation for distant vision because the associated
reflex stimulation of the pupilo-motor centre with accommodation is no
longer called into play.
(3) Eeflex dilatation of the pupil can be excited by the stimulation of
any sensi iry-nerve. This may be due to some of the afferent impulses reach-
ing the cilio-spinal sympathetic nerve centre in the cord.
(1) The pupils are frequently found to dilate in such emotional states as
fear, anxiety, exhaustion and dyspnoea, and also at the moment of death.
(5) Dilatation is also found to accompany extreme exhaustion of the
central nervous system, when the activity of all nerve centres is low,
such as in deep chloroform anaesthesia, and in the coma produced by
alcohol poisoning. Many other drugs such as atropine and homatropine
cause dilatation, as will be described later.
(6) Dilated pupils inactive to light are found in injuries of the 3rd nerve,
or its nucleus.
(7) Dilated pupils are also found when the intraocular pressure is abnor-
mally high, as in glaucoma. This appears to be due to constriction of the
vessels of the iris owing to the lygh external pressure to which they are
.subjected.
(8) Dilated pupils inactive to light are found in compression and severe
concussion of the brain. This is probably due to the abolition of the normal
nervous impulses to the muscles, so that the pupil dilates under the
influence of its radial elastic fibres.
(9) Dilated pupils are found to accompany hyperactivity of the supra-
renal glands, owing to the presence of considerable amounts of adrenaline
in the blood. This occurs for example in oxygen want, dilated pupils being
one of the characteristic signs of that condition.
510
I'HYSIOUMJY
INNERVATION OF THE IRIS. Before the work of Langley and Anderson
on the iris there was doubt as to the method by which dilatation was brought about :
some thought that it was due to inhibition of the sphincter, thus allowing the iris to
open because'of the radial clastic fibres which it contained ; others that it was due
to the emptying of the iris of blood from the contraction of the arterioles following
stimulation of the sympathetic; others again that the cause was the longitudinal
contraction of the radial arteries. But Langley and Anderson showed thai a radial
strip of iris, isolated except at its ciliary attachment, shortened to half its length
when the cervical sympathetic was stimulated. It has been found further thai
local stimulation of I he iris near its periphery causes a local dilatation of the
pupil, and that cutting the sympathetic causes lasting constriction of the pupil.
Km. 255. Effect on iris of cat of local stimulation.
The first effect, as in A, is to cause contraction of the constrictor pupillse below
the electrodes, and this is succeeded in b by a strong localised contraction of the
radiating fibres. (Langley and Anderson.)
Muring these experiments they proved by microscopic examination (hat the dilata-
tion of the pupil was wholly independent of the contraction of the blood vessels of
the iris, and that draining the animal of blood did not influence the contraction of the
iris. Later it was proved by histological technique that there are radial muscle
fibres in the iris. These are poorly developed in mammals but are well marked in birds
and in the otter. These facts together prove definitely that there exists a dilator
muscular mechanism in the iris.
The. sphincter muscle is supplied by nerve fibres which arise from the
upper portion of the 3rd nerve nucleus in the ventral part of the Sylvian
grey matter (see Figure 247). They travel down in the nerve as far as the
ciliary (or lenticular) ganglion which is situated behind the eye close to the
optic nerve. Here a branch from the nerve enters the ganglion to anasto-
mose with its nerve cells. These nerve cells send off numerous small nerves
called the short ciliary nerves (Fig. 253) which enter minute apertures in the
sclera arranged in a ring round the optic nerve. Having entered the peri-
choroidal lymph space the nerves form a plexus from which are supplied the
local blood vessels, the ciliary muscle (thus causing accommodation) and
THE STRUCTURE OF THE EYEBALL 511
the sphincter of the pupil. The dilator muscle of the iris is supplied by
nerve fibres which originate in nuclei situated near that part of the. 3rd
nerve nucleus which supplies the sphincter fibres ; this must be the case
in order to explain the reciprocal innervation of the two antagonistic sets
of muscles. From these nuclei nerve fibres travel down the cord as far
as the 8th cervical and 1st dorsal ventral nerve routs, with which they leave
the cord. They then proceed as part of the white rami communicantes to
the superior thoracic ganglion, and thence by the sympathetic chain to
the superior cervical ganglion, with the cells of which they anastomose.
From these nerve cells the terminal nerve fibres for the dilator muscle of the
iris arise ; they appear to travel by two distinct routes : (I) from the superior
cervical ganglion to the Gasserian ganglion of the 5th nerve along the nasal
branch of its 1st division, to turn off with the two long ciliary nerves to end
l>v entering the sclera and joining the perichoroidal plexus, and thence to
the dilator muscle; (2) from the superior cervical ganglion grey rami are given
off which travel with and form plexuses on the various branches of the in-
ternal carotid artery. One of these is the cavernous plexus which sends
a fine branch to the ciliary ganglion. From here the fibres travel with the
short ciliary nerves as already described.
It is clear therefore that the short ciliary nerves contain both pupil-
constrictor (3rd nerve) and pupil dilator (sympathetic) fibres, so that when
these nerve fibres are stimulated electrically both the sphincter and the radial
muscles of the iris will contract. But the sphincter fibres being the more
powerful will overcome the others and therefore cause contraction of the
pupil.
The nerve paths above described and the effects on the pupil which
excitation of the nerves produces have been ascertained by the employment
of the well-known methods of cutting the nerves, stimulating the cut ends,
and also by following the tracts marked by degeneration. Thus cutting
the sympathetic anywhere causes contraction, while cutting the 3rd nerve
produces dilatation. Stimulation of the peripheral cut ends causes the
opposite effects. The course of the dilator impulses down the cord to the
cervico-dorsal region explains the contraction of the pupil which sometimes
accompanies injuries to the cervical spine, and explains the origin of the term
cilio-spinal centre.
Since the dilatation of the pupil is accompanied by contraction of
the radial fibres on the one hand, and inhibition of the sphincter fibres on
the other, and vice versa when contraction takes place, it would seem
almost necessary to assume that there is some system of reciprocal innerva-
tion, like that found by Sherrington in the case of the limbs. Experimental
evidence would point to such being the case. Thus stimulation of
a part of the sensori-motor area of the brain is followed by dilatation
of the pupil, which occurs even when the sympathetic has been
cut. Since this excludes the possibility of an active contraction of the radial
fibres (their nerve supply having been cut) it appears to prove that a
reciprocal inhibition of the sphincter has been produced. The existence
512 THYSIOLOGY
of this reciprocating mechanism must greatly increase the efficiency with
which the pupil works.
The above experiment also shows that there is a connecting nerve
path between the pupilo- motor centre and the cortex of the brain. The
reaction of the pupil to light and the association which exists between pupil,
accommodation and convergence indicate that there are a number of other
important connections between the pupilo-motor and other centres. The
more important of these will be therefore traced.
The light reflex in certain animals such as frog ami eel is assisted by a
local sensibility of the iris to light, while in birds on the other hand it is
to a considerable extent under voluntary control ; but in man and in most
other higher vertebrates the control is involuntary and unconscious, the size of the
pupil being determined by tin- intensity of t ho light which is reaching the retina. Thus
in bright light the pupil may be less than - 6 mm. in diameter, while in the dark it may
In luger than 10 mm.; such achange will cause the intensity of the light with the
pupil contracted to be nearly one two-hundredth part of the intensity when the pupil
is dilated. This indicates an extraordinary range of variation in the length of the
sphincter muscle fibres. The reaction of the pupil to light varies with the rate at which
change of intensity occurs. When the alteration is sudden the amount of contraction
was found by Haycraft to be equal to the logarithm of the intensity of the light. When
however the alteration is so gradual that the retina can become adapted to the change
as it proceeds, then little or no change in the size of the pupil occurs. The function
of the pupil appears rather to protect the retina from any sudden change of intensity,
than to control the actual intensity of the light. With regard to the reflex an the
connection of the iris with the pupillo-motor centre has already been described. The
connections of the retina with this centre appear to traverse the following course,
Starting from the retina on one side the impulses travel up the optic nerve as far as the
chiasma, where they travel on without decussating, and end by anastomosing with nerve
cells in the anterior corpora quadrigemina. These nerve cells correspond with second
order neurons and proceed to the pupillo-motor centres of both sides. It is found by
experiment in monkeys that dividing the chiasma in the middle line docs not stop either
the pupil reflex in the eye stimulated or in the other eye. This shows that the nerves
concerned with the pupil reflex go to the anterior corpora quadrigemina of the same
side, and that the consensual reflex is due to the fibres from each anterior corpus quad-
rigeininum supplying the pupillo-motor centres of both sides. The appreciation of ligl 1 1 I ly
the retina is exceedingly rapid, whereas the response of the pupil to light action is very
delayed. This is due in part to the fact that the muscles of the iris arc composed of
involuntary, smooth fibres. There is however a pathological condition called Hippus, in
which the pupil alternately expands and contracts at a rate that would be impossible if
the attempt were made to produce this effect by alternately exposing the eye to light.
This proves that the muscle fibres can react more quickly and therefore that there is
somewhere in the reflex arc a delay action mechanism. The object of this mechanism
would appear to be to render the pupil stable and to prevent 'hunting.' When this
mechanism is diseased Hippus results.
The accommodation reflex has been already considered. The close anatomical
association of the 3rd nerve centres for pupil sphincter, accommodation and convergence
by the internal recti is shown in Figure 247. When volitional impulses therefore
come down via the frontal lobes of the cerebral hemispheres, they are conveyed to this
group of centres, and the associated reflex results.
ARGYLL - ROBERTSON PUPIL. The diagnosis of interference
with the pupillo-motor reflex is of considerable practical import-
ance, because these paths appear to be particularly sensitive to
THE STRUCTURE OK T1IK EYEBALL
513
the presence of certain specific toxins in the blood. The com-
monest type is one in which there is contraction of the pupil on
accommodation, but little or no reaction to the stimulus of the retina by
light. This condition of the pupil is called the Argyll-Robertson pupil.
The seat of the injury appears to be either in the fibres travelling from
the retinae to the anterior corpus quadrigeminum or those coming from
these centres ami travelling to the 3rd nerve nucleus.
ACTION OF DRUGS. The following Table shows the action of certain
drugs on the pupil : —
Table to show Action of Drugs on Pupil.
Name of Drug
Pupils
Action.
Morphia . )
Opium . . J
"Small
Stimulate 3rd nerve nucleus.
Pilocarpine . \
Physostigminc.
Eserine . 1
Stimulate 3rd nerve endings in sphincter pupillsa.
( 'hloroform . )
Ether . . )
Atropine . 1
Homatropine . j
"
At first act like morphia. In larger doses cause
paralysis and therefore large pupils.
Large
Paralyse 3rd nerve endings in sphincter pupillse.
Adrenalin . }
Cocaine . J
Stimulate the sympathetic nerve endings in the radial
muscle fibres.
Curare . . )
Nicotine . j
Small or By paralysing the synapses in the ciliary or superior eer-
Large vieal ganglia if painted on them.
SECTION IV
THE NOURISHMENT AND PROTECTION OF THE
EYE
ANATOMY OF THE LIDS. Closing the orbit in front and in close relation-
ship to the eyes are the lids or palpebrse. The upper, which is the larger and
the more movable, is provided with a special muscle, the levator palpebras
superioris. This is supplied by a branch of the oculo-motor (3rd) nerve. The
two lids meet at an angle on both sides, forming the inner and outer canthi.
They are stiffened by two plates of dense fibrous tissue, parallel to their edges,
which are called tarsi. Near these and embedded in the substance of the
lids are two sets of glands, the Meibomian glands and those of Moll. These
secrete a greasy material which spreads over the lids. Superficial to these
structures but under the skin is a ring of smooth muscle fibres which is
common to both lids, the orbicularis palpebrarum, innervated by the 7th
nerve. Its contraction closes the lids. Lining the inner surfaces of the eye-
lids is a thin layer of mucous membrane, the conjunctiva, which is reflected
on to the front of the eye, and is continuous over the cornea as the anterior
epithelial layer.
CLOSURE OF THE LIDS occurs: (1) during sleep; (2) if a very
luight light enters the eyes; (3) by the sudden approach of some foreign
body ; (4) by contact of a foreigii body with the lashes ; (5) by irritation
of the cornea or conjunctiva; (6) in sneezing; (7) in order to renew the
fluid film on the cornea and conjunctiva. The reflex closure of the lids is
therefore a very important function in affording protection to the eyes. The
reflex apparently can be initiated by the stimulation of any of the branches
of the ophthalmic (1st) division of the 5th (trigeminal) nerve. From the
nucleus of this nerve in the pons Varolii fresh fibres take the impulses, it
is believed, to the upper part of the facial nuclei of both sides (7th nerve),
and from these to the orbicularis palpebrarum. This reflex is one of the
last to be abolished by anaesthetics and is therefore used as a convenient test.
It is called the corneal reflex.
The conjunctivae and the cornea are kept in a moist condition by the
tears, which are secreted by the lachrymal gland, situated in the upper and
outer part of the orbit. This is a small acino-tubular gland, in microscopic
structure similar to the parotid. Its secretion issues through several ducts,
the mucous linings of which are continuous with that of the conjunctiva.
Normally the secretion is just sufficient lo keep the surfaces of the lids and
514
NOURISHMENT AND PROTECTION OF THE EYE
515
Under
cornea moist, the evaporation keeping pace with the production.
certain circumstances there is excess, and tears are produced.
TEAR FLUIDconsists chemically of an aqueous solution oi sodium chloride
and carbonate containing mucus, albumen and debris. It is found to have
a bactericidal power which is lost if the fluid is boiled. Its functions are
to keep the surfaces of the conjunctiva and cornea moist, and to remove
foreign bodies and organisms. The secretion of tears is increased (1) by-
irritants and foreign bodies coming in contact with the cornea, conjunc-
FlG. 250. Diagram to show origin and fate of tear fluid.
tiva or lids ; (2) by irritation of the nasal mucous membrane ; (3) by power-
ful illumination of the eyes ; (4) By the incidence on the eye of infra-red
(heat) and ultra-violet (actinic) rays; (5) under the influence of emotion.
When excessive tear formation occurs the fluid either escapes over the
front of the lids, or is drained away through the lachrymal duct into
the nasal sinus. Three theories have been advanced to explain the
latter: (I) syphoning, owing to the mouths of the ducts being at a
higher level than their exit into the nose ; (2) capillarity, owing to the tendency
of the liquid to flow into the ducts through surface tension ; (3) active
removal by the act of blinking. It is not at the present time definitely known
how this occurs. Some say that on closing the eye the internal palpebral
ligament tends to be pulled on, and that this dilates and fills the lachrymal
sac ; others that the sac fills automatically through having been previously
emptied by the contraction of Horner's muscle. It is possible that both
processes occur.
The eyes of some fish and nearly all birds are provided with a nictitating membrane,
a semi-transparent shutter which can be brought over the surface of the cornea.
In the fish its possible function is to prevent the irritation of fine sand particles when
swimming in rough water, without at the same time disturbing vision, [n the case
of the bird n might be used (1) to moisten tin- cornea during flight without interrupting
,16
PHYSIO LUCY
vision: (•_') to reduce the light intensity when flying a( high altitudes or when travelling
towards the sun; (3) to reduce the irritation caused by ultra-violet orinfra-red rays
which are present in excessive amount at high altitudes.
NUTRITION OF THE EYE
The eyeball is richly supplied with blood vessels, which form numerous
anastomoses. Among these may be mentioned the arteries of the optic
nerve sheath, the long and
short posterior ciliary arteries,
the anterior ciliary arteries
which are branches from the
muscular vessels, and the con-
junctival arteries. These pierce
the sclera to ramify freely in
the choroid and the ciliary
bodies. The iris is supplied
by two concentric vessels, the
circulus major and the circu-
lus minor. Between the two
pass a number of radial fibres.
The retina, as will be shown
later, has a separate blood
supply through the central
artery of the optic nerve.
Other structures, notably the
transparent optical media of
the eye, have no direct blood
supply and therefore depend
on the flow of lymph from
neighbouring structures for
their nutrition. This fluid is
formed principally by the cili-
ary bodies, and is called aque-
ous humour.
AQUEOUS HUMOUR. The
chemical composition of this
fluid is water containing salts,
traces of albumin and glob-
ulin, and a reducing sugar;
it is probably freely oxy-
genated. This fluid after
secretion leaves the eye in one of three ways. (1) By travelling
through the pupil into the anterior chamber of the eye and then through
the spaces of Fontana at the edges of the iris (the so-called filtration angle)
into the canal of Schlemm and thus into the ciliary veins. (2) Through the
crypts in the anterior surface of the iris into the veins of that structure.
Fig. -■')'. Diagram to show the blood supply
of the eyeball. Arteries 'lined,' veins 'black.'
NOURISHMENT AND PROTECTION OF THE EYE 51?
(3) Between the suspensory ligaments of the lens, to the anterior surface of the
vitreous, then down the hyaloid canal to the papilla of the optic nerve, and
thus out via the lymphatics of the nerve sheath or the retinal vessels. But
whatever the fate of the liquid may be, it is clear that the amount secreted
must be the same as that which leaves, because otherwise there would be
a variation in the intraocular pressure. Insufficient pressure will tend to
disturb the correct relationship between the internal structures of the eye,
and at the same time will prevent the proper action of the ciliary muscle in
causing accommodation, because the suspensory ligaments of the lens will
already be relaxed. Too great a pressure on the other hand will interfere
with the proper blood supply to eye, and will prevent accommodation
because the tension in the choroid will be too great for the ciliary muscles
I'm. L'.jS. Diagram sin
origin and fate of aqueous humour.
to overcome (see page 52C>). It is therefore important that there should
be a proper control of the intraocular pressure. Experiments by Starling
and Henderson in which the intraocular pressure was determined by a
null method showed that such a mechanism exists, because as the arterial
pressure increased, so also did that in the eyeball.
Whereas the arterial pressure varied between 70 and 180 mm. (by a
difference of 110 mm.) the intraocular pressure was found to vary between
23 and 40 mm. (that is by 17 mm. only). The change in intraocular pressure
is therefore less than one-sixth that taking place in the blood ; the control
mechanism would therefore appear to have very considerable efficiency.
GLAUCOMA. The normal intraocular pressure in man is found to be
between 25 and 30 mm. of mercury. The tension thus set up in the walls
of the eyeball is principally borne by the sclera ; to some extent however
assistance is rendered by the choroid owing to its elasticity, and by Tenon s
capsule owing to the tonic contraction of its smooth muscle fibres (inner vafri I
by the sympathetic).
In abnormal conditions the efferent channels may become closed, either
from pressure of the lens on the iris (as in hypermetropia),oi from the presence
518
PHYSIOLOGY
of epithelial debris in the anterior chamber. The int radicular pressure under
these, circumstances becomes very high, the disease being known as glaucoma.
The principal symptoms of glaucoma are pain and impaired vision.
The chief diagnostic signs are a stone-hard eyeball, sluggish rather dilated
pupils, and the retina when examined through the ophthalmoscope is found
to show cupping of the optic disc, and vessels which an- thin and show pulsa
FlG. 259. Arrangement of apparatus for measurement of intraocular pressure.
(Henderson and Starling.)
c, is a piston-recorder for recording graphically the changes in pressure.
tion. In treating glaucoma operative measures to lower the pressure
should be taken immediately, because the high pressure interferes with
the proper blood supply to the eye. Since all hypermetropes (persons with
long sight) have a tendency to suffer from glaucoma, care should be taken
against giving drugs such as atropine which cause dilatation of the pupil,
since this increases the resistance to the escape of fluid at the filtration angle,
and therefore predisposes to an attack of glaucoma.
MALNUTRITION OF THE EYE shows itself in many ways : (1) as phlyctenular
conjunctivitis in young children ; (2) as myopia in school children in whom the sclera
being ill-nourished is unable to withstand the intraocular pressure, so that the sphericity
of the eyeball is destroyed; (3) as night blindness in middle age, the rod elements of
the retina being affected ; (4) as cataract in old age. In this condition the nutrition
of the crystalline lens is impaired, and as a result it loses its normal transparency. The
opacity develops sometimes at the centre (nuclear), sometimes in the cortex. The condi-
tion is treated by removing the lens (extraction of cataract).
SECTION V
THE OPTICAL SYSTEM OF THE EYE
The optical system of the eye consists of those structures which together
locus an image of external objects on the retina. In the mammalian
eye bhere are four concerned : the cornea, the" aqueous humour, the crystalline
lens and the vitreous humour. The histology of the cornea has already been
considered. The aqueous humour is a structureless liquid. The vitreous
humour consists of anastomosing trabecule of collaginous material, the
interstices of which are filled by a slowly circulating fluid similar to aqueous
humour. The vitreous is enclosed in the hyaloid membrane, and through
the middle of it runs the hyaloid artery during foetal life, which goes from
the central artery of the retina to the posterior surface of the lens.
THE CRYSTALLINE LENS is a biconvex transparent elastic
body, enclosed in an elastic membrane called the capsule. To the
periphery of the capsule are attached the suspensory ligaments
of the lens, which are formed by the anterior radial fibres of the
thickened portion of fchehyaloid membrane (the zonula of Zinn). Between
- 5/nus venosus
Conjunctiva
Retma
Fig. 260, Sectii
through anterior part of eyeball to show mode of suspi
of lens. (After Mkrkki. and Ku.i n
520
PHYSIOLOGY
the suspensory ligaments are shallow pockets into which the ciliary processes
fit closely. In this way the lens is held firmly in position, while at the same
time by the movement of the ciliary processes under the action of the ciliary
muscle, traction can be applied to the suspensory ligaments, thus effecting the
change in curvature of the lens, which will be shown later to be necessary
for accommodation.
Histologically the lens is composed of a number of radially arranged fibres
each of which is a modified epithelial cell. These fibres are arranged in
concentric layers, the more peripheral being soft, nucleated and of low
refractive index, while the central form a dense non-nucleated mass of high
refractive index, the fibrous layers between having an intermediate structure
and index.
REFRACTION BY THE CRYSTALLINE LENS. Refraction occurs
whenever light passes from a medium of one optical density into another.
It is due to the fact that the waves of which the beam of light is com-
posed travel more slowly in a dense medium, than they do in one of less
density. Some of the effects which this produces are shown in the diagram
below.
Fig. 261. Diagram .showing refraction of light.
(A) By an inclined surface, (B) by a lens, (C) by a plate of greater density at
its lower end than at its upper, (D) by a plate of greater density at. its centre than
at its edges. (E) by a lens of greater density at its centre than at its edges.
At A plane waves are seen entering a dense medium at an angle. At
B the medium is lens shaped. At C the medium has a plane surface but
has a greater density on the right than on the left. At D the medium
has a plane, surface but a greater density at its centre than at its edges.
At E the medium is lens shaped as at B, and also varies in density as at D.
The very great refracting power of such a structure is well shown. Since
THE OPTICAL SYSTEM OF THE EYE 521
this is the arrangement found in the lens of the eye, the power of
refraction is very much greater than an ordinary lens would possess of the
same curvature as the lens and the same refractive index as the average
density of its substance. The optical properties of the lens are therefore
unique, and it is interesting to find the same chemical substance in the lens
of different morphological groups of animals. This would point to the
substance with the required optical properties being somewhat rare. To
show the effect which the increasing density of the lens produces, the refrac-
tive indices of its parts may be compared with its equivalent R.I. (that is
the refractive index of a glass lens of the same size, shape and focal length).
The refractive index of the periphery of the lens is 1-37, and that of the central
nucleus 1 - 41 , the mean being about 1 -39. But the equivalent density of the
lens is found to be 1 '42, that is, greater by -03 than the mean refractive index
of its substance. The lens lies in contact with tw T o transparent media
both of which have an approximate refractive index of 1'34. The power
of the lens if its composition was uniform would therefore be proportional to
the difference between its own mean R.I. (1-39) and that of its surroundings
(1"34), that is to 0-05. Owing to its peculiar structure its equivalent R.I. is
1-42, and therefore its power is proportional to the difference between
that and 1-34, that is to 0-08. Owing to its structure the lens has
therefore increased in power in the ratio of 0-08 to 0"05. Now since the range
of accommodation depends, other things being equal, on the power of the
lens, we see that the peculiar structure of the lens has nearly doubled its
range. The graduation in the densities of the different layers of the lens
has a further advantage which will be described later, in that it reduces
the spherical aberration of the eye as a whole (see page 531 ) and also reduces
the amount of scattered light within the eyeball.
THE OPTICAL CONSTANTS OF THE EYE. In the case of the
crystalline lens, two methods are available for the determination of the radii
observers Ere
Fig. 262. Diagram to show a method of determining the curvature of the anterior
surface of the cornea. The images of the lamps A and B are caused to coin-
cide by shifting the position of the double image prism. The greater the
curvature of tin- cornea the closermust the double image [irism be to the eye.
of curvature of the anterior and posterior surfaces, namely measurements
mi the excised lens, either in the air or preferably suspended in a fluid oJ
522 PHYSIOLOGY
known optical properties, or by estimating the apparent size of the images
of an object which are formed by reflection at its surfaces. In order that
the latter method shall succeed, a device must be employed for eliminating
the effect of chance movements of the eye while under observation. This
was first done by Thomas Young, by employing a method used in astronomy
namely that of doubling the image to be measured and then adjusting t In*
lower edge of one image to be in coincidence with the upper edge of the
other. If the eye moved (luring the determinations, both image.-, moved
together and therefore difficulties in adjustment were avoided. Jn the case
of the cornea this method is alone available because only in the living state
is the true curvature preserved. In the case of the lens the determinations
are complicated by the fact that the refraction of the cornea has to be allowed
for. Further, the images that are seen are neither bright nor sharply defined ;
but in spite of this considerable accuracy is attainable. The following
are the approximate values given by these methods.
Radius of cornea ........ .8 mm.
Radius of lens, anterior surface ...... .10 mm.
Radius of lens, posterior surface . . . . . . i> mm.
THE REFRACTIVE INDICES (optical densities) of the eye media
are determined on the excised eye by means of the Abbe refractometer. It
is found that the cornea and aqueous are so nearly alike that for all practical
purposes they may be regarded as one, particularly as the posterior corneal
surface has nearly the same centre as the anterior. The refractive indices
may therefore be given as follows: — ■
Refractive index'of cornea and vitreous ..... 1-34 ■
Refractive index of lens (equivalent) ..... . I "42
Refractive index of aqueous humour ..... .1 -.'!.'i
THE APPLICATION OF GAUSS' THEOREM. In addition to the
above data we require to know the distance between the principal
surfaces; these are found to be: —
Distance from cornea to anterior lens surface .... 3-6 mm.
Distance from cornea to posterior lens surface . . . 7-6 mm.
Distance from cornea to the retina ..... 220 mm.
These values being known it is possible by calculation to determine the
path of any ray through the eye. The problem is however made very much
simpler by the application of Gauss' theorem, which may be briefly stated
as follows. Any system of spherical optical surfaces, the centres of which
lie along a straight line, possesses six cardinal points, namely — two principal
points h and h', two nodal points K'andK',andtw T o focal points, the anterior
and the posterior <$>' . It is found that these have certain properties which
may be summarised as follows : —
An object placed at the first principal point is found after refraction
to be at the second. Further, the image and its object are found to be of the
same size. A ray passing through the first nodal point on its way into
the system appears to come from the other on its way out, hut its direction
THE OPTICAL SYSTEM OF THE EYE
523
is still parallel to the path which it travelled initially. A ray passing through
either focus leaves the lens system on the other side parallel to the axis. It
is further found that the distances between some of these points are equal,
for example : — h = K'4>' and h'<£' = <£K. Also hh' = KK'. The
positions of these cardinal points has been determined in the case of the
eye with considerable accuracy ; the following approximate values may be
given : —
Distance from front of cornea to first principal point h
to second principal poinl h'
to first nodal point
to second nodal poinl
to anterior focus
to posterior focus
to retina.
K
K'
1 -7 mm.
2-0 mm.
7-0 mm.
7-3 nun.
136 mm.
22'6 mm.
22'6 mm.
The position of these points being determined, the direction of the rays
of light through the eye can be easily obtained, and is shown diagrammatically
in Fig. 263.
Fig. 263. The optical system of the eye shown diagrammatically,
H and H' principal points. K and K' nodal points. and 0' anterior and
posterior foci.
It is of some interest to know the relative part taken by the various
refractive media of the eye in the formation of the image. By far the
greater part is performed by the cornea. The following values in mm.
and dioptres may be given : —
Mm, Dioptres.
.24 .. 42
.44 .. 23
. 15-5 .. 65
Focal length of the cornea .
of the lens
of the whole eye
When opacities form in the lens (cataract) this structure "is
removed by operation. It is then found that a lens of approximately
23 dioptres has to be worn by the patient in order that he may
see distinctly. When the eye is placed under water the refraction <>l the
cornea is necessarily abolished because water has approximate]}' the same
refractive index. Underthese conditions the eye becomes too long sighted
for distinct vision. The eye of the fish has met this difficulty by the provision
524 PHYSIOLOGY
of a small, nearly spherical lens of very great density. In the fish therefore
the lens takes the principal part in the refraction of the ilight so as
to form an image.
REDUCED EYE. It is an interesting fad that, owing to the closeness
of the principal and nodal points to one another, it is possible to imagine the
media of the eye replaced by a single optical surface without introducing
any appreciable error. To this system is given the title ' reduced eye.'
Its constants are given in the following Table: —
Radius of surface . . . . . . . "> in in.
Position of principal point ...... . 215 mm.
Position of nodal point . . . . . . . 71 mm.
Position of retina . . . . . . . 22 C mm.
Refractive index . . . . . . • . .1 '33 mm.
Focal length ........ . 15'5 mm.
THE ACCOMMODATION OF THE EYE
The above description has been made on the supposition that the rays
entering the eye consist of parallel bundles, or in other words that the objects
seen are at an i nfini te distance from the eye. But during near vision such
is by no means the case. If there were no means of varying the focus of
the eye it would not be possible for divergent rays (those coming from near
objects) to be brought to a focus on the retina. The mechanism for varying
the focus of the eye is called the accommodation.
THE THEORIES OF ACCOMMODATION. Of these three are of historic interest
only. (1) That during accommodation the cornea increases in curvature (similar
to the bird's eye). This was disproved by Thomas Young who placed his eye under
water, replaced the corneal refraction by a convex lens, and then found the amplitude
of accommodation unaffected. (2) That the eye elongates in near vision, thus causing
the rays from near objects to focus on the retina (similar to the arrangement in the mollusc
Fig. 204 Methods by which accommodation of the refraction of the eye for objects
at different distances could be effected.
(A) By lengthening the eyeball. (B) By increasing curvature of cornea.
(C) By moving lens forward. (D) By increasing curvature of lens.
Pecten). This also Thomas Young disproved by placing two iron rings which could be
clamped together, one in front of and one behind the eyeball. Having very prominent eyes
he could do this if the eye being tested were rotated strongly inwards. The phosphene
caused by the pressure of the posterior ring, which extended to the fovea, did not change
in appearance during accommodation. He thus found no evidence for an elongation
of the eye during accommodation. (3) That the lens during near vision advances
towards the cornea (similar to the mechanism in the fish's eye). This view was
disproved Ijv Tscherning, who calculated that the lens would have to advance
nearly 10mm. in order to give the lull amplitude found for the eye, whereas the anterior
THE OPTICAL SYSTEM OK THE EYE
525
chamber of the eye is, as we have seen, approximately, --6 mm. only. This brings us to
the two modem theories, that of Hehnholtz and Tscheming. The theory of the former
(which is the one most generally accepted) supposes that the lens when removed from
the eye is strongly convex and is accommodated for near vision. When in the eye
however, it is caused to become flatter through the traction of the zonula of Zinn (suspen-
sory ligaments) on the edges of its capsule, and is therefore focussed for distance. But
when the ciliary muscle contracts, it removes the tension on the zonula and therefore
allows the lens to return by its elasticity to its more spherical form. Before describ-
ing the rival theory it would be well to examine the principal evidence on which
Helmholtz' theory has been based. During near vision measurement by means of
the ophthalmometer shows that the anterior surface of the lens advances slightly and
becomes at the centre of much greater curvature (10 mm. radius for distant vision, to
fi mm. for near). There can thus be no question that tin- change in the curvature
nt the lens is responsible for accommodation. The posterior surface is found to change
Fig. 265. Diagram to show the changes in the position and shape of the eye structures
ilurirc< accommodation. Thin line at rest ; thick line during accommodation.
but little ; almost the whole range is therefore produced by the anterior surface. The
i bangee found to occur in the lens may therefore be summarised as follows: —
Distance Near
Radius of anterior surface . . . . .10 . . 6
Radius of posterior surface . . . . .6 . . 5-5
Thickness of lens . . . . . . .3-0 . . 4
Focus of lens in mm. ...... 44 30
Focus of lens in dioptres . . . . .23 . . 33
If the lens in near vision becomes more spherical owing to the relaxation of the
zonula, as Helmholtz supposed, we should expect a lens removed from the eye to be
more spherical still, that is in a state of strong accommodation. Tscheming stated that
the changes in the curvature of the lens are much more complex than those given above.
During accommodation not only is there, he says, an increase in the curvature near the
centre of the lens, but at the same time a decrease in the curvature at the periphery.
This view he supported by quoting the careful measurements which Young made by
means of his optometer, and which have been confirmed by other observers. There
is found to be a zone about 1-4 mm. from the centre of the lens where the curva-
ture does not change appreciably. Inside this zone the curvature increases during
accommodation, whereas outside the lens becomes flatter.
Tscheming supposed that these changes of curvature are produced by increase in the
tension of the zonula during accommodation, in other words exactly the opposite action
to that which Helmholtz supposed to occur. This question as to whether contraction
of the zonula is associated with near or distant vision can therefore be used as a criterion
between tin- rival theories. Experiments have shown that tin- choroid moves
526 PHYSIOLOGY
forward during accommodation in both man and animals; further, Hess has shown that,
when lull accommodation has been performed, the lens is only loosely supported, so that
gravity can act on it and cause it to sink slightly in relationship to the other eye struc-
tures. These i-ITeets appeal- to he definitely in favour of Helmholtz' theory, and against
that of Tscherning. The way in which the contraction of the ciliary muscles causes
slackening of die zonula may therefore be given with some degree of confidence on
Helmholtz' theory.
THE MECHANISM OF ACCOMMODATION. The ciliary muscle con-
sists of two separate sets of unstriated muscle fibres, the more superficial
set of radial or longitudinal fibres, the deeper of bundles of radial fibres.
The former take their origin from the sclero-corneal junction, and are attached
to the anterior part of the choroid coat behind the ciliary processes. When
these fibres contract, they draw the choroid forward and inward, the
ciliary processes tending to occupy a smaller circle. The circular
fibres lie in the substance of the base of the ciliary processes so that,
when they contract, they cause the apices of the processes to come
together. In addition to these two sets of fibres a third set has been
described as meridional. These are however part of the radio-longitudinal
set from which there does not appear to be much object in differentiating
them. The ciliary muscles therefore have a common action, causing the
ciliary processes to form a smaller circle. The zonula of Zinn, or sus-
pensory ligament, is formed of a large number of very fine fibres which
run from the ciliary processes to the capsule of the lens. Further those
which arise posteriorly are attached anteriorly and vice versa. When the
ciliary muscle is in a state of rest, the tension in the choroid set up
by the intraocular pressure causes the ciliary processes to be pulled
in an outward and backward direction and therefore puts tension on the lens
capsule through the zonula. The lens therefore tends to be flattened and
accommodated for distance. On stimulating the ciliary muscle the tension
in the choroid is opposed and the ciliary processes approximated. The
zonula thus becomes slack, and the tension of the lens capsule decreases,
allowing the lens to take up its more natural spherical shape, and thus to
focus the rays from nearer objects.
Fig. 266. Accommodation in the cat's eye. R, distance ; a. for near vision.
(After Beer.)
Two needles have been passed through the edge uf cornea into the ciliary
bodies, to show forward movement of the hitter during accommodation.
THE OPTICAL SYSTEM OF THE EYE 527
INNERVATION OF MECHANISM OF ACCOMMODATION. The ciliary
muscle is innervated through the 3rd nerve, its nucleus being situated near
the mid line under those of the pupils. Owing to the close association
of the nuclei on the two sides it is impossible to cause accommodation of
the eyes separately. From these nuclei the fibres travel down with the rest
of the nerve through the outer wall of the cavernous sinus, and when they
reach the orbital cavity are given off to the ciliary (lenticular) ganglia, where
they anastomose with nerve cells the processes of which then proceed through
the short ciliary nerves to the eyeball.
The position of the higher centres connected with the nuclei concerned
in accommodation are not definitely known ; it is believed that theycomefrom
the occipital cortex. But since it is possible to carry out willed changes of
Eocus as well as subconscious ones, there must be connections with other
parts of the brain as well.
THE AMPLITUDE OF ACCOMMODATION in the emmetropic (normal) eye is
measured by ascertaining the nearest point from the eye at which perfect vision can
be obtained. Since it is possible that the eyes, when examined separately, can focus
nearer objects than they can when used together (owing to the limitation in the power
of convergence), one of the eyes should be closed when making the determination. In
the ametropic (abnormal) eye it is necessary to determine the far jxiint as well as the
near, since the former is not at infinity as it is in the emmetropic eye. But other diffi-
culties are encountered, because in the case of hypermetropic (long-sighted) eyes an
object placed at infinity still requires some accommodation in order to focus it. Lastly
there comes the personal equation of the patient, because it is found that even when
apparent Ly fully relaxed, the instillation of atropine usually causes some further relaxa-
tion of the accommodation ; so in the same way the instillation of eserine is usually
Followed by a definite increase in the accommodative effort over that which can be
voluntarily exerted. To obtain the maximum amplitude of the accommodation these
drugs should therefore be used. Where a comparative and relatively inaccurate value
is alone required they may be omitted. Of the many methods that may be employed
probably the simplest is by the use of the set of trial lenses, which vary in their curvature
by small uniform amounts from strongly convex (plus) to strongly concave (minus).
Tin- test object consists of a pin placed vertically in a board at any fixed distance from
i he eye. a white surface being arranged behind it. A pair of spectacles to hold the trial
lenses arc placed before the eyes, and in them are inserted two metal plates witl two
vertical slits in them, so that each eye in turn may look at the test object through the
slits in the plate opposite it. To determine the near point, minus (concave) lenses of
gradually increasing power are placed before one of the eyes, the other being closed,
until one is found that just causes the image of the pin to appear double. The power
of the next weaker lens is therefore taken to be the correct one. To determine the far
point, plus (convex) lenses of increasing power are tried in a similar manner, and that
one taken which just does not cause appreciable doubling. The difference between the
] >ower of the two lenses found in this way gives in dioptres the value of the amplitude of
the aeeonmioil.il ion. ( 'are should be specially taken to see that the value found for the
concave lens has the minus sign placed in front of it. Thus if it was found that the
far point was reached by the use of a convex lens of 2-2S dioptres, and that the near-
point required a concave one of 7-5 D., then the amplitude is not 5-25 D. but 9-75 D.
Careful measurements made in the above manner show that there is for different
ages a.n average amount of accommodation. In youth the amplitude is large, but h
decreases uniformly to old age. and this decrease is called presbyopia (old-sight). The
amplitude found as a, rule at different ages is approximately constant and is given in the
Table below.
528 PHYSIOLOGY
Age iii years. Accomi lotion in dloptffea.
10 13-8
15
20
25
30
35
4(1
45
50
55
fin
12-6
1 I -5
10-2
8-9
7-:<
5-8
3-7
2-11
[•3
11
This gradual reduction in the amplitude oi the accommodation is caused by the
hardening of tin- crystalline lens, which with the advance of years robs it of the elasticity
of youth. As a rule the change goes on unheeded till the time comes when the near
point of vision has receded so far from the eye that the I k lias to be held at a distance,
in order to be focussed clearly. Then it is found that the print, particularly if it is fine,
becomes unreadable, and convex glasses have to be worn. It is at that time that
presbyopia may be said to begin, usually at an age of 45 to 50, in emmetropia. In
hypermetropia, presbyopia shows itself earlier than normal, and in myopia (short-sight)
later. The reason for these differences will be described later when dealing with these
conditions.
The mechanism of accommodation is affected in a number of pathological con-
ditions ; the principal ones will be given. Paralysis of the ciliary muscles frequently
occurs after diphtheria and influenza: it is probably due to bacterial toxins
circulating in the blood. The paralysis usually disappears during convalescence. Loss
of accommodation is frequently one of the first symptoms of glaucoma: in this case the
cause is the abnormally high intraocular pressure, since that will cause so great an
increase in the normal tension of the choroid that the ciliary muscles have not sufficient
power to draw the edges of the choroid and ciliary bodies into a circle of smaller radius,
and thus to allow the lens to accommodate. Apparent diminution of the amplitude of
accommodation combined with apparent myopia (short-sight) occurs in patients who
have spasm of the ciliary muscles. This is found in two types of cases, children with
eye-strain, and women with hysteria. In both the employment of atropine yields the
normal amplitude and at the same time removes the apparent myopia, thus indicating
the cause of the trouble. Occasionally the amplitude of accommodation is different
in the two eyes, and is accompanied by unequal pupils. Such a condition may follow
an accident or be caused by specific toxins.
THE EFFECT OF DRUGS on the accommodation has already been alluded to.
In ophthalmic practice three are used in order to paralyse the ciliary muscle, namely
atropine (one- half per cent, solution), homatropine (2 per cent.) and scopolamine (one-
fifth per cent.). One of these drugs is placed within the conjunctival sac, and from here
it slowly travels by an at present unknown route to the ciliary and iris muscles, both of
which are paralysed. This fact is of the greatest importance, for if this path did not
exist the use of these valuable drugs would hardly be possible. Contraction of the
ciliary muscles and of the sphincter pupilhe is caused by the three drugs eserine.
pilocarpine and physostigmine, One of these is often used to counteract the effects
of the atropine group.
SECTION VI
THE REFRACTION OF THE EYE
Since the eye forms an imago of external objects by means of its refracting
media, it is found to have properties and to sutler from defects similar to
those met with in the case of other optical systems. We may therefore
treat the eye as if it were an optical instrument and estimate its efficiency
from that point of view. In the first place therefore we must consider what
kind of an image it would form if it were a perfect lens system, suffering from
no kind of aberration. Our experience of other lens systems, well-
nigh perfect, has shown us that the image of a distant point source of light
is nut a mathematical point, as geometrical optics would have us believe,
but is on the contrary a definite pattern of quite considerable size, the shape
and dimensions of which can cither be calculated from the conditions, or
may be seen, measured and photographed by appropriate means. The
formation of this pattern is flue not to any defect of the lens, but to tin-
fact that light is a form of wave motion, which exhibits a property called
diffraction.
DIFFRACTION OF LIGHT. When a broad wave of light surges through
the other from a distant source of light, its front travels straight and inflexible
under the influence of certain well-known laws. These in popular language
lest rain the tendency of a portion of the wave front to deviate, because of
.in equal efi'ort of a neighbouring portion of the wave front to do the same
thing, only in (lie opposite direction. At the edges of the wave on the other
hand there is no neighbouring portion from which to obtain support, and
therefore these edge portions tend to spread sideways more and more from
the main wave. A narrow ray of light therefore after passing through the
pupil of an optical system, will show this phenomenon to such a marked extent,
that only a small portion of the total amount of light will actually reach
the goal defined by the original wave front. The smaller the pupil and
I herefore the narrower the beam of light, the greater the amount of spreading
that we should expect to find. And experiment shows that this is the case.
Further, we should suppose that in the case of any one beam the more spread-
ing would occur the further the ray has to travel. This also is found to
be the case. Lastly if waves of different wavelength were tried, we would
expect a short wave to suffer more than a long, because to the short wave the
distance travelled would seem relatively greater. And so it is. We can
therefore summarise the above by saying that the size of the diffraction
pattern formed by any lens system varies directly as the focal length ol the
system anil the wavelength of the light, and inversely as the diameter of
529 34
530 PHYSIOLOGY
the pupil "through winch the lighl passes. In the caseoJ any lens system
such as the eve in which the pupil is circular, experimenl and calculation
are agreed thai the image of a point source consists of a series of concentric
rings of light, having a bright spot at their centre. The diameter of this
spot in the case of the eve is found to be 0'0] mm. with a pupil of '1 mm.
diameter. No matter how perfect the eye be as an optical instrument, diffrac-
tion sets a limit in this way to the perfection of the image that can be formed.
This should not however be thought of as a defect but as a property, since
it is caused by the nature of light itself. In the consideration of the principal
optical errors of the normal eve we have to decide in each case not only
to what extent the defect is present, but whether the defect produces any
noticeable change in the diffraction pattern which may affect definition.
DEPTH OF FOCUS, like diffraction, is a property of a lens system and not an
aberration. Its origin may be explained as follows: — Suppose objects 100 metres
awaj lo be forming sharp images on the retina, then objects at 200 metres will form
images which come to a focus slightly in front of the retina, and objects at f>0 luetics
images that are slightly behind. If however the focussing paints arc only a short
distance In front of or behind the retina, the image of a distant point which fell on a
single .one would still do so because the cone has a certain diameter, although its distance
from the eye hail been altered. Depth of focus in the ease of the eye is the greatest
distance through which a point can be moved, and still produce an image which tall.,
exactly on a cone without spreading at all on to neighbouring ones. For example,
in the above case the distance moved was from lit K > to oil metres, that is. the depth of
torus was 150 metres. Now it is found in the case of any lens system that depth varies
with the aperture of the pupil. Thus in the case of the eye the following values are
obtained.
Pupil diameter, Dspthat infinity. Depth at 25 cms.
1 mm. From inf. to S metres .... 3-2 cm.
2 .. .. „ 16 .... Mi .,
3 „ .. „ 24 .. .... II ..
4 „ . . .. ,. 32 .. .... -8 „
We see therefore that not only does depth decrease as the aperture of the pupil
increases, but that it also decreases as the mean distance of the objects from the eye
decreases. Thus with a pupil of 3 mm. the eye if focusscd sharply on objects 24 metres
away, would also be in focus for objects at infinity and also for objects at 12 metres.
Depth of focus is therefore considerable at this distance. But if the eye is working at
the ordinary reading distance (25 cm.) depth would be IT cm. only. At a pupil diameter
of 1 mm. depth would be increased threefold, and therefore the closure of the pupil,
which accompanies accommodation and convergence for near objects, has the valuable
property of increasing the depth of focus at the same time.
CHROMATIC ABERRATION OF THE EYF. It was shown in Section 1
that white light consists of a number of rays of different wavelength.
and that the short rays on refraction are more bent than the long.
When therefore white light is incident on a lens, the rays of short
wavelength come to a focus in front of those of longer wavelength. This
difference of focus for rays of different colour is called chromatic difference
of focus. Experiment show's that, when such a series of foci are formed
by the eye, the accommodation is so adjusted that the rays of greatest
intensity (usually yellow rays) form the most sharply focussed image, and
the colours of longer and shorter focus form blurred discs of light of
THE REFRACTION . OF THE EYE 531
relatively low intensity on top of this. Under these conditions it is found
that quite well defined images are produced. Tims, with a pupil of 2 mm.
diameter, approximately 70 per cent, of the light falls in an area of
0*005 mm. diameter. Further it may be shown that a lens system such as
the eye, which suffers from chromatic alienation, produces an image that
is only just appreciably worse than one that is perfectly corrected, when
the effects of diffraction are taken into account in both" cases. Bui since the
effects of chromatic aberration increase as the pupil enlarges, while those
caused by diffraction decrease, it is clear that the larger the pupil the more
does chromatic alienation tend to spoil definition. But as this is accom-
panied by decrease in diffraction, the two changes taken together have the
cll'cct of leaving the actual definition practically unchanged. This important
conclusion will be referred to again more fully in the last section.
Beside effects on definition, chromatic aberration causes small bright
points of light on a dark ground to form images which are largely
composed of yellow rays, and on the other hand small black objects
on a bright ground to be purple in colour-. The reason for these colours
being unnoticed in ordinary circumstances is due to the recognition by
the eve of the presence of the complementary colour which forms a fringe
round the central point.
SPHERICAL ABERRATION OF THE EYE. The employment of
spherical surfaces to bound optical media leads to a difference in the
position of the foci of rays that have passed through the centre of
the lens anil those that have passed through the more peripheral parts.
The latter usually form a locus nearest to the lens,. Since the eye is
bounded by nearly spherical curves it has keen assumed thai this aberra-
tion must be present in this organ. It should be remembered however
that the crystalline lens has a structure quite different to that found in
the lens systems of optical instruments. For the presenc I a, graduation
of optical density, culminating in a nucleus of relative great curvature, causes-
rays passing through the centre of the eye to be refracted to a greater
extent than more peripheral rays, or in other words exactly the opposite
effect to that produced by spherical alienation. .Measurements on the eyes
of different individuals therefore show the presence both of small amounts
of under correction (when the correcting effect of the lens nucleus has not
1 cm enough) and also actually of over correction (when the lens nucleus
has had too big an effect). In quite a number of cases the amount
of spherical aberration is negligible even with pupils of 4 mm. diameter-.
With larger pupils there is probably a certain amount of under correction,
but this again is less than would be found in the case of spherical surfaces
because the more peripheral parts of the cornea are flattened and therefore
refract less (as Gullstrand has shown). We may say therefore that in every-
day life the effects of spherical aberration are altogel ber negligible, compared
with those of diffraction and chromatic aberration.
PHYSIOLOGY
PERIPHERAL ABERRATIONS OF THE EYE.
So far the definition of an image lying on the principal axis of the
lens has alone been considered. When this is not the case other conditions
are encountered which introduce less favourable conditions. In the first
place the rays that form images on the peripheral parts of the retina make
considerable angles with the surfaces of the eye media. This will cause
chromatic difference of magnification, since blue rays will be more bent
and will therefore form smaller images than red rays. It will also introduce
' comma,' that is, the effect due to disobedience of the sine condition. It
is seen at once therefore that the image formation by the periphery of
the eye is altogether more imperfect than it is at the centre.
The presence of the nucleus of the lens still further impairs the marginal
definition. In fact we may say that in the eye, as in the. microscope objective,
the marginal images have been sacrificed in order thereby to improve the
central ones. That this has been a very valuable policy will be shown later.
1 1 will be shown in the next section that the most sensitive region of
the retina is not exactly in correspondence with the optical axis of the lens
system of the eye, being displaced approximately - 5 mm. to the temporal
side. We must therefore consider briefly to what extent the peripheral
aberrations of which we have just spoken will interfere with the definition.
THE SINE CONDITION (COMMA). This aberration is found to show itself in
optical instruments by a difference in the position of the various parts of the image
produced by the separate zones of the lens. Instead of rays from a point source
coming to a focus at one and the same point, they are found to form a fine
line in comma, the tail of which points towards the optical axis. If the optica]
system obeys a rule called the sine condition, comma is corrected. The eye appears
to obey this condition exactly, and therefore so far as comma is concerned the dis-
placement of the fovea to one side of the optical axis is no disadvantage.
CHROMATIC DIFFERENCE OF MAGNIFICATION, like chromatic difference
i if focus, is caused by the unequal refraction of light rays of different wave-
length. But since on refraction violet rays are more bent than red rays, their
foci form not only at different distances from the cornea, bat also at different angles
with the optical axis. It follows from this that objects, subtending a consider-
able angle at the eye, produce images which are smaller for violet rays than they
are for yellow rays, while those for red rays are larger still. Images produced by rays
of different wavelength therefore vary in size. Since that part of the retina which
possesses the best vision (the fovea) is situated to one side of the optical axis, all images
formed on it must suffer from this error. Far from this being a disadvantage however, if
is surprising to find that there is because of this an actual diminution of the effects of
chromatic aberration, ami thai the displacement is therefore a wholly beneficial one.
That this is probably the explanation of the development of the most sensitive part
of the retina at this point hardly requires indication.
RADIAL ASTIGMATISM must, according to optical theory, be present in the
image, formed on the fovea. Experiment shows however that its effects can be to a,
considerable extent neutralised by positive axial astigmatism such as is found in the
eye of emmetropes. The presence of this aberration may therefore be ignored so far
as the fovea is concerned.
STRUCTURE OF FOVEAL IMAGE may be determined approximately by con-
sidering in turn the effects of different aberrations on the light rays which enter the
eye, For this purpose the only errors of importance a.re chromatic differences of focus
THE REFRACTION OF THE EfE 533
and magnification. In addition however we must, take into account the very important
effects of diffraction. The final results of such a calculation show that
the images of rays of different wavelength overlap one another. At the
centre of the image is seen the sharp yellow focus of the highest intensity.
Eccentric to it and overlapping one another are seen the diffuse red and green
foci, which are of much less intensity. Where these overlap they produce a
compound yellow according to the rules of colour mixture. Further outwards is
the still more diffuse image of the bine rays, which is of almost negligible intensity.
It is seen therefore that the centre of the image is entirely occupied by the sharp and
intense focus of the yellow rays. Not only are these rays the brightest in the spec-
trum* but they are also those nearest to white light in their physiological properties.
It is because of this structure of the image that the acuity of vision is so great at the
fovea.
PERIPHERAL IMAGES have, as stated above, been to a considerable extent sacri-
ficed, so far as their definition is concerned, in order to obtain the best possible conditions
at the fovea. We find therefore at the periphery, images that in no way compare
with those formed near the optical axis of the eye. Even here however there is
evidence (bat the eve lias been designed to give the best results obtainable. The two
aberrations which must concern us other than those already mentioned are curvature
uf tin- field and distorsion.
CURVATURE OF THE FIELD is found in all positive lens systems of simple
formula. Since the photographic plate is Hat it is one of the principal errors to be
corrected in the photographic lens. In the eve on the contrary the effects of the
aberration have been avoided not by correcting the lens system but by curving the
sensitive surface to correspond. Calculation shows that, for correction, the radius of
the surface of the retina should be somewhat shorter than the equivalent focal length of
the lens system. Hut we know that the radius of the retina is approximately 10 mm..
while tin' focal length of the eye is 15-5 mm. The required conditions therefore appear
to ha ve been fulfilled.
DISTORSION shows itself in photography by a curving of lines which are known
by experience to lie straight. But this straightening, which can be readily effected by
suitably designing the lens system and by using a flat plate, is found to be accompanied
by a change in the size of an image, according as it is formed at the centre or the edge
o! the plate. Hut such a change in size would be most disadvantageous in the case
nf the eye. Iierause not only would the apparent size of objects vary, according as their
images fell mi the centre or tile periphery of the retina, but also the perception ot
perspective, which, as we shall see later, depends mi the correct estimation of the differ-
ences between the position of near and distant objects, would lie seriously inter-
fered with. In the eye it is very much mure important that images should
keep the same size, than that distortion should be corrected by optical means. In order
that images shall be constant in size, the retina must be curved to approximately
1 hr sa me extent as is required for the correction of curvature of field. We see therefore
t ha i l lie shape of the retina has a very important effect on peripheral vision, and further
that, so far as we are able to judge, the best shape has been adopted.
OTHER OPTICAL DEFECTS. The analogy between the eye and the photo-
graphic camera shows that there are a number of other defects from which the eye
may suffer; these are (1) the presence within the eyeball of light scattered from one
part of the retina, to another (equivalent to shiny bellows in the camera) : (2) the
spreading of the image formed on one part of the retina to neighbouring portions
(equivalent to halation) ; (3) the illumination of the retina by light internally reflected
at the different optical surfaces (known in photography as flare) ; (4) the exposure
of parts of the retina close to those receiving the image because of imperfection in the
optical system (called irradiation).
Scattered Light. In describing the histology of the retina it will be shown how
generously tin- layer ot cells lying immediately under the sensitive layer of mils and
v;i PHYSIOLOGY
cones is supplied with pigmenl ; the objeot of these is clearly to absorb scattered light.
In spile of this however we find considerable amounts of light being reflected baok
, ii,, by the retina ; in fad ii is this ligh.1 thai enables us to see the retinal nerves
and vessels through the ophthalmoscope (sec page 554). The spherical shape of the
eyeball will cause the greater pari of this reflected lighl to travel towards the front of
the rye and to fall on an insensitive layer of iris or retina anterior to the ora serrata.
From here it will be reflected again on to the retina, bul with such reduced intensity
as not to cause stimulation. Light reaching the anterior pari of the retina through
the | in | ii I would after reflection tend to travel towards the posterior pari of the retina,
thai is the part most sensitive to light. The intensity of these peripheral rays is how-
ever diminished in a number of ways: firstly by the eyebrows, cheeks and nose;
econdbj by the eye-lashes when the lids are approximated, as they are when looking
towards a bright light ; thirdly by the relative smallness of the pupil for oblique rays
(the pupil being a slit shaped instead of a circular opening for such rays). The effect
of scattered light in the eye is therefore eliminated in tins way. It should be noted
thai in certain animals, which have very acute night vision, the pigment cells of the
choroid at the posterior pole of the eye are iridescent, and form a highly reflecting
urface behind the retina, which is called the tape 1 turn. The object of this would seem
to he to increase the stimulus of a given intensity of light, bul the presence of this
reflecting layer must increase tin- amount of scattered light in the eye, and would
therefore appear to he of disadvantage in day vision.
Halation. This is caused in the camera by the image that has formed on the plate
Inn i." idler ird back again on to the plate from the internal surface of the glass. This
is not apparent in the photographic film, because owing to the thinness of the gelatin
film flic reflected image falls back on to the same part of the plate again. In the case
of the retina the reflecting layer must lie exceedingly close to the sensitive layer, if
indeed tin- two are not identical: halation in the eye would therefore appear to be
negligible in amount.
Flare. The amount of light reflected by the surface bounding two optical media
increases as the difference between their refractive indices increases, and also with
the angle which the light makes with the surface. Therefore, other things being equal,
I he mailer the angle of incidence and the more nearly the refractive indices are identi-
cal, the less the amount of flare will he. In the eye the lens system is as i I were immersed
in a medium of almost the same refractive index as itself : and furl her even that differ-
ence is reduced by (he fact that the actual refractive index of the crystalline lens is
very much less than its equivalent R.I. owing to its peculiar structure. Flare in the
eye must therefore be quite inconsidera ble in amount.
Irradiation. That this phenomenon is present in the eye'may he shown directly
by experiment. If for example an electric light filament be looked at before and after
(he switching on of the current, the increase in thickness on illumination is obvious.
Its cause appear- to be imperfect definition, spreading of the lighl from one retinal
element to its neighbours, or .spreading of the nerve impulse cither at the retina or
even in (he brain itself.
ABNORMAL REFRACTION OF THE EYE
It would almost ho anticipated that such a complicated organ as
the eye would he found to show individual abnormalities. A further con-
sideration would probably suggest to us that, considering the smallness of the
change that is necessary in any one of the optical media in order completely to
destroy definition, if is nothing short of astonisbing that abnormality of refrac-
tion is relatively so uncommon. In the newly born the eye is almosl always
long-sighted (hypermetropic) : this is due to the eyeball being too small for
the optical system which it contains ; the image formed by the latter is there-
fore focussed behind the retina. As age advances the eyeball grows until
THE REFRACTION OF THE EYE 535
the point is reached at which the eye is emmetropic (normal). It' however
the child is allowed to use its eyes too much for near work, the eyeball
goes on increasing in size until it has overshot the mark and has thus caused
the eye to become short-sighted (myopic). There would appear to be
some kind of automatic control, which causes the eye to grow till it
is in adjustment with the conditions most frequently encountered. This
hypothesis is confirmed by the fact that if a child which is beginning to
develop short-sight is prevented from using near vision for a year or two,
the development of short-sight stops. The importance of the early detection
of the onset of short-sight therefore cannot be too strongly urged.
THE METHODS OF DIAGNOSIS. The Setection (.tennis of refraction in the
,i\ be effected in various ways, each of which is said to possess advantage. Some
of these have come into such general use that they may be briefly considered as an
introduction to the description of the more important types of error which thej are used
to investigate.
THE DETERMINATION OF THE VISUAL ACUITY. It lias been found by
experiment that persons with normal sight can distinguish between objects when the
angle separating them is not much less than One minute. Test type lias therefore
been prepared in which the letters are composed ol lines which subtend this angle at
the eye. when the type is placed at a standard distance of six metres. Persons who
are aide to read the type at this distance arc said to have normal vision. Above these
standard letters are placed a series of larger letters, which al two, three or four
times the standard distance would subtend the standard angle. A person with reduced
acuity might be able to read at six metres the type that should he read at sixty. He
therefore has vision which is one-tenth th" normal. Such a person might have
long-sight,. short sight or astigmatism : to determine which is present a pair of spectacles
is placed before his eves into which can be inserted any two of a la ice selection of glasses
of different power, which are known as (rial lenses. These are tried in turn ill an orderly
manner until some are found which allow the man to read the standard type at the stan-
dard distance. His visual acuity is now at the normal and the strength and shape of
the glasses in front of his eyes is carefully noted, so that others of the same power may
in fitted I" spectacles tor him to wear. If the glasses are found to he convex (plus).
then lie was suffering from long-sight (hypermetrqpia), and if com -a ve (minus) from short -
ii 'lii (myopia). But if on the other hand cylindrical lenses had to be used, then be
had astigmatism, cither alone or in conjunction with long- or short-sight.
THE METHOD OF RETINOSCOPY. Such a method as that just described
could only succeed if the person tested were an intelligent adult, because we depend
entirely on his giving the correct answer when wc ask, if the substitution of a different
lens to the one we have already placed before him makes vision better or worse. With
a child such a method could never succeed. Another method is therefore practised,
which has the great advantage of being independent of the patient; in fact for the
purpose of the test he might be blind. This method consists in throwing into each of
his eyes in turn, a beam of light reflected off a plane mirror, in the centre of which is
a hole, through which the doctor looks. When 1 1 it ■ beam of light is directed into the
patient's eye the doctor sir., a pink reflected beam of light coming to him through
the patient's pupil. As the mirror is gently tilted, SO as to throw the beam slightly
upwards and slightly downwards, so the pink beam appears to move up and down
behind the patient's pupil. If it moves down as the mirror is tilted down the move-
ment is said to be WITH the mirror, and the patient is hypermetropic, requiring plus
spectacles. If on the other hand the beam mows m:\i\si. minus spectacles are
required since the patient is short sighted. By placing glasses of different power in
front of his eye until oneii found which cau es I Ik- pink beam to move neither with nor
i the mirror, the actual power for the spectacles required by the patient i .1 111
536
PHYSIOLOGY
tinned. It should be carefully noted however that, since the doctor is standing at
about a meter distance from the eyes of his patient, plus one I) must be subtracted from
the power of any glasses that are found to be necessary. Thus it the patient was
found to be myopic and minus 7 D spherical lenses were required to neutralise the
movement of the beam, then the power that should be ordered is minus 8 l» spherical.
This test is found to work admirably in practice. It is better to have paralysed the pupil
reflex and the accommodation of the patient previous to the test by the use of atropine.
but some say that this is unnecessary.
OTHER METHODS. Of other methods of testing vision little requires to be said :
some require the use of special instruments such as the optometer and the refractometer.
Another again depends on the determination of both the far and near points. This is
of distinct value because it at once gives the amplitude of the accommodation, which
is an important determination. Others are based on the use of the ophthalmoscope.
But none of these methods are so simple or accurate as the method of retinoscopy
described ah ive.
STENOPEIC APERTURE. Often in practice the question arises as to whether
low visual acxty is due to defect in the optical media of the eye, or to disease of the
retina,. This question can be readily answered by placing in front of each eye in turn
a metal disc in which has been drilled a one- third millimeter hole. If this improves acuity
the defect is not ill the retina ; if it does not it is. This test should lie done in a good
light because of the small amount of light passed by the hole. A hole used in this way
is called a stenopeic aperture.
HYPERMETROPIA OR LONG-SIGHT. There are two principal varieties of
long sight, firstly that in which the eyeball is too small and too short for the normal
optical system, secondly that in which the eyeball is normal hut the refracting power
of the lens below the normal. The first variety is found in childhood, because the optical
system reaches its adult size much earlier than does the eyeball. In the majority of
children the eyeball continues to grow until it is the correct size, and therefore long-sight
disappears. In a certain number of cases this does not happen and therefore long-sight
remains through life. The second variety is found in old age, and appears to be due to
the absorption of water by the lens; the result in both cases being that the rays of
light from distant objects are brought to a focus beliind the retina, and therefore in order
to focus them the accommodation has to be used (see Fig. 2f!7). It follows from this
luo. 267. Hypermetropic eye.
The eyeball is too short and therefore
rays from a distant object come to a
focus beyond the retina.
Fiu. 2G8. Myopic eye.
The eyeball is too long and therefore
rays from a distant object come to a
focus in front of the retina.
THE REFRACTION OF THE EYE 537
that there is less accommodation remaining for the focussing of near objects, and there-
ion- an inability to see. distinctly at relatively short distances from the eye. Thus the
use of the term Long-sight.
Hypermetropia in adults is therefore more an abnormality than a disease ; it causes
a disposition however to three more serious conditions, namely glaucoma, internal strabis-
mus and eye-strain. Glaucoma has already been described (see page 517) ; it is due to
an abnormal rise in the intraocular pressure, which occurs owing to the free escape of
the aqueous humour at the filtration angle being checked. Now in hypermetropia we
have seen that the eyeball is too small for its optical apparatus, and therefore the lens
occupies too much of the space in the small anterior and posterior chambers. This
causes the ciliary bodies and roots of the iris to be squeezed and greatly reduces
the space at the filtration angle. An attack of glaucoma is therefore more liable to
occur in the hypermetrope than in a person with normal refraction.
Internal strabismus is caused in hypermetropia by the accommodative effort that
is made in order to focus an image on the retina, because, as we have seen above (page
497), convergence and accommodation are associated actions. When therefore the long
sight has been corrected by means of spectacles, ami the accommodation is no longer
called into play for seeing at a distance, the associated convergence no longer occurs
and the strabismus disappears.
Eye-strain is caused in hypermetropia by the continual call for accommodation.
Further, this must occur without convergence, for otherwise diplopia (seeing double)
and strabismus develop as just described. A special strain is therefore placed not only
on the ciliary muscles but also on the external eye muscles. This state of affairs \ el A
rapidly causes fatigue, headaches are therefore common.
The treatment of long-sight consists in prescribing suitable convex spectacles. It
should be noted that the amount of long-sight actually present is shown only when the
accommodation has been paralysed by atropine, because the patient has grown so accus
tomedtouse his accommodation in ordinary vision thai he is unable voluntarily to relax it.
There is a certain amount of spasm of the accommodation. Because of this the glasses pre
scribed should he iess strong ai first than the full correction shown to be necessary.
These may lie substituted by more powerful ones later.
MYOPIA OR SHORT-SIGHT. In this condition parallel rays. that, is those coming
from distant objects, come lo a focus so far hi front of the retina, that the image appears
blurred (see Pig. 268). Myopia may be caused in two ways, which are similar to.
hut opposite in action to 1 1 lose that cause hypermetropia; the first type is caused
b\ the eyeball being too long, and the second by the refraction of the lens being too
high. The former, which is (he more common, usually develops in youth, particularly
at the school age when the growth of (he body makes special demands on the system,
and at the same lime feeding is usually bad. The constant use of the eye for near work
causes them considerable strain which they are unable to withstand owing to their
being unable to compete for nourishment with the rest of the body. The choroid and
si (era t herefore become thin, are no longer able to stand the tension set up by the intra-
ocular pressure, and therefore expand, causing the eyeball to become larger than normal.
and taking the retina beyond the focus of the optical system. The treatment
of myopia is therefore not only the wearing of spectacles, but the absolute prohibition
of near work or close study, the administration of extra-nourishing food and an
open-air life for a year or more. If these steps are taken at once, the myopia, may
get no worse, and may in fact get better. But if neglected the condition will almost
certainly get worse. As myopia is a disease, particularly liable to occur at the school
age, schoolmasters and others associating with children should be on the look out for
conditions likely to cause it, such as bad light, bad food and poor ventilation, and tor
its presence in any of the children. Glasses should always be prescribed and care taken
that, the child wears them constantly, because it is found that beside assisting good
definition and relieving eye strain, they actually tend to cheek the further development
of the trouble.
538
PHYSIOLOGY
■yeball
3ed by
Certain complications sometimes attend myopia; these are divergent strabismus'
eye-strain, and spasm of the accommodation.
The divergent Btrabismus lias a similar origin to the convergenl strabismus met
with in nypermetropia, namely association of deviation of the eye axes with the adjust
ment el the ac imodation. Now- since in the normal individual the relaxation of the
aceommodal ion of the eye is associated
with parallel axes "1 the eyes (in order
in look at distant object! ). in myopi i
the disuse oi the accommodation for
near vision causes theeye axes to re
main straight and therefore produce
the effects of an external strabismus.
The use of glasses introduces again the
necessity of accommodation, exactly as
if the eye was 'mal, and therefore
abolishes the strabismus. In the ma
jority of ease, an actual strabismus
does not develop, but there is never-
theless a strong tendency to diplopia.
especially when the eyes are tired.
The eve-strain which frequently ac-
companies in\ opia proba bly hai it
origin in the effort to converge the
eye axes Without at (he same time
calling the accommodation into play.
Spasm of accommodation fre-
quently accompanies myopia, and has
the effect of making themyopia seem
greater than it actually is. The true
state of affairs is at once found when atropine is used, because the accommodation is
thus abolished. Sometimes in children spasm of accommodation occurs without any
actual il' 'mality of refraction. Such cases should he treated with the same care
as those that are already developing myopia.
ASTIGMATISM. The condition of the eye called astigmatism is one ill which
parallel rays arc not brought to a focus in a single plane, but in a number of different
planes. There are two different varieties of astigmatism. In the first or irregular
variety the separate parts of one meridian of the eye form different foci.
This is found to occur during the development of cataract in the crystalline
lens, and also after ulceration of the cornea. The effects of this form of astigmatism
on vision vary with the severity of the condition : in moderate cases a frequent pheno-
menon is the formation of a double image in the affected eye. Glasses as a rule do not
give benefit. In severe types the use of a stenopeic aperture may improve definition.
In the second variety, or regular astigmatism, the parts of any one meri-
dian give the same- focus, but the different meridians have different foci.
There are however two meridians at right angles to one another, one of
which has the longest and the other the shortest focus, the meridians
in between showing an orderly sequence between these two extreme values.
Thus the use of the term regular astigmatism. Two types of patient are found to
Buffer from fins condition, those who have inherited and those who have acquired it
as a sequence to injury, operation or disease. The effects on vision are varied, but
the characteristic features ate distortion of objects looked at, and indistinctness of
lines in one direct i. .n. while those at right angles are quite sharp. Headaches, eye-strain
and dimness of vision are very common. Many types arc met with because the maximum
anil minimum meridian may occupy any angle so long as they arc at right angles to
one another, and they may have any degree of myopia or nypermetropia.
Fig. 269. The asymmetry of tin-
anil kinking of the optic nerve ca
high myopia.
THE REFRACTION OF THE EYE
539
70. Showing the shape of foci at different position
The diagnosis and measurement of astigmatism presents no difficulties. Its exist-
ence may be readily proved by causing the patient to I > •< > 1^ at a figure consisting of a
.scries of lines radiating from a common centre. It is then found that while sunn' of
the lines are sharp those a1 right angles are indistinct. This test also slums the axes
of the principal meridians. By retinoscopy (seepage535) the axes and the antounts
i the abnormality in those axes may be readily determined. The treatment con d I ■
in giving spectacles which have been ground on one side to a cylindrical surface. The
axis of this cylinder is adjusted to correspond with one of the principal meridians of
the eye of the patient. The curve given to the cylinder is that which will cause th<-
focus of the meridian with which it corresponds to be equal to the focus of the other
meridian. The other side of the spectacle lens is ground to that spherical surface
which will make the eye emmetropic after it has Keen corrected by the cylinder.
ANISOMETROPIA. Tin last abnormality of refraction, which we have to consider,
is called anisometropia; It simply means difference between the refraction of the
two 1-ytv. The effect on vision is very slight, since it is found that as a rule eye
docs all the work and the image of the other, which is necessarily indistinct, is prevented
from reaching consciousness. The result in course of time is that the unused eye loses
to a considerable extent it i power of seeing and as a result strabismus develops. Treat-
ment consists in giving glasses w hi h correct each eye separately, ami then instituting
ci es for the poorer eye. in on lei' to improve it-- vision. The results of this treatment
are good.
SECTION VII
HISTOLOGY OF THE RETINA
The retina is a delicate membrane lying inside the choroid coat of the eye.
Its internal surface lies in contact with the hyaloid membrane of the vitreous
body. It is thus supported on both sides. The retina itself consists of
two layers, tin' outer or pigmented, and tin- inner or nervous. Whereas
embryologies 11 v the retina covers the whole internal surface of the eye includ-
ing the ciliary processes and the iris, this is not the case with the nervous
layer, because this stops near the equator of the eye at the ora serrata, and
is here replaced by a layer of columnar epithelium. Opposite the pupil a
yellow spot is seen on the retina, the macula lutea, and in the centre of
this there is an oval depression, the fovea centralis. The optic nerve enters
the eyeball through an aperture in the sclera and choroid, and then passes
through the posterior surface of the retina to spread out over the internal
surface. In the fovea however this is not the case, for the depression at
this point is caused by the absence of nerve fibres. The point at which
the optic nerve enters the eye is easily recognised from inside the eyeball
because the numerous white nerve fibres, as they bend over the edge of the
aperture in the retina, form a characteristic white mound called the colliculus,
at the centre of which is a depressed portion called the optic cup. It is in
the centre of this cup that the central artery of the retina and the cone
s ponding vein first make their appearance. These have the important func-
tion of nourishing the retina; the additional blood supply through the inti-
mate contact between the retina and the vascular choroid, althoughimportant,
is quite insufficient to supply the needs of vision, as is shown by the immediate
and permanent blindness which follows blocking of the central artery of the
retina.
When sections of the retina are examined under the microscope it is found that
they consist of (lie following layers from within outwards:
1. Layer of nerve fibres and vessels
2. Layer of ganglion nerve cells
X Inner molecular or plexiform layer I ,. . , , ,
r • DeveloiM-d from anterior layer
4. Inner nuclear or granular layer - , . ,.
, , , "I optic vesicle.
5. Outer molecular or plexiform layer
fi. Outer nuclear or granular layer I
7. Layer of rods and cones (bacillary layer)
8. Layer of pigmented epithelium .. •■ Developed from posterior layer.
540
HISTOID »<;V OF THE RETIN \
541
In order to understand the structure of these layers, it is necessary to keep
the lnt in mind that the optic nerve and cup arc outgrowths of pari of the
EXTgRNAL
GANCLICHIC LAYfR
STRATUM QPTICUM
■NJ£RHAL
Fig. 271. Diagram of transverse tion oi retina.
brain. We must therefore be prepared to find in the retina, the presence of all those
structures winch are found in the case of every sensory nerve to intervene
between the sense cell and the brain nucleus. Be it taste-cell or touch-cell, m-
\ cell of any cither kind, the stimulus is conveyed in every case through three
sets of neurons or relays before it reaches the brain. We must therefore expect to
find m the retina all these three sets of neurons represented.
THE NERVE FIBRE LAYER (stratum opticum) consists of the non -myelinated
(noii-nicdullated) axons of the large ganglion cells found in the second layer. These
axons are the third order neurons which become myelinated after tiny have passed out
of the eyeball and travel bypaths to the occipital cortex described on page 532.
Beside the fibres conveying visual impressions there are others which belong to the
pupillo-motor reflex. Others again bring impulses from the- brain to the retina; their
functions will be considered below.
THE GANGLION NERVE CELL LAYER consists of a single layer of large oval
cells. These are nucleated and give off the axons which we have already described
>42
PHYSIOLOGY
and .' bunch of dendi iti s h hich ramify with others in thi inner molecular layer. < Inly
al the macula is more than • layer of ganglion cells presenl ; this is due to their almost
complete absence at the fovea. The macula therefore not only has its own relays but
tlu.se of the fovea as well.
THE INNER MOLECULAR LAYER consists of a felt-work mad.- up by the
interlacing dendrites of the ganglion cells with those of the inner nuclear cells or second
order neurons. There are also the dendrites of horizontal cells or spongioblasts, These
possibly serve to associate the impulses from different parts of the retina, such as is
supposed to occur in the brain, it should be noted that they appear to be absent in
the fovea and macula.
THE INNER NUCLEAR LAYER largely consists of bipolar second order neuron
cells. There are however also present the nuclei of the horizontal cells, and also the
nuclei of similar cells, whose dendrites travel in the outer molecular layer. The bipolar
cells, which arc fusiform in shape and nucleated, ale of three kinds : (a) those which
connect with rods. (6) those which connect with cones, and (c) giant bipolars which
connect with either.
the different cellular structures found in the retina.
THE OUTER MOLECULAR LAYER is much like the inner; it consists of the
dendrites of the second order neurons and the first.
THE OUTER NUCLEAR LAYER consists of the cells of the first order neurons
or the granules of the rods and cones. The cells arc nucleated, somewhat smallci than
the dipolar cells, and their nuclei are striated. They give off two processes, one of which
forms dendrites in the fifth layer, the other connects with either a rod or cone as the case
may be.
THE BACILLARY LAYER of rods and cones is separated from the previous layer
by the externa] limiting membrane. Both rods and cones consist of an outer and inner
Limb, the forms of which are well shown in Fig. 273. It will he seen that the outer
limlis arc striated, the cones coarsely, the rods finely. Like some types of striated
muscle they tend after hardening to break up into discs. The inner Limbs of both rods
and cones have a strong affinity for dyes.
THE STRATUM PIGMENTI is the only one that is developed from the external
layer of the embryonic optic cup. The epithelium consists of a single layer of hexagonal
nucleated cells containing numerous pigment granules. The cells send fine processes
HISTOLOGY OF THE RETINA
543
•h they
between the limbs "I the mils. The bases of these cells are firmly attached to the
choroid and thus give support to the resl of the retina.
The object ■•! these cell processes and the pigment granules wl
contain would appear to be either the preven-
tion of an image formed on one part of the
retina from spreading to the sensitive elements
of surrounding portions, or elsethe protection of
these elements from excessive light action. But
it has been definitely proved that the cells
themselves have another and important func-
tion to perform, namely the secretion of the
pigment called visual purple (rhodopsin). The
important functions of this pigment "ill be
described later.
It should be noted that beside the struc-
tures described above, which have the func-
tional activities of the retina to perform, there
are a number of connective tissue elements
which form the retina into one coherent struc
tine. Since the retina is developed from an
outgrowth of the brain, these structures are
mi i I 1 1 iii type to those met there; we there-
fore find neuroglia and also long cells which
extend through the first seven layers and hold
them together, namely the fibres of Miiller.
THE DEVELOPMENT OF THE RETINA.
The complex Series of layers of which the
retina consists are developed from the two walls
of the primitive optic cup, which grows as a
hollow laid from the anterior cerebral vesicle "I
t!n embryo. At first the tun layers are of the
same thicknees, hut the outer becomes reduced
t'i a single layer ol flattened cells; which become
pigmi nted, forming the stratum pigmenti. The
i ini i layer consists at first of a single layer of
elongated nucleated cells, which become differ-
entiated into spongioblasts, germinal cells and
neuroblasts, similar to those found in the de
velopmont of the spinal cord. The spongioblasts I
form the inner and outer limiting membranes,
and a groundwork within which the functional
elements develop. The germinal cells give rise
to three series of neuroblasts in all. The first
Fig Jt:>.
I, a rod : 1 1 . a ei
of mammalian
retina ; h, external limiting membrane.
(It. Gbeefe )
set are much larger than the others, and become
tin- ganglion cells (these appear to he formed by mitotic di\ ision). The next two ' l ■
are much smaller, and become the first and second nuclear layer (these seem to be
formed by amitotic division). Lastly the germinal cells themselves become trans-
formed into the rods and cones. The molecular layers are formed of the arborisations
of the processes of the cells between which they lie. The innermost layer of nerve
fibres is formed by th i growth of long processes from the ganglion cells, which make
their u:i\ from the retina into the brain.
THE DIFFERENT PARTS OF THE RETINAslmw marked variation in detail.
At the fovea cones alone are found; each of these connects to one axon only.
Other structural differences are found beside (1) absence of rods, namely
(J) the cones are longer, more highly developed, and some say mure rod like than
&a
I'l I ^ si< M,< m ;^
those found elsewhere. Thej an very cloaeTy packed, so that their inner limbs
arc seen in transverse section t>> h;i \ >■ a hexagonal slu> ] ><■, the fiat surfaces being
in contact with those Of their neighbours. (3) The rows of nerve cells and
ili mlntes. which iii the rest, of the retina lie approximately in line with the rod
or cone to which they belong, are in the fovea pressed to one side, in a direction away
from the centre. In this way a cone may have the nerve cells to which it is connected
placed at a considerable distance away in the surrounding macula. It is this displace-
ment of the nerve fibres and their cells that causes the fovea to appear hollow. The
Fig. 274. Section through half the fovea centralis
and GOLDING l'.IR!>.)
purpose of this physiological arrangement would appear to be without question the
avoidance, at this important region of the retina, of the scattering of the image which
passage through the nerve cell layers would introduce. (4) The fovea unlike the
rest of the retina is devoid of blood vessels. The purpose of this arrangement would
appear to be similar to that just given. (5) Visualpurple is said to be absent from the
fovea, This would appear to be connected with the absence of rods.
Hound the fovea is a ring in which rods and cones arc present in almost equal
number. In still more peripheral regions cones are relatively few, and several rods
connect with each axon: this reduces the relative number of nerves.
CHANGES IN THE RETINA ON EXPOSURE TO LIGHT
A light stimulus falling on the retina causes a number of changes to occur
which may be classed as structural, physical, chemical and physiological.
STRUCTURAL CHANGES occur on exposure of the eye to light :
firstly, movement of the pigment from the outer epithelial layer into
the space between the rods and cones, secondly, shortening of the
cones themselves. These changes occur only when the connections of the
eye with the brain are intact. The rate of movement appears to vary with
intensity, and violet light is said to be better than red. It is interesting to
find that electrical stimulation of the optic nerve or the falling of light on
the other retina to that of the eye observed also causes these cone move-
HISTOLOGY OF THE RETINA
545
i niMiis. It is supposed that the impulses which effecl these movements i ravel
through the nerve fibres already described as descending from the brain tothc
retinae; it is for this reason that Engelmann called these fibres ' retinomotor.'
Others! ructural changes that arc ton ml, by histological investigation, to follow expo-
sure of the retina to light, arc swelling of the oufer limits of the rods, and the disappear
ance of chromatin granules from the ganglion cells. Both these changes are said to
occur more rapidly under the action of rays of short wavelength.
PHYSICAL CHANGES are also bund when the retina is stimulated
by light, namely an electrical response somewhat similar to the current
A B.
Fig. 275. Sections of the frog's retina.
\. kept in the dark; n. after exposure to the light, showing retraction of the
cones, and protrusion of the pigmented epithelium between the outer limbs of the
rods. (Engelmanit.)
"I action in nerve. Three typical curves and the conditions under
which they were obtained are shown in Fig. 276. One point of particular
interest should be noted, namely the response to darkness. The complicated
nature of these curves has been explained on the supposition that there
are three substances present in the retina of different reaction time. It
has not however been found possible to identify any of them. The difference
in the electric response to light of different colour and intensity has been
found to give the following results. With light of any one colour a geometric
; ise of intensity causes an arithmetic increase in the current. With coloured
i apparent equal intensity yellow rays are said to give a larger current
in the light adapted eye. and green in the dark adapted eve. It is interesting
to observe that the current commences after a latent period which
is of the same order as that found for the perception of light by the eye
This and other facts mentioned above, would seem to point to the currents
observed being the accompaniment of the passage of the nervous impulses
to the brain. .
CHEMICAL CHANGES in the retina on exposure to light are ol
two kinds, firstly a tendency of the retina as a whole to become acid
in reaction, as is shown in the change in its behaviour to certain stains,
and secondly the bleaching of two pigments, namely, the visual purple and
fucsin, With regard to visual purple (or rhodopsin) a large number of facts
35
546
PHYSIOLOGY
have beenmade out. In tin' lirsl place it is found In association with the
rod retinal structures only, and is therefore absenf from the human Eoven
cenl ralis. It is bleached on exposure to light, both in the retina and also in
1.
'
.
'
;
■
J^A ^j
Fig. -7
-l t^^v
' s ^
S~"n
"^•-^^
Xj:
o o— L_ — .— — .i ii —J —
g
Fig. 277. Shows the similarity between the curves representing the rate of bleach-
ing of visual purple by light <>f different wavelength ami the luminosity curve
of twilight vision.
vision. When the visual purple in the retina has been bleached
by exposure to light, there follows a gradual reformation of purple
which is independent of nerve connections, but occurs only so
long as the stratum pigment] is in contact with the rod epithelial layer.
If we suppose that the product formed by the bleaching of the visual
purple stimulates the rod appa rates, causing it to send impulses to the 1 rain,
we have at once obtained some idea of tin 1 mechanism used for night vision.
This we may briefly describe as follows: when light falls on the retina
i ertain rays, particularly those near the middle of the spectrum, are absorbed
by the. visual purple. The pigment is bleached in proportion to
the light absorbed, forming a new product : this acts on the rods, causing
them to send impulses to the brain which continue so long as the light falls.
When the light stops the stimulating product is no longer formed, therefore
the stimulus to the rods ceases.
It is stated that in diseases of the liver, in which there are 1 He salts circulating in
the blood, twilight vision is found to be impaired. This condition is ascribed to the
solubility of visual purple in bile salts, and it is thought that tin- removal of i he pig-
ment from the retina prevents the rod apparatus from functioning.
548 PHYSIOLOGY
A picture formed by the bleaching of 1 1n • visual purple iu those
parts of the retina which correspond to the high lights of the image
formed by the lens, can be fixed, much like a photograph, by immersing
the retina in a solution of alum. Fuosin is the pigment found in the
form of needles, plates or prisms in the processes of the cells of the stral urn
pigmenti (the outer layer of the retina). The object of tins pigment is
apparently to absorb light which might tend to spread from those retinal
elements, on which an image of a light source is falling, to neighbouring ones.
Some of this pigment is bleached by strong light, but so far as is known
tlic break-down products have no visual function to perform. The presence
of other pigments has been described in the retina, such as visual yellow and
the bright pigment granules found in birds. Their presence is too variable
for them to be considered to take any essential part in the visual mechanism.
PHYSIOLOGICAL CHANGES produced by light depend greatly on
the region of the retina on which they fall, since this may contain rods
only, cones only, both rods and cones, or neither rods nor cones. The
peripheral parts of the retina contain numerous rods and very few cones.
When stimulated by light of low intensity, this part of the retina is found
to be exceedingly sensitive, particularly if the eyes have been closed or
kept in the dark for a time. Tests with light of low intensity and of different
colour shows that the region is colour-blind, but that rays in the middle of
the spectrum are more readily appreciated than others. We have here
well developed the so-called twilight vision, which is associated with the
rod-visual purple mechanism just described. Besides being very sensitive
to light of low intensity, the periphery of the eye is particularly perceptive
of light of low intensity and short duration. This part of the retina there-
fore apj:>reciates movement at night very readily. Lastly, owing to the fact
that a number of rods connect with one nerve fibre which conveys the
impulses to the brain, the periphery of the eye has a poor perception of
detail.
THE FOVEA CENTRALIS is found to contain cones only. The vision
in this region is therefore the antithesis of that found in the periphery. The
appreciation of light of low intensity is bad, but when an image is sufficiently
bright to cause stimulation, its colour is perceived. When light is
poor, rapid motion is not so well observed as it is by the periphery.
There is an extraordinary acuteness at perceiving fine detail. This is due
to the fact that the cones in the fovea are very closely packed, so
closely that they become flattened where they touch one another
and thus have a hexagonal shape in transverse section. Further
each cone is connected to its own nerve fibre, so that no cyphering of the
impulses can occur on the way to the brain. Experiments on visual acuity
definitely show that the fineness of the detail, which the eye can perceive
at the foveal region, is fully as great as that which we should expect
to find, if each cone acted quite independently of its neighbours. Parts of
the retina around the macula lutea, since they contain both rods and
cones, possess as we should expect both the power to perceive colour found
HISTOLOGY OF THE RETINA
549
at the fovea and the ability to react to light of low intensity without colour
vision which is possessed by the periphery of the retina. The presence of
rods scattered between the cones naturally impairs to some extent however
the appreciation of fine detail. At the white papilla where the optic nerve
enters the eye, there are neither rods nor cones, and therefore as we should
expect this region is quite blind. This fact can be readily proved by looking
Fro. 278. Look at cross with right eye, hold book at about 10 inches.
with the right eye at the cross in Fig. 278. If now the book be held about
10 inches from the eye the white disc will be found to disappear. By a simple
calculation it is found that the disc
corresponds with the papilla of the
optic nerve.
THE VISUAL FIELDS. Since
the appearance of an external object
will vary to a considerable extent
according to the region of the retina
on which its image falls, it is a mat-
ter of considerable interest to deter-
mine the positions at which the
appearances undergo change. This
is also of practical value because the
positions are found to be affected by
disease. The determinations are
usually made by means of an instru-
ment called a perimeter. .
This will beseen from Fig. 279 to consist
of a metal arm bent to the segment of a
circle. This is so mounted in relation-
ship to a horizontal bearing that the
segment always has its centre in corre-
PlO. - Tit. Priestley Smith's perimeter.
spondence with a fixed pointer which is seen on the left of the diagram. If the eye
of the patient is placed close to this pointer and looks towards the centre of the
bearing, the degrees marked on the metal segment show the actual angle at which an
index is .situated in relationship to the eye axis, no matter what meridian the metal
Begment may lie in. The index mark usually consists of a small disc 2 mm. diameter
cither of white or of coloured pa per, according to whether the rod or cone area is to
be determined.
550 PHYSIOLOGY
The values obtained by means of this instrument are shown in Pig.280,
which give; a typical curve for the right eye. The shaded area on the
Left of the diagram is due to the obstruction of the eyebrow, nose and cheek
of the patient. The visual field on the outer side will be seen to extend
actually 11 degrees beyond the right angle. This result, which at first sight
appears to be impossible, is in fact due to the considerable refraction of the
Fig. isO. Field of vision for white and colours of a normal right eye as obtained by
the perimeter. (Hyrtkidge.)
light rays that occurs at the extreme edge of the cornea. The direction of
the beam of light entering the eye under these circumstances is shown in
Fig. 281 X below.
It will be observed that even when looking straight in front, a man
can see to a considerable angle behind himself. By deviating the eyes only
slightly to either side, this angle can be increased to 40 degrees in the average
case as shown at Fig. 281 Z. This ability to see to a considerable extent
behind him is due to the narrowness of the head between the
frontal processes and zygomatic bones. In those animals in which
the eyes are placed on the sides of the head, and the visual axes are diametri-
cally opposite to one another, the visual fields will actually overlap a short
distance from the head, so that there wall be no direction from which an
enemy can attack without being observed (Fig. 281 Y).
HISTOLOGY OF THE RETINA
551
UTILITY OF PERIPHERAL VISION. The high visual acuity of the fovea and
the great facility with which the eyes can be directed, so that imagi s form onthisregion,
might raise the question as to the utility of peripheral vision. This question may be
investigated experimentally by placing restricting screens in front of the eyes, or by
ascertaining the experience of persons who are suffering from blindness in the periphery
as the result of disease. e.g. retinitis pigmentosa. Both methods show that the periphery
is of great value in directing attention to outlying obstacles. Our attention being excited
we direct the gaze in the direction indicated, in order to bring into action the greater
power of analysis of the fovea.
'XTK i%
*-»
I'm:. 281. Diagram '/, shows size of blind zone in man. (II vrtridoe.) Diagram
\ shows how extremely peripheral rays cuter the eye and reach the retina.
i lib Y shows absence of blind zone in certain birds and animals.
CENTRAL CONNECTIONS OF THE RETINA. The connecting paths
between the retina and the brain are formed by the optic nerves. At first
i licse are hollow tulles to which tin- optic cups are attached. After the retinal
artery has Pound its way through the cleft in the optic cups, the nerves fold
round it ami become solid, and through their substance the nerve fibres from
the ganglion cells of the retina grow toward the brain. The primitive ground-
work of the nerve is also invaded close to the optic cup by mesoblast forming
the cribriform plate of the sclera. Through the meshes of this plate the
nerve fibres have to pass. Traced backwards the optic nerves leave the orbit
through the optic foramen accompanied by the ophthalmic artery. The
optic nerve lias sufficient slack in order to permit free motion to the
Having entered the cranial cavity the nerve pierces the dura mater, and
meets its fellow from t he other eye ; with this it connects, forming the chiasma,
and the fibres partially decussate. The fibres thus torn: the optic tracts
552
I'HYSIOLOCY
which travel round under the crura cerebri and then divide to end in cells
in three different nuclei, (a) the anterior corpus quadrigeminum,
(/>) the external geniculate body and (c) the pulvinar. The optic nerve
contains four different sets of fibres: (1) those which convey visual impressions
to the brain; (2) those going to the pupillomotor centres; (3) those which
come down from the brain to the retina?, the so-called retinomotor fibres,
which may have trophic fibres associated with them; (4) nerves travelling
from one retina to the other. The courses of these separate fibres must now
be traced.
LEFT RETINA right retina (1) From each retina three
separate bundles of visual fibres
arise : (a) those from the right
halves of the retinas, which join
at the chiasma and travel to
the brain via the right optic
tracts ; (b) those from the left
halves of the retinas which travel
via the left tracts ; and (c) those
from the foveae centrales (in man
and monkey only) which partly
travel via the tract of their own
side and. partly cross to that
of the other. The right optic
tract thus contains all the visual
fibres from the right sides,
and half those from the centres
of the two retinae, which travel
to the right occipital cortex
through the pulvinar and exter-
nal geniculate body of that side.
The left tract travels to the left
occipital cortex in a similar man-
ner. These connections are
represented diagrammatically in Fig. 282.
(2) The pupillomotor impulses travel up without crossing, as I have
already described on page 510, to the anterior corpora quadrigemina (see also
Fig. 203 and page 406).
(3) Nothing is I believe known as to the fate of these so-called retino-
motor fibres ; some of them may, in fact, be trophic or vaso- constrictor fibres.
(4) The function of these inter-retinal fibres are not known definitely.
It has been suggested that they cause changes in one retina wheD light
falls on the other, as for example cone movement. It has also been sup-
posed that the sympathetic inflammation which occurs in one eye after
certain injuries to the other, is due to impulses which have travelled via these
nerves ; lastly binocular contrast and after images have been ascribed to them.
It is of practical importance to be able, to locate an injury to the visual
Fig. 282. Diagram showing the probable
relations between the parts of the retinae
and the visual area of the cortex. (Schafer.)
HISTOLOGY OF THE RETINA
553
nerve paths. Injury to the optic nerves causes blindness of the eye to which
the nerve belongs, and stimulation of the eye by light will not then elicit
the pupil reflex. Injury to the optic tract causes blindness of the halves
of both retinae on the same side as the lesion, that is to say blindness
to external objects on the opposite side to the injury. It is interesting to
note that, whereas, in most other nerve paths, crossing of the impulse occurs
from one side to the other as it travels to the brain, so that the left side
of the brain corresponds to the right side of the body, this is not the case
with the optic impulses. These are already crossed by the optical apparatus
of the eye and therefore crossing of the impulses is rendered unnecessary.
Injury to the optic radiation or the occipital cortex will cause blindness of
both retina? on the same side, but will not affect the pupil reflex, because
these fibres have already turned aside to go to the anterior corpora quad-
rigemina. Injury of the middle of the chiasma, such as may occur in
tumours of the pituitary body, affects the nasal halves of both retinae and
produces double temporal hemianopia.
THE OPHTHALMOSCOPE. If the retina of a patient be illuminated by causing
a beam of light to enter the pupil, the reflected light will cause the interior surface
(■I the retina to be visible. In order to see the image distinctly it is necessary either
that both the eye of the patient and also that of the observer should be focussed for
infinity (the direct method) or that both eyes should be focussed for oneand the same
intermediate plane (the indirect method). The former has many disadvantages which
are not found in the case of the latter, and therefore will not be considered further.
The indirect method is carried out as follows : — A bright source of light having been
placed behind and slightly to one side of the patient, the observer standing about half
a meter in front of him reflects by means of a convex mirror an image of the light into
his pupil. At the centre of the mirror is an aperture through which the doctor sees
i in light which is reflected back from the patient's retina. The observer now holds a
bici m vex lens of about G cm . focal length about 8 em. in front of the patient's eye, while he
si ill directs the beam of light into t he pupil as before. The image of the retina, which would
normally be focussed by the lens system of the patient's eye at infinity, is now brought
to a focus by the convex lens, forming what is called an aerial image (see Pig. 283).
It is this image that the observer sees, and in it are shown all the particular features
of the vessels and nerves of the patient's retina. Beside its very great utility to the oculist,
the ophthalmoscope is a very valuable instrument to the physician, for retinal vessels
and nerves frequently show the evidences of constitutional disease, which are of great
assistance to diagnosis, ophthalmoscopes are usually fitted with a number of small
lenses of graduated power, u Inch may be introduced as required behind the mirror. For
the indirect method they are seldom required. The magnification of the retina given
by the direct method is usually about 3. while that provided by the direct is 12. If
a higher magnification is an advantage it may lie obtained by using a, biconvex lens of
longer Focal length (saj 12 em.).
I h M Diagram In show paths of rays from eye of patient t" doctor when
the indirect method of ophthalmoscopy is in use. (Habtkidqe.)
m i
PHYSIOUMJY
The image seen in the ophthalmoscope is shown in Pig. 284.
( to examining the back of the eyeball by .either of these methods, the must prominent
object is tin- optic disc- or optic nerve-papilla, which marks the point of entrance of the
optic nerve. It is seen as a pale oval disc surrounded by a deep red background (Fig.
284). From the middle of the papilla the retinal vessels pass into the eyeball, and
they ate seen diverging from the papilla to ramify over the rest of the retina. The
arteries can be distinguished from the veins by their brighter red colour as well as by the
stronger reflection of light from their surfaces. The yellow spot is very difficult to see,
except in atropinised eyes, since it comes into view only when the observed eye is looking
straight into the ophthalmoscope. Under these conditions there is a strong Might
/4
Km. 2s4. Ophthalmoscopic view of fundus of
eye, showing the optic disc, or point of entry
of the optic nerve, with the retinal vessels branch-
ing from its centre.
a X>
Fig. 285. Diagram of tin-
path of the rays of light in
the formation of Purkinje's
figures.
v represents a retinal vessel.
When this is illuminated from
A, a shadow is formed on the
hinder layers of the retina at
it'. This is projected along a
line passing through the optic
axis, and appears to come from
a point ('/") on the wall. (In
moving the light from a to
B, the image of the vessel
appears to move from a" to /,.
reflex,' and the pupil contracts up to a pin-point, unless paralysed by means of atropine.
In order to see the blind-spot, or optic disc, the observed eye must he directed inwards ;
thus if A is looking at the right eye of B, B must be told to look over A's light shoulder.
By projecting a highly concentrated beam of light on to the side of the eyeball,
it is possible to cause sufficient light to pass through the wall that the retina perceives
the stimulus. When that is the case it is found that the retinal arteries and veins are
seen as dark images on a bright ground (Purkinje's figures). By moving the point of
illumination and then measuring the apparent shift of the vessels which occurs, it
has been found possible to estimate the depth below the vessels at which the re-
ceptive surface of the retina is placed, namely -17 to -30 mm. Now the average
distance between the vessels and the layer of rods and cones is found to be -2 to -3
mm. ; it must therefore be the layer of rods and cones which forms the sensitive
layer. The directions taken by the light rays are shown in Fig. 285.
Another method of viewing the vessels in one's own eye is to look through a small
hole in a met il plate at a smooth white surface. < hi oscillating the aperture in relation
ship with the pupil about once a second, the vessels will he seen as shade us on the bright
background.
SECTION VIII
THE RELATIONSHIP BETWEEN STIMULUS AND
SENSATION
In the introduction I have pointed out that, since we are unable to express
our sensations in terms of physical units (we cannot say, for example, when
one source is twice as bright as another), two methods of investigation are
alone available, namely, that which, involves the determination of threshold
values, and that which depends on the making of comparisons.
In order that a source of light shall be perceived, the image which is
formed on the retina must have certain properties. In the first place it
must last for a certain finite time, for if it be of shorter duration than this
it will not be perceived. Secondly it must be larger than a certain
size Thirdly its intensity must be greater than a certain limiting
quantity. Fourthly the rays which it emits must have wavelengths
which lie between certain limits So that in the case of each of
these four properties there are limiting values which must be
exceeded ; these values are called thresholds. The retina has
distributed over its surface two different types of sensitive organ, the
cone apparatus, which has the function of perceiving colours and is
used in day vision, and the rod-visual purple apparatus, which is colour-
blind but verj' sensitive to light of low intensity and is therefore used for
twilight vision. Owing to the fact that the distribution of these organs
is not uniform, we have to state the part of the retina which is being stimu-
lated when assigning a value to any of the above-mentioned thresholds. For
example, the threshold for intensity may be that which just actuates the
rods, that is the achromatic limit, or that which is sufficient to affect
the cones and therefore causes an appreciation of colour. Moreover
the value of any one threshold is to a considerable extent [controlled
by the value of the other factors which 1 have mentioned; for example,
tin- time- threshold is shinier the greater the size and intensity of the light
source. The exact conditions must therefore lie carefully stated in quoting
the value of a threshold. Lastly we must consider the personal equation
of the observer, and also the state of his vision, for both are affected by
constitution, health, fatigue, &c, to an important extent.
INTENSITY THRESHOLD FOR LIGHT (ACHROMATIC)
II a spectrum be gradually reduced in intensity, it loses its coloui and
finally appears to the eye as a bright band which has its greatest lumi
nosity in the green region of the spectrum and gradually fades towards both
555
556
PHYSIOLOGY
the red and violet ends. Since the band is colourless, any one part mas-
he matched by any cither part by suitably adjusting the intensities. But
compared with the appearance under ordinary intensity, the red region
of the spectrum has become greatly reduced in visibility, while the blue has
become relatively brighter. The part of the spectrum with maximum
luminosity is found to be the yellow when the intensity is high, but to be
the green \\ hen it is low. It is therefore this shifting of the position in the
spectrum of the maximum which lias caused red to darken and blue to
become lighter. The relative forms and positions of the luminosity (apparent
brightness) curves for spectra of various intensity are shown in Fig. 286.
3-8
8-6
\
3 4
' r
\
Light intensiti
SSH
3-2
30
'
\e
F
2 8
1 J
%\
E
2-6
Ijj
i
D
2-4
v(
"..".
C
B
2-2
i
\
\\
A
20
\
18
A
1-6
v
.1-4
1
\\
1-2
-■•
— '■
---
-X
10
1"
,.;
"'■'
(^■■;
0-8
' !
;
■'/.
s N 'v
I]
•
'
\
0-4
/
,
,,
.'
\
: $>*
0-2
_,
■' ,
'
^!l
^{';I
-
>,,
-i
1 L.
^-■ K *"*"*"-- '
670 660 625 605 590 575 555 535 520 505 490
470
450
430
Fig. 286. Luminosity curves for spectra, of different intensity. A = highest,
H = lowest. Abscissae = wavelengths, ordinates luminosities (Konig).
The maximum of curve for light of high intensity is seen to !«■ at 6100 A.l*.
that at low intensity 5150 A.U.
If the spectrum of low intensity be still further decreased, a point will
be reached at which the different parts become invisible to the eye; this
will occur first with the ends, and last with the middle (at about 5271 A.U.).
It is found however that the intensity values at which visibility ceases
decrease the longer the eye is kept in the dark, that is to say the retina
gradually becomes 'dark adapted.' The curves obtained for different
degrees of dark adaptation are also shown in Fig. 286.
We must now consider the effects on the achromatic threshold
of size of light source, duration of stimulus and part of retina illuminated.
With regard to size, experiment shows that as the size of the
source decreases so the intensity at which extinction occurs increases, in
fact that the area of the source multiplied by its intensity is constant.
With regard to the region of the retina that is stimulated, it is found that the
RELATIONSHIP BETWEEN STIMULUS WD SENSATION 557
rod-visual purple apparatus is responsible for the appreciation of the light
of low intensity ; it is therefore found in all parts of the retina other than
the Eovea centralis from which rods are absent. The effect of time of stimulus
will be considered shortly.
INTENSITY THRESHOLD FOR COLOUR
If a spectrum of low intensity which appears colourless to the eye be
graduallyincreased in brightness,a point will be readied at which the colours
begin to lie recognisable, first yellow and green, then blue and lastly red and
violet. If the intensity at which the colour just vanishes is measured,
the curve obtained is similar to that shown in Fig. 287. As the
s
10 15 20 15 30 35 40 15 SO S5
!\\t inction of colour ' curve. Abscissae = wavelengths; ordinate
sity in candle feet when colour just vanishes. (Aunev.)
intensity is increased, the point of maximum luminosity gradually
shifts from the green to the yellow. As a coloured object is
gradually increased in intensity, it is first seen without colour, but
after an interval the colour also is recognised ; this is called the photo-
chromatic interval. It follows from what we have said that the interval
is greatest for colours of short wavelength (blue) and least for long (red)
(the I'urkinje phenomenon). The thresholds for light and colour differ in
another important respect, namely that whereas that of light varies with the
degree of dark adaptation, that of colour is found by experiment to lie nearl)
constant. With regard to the effect of area of light source, it is found that
the same type of relationship exists in the case of colour as for light,
namely, that as the area is decreased, so the intensity must be correspond-
ingly increased. The area and intensity, multiplied together, do not how c\ er
equal a constant as they do in the case of light. The appreciation of colour
is associated with the cones and is therefore most highly developed at
,vs
PHYSIOLOGY
the fovea. As the periphery of the retinaB is approached the number oi
the cones very rapidly decreases, and we should therefore expecl to Bnd a
1 1 n 1 1 1 in the size of the visual field for different colours. This may be tested
by means of the perimeter (Fig. 279) and small coloured discs, <>r more
accurately by suitable apparatus for employing spectral colours. By these
methods it is found that the colour fields are smaller than those for light,
hut more or less concentric with them (Fig. 288). The actual size of the
fields varies with (he intensity
and size of the test light source,
or object. The order in which
the colours disappear varies some-
what but appears to be usually
as follows-: — First green, then
yellow, then red, and lastly blue.
The determination of the size of
the colour fields is a technique of
considerable practical importance,
because they are found to be-
come restricted in those progres-
sive lesions of the optic nerves
which may finally lead to total
blindness, and also in inflamma-
tory conditions of the retina and
choroid. Careful examination of
the apparent limits of the blind-
spot by means of similar appa-
ratus was found by Haycraft to show that there is a similar variation in
the relative sizes of the fields for different colours (Fig. 288). The same
phenomenon is also found round the Mind-spots formed in the retina by
disease.
Fig. 288. Limitation of colour fields round
the blind spot. (Havi b \kt.)
SIZE THRESHOLD OR VISUAL ACUITY
If a small source of light be gradually reduced in size, a point is soon
reached at which it becomes invisible. If it is a coloured source, it as a rule
shows a well-marked photochromatic interval, that is, it first loses its colour
and then disappears later. If the intensity of the source is very great, the
size has to be greatly reduced before it becomes invisible : it is because
of this that we see the stars. If the size and intensity at the point of dis-
appearance be measured, it is found that when multiplied together they
equal a constant, so that as in the case of the light threshold the determining
factor appears to be the amount of light which falls on the retina. In
the case of intermittent illumination a similar relationship is found.
Visual acuity is the ability to see as separate the images of small bright
light-sourCes of any shape placed very close together. Experiment
shows that the distance between the sources must be increased as their
distance from the eye is increased. In other words that the angle which
RELATIONSHIP BETWEEN STIMULUS AND SENSATION 559
(hey make at the eye must be greater than a certain limiting value. The
angle usually obtained is an angle of one minute, and on this I lie lettering
used in practice for testing the visual acuity of patients is based (see
page 535). Persons with exceptionally good vision are able to see
the images separated when the angle which the sources make at thi-
eve is very much less than this, namely U I seconds. Assuming that
the posterior nodal point is 156 mm. from the retina (this being the
distance in the normal eye, see page 523) '2 ! seconds corresponds with a
distance between the images at the retina of "0018 mm. The diameter
of the cones is between "0020 and 'C030 mm., and in the fovea they are
very closely packed so as to present a hexagonal section. The maximum
visual acuity is therefore certainly as great as the size of the cones would
lead us to suppose possible.
The case of a dark spot on a bright ground is similar to the case just
considered, because for the dark spot to be recognised it must subtend
at the eye the minimal angle mentioned above. Increasing the intensity
of the ground or the blackness of the spot will make a very small difference.
The case of the black spot is therefore very different to that of the white
in which an increase in the intensity is sufficient to make up for a difference
of size.
TIME THRESHOLD
In considering the time threshold two different sets of conditions require
description, firstly the minimum time during which a given stimulus must-
art m order to reach consciousness, and secondly the minimum rate at which
a series of stimuli must follow one another in order to give a uniform impres
sion without flicker. Both are of considerable importance since the first
enters such problems as the determination of the length of time during
which a lighthouse beam should be caused to travel in a given direction,
the second because it gives a reliable method of comparing the
intensity of lights of different colour. Experimental investigation of the
first type of time, threshold is effected by measuring the length of stimulus
necessary to cause a source of a certain intensity to affect the retina, and
it is found that the lower the intensity the longer must the image fall on the
retina. But if the eye be dark adapted, if the time and the intensity
values be multiplied together, then within limits a constant is obtained.
On the other hand, in the light adapted eye, the value is found to vary
somewhat, but is sufficiently constant to show that, the relation between
intensity and time is approximately the same. Within limits therefore we
find that at the threshold the total amount of light is constant whether if
be of high intensity for a very short period of time or of low intensity for
a correspondingly longer one. This relationship ceases to be true if the time
of stimulation is longer than about one- tenth of a second, and this is appar-
ently due to the fact that the retinal apparatus reaches a steady state in
about one-quarter of a second in the dark adapted eye (rod-visual purple
apparatus). A lighthouse flash should therefore be visible to the ej e for t his
560 PHYSIOLOGY
length <>f time in order to make the greatesl impression possible.
For coloured lights approximately the same values are found, pro-
vided that allowance is made for the comparative intensity of the colour.
Since the time required for the retina to reach a steady state is
nearly that at which a series of stimuli must, fall on the retina in order to
produce a uniform sensation, for intensities near the threshold
the rale at which flicker disappears is one stimulus every quarter
oi a second. But it is found that as the intensity rises the rate must be
increased in order to abolish flicker. The rule which most nearly expresses
the relation appears to he that geometrical increase in the intensity requires
an arithmetic increase in the rate. Sherrington showed however that the
results are affected by simultaneous contrast.. This phenomenon of flicker
is. as I have said, used in practice for measuring the intensities of light sources.
Two methods are employed, firstly that in which the two light sources to be
compared are measured separately for the intensity at which flicker ceases
when the same rate of stimulation is used for both; and secondly that in which
the two sources are caused to fall alternately on the eye, and are adjusted
in intensity until flicker ceases. Of the two methods the latter is
the more accurate. The value of these methods lies in the fact that
they measure brightness independently of colour. The shape of the curves
obtained by plotting the luminosity of different parts of the spectrum has
been shown in Fig. 286.
Lastly we have to consider the relationship between time intensity and
apparent brightness in the case of an intermittent source, the rate of which
is sufficiently great to avoid flicker. Experiment shows that the brightness
increases in proportion as either the intensity or the time is increased,
and further that equal brightness is obtained if the time multiplied by the
intensity is constant. This statement is true of both the cone and the rod
apparatus, and is known as the Talbot Plateau Law. Use is made of this
law in the sector method of controlling intensity (see page 56-1) because the
intensity is proportional to the time during which the light is allowed to
pass through, which is in its turn controlled by the angle between the
blades of the sector.
COLOUR THRESHOLD
On testing the violet end with a photographic process, or the red end
by a thermopile, it can readily be shown that the spectrum extends at
both ends far beyond the visible limit. The visible limit at the red
end under the most favourable conditions has been found to be 8350 A.U.,
while under ordinary circumstances it is difficult to go beyond 8000 A.U.
Since rays beyond this reach the retina in considerable amount, the limit
cannot be caused by opacity of the eye media, and must therefore be due
to an actual inability on the part of the retina to record their presence.
Of several hypotheses which might be advanced for this inability, the
most probable is that the retinal pigments are unable to absorb rays in the
infra-red part of the spectrum, and therefore according to Draper's law such
RELATIONSHIP BETWEEN STIMULUS AND SENSATION 561
rays cannot produce photochemical change and cannot be perceived
by the eye. It may be mentioned in this connection that few organic
pigments absorb strongly in the infra-red.
The limit at the violet end islesseasy to determine because the eye media,
in common with a large number of other bodies, have the property of fluoies-
cing when the ultra-violet rays fall on them, i.e. they convert them
into rays of longer wavelength and therefore make them visible. The
resulting impression is however quite different because, since these rays
are generated in the eye media themselves, they are spread over the re-
tina as a haze without there being any proper image formation. The limit of
the visibility of the violet end of the spectrum appears to be at about 3800
A.U., while the portion which is seen because of the fluorescence which it
produces, and which appears a pale lavender, ends at about 3200 A.U. Since
the wavelength of the extreme red rays is a little more than double that of
the extreme violet, the eye is sensitive to a little over an octave. The range
of appreciation of the eye is therefore very much smaller than that of the ear,
which is about 10 octaves. As age increases the eye media become
yellow in colour: this change particularly affecting the lens, the violet
end of the spectrum becomes shortened owing to absorption. On
removing the lens of the eye as in an operation for cataract,
the sensitiveness to the violet end of the spectrum is considerably
increased. It would therefore seem certain that the. limitation of the
spectrum of the violet end is largely due to absorption by the eye media and
not to inappreciation on the part of the retina. The causes of the limitation
of the two ends of the spectrum are therefore different.
DIFFERENCE THRESHOLDS
Beside the thresholds for light, colour, time, and wavelength, which
we have considered above and which may be called absolute thresholds,
there are certain difference thresholds that must be considered. Thus, for
example, a certain finite difference must exist between the intensities of two
sources of light of the same colour for a difference between them to be appreci-
ated by the eye. There are four principal types of difference threshold, that
of intensity, that of colour, that of saturation, and that of size.
Difference Threshold of Intensity
It is found by experiment that a just perceptible difference between the
intensities of two surfaces varies with the mean value of their intensities.
Thus supposing that it had been found by one experiment that a difference
of intensity of one foot candle was necessary in order that two sources should
lie just distinguishable, the average inteiisities of which were one hundred
foot candles, then in another case in which the average was 25 F.O. the least
perceptible difference would be found to be one-quarter F.O This condition
is known as Weber"s law. It appears to be true for light of medium intensity
and for sources not separated by more than a small interval. But the least
perceptible difference is found by most observers to be less than that taken
for purposes of illustration above, namely one-hundredth part of the mean
36
562 PHYSIOLOGY
intensity ; thus Helrnholtz found it to be a |,';;tli, other observers have
obtained even higher fractions. It is interesting to find that the results are
not influenced by the size of the pupil.
Difference Threshold of Colour
I [ the range of colours exhibited in the spectrum be carefully examined) it
will be seen that there are certain parts, notably at the red and violet ends,
at which the change of colour with wavelength is a very gradual one. At
ot her parts on the contrary 1 he change of hue is very rapid, the yellow region
at 5800 A.U. may be given as example. If therefore we determine by experi-
ment what difference of wavelength is just perceivable by the eye, we find
that it varies with the part of the spectrum under observation. We may
therefore conveniently express the difference threshold in different parts
of the spectrum in the form of a curve, as in Fig. 289. In persons with normal
vision the total number of different hues in the spectrum is calculated to be
165. In persons with colour-blindness the number is greatly reduced.
Fig. 289. Curve showing difference threshold for colour at different pints of the
i spectrum.
7 Abscissa© = wavelengths. Ordihates = difference between wavelengths call-
able of being discriminated. (Steindler.)
Tins fact has been applied by Edridge Green for the detection of colour-
blindness ; details of the method will be given later. It should be pointed
out that, since in this method the spectrum itself is presented to the
observer so that there is a gradual change from one colour to the next, it
is the threshold of rate of change of colour that is determined, and not differ-
ence threshold of colour.
Difference Threshold of Saturation
By saturation is meant the amount of white light which is present with
and is therefore diluting a colour. The threshold would appear to be
RELATIONSHIP BETWEEN STIMULUS AND SENSATION 563
of the same crder as that of intensity given above, namely, that a differ-
ence in the amount of white light diluting a colour by , , ! ;7l th of the total
intensity present can be just appreciated by the eve.
Difference Threshold of Size
If two objects are the same distance from the eye, and are close to one
another and in similar positions, a difference of one-hundredth the mean size
ran as a rule be appreciated. If, they are at different distances from
the eye, or are far apart, or are not in similar position {e.g. one perpendicular
and the other horizontal), then considerable errors may occur.
THE METHOD OF COMPARISONS
In the application of this method three different series of investigations
have been carried out. (1) To determine the intensities of three primary
colours which when mixed together will match the different spectral colours
or white light. (2) To determine the intensities and wavelengths of the
complementary colours. (3) To ascertain the intensities and wavelengths of
red and green rays which when mixed together match a pure spectral yellow.
The colour box in some form or other is used for these tests. Abney's
apparatus may be described as a typical example. Light from an arc lamp
is focussed on to the slit of a powerful spectroscope, which consists of a colli-
mator, a train of prisms and a telescope. The spectrum thus produced is
caused to fall on three slits, one of which corresponds with the red, another
with the green, and the third with the blue. The light having passed through
the slits falls on a lens which forms an image of the prism faces on a screen.
The light from the slits thus recombines on the screen to produce a bright
patch, the colour of which alters according to the intensities of the three
components. To one side of the patch a second patch of light can be thrown '
from the arc lamp, and this also may be varied in different ways according
to the nature of the experiment. The intensities of the different beams could
be modified by altering the widths of the slits ; a preferable method is
to employ rotating sectors, the angles between the blades of which can
be varied at will (see Fig. 290).
COLOUR MIXING EXPERIMENTS performed with this apparatus
give results that have already been briefly considered in Section I. It is
found that, not only do the three primary colours when mixed together in- the
right proportions form a white light that is indistinguishable from ordinary
white light, but they can also be made to match the whole range
of colours both of the spectrum and of pigments. It was also described how
that certain pairs of colours when mixed in the right proportions are able
to match white, and that these pairs are called complementary colours.
If the colours that are mixed are further apart than are the complementary
colours, then the mixed colour is found to be a shade of purple ; but if nearer
together than the complementaries. then the'colour formed by the mixture
corresponds to an intermediate part of the spectrum. Thus, if the colours
mixed are red and green, the intermediate yellow and orange portions of the
564
PHYSIOLOGY
spectrum can l>c matched. As a rule the mixed colour is not so pun'
as the corresponding spectral colour, being less saturated (thai is diluted with
a certain amount of white light). The mixture of red and green is an excep-
tion because it is found that accurate matches with spectral yellow can be
una
.% COHOCm
VERTICAL STOP
SCREEN
COIOLIK WXTURt PATCH ' ^COHRWSOH miTC U6HT ,
Fig. 290. Colour patch apparatus for mixture and comparison of pure spectra!
colours. (Abney.)
made if the green component be not shorter in wavelength than 5400 A.U.
These facts can be expressed diagrammatically in the form of a
geometrical figure, the colour triangle, in which the three fundamental
colours occupy the corners and white the centre (see Fig. 243).
Matches made by light of one intensity require readjustment if
the intensity be changed, and matches made by one observer are
different to those made by another. The variation with intensity is
readily explained by the shifting of the centre of the luminosity curve
from the yellow towards the green, as the intensity is lowered.
The amount of red required in a match will become increasingly greater, and
that of the blue less, as the intensity is lowered. The variation with the
observer, when small, is explained by individual peculiarity in the pigmenta-
tion of the eye media or the fovea centralis ; but when considerable, by abnor-
RELATIONSHIP BETWEEN STIMULUS AND SENSATION 565
mality in the response of the retina to colours. Because of this the method
of colour mixtures forms a very valuable technique for the investigation of
colour-blindness.
THE FLICKER METHOD. The majority of observers can only
obtain consistent measurements of intensity with the above method
when the colours of the two patches are exactly alike. Thus it
is difficult to adjust a green light to be of equal apparent brightness
(luminosity) with a red because the difference in colour makes the judgment
of brightness inaccurate. Abney found that in his own case practice
greatly increased the certainty with which the measurement could be
made. A more reliable technique is given by the flicker method
(see page 559). The two patches are viewed through a rotating sector,
the speed of rotation of which can be controlled. The'intensity of one of them
is now adjusted so that, when the speed of the sector is altered, both commence
to show and to cease showing flicker at the same time. By applying this
method to the colour-mixing apparatus the luminosity of the different parts
of the spectrum can be determined. The curves obtained at different lumino-
sities have already been given in Fig. 286. Tested by this method different
observers show individual peculiarities, which amount in some cases to a
greatly diminished perception of a certain part of the spectrum. Some of
the types met with will be described later.
SECTION IX
THE) SUBJECTIVE PHENOMENA OF VISION
By ' subjective * we mean that the sensations under consideration cannot
be directly traced to the stimulus which initiated them. Thus
at a certain rate, intermittent stimuli presented to the eye form
a continuous sensation, so that flicker appears to have ceased. But
the carrying on of the sensation from one stimulus to the next is performed
by some part of the visual mechanism, and has nothing to do with any physi-
cal peculiarity of the light. It is therefore an example of a subjective
phenomenon.
ORDINARY CONE RESPONSE.
ROD RESPONSE
Fig. 291. Curve representing diagrammatically the sensations aroused when the
eye has been stimulated by a flash of light. Intensity of sensation-vertical.
Time-horizontal. (Hartridoe.)
THE SENSATION CURVE. When a light
stimulus enters the eye a certain period of
time elapses before a sensation is perceived.
This latent period may be compared with that
which occurs between the stimulus and con-
traction of a muscle. After its commencement
the sensation rapidly rises to a maximum (see
Fig. 291) and then shows several rapid fluctua-
tions as it reaches its mean value. These
fluctuations are called Charpentier's bands, and
are well seen after stimulating the eye by
means of the flash from an electric spark.
They have been compared to the oscillations
which occur when an electric current is passed
down a telegraph cable, and which are caused
by the inductance and capacity of the circuit.
566
Fig. 292. Charpentier's bands
as seen when a disc with a
narrow radial slit is rotated
in front of an illuminated
screen about once a second.
THE SUBJECTIVE PHENOMENA OF VISION 567
Similar oscillations occur when the telegraph circuit is broken ; these
oscillations also have been witnessed and described by Bidwell at the
end of the primary visual response. The time taken for the sensa-
tion to reach its maximum varies from 0"16 to 007 sees., being shorter
the greater the intensity of the stimulus. This so called primary
image is followed under certain conditions by a less definite and less
intense image, which has the following characteristics: (1) It is not
seen when the eye is light adapted. (2) It is strongest for green light, and
is absent for red. (3) It is absent from the fovea. (4) It is not seen by
persons suffering from night blindness. (5) It is always of a bluish grey
colour. All the above facts fit in with the view that, whereas the primary
response corresponds with the reaction of the cones to the stimulus, the
image which is sometimes seen to follow belongs to the rod apparatus.
THE AFTER IMAGE. Following these responses of the cone and rod
end-organs is the so-called secondary image, which certainly concerns the
cones and may concern the rods as well. This image is of longer duration
than those already considered, and it is of much lower intensity. It has
however the peculiarity that, so long as it lasts, the part of the retina affected
gives a diminished response to a stimulus of the same type as that which
it had previously received. For exampe, if the first stimulus was one of
white light, then a second white lighl stimulus falling in the period occupied
by t he after image of the first, would not be recorded by the retina with the
normal intensity. It has been pointed out that the after image period in
some ways resembles the refractory period which follows the activity of
muscle and nerve. If the second stimulus occupies a larger area of the
retina than that on which the first stimulus fell, the first area stimulated
appears dark on the bright ground corresponding to the second area. If
the first stimulus is coloured, and no stimulus follows, the secondary
image is found to have the same colour ; but if a second stimulus of the same
colour falls on the retina during the secondary image, then as before the
area first stimulated appears dark on the bright area occupied by the second
area. If on the other hand the second stimulus he one of white light,
the sensation received is one of the complementary colour, the reason being
that the red constituents of the white light are partially excluded
by the after image of the first stimulus, but not so the other spectral
colours, and the image which is seen is therefore a blue-green one. Because
of these peculiar properties the after image is said to have two phases : being
called positive when the eye receives no second stimulus, and the appearance
(it t he after image is the same as thai of the first stimulus ; and being called
negative when, owing to the incidence of a second stimulus, the after image
shows the opposite intensity or colour to the stimulus which originated it
Since absence of the second stimulus causes the after image to be positive
and the presence of a second stimulus makes it appear negative, we should
expect a second stimulus of the right intensity to cause the after image to
disappear altogether, since it would stimulate the surrounding retina with
the same intensity as does the after image of the first stimulus. Experiment
068 PHYSIOLOGY
shows that this result can be achieved. Because of the importance of these
properties of the after image we may with advantage recapitulate as follows :
— -As a result of a stimulus the region of the retina affected gives a response
which is followed by a second or after image. During this after image
this area is incapable of reacting with the normal intensity to a like
stimulus, but shows increased excitability to a stimulus of the opposite
kind. For example, after a green stimulus the retina is unable to
respond fully to another green stimulus unless it falls either before
or after the period (if the after image. Therefore if during that period a white
stimulus be caused to fall on the retina, it will cause a purple sensation (purple
being white minus green) in that part of the retina first stimulated. The
duration of the after image is variable, but is found to correspond roughly
with the intensity and duration of the stimulus. Thus after a few seconds'
exposure to a bright light the after image may be noticeable for two or three
minutes, its intensity waxing and waning in an irregular maimer. Successive
images are often found to show a series of colours, a common series is bluish-
green, violet, rose, and finally orange or green ; the phenomenon is however
very variable. The colours may be explained by assuming a difference in
the rate of oscillation for the after images of the different colours. For
example the above series would point to green being more rapid and red less
rapid than blue.
FLICKER AND VISUAL PERSISTENCE. A study of the character-
istics of the sensation curve provides
an explanation of a number of the
subjective phenomena of vision. For
example, if a cardboard disc marked
as shown in Fig. 293 be 'caused
to rotate slowly, while the J black
and white sectors are readily j recog-
nised, their radial margins appear
blurred. This blurring is due to the
slow rise and fall of the primary image
of the sensation curve. If the speed
be increased, a point is reached at
which the disc gives an unpleasant
glittering appearance ; this would
appear to be due to one stimulus occurring during the after image of the
previous one and thus becoming suppressed, but being followed in its turn
by a fresh stimulus which is caused by contrast (see later) to have a greatly
increased intensity. If the rate of rotation of the disc be still further increased,
a point is reached at which a stimulus falls during the primary image of
the previous one. The persistence of the primary image after the cessation
of the stimulus causes the stimuli to fuse to give a uniform sensation without
flicker, which may be compared to the complete tetanus of a muscle. Since
the primary response is more abrupt the greater the intensity of the
stimulus, a more rapid rate of rotation is required to produce fusion at high
intensities than at low.
THE SUBJECTIVE PHENOMENA OF VISION 569
PERIODIC STIMULI. We have seen that, if a stimulus falls dur-
ing the after image of a previous one, its character is altered. If the two
stimuli are similar the second tends to be suppressed, but if dissimilar
the .second appears to be increased. If on the other hand the second stimulus
falls either before or after the after image, it appears to be unaffected. But
the experiments on flicker show us more than this, because even in a case
where a second stimulus comes before the after image of the first, it is clear
that the third would at a certain speed coincide with it and would therefore
be modified. Experiment seems to show no evidence for such an effect,
and we must therefore conclude that the occurrence of the second stimulus
in some way inhibits the after image of the first, so that its effects are not
apparent. Further evidence for this view is to be obtained from continuous
stimuli, for we do not find a sudden diminution in the intensity of the response
a moment or two after a continuous stimulus has begun, such as we should
expect if the after image of the commencement of stimulus were suddenly
after a short interval to assert itself. What happens to these suppressed
after images ; are they entirely destroyed, or are they caused to accumulate
until the end of the stimulus ? The evidence appears to be in favour of the
latter view, because an after image has a more definite character the longer
the stimulus. Moreover if the gaze be directed towards a fixation point, and
the inclination to blink be rigidly suppressed, after a few seconds the images
of objects which fall on the periphery of the retina begin to appear milky,
particularly in the shadows. At the same time the brightness of the high
lights seems to be reduced so that it approximates more and more closely
with the milkiness of the shadows. When this stage is reached objects appear
in outline, the contours being produced and renewed by imperfect fixation.
If fixation can be retained for a short period, it will be found that the
whole field becomes blank with the exception of the fixation mark. If this
also disappears momentarily, then fixation is lost, the eye makes an involun-
tary movement and the whole field immediately fills with detail again. In
this experiment, two processes seem to be going on : firstly, in the shadows,
the disappearance of the after images of previous impressions, the replace-
ment of the visual purple previously bleached, and possibly also the recovery
of these parts of the retina from the effects of previous stimulation, all of
which will increase the sensitiveness of the retina so that it now responds
to the light reflected by the shadows ; secondly, in the high lights, the accumu-
lation of after images, the bleaching of the visual purple, and possibly the
effects of fatigue, all of which tend to reduce the intensity of the
impression. So that these processes, tending to increase the brightness
in the shadows and to decrease that of the high lights, finally brings them to
the same level. In these processes the accumulation and removal of after
images would appear to take a considerable part. The conclusion to which
we are forced is that at the beginning of a continuous stimulus the after images
are effectively removed until such time as the stimulus shall cease, when
they can be permitted to assert themselves. But if the stimulus be pro-
longed the suppression becomes more and more difficult, imtil the accumula-
570 PHYSIOLOGY
tion of after images is so extensive' that they begin to obtrude more
and more on the impression conveyed to consciousness.
FATE OF AFTER IMAGES. If the conclusion drawn from the
above experiments is valid, the question arises as to the apparent unimpor-
tance of the after image in ordinary vision. The answer is to be obtained
from experiments like the following: — If fixation be continued until the
images formed on the retina appear in outline as in the previous experiments,
and the gaze be then quickly turned to a second fixation mark placed some
distance from the first, it is found that, on returning to the first mark,
some time lias to elapse before the appearance in outline is obtained
again ; in fact the time taken is not very different to that required to reach
this stage at the beginning of a new experiment. The second impression
had effected an almost complete removal of the after image of the
first, so that on returning to the first again, the slate had as it were been
wiped clean, and the first impression therefore acted as if it were a new one.
This conclusion is entirely in agreement with our previous conclusions with
regard to the after image, namely that it corresponds to a period in which
a stimulus, similar to that to which the after image belongs, is inhibited, while
that of a different kind is favoured. If therefore during fixation the gaze
be directed elsewhere momentarily, the after image that had been
set up is quenched by the new impression, and on returning the
gaze to the fixation point the old image behaves almost like a new one.
The non-intrusion of the after image in ordinary vision is therefore due to
a considerable extent to the continual and rapid replacement of one impres-
sion by another, by the shifting of the gaze, and also to the spreading of the
accumulation of partially effaced after images more or less uniformly over
the retina. It has been suggested that impulses may be originated from the
external eye muscles on movement, which on reaching the brain assist in
the removal of the after images of previous stimulation.
ADAPTATION. If the eye after being in the dark is rapidly
removed to the light, at first, the sight is confused and the eye
dazzled in spite of the powerful constriction of the pupils. The
eve however very quickly becomes accustomed to the greater in-
tensity, or as we say. it becomes light adapted. In a similar manner
on entering the dark from the light the eve can at first see nothing,
but by degrees it becomes accustomed to the new conditions and objects
begin to be recognised ; the eye has therefore become dark adapted. In
the first case the initial light stimulus reduced the sensitiveness of
the eye to light to such an extent that the eye ceased to react to an excessive
degree as it had done at first. Dark adaptation appears to consist of two
separate processes : (1) the removal of after images from the cone light-
receiving mechanism, and (2) the replacement of visual purple for the rod
apparatus ; the former predominating at high intensities and the latter at
low.
FATIGUE OF THE RETINA. If the eye has been exposed to a
very bright light for a considerable time, there is at first inability
THE SUBJECTIVE PHENOMENA OF VISION 571
to see with the dazzled part of the retina. If a field is looked
at, a black spot appears to lie in front of it ; if on the other
hand the field subsequently looked at is dark, this same area of the
retina appears to be filled by a bright haze. If the dazzling light be
restricted to one colour, there is an inability to see the same colour,
if of lower intensity, immediately afterwards. The power to see other
colours is apparently quite unaffected ; in fact. Burcli stated that the
complementarj colour actually appears to be more vivid than usual.
These changes are similar to those caused by after images. The negative
after image causes diminished appreciation of colours similar to itself, while
the positive shows itself as a bright image similar in colour to the original
stimulus when a dark field is looked at.
SUCCESSIVE CONTRAST. Visual impressions are affected by tin-
previous history of the retina ; thus after the eyes have been directed
towards a red surface, a grey surface appears to be tinted green, a green
surface seems a more vivid colour than normal, while a red colour is relatively
dull. In other words, after stimulation by one kind of source, another of a
similar nature is inhibited, while that of a different nature is either unaffected
or may be even increased. This effect is called successive contrast. Experi-
ment shows that the change of the second stimulus is such that it favours
the colour complementary to the first stimulus. These effects are
similar to those already described under adaptation and fatigue, and the
causation of the phenomenon is the same as that given above, being due to
the presence of an after image.
SIMULTANEOUS CONTRAST. If the retina is stimulated by two
separate impressions, any differences between the impressions will be
found to be accentuated. Thus if a small grey surface be placed on
a white ground, the grey will become darker and to a less extent
the white ground will become lighter. If now the same grey surface be
placed on a dark ground, it will be found to become lighter and the field
darker. The nearer the surfaces are together the greater are the effects
of contrast, the edges shewing the effects of contrast most. In
the case of colours similar changes take place ; thus two similar'
colours of different intensity placed together appear to be more
different; two colours of different sat mat ion change, the one to
greater, the other to less saturation; while two colours of different
wavelength appear under the influence of contrast to sutler ;. varia
fcion towards the complementary colour. A similar change is observed if
contrast is occurring between a colour and a grey surface of approximately
the same intensity, [or we find that the grey is very obviously tinted with
a colour that is very nearly the complementary of the colour in question
It has been stated that the light which reaches the eye other than through
the pupil (e.ij. the sclera) and which is coloured an orange-pink in consec |
of its partial absorption by the blood pigment in the capillaries, is re-
sponsible lor the contrast colours not being strictly complementarj to
those which produce them. It is also found that separation of the
572
PHYSIOLOGY
surfaces, or the demarcation of the junction of the two surfaces by means
of a narrow black or white line, or even the existence of small marks or
creases, reduces the effects of contrast to a considerable extent.
We can summarise the effects of simultaneous contrast in the following
way : — if one part of the retina is being stimulated, the part surrounding it
not only tends to discourage a similar stimulus but also favours one of a
complementary nature (black in this connection being considered as being
complementary to white). But this statement is similar to that which we
have already made with regard to the effects of the after image on the same
part of the retina which has received stimulation. Simultaneous contrast
would therefore appear to be simply an extension of the after image phenome-
non into a region of the retina outside the confines of the original stimulus.
Kxperirnent shows that this extension does not go far from the excited area,
for the contrast effects, which may be considerable near the contour,
rapidly decrease as the distance from the contour increases.
BIDWELL 'S EXPERIMENT. If a short white light stimulus be caused
to fall during the after image period of a previous red stimulus, we
should exj>ect the white fight to be tinted blue-green, because red light
is suppressed and its complementary increased. If the intensity and time
intervals are carefully chosen, the blue-green sensation may be made
stronger than the original red stimulus to which it owes its colour. The
persistence of vision causes this blue-green response to last an appreciable
time, and therefore if another red stimulus rapidly succeeds the white one
Fig. 294. Bidwell's rotating disc; an object looked
through it appears in complementary colours.
(the one which is coloured blue-green) it will tend to be suppressed from con-
sciousness. But the white stimulus succeeding this second red one will be
THE SUBJECTIVE PHENOMENA OF VISION
573
coloured blue-green by its after image, because it has left its impression on
the visual mechanism, although that impulse has not been conveyed to
consciousness. If therefore a series of such red and white impulses be caused
to fall on the retina, each white one will he tinted blue-green, and each
red one will be suppressed, the result being that the complementary
colour is alone seen. This interesting phenomenon was discovered by
Bidwell. He took a disc of tin plate about 8 inches in diameter, and
arranged so that it could be rotated by an electric motor 6 to 8 times a second.
From this disc a sector was cut of approximately 60 degrees ; half the
remainder was covered with black velvet and the other half with white
paper. Behind the disc were mounted two pieces of silk, one red, the other
blue-green. The order in which the images were presented to the eye on
rotation of the disc were : (1) coloured silks, (2) white sector, (3) black sector,
and so on. The result was found to be that the red silk appeared pale blue-
green, and the other pink ; that is in both cases the complementary colour
was alone seen. This experiment brings out very clearly the fact that the
after image process is entirely subconscious. The following observations
confirm this conclusion.
BURCH'S EXPERIMENT.
It has been much discussed in
the past whether contrast phe-
nomena are due to errors of judg-
ment as Helmholtz supposed, or
due to physical or physiological
changes taking place in the retina
or in the conducting paths leading
from it to consciousness. Burch
disproved Helmholtz' view by the
following simple experiment. A
box (Fig. 295) is divided into
two long compartments, a b and
c d. At a the com part mint is
closed by a red glass-plate and
at e by a blue glass-plate. Aper-
tures are provided at b and d for
the observer's eyes. At + and +
two small grey crosses are fixed
about the middle of the compart-
ment on sheets of transparent glass. On looking through the openings b and d and run
verging the eyeballs, so as to fix the line «. we gel a fusion more or Less complete of the
two colours red and blue, so that the background appears purple ; or there may be a
struggle between the colours, at one time blue, at another red predominating. To
the judgment however, there is one background and not two, and therefore, accord-
ing to the theory of Helmholtz, the grey crosses should by contrast both acquire H)<
same induced colour, which would be complementary for purple. But it is found that
the two crosses are perfectly distinct in colour, that which is seen by the eye again I
the blue ground being yellow, while that on the red ground is green, showing thai thi
phenomena of simultaneous contrast are not due to an error of judgment.
SHERRINGTON'S EXPERIMENT. The same fact.is very definitely established
by the following experiment devised by Sherrington. The disc (Fig. 29fl) present t\\<>
rings, each half-blue and half-black. The outer ring is intensified when at rest by
Purple
Purple
Yellow Green Purple
Purple
Fig. 295.
574
PHYSIOLOGY
simultaneous conl ra
i be luminosity of i h
Fig. 296.
I. 1 1:<- M. "Is halt lieing seen against the surrounding yellow, while
■ blue half is incieased bj the effect oi the surrounding black. In
the inner ring the blue half is dark-
i'ihiI l.\ contrast with the surround
ing yellow, while the black half is
ii"* evident at all. If the disc be
rotated, we gel two concentric rings
on an apparently homogeneous
Beld. Il is found however that
the outer ring flickers long after
complete fusion has taken place in
the inner ring, showing that the
stimulation of the retina by the
outer ring is increased under the
influence of contrast.
CAUSE OF AFTER IMAGE.
Sherrington has shown that
in the case of muscles there
is what is called reciprocal
innervation. Thus stimula-
tion of the cortex which, causes the contraction of one muscle also
brings about a corresponding relaxation of its antagonist, in order
that a rapid and economical motion ma)' take place. The contraction and
corresponding relaxation are therefore analogous to the response of one
part of the retina, which is accompanied by an inhibition of the surrounding
parts of the retina to the same kind of stimulus (simultaneous contrast). In
a similar manner the inclination to extension which is found to accompany
the prolonged flexion of a limb, finds its analogy in the phenomena of after
images and adaptation of the eye, since the tendency is to suppress a similar
stimulus in the part of the retina stimulated and to encourage its comple-
mentary. The inference to be drawn from these analogies is that the after
image and its allied phenomena are caused by changes in the conducting
paths of visual impressions which are similar to those found to exist in paths
belonging to the motor system. What the nature of these changes in the
conducting paths may be is at the present time undecided. McDougall has
suggested that they are fatigue effects in the synapses of the higher conduct-
ing paths. If this view is correct it would seem difficult to explain why after
images and contrast phenomena are best seen with a rested eye.
UTILITY OF THE AFTER IMAGE. We have seen that the
effect of the after image is to inhibit the possible repetition of a
similar stimulus, and at the same time to favour the reception of one
of a different nature. The process is therefore one which favours change,
for not only is there a tendency to efface an old impression but also to welcome
a new one. Such effects must be of great value to an organ such as the eye
the function of which is to a considerable extent, in everyday life, to present
to consciousness the greatest number of impressions in a given time. For
example, by measuring the time taken to read a passage in which almost
every word was of importance, it was found that on an average eight words were
THE SUBJECTIVE PHENOMENA OK VISION
57:»
read in each second, and that the eight w ords had an average of forty lei ters.
It is clear from this that between eight and forty different impressions must
be presented to consciousness in each second. The function of the after
image in preparing the retina for the reception of new impressions would
therefore appeal to be a very important one. The effects of simultaneous
contrast are equally important to vision, because the changes produced
by it are such that the images falling on contiguous portions of the
retina are made as unlike as possible. Not only are the intensity and colour
of adjacent parts of the image made more definite (this process being compar-
able to the effects of intensification on a photograph), but the blurring at the
edges of contours due to imperfections in the image formed on the retina are
also largely eliminated (this comparing with retouching in photography).
BINOCULAR RIVALRY must be briefly referred to here because of
the similarity which it shows with the phenomena described above.
If for any reason the images formed on the retina have
dissimilar contours, rivalry ensues, first one image and then the other
reaching consciousness. This process usually occurs independently in differ-
ent parts of the Held, so that the visual impression consists of a patchwork
LLFT
LYE
%
////
y//,
RIGHT EYE
STEREOSCOPE.
Fir;. 29". Diagram to show how the binocular combination of
two dissimilar images produces a fluctuating image con-
taining parts of both of them.
of the two image.-. Seldom if ever are both images seen in the same
part of the retina at the same time. It is found that a number of
factors can cause one image totally to suppress the other ; these are interest,
novelty, and brightness. The importance of this suppression can be apprecia
ted by picturing the confusion which would occur if two different images were
.simultaneously presented to consciousness, as would happen in animal:, in
which different images are formed in the two retinas and in cases of strabismus
in man. The parallelism between this process and those which we have already
described can be traced by regarding for one moment one of the images as
576 PHYSIOLOGY
the primary one. This causes impulses to travel to the visual centres un-
affected at first by the effects of other images, but these tend to accumulate
more and more until the primary image is overcome, and that of the other
eye put in its place. But this image in time suffers in the same way, so that
the images alternate. The fact that a new image can suppress an old is due
to the absence of after images in the first and their presence in the second.
The predominance of a bright image can be explained by the longer time
required for the after image to reach such a level as shall cause suppression.
The preference for an image with contours would seem to be due to the greater
ease with which the after image may be removed by small deflections of
gaze.
SECTION X
ERRORS OF APPRECIATION
Under this heading we include all types of abnormality in the retinal
apparatus or in its central connections. The class therefore includes cases
in which the image formed on the retina is in every way normal, and those
in which the optical defects do not adequately explain the whole of the visual
disability, which experiment shows to be present. The class is found to
include cases which range from slight impairment to complete blindness.
The following classification may be used : — ■
Group 1. Both rod and cone vision are affected, and there is thus
both night blindness and total colour blindness.
Group 2. Rod vision is either affected alone, or there is slight defect in
cone vision as well.
Group 3. Rod vision is unaffected, while cone vision is either altogether
absent or is found to show abnormality, which affects certain colours only.
Note that any one of the above groups may be found to affect either one
or both eyes, and may involve the whole or only a limited part of the retina.
COMPLETE BLINDNESS (group I) may affect the whole of one
or both eyes, or may occur in half the visual fields only. It may be
limited to irregular-shaped islands or patches, or it may be found
associated with central or peripheral vision. The shape of the affected
area frequently gives a direct clue to tha cause of the condition. The
shape is best determined by means of the perimeter (Fig. 279).
(a) The whole of one or both eyes is found to be blind. The disease may
be congenital or may be the result of inflammation affecting the posterior
parts of the eye (ophthalmoscope will confirm). Injury involving the whole
of the optic nerve trunk will also cause blindness of the corresponding eye.
(b) The blindness involves the right or left halves of one or both retinae
only. The lesion in such cases involves the optic tracts. Tumours are the
commonest cause.
(c) The blindness is limited to a segment of the retina when the retinal
vessels are affected (e.g. by embolism). The ophthalmoscope will confirm.
(d) Blindness which affects the periphery of the retina only is due either
to deficiency of blood supply (as may occur in glaucoma), defective blood
(severe anaemia), or the presence of poisons in the blood.
(e) If blindness affects the centre of the retina chiefly, the cause is prob-
ably poisoning by either tobacco, alcohol, or both. At first vision is impaired
for certain colours only, but the blindness quickly becomes complete if the
absorption of the poison continues.
• 577 37
578 PHYSIOLOGY
(/) If irregular blind islands called scotomata an Eound in the visual
fields, the cause may be inflammation of the choroid or of the retina itself,
or the detachment of the retina from the choroid.
NIGHT BLINDNESS (group 2) is found in four different types of case.
(a) As an inherited condition, (b) In diseases of the liver in which bile
salts are found^ to circulate in the blood, since these dissolve the visual
purple out of the retina and therefore impair rod vision, (c) As a symptom
of insufficient food, (d) In disease of the retina or choroid (e.g. retinitis
pigmentosa). In the last two cases it is usual to find colour vision affected
to some extent.
The symptoms of night blindness are well described by the name. The
eye does not possess the power of becoming fully dark adapted, and even
a moderate degree is only attained after a prolonged stay in the dark. A
photochromatic interval is not found, that is to say, when the intensity
of a colour is reduced it does not pass through an uncoloured stage (due to
the rods). Purkinje's phenomenon is usually poorly developed or not seen
at all. There is no cure in the congenital cases.
COLOUR BLINDNESS. The detection of this condition is important
because of the use of coloured signals in the railway and marine services. The
employees of such services should be tested at stated frequent intervals,
because colour blindness may develop (e.79
driver of a train sees a signal, he says to himself " that is a green signal and
therefore my train may proceed.'' But supposing all the time it were a red
SIGNAL OR£EN
ed in practice for tin detection
(Edridck Gbeen.)
signal, and that he called it green through colour ignorance, that man
is as much a danger to the community as if he in fact were colour-blind. No
lest can he too searching, and no borderline case should ever lie passed; the
risk is too serious.
Of tests of theoretical importance some have already been described, namely the
measurement of the thresholds for light and colour, the colour-mixing apparatus and
the nicker method of photometry. There is however another test which is found
to give valuable information, namely the spectroscope test of Edridge Green. The
instrument consists of a spectroscope to which is fitted two shutters, one of which
may be caused to obscure the spectrum from the red end and the other from the violet.
The patient commences the test by placing the shutter on the red side at the place
where lie sees the red begin. The doctor notes this position on the wavelength scale
of the shutter. The patient is then told to move the other shutter until it reaches the
place where red changes to orange. This wavelength also is noted. The red side
shutter is now moved until it occupies the position of the violet side shutter, and the
violet side shutter is now moved until a difference in colour at the two sides of the
spectral area, which is thus isolated is just not able to be seen. The wavelengths are
again noted, and the next area measured off, and so on until the violet end of the pi
tram is reached. A person with normal vision will with this instrument map out
between 20 and 30 distinct areas. Abnormal vision may lie shown in two ways, first!}
by the ends of the spectrum being found in abnormal positions, the spectrum
shortened at the red or the violet or both, secondly by the isolated areas being too
large and too few, and thirdly by wrong names being applied to some of them. The
value of the method is considerable because it shows the presei ce oi > I threi
of defect, those due to blindness, those cawed by ignorance of colour names, and those
in which the appreciation of colour is deficient.
5K0 PHYSIOLOGY
Cases of colour blindness, when tested by the above* methods, are
found to show every possible variation between complete blindness
and slight impairment of the colour sense. Their classification is as a rule
complicated by the fact that cases are usually described in terms of one of
the theories of colour vision. Most varieties of colour blindness are inheritei I .
and are commoner in men than in women. But it may also be acquired,
as explained above, in poisoning by alcohol and tobacco. Cases of colour
blindness may be grouped as follows : —
1. Cases in which the cone mechanism of the retina is not functioning.
The patient is found to be colour and day blind, red is not seen at all, while
the other colours are seen as different shades of grey. Vision at night is
good, vision by day is complicated by the fact that the patient must ;m1
expose his eyes to a bright light, for otherwise his visual purple will
become bleached and his rod apparatus therefore cease to function. Owing
to the absence of rods from the fovea, this part of the retina is blind.
Visual acuity is low therefore. When tested by the flicker method his
luminosity curve is found to correspond to that of twilight vision. His
condition may be improved by using neutral tinted glasses fitted with a sky
shade.
2. Cases in which the cone apparatus is apparently normal, that is to
say, there is no avoidance on the part of the patient of strong light, no
diminished visual acuity, no fovea] blindness and no inability to see red
light. Yet there is absolute inability to recognize all colours, any one pari
of the spectrum being able to be matched by any other. Tests by means
of the flicker method show a luminosity curve which corresponds to that
of day vision. It would seem clear that the retinal apparatus is in every
way normal ; one is therefore forced to the conclusion that the defect concerns
the brain centre which subserves the appreciation of colour. This view is
supported by the fact that, between this extreme type a^td normal colour
perception, there are a large number of cases which show various grades
of defect. Some, for example, see two colours at the ends of the spectrum
only, the intermediate portion being a neutral colour ; others see three only,
at red, green and blue, and so on. Since in all these cases the cones are appar-
ently normal, there woidd appear to be a parallel with cases in which there
is no trace of deafness, and yet there is an inability to appreciate harmony
or to tell when two notes are in tune. In both types of cases it would seem
that the higher centres of jjerception and appreciation are either absent or
are undeveloped. As might be anticipated therefore, instruction and practice
at colour naming and colour matching benefit a certain number of these
cases, so that it is sometimes found that after such instruction the less abnorma 1
cases are not readily detected. If however they are tested in a poor light,
they are found to make mistakes which a person with normal vision would
not commit. But these are the circumstances under which signals have
frequently to be recognised, and it is for this reason that the lantern test
with its modifying"glasses is so valuable.
3. Cases in which certain parts of the spectrum are not seen at all. This
ERRORS OF APPRECIATION r„s|
condition frequently affects the red end of the spectrum, but it may be found
in other parts. The principal effects to be noted are : ( 1 ) an abnormal type
of luminosity curve, as examined by means of the flicker method : (2) the
requirement of different amounts of the primary colours in order to match
a given spectral colour, as compared with individuals with normal vision ;
(3) inability to recognise the normal number of different hues in the pan
of the spectrum affected, as shown by the spectroscope test ; (1) shortening
of the spectrum, if either of the ends of the spectrum is affected. The
condition would appear to be directly traceable to abnormality in the colour
receiving apparatus of which the cones form an important part. These
cases therefore show quite distinct features which at once differentiate them
from those of class 2. For in that class, so far as can be ascertained, the peri-
pheral receiving apparatus is normal, and the error lies with the higher
centres in which the resulting nerve impulses are interpreted. A typical
example of a case belonging to class 3 will now be described, namely, that
in which there is shortening at the red end of the spectrum. The flicker
test shows that the luminosity curve for different parts of the spectrum
lias its maximum in the green, instead of in the yellow. Further, the curve
does not extend so far into the red, or show such high values in the orange
as the normal curve. This curve therefore explains the apparent shortening
of the spectrum. Colour mixture experiments show that the patient can
match mixtures of green and blue with white light. When required to match
yellow, he uses an excessive amount of red, and correspondingly less
green than the normal sighted ; this test again shows the deficiency of
the red sensation. Tested by the spectroscope it is found that, beside the
shortening at the red end of the spectrum, there is also an inability to distin-
guish the normal number of hues at the green and yellow. This effect is
readily explained, because the difference between green and yellow shades
largely depends on the varying extent to which they stimulate the red
sensation. When the red sensation is absent, it is clear that the differen-
tiation of greens and yellows must suffer.
EFFECT OF INTENSITY ON COLOUR VISION. It is well known
bhal there is a certain range of intensity over which the appreciation of
colour is a maximum, and that at high and low intensities appreciation
is diminished. Thus at low intensity the spectrum will appear shortened
at both red and violet ends, and with the spectroscope test perhaps In
monochromatic areas will be mapped out instead of the normal 20 to 30.
At high intensity on the other hand, the. spectrum appears to extend further
than usual at both red and violet ends, but again it is found that the number
of apparently monochromatic areas is considerably reduced. In the one
case it would seem that the impulses received by the brain from the cone
mechanism are so feeble that appreciation is diminished, and in the second
that a powerful colour stimulus arouses all three sensations indifferenl ly and
therefore makes the differentiation of colour difficult.
PERIPHERAL VISION. Experiments with the peri] how that
there is under ordinary circumstances a reduced appreeiation ol colour in
582 PHYSIOLOGY
the periphery of .the retina. Thus in an annular zone round the macular
region there is red-green blindness but full appreciation of yellow and blue.
Outside this area coloured objects are seen in different shades of grey. More
careful experiments show firstly, that there is no hard and fast line limiting
the zones, but a gradual diminution of colour perception on passing in any
direction from the centre to the periphery; and secondly, that intensity plays
a most important part, an increase being sufficient to effect normal colour
perception even in quite peripheral vision. The red-green blindness
found at one intensity might be due either to an absence or more probably
to a weakness or deficiency of cither the red or the green sensations, or to
defective appreciation on the pari of the higher centres in the brain. In
the first case there would be an abnormal shape to the luminosity curve, such
as is found, in fact, in red or green blindness, whereas in the second case the
luminosity curve would be similar to that of normal vision. Experiments
aresiid toshowthat the curse is normal, and therefore the cones in the peri-
phery must be in every way normal, a supposition which is borne out by t he
correct appreciation of colour at high intensity. Whythenit may be asked is
colour vision reduced at the periphery if the cones are normal ? The answer
is, 1 think, firstly that the number of cones is greatly diminished, and secondly
that the effective area of the pupil is much less at the periphery than it is at
the centre of the retina. We have seen in a previous section (1) that the
threshold necessary for the appreciation of eolour depends on the size of the
area of the retina which is receiving stimulation. The larger the area the
lower can the intensity be. Therefore one unit of intensity falling on
ICO cones is equivalent to 100 units falling on one cone. Now consider
the relative conditions of the fovea and the periphery ; at the fovea let us
suppose there to be 100 units of intensity falling on 100 cones, then at the
periphery there will be but 50 units (because the effective area of the pupil
is less owing to the rays entering obliquely), and these will fall on perhaps
two cones only. Whereas in the first case there are 10,000 cone-units, in the
second there are Kin cone-units only, and it is therefore to be expected that
appreciation of colour would be decreased in the same way as it is at the fovea
under reduced illumination. 1 That blue is perceived at a greater angle than
yellow is probably due to the greater refraction of blue than yellow rays when
they strike the eye surfaces obliquely. For a blue ray and a yellow ray to
meet on the retina, the angle subtended by the blue must be 5 per cent, larger
than that of the yellow.
1 The above explanation dues not however adequately account for the fact that
peripheral vision does not lose its colour appreciation for blue and yellow so readily
as it does that for red and green. The phenomena of peripheral vision still require
further investigation.
SECTION XI
THEORIES OF COLOUR VISION
The value of a theory 60 science is as much due to the fresh lines of research which
it indicates, as to the explanation which it offers of the already ascertained tacts. The
theories of vision therefore are of value in spite of the fact that they do not at tin-
present time offer a complete account of the retina and its functions.
THE DUPLEX THEORY of von Kries states that there are in the retina two entirely
separate mechanisms, namely that used for twilight vision which is colour blind, and
that used for day vision which responds to colour. Tin- view that the rods with the visual
purple supply the former whereas the cones provide the latter, is already familiar
because it has been made the basis of the description already given in previous section
The evidence on which this opinion is based may with advantage be repeated because
of its importance.
Twilight vision is found in those parts of the retina where there are rods; it is not
found therefore at the fovea centralis (because cones alone are to be found there), if a
spectrum be examined it is found that the colour with the greatest luminosity is the
green, but that red rays are not seen at all. The form of the luminosity curve is identical
with the bleaching curve of visual purple, and this pigment is found only where there
are rods. The visual acuity of twilight vision is low, and is explained by the fact
that many rods as a rule send their impulses through one and the same nerve fibre.
In addition to this experimental evidence, there is the statement that animals (e.g.
bats and hedgehogs) and birds (e.g. owls) which are nocturnal in habit, have rods in their
retinae and not cones.
Day vision is found most highly developed in the fovea, from which rods an- absent .
Not unly arc the cones at the lovea placed very closely together, but it would appear
that each cone connects to one nerve fibre only; in this way the high visual acuity is
explained. Further it is stated that animals (e.g. tortoises) and birds (>.■
■'<<
■&
ON_
t-
1
4
/
.#
^y
r
w
err.
S/*r,o/vt"^T=SS
64 62 60 58 56 54 52 50
46 44 42 40 38 36 34 32 30 28 26 24
FlO. -!)9. The red, green and blue sensation" curves and the luminosity curve of
white light. Luminosity vertical wavelengths horizontal. (Abney.)
Having thus briefly outlined the hypothesis of Young and Helmholtz.
ship with the results of experiment may receive consideration.
relation-
THEORIES OF COLOUR VISION 585
1. The results of colour mixture are all adequately explained. Since to each of
the fundamental colours there is a corresponding sensation, and since mixtures of the
fundamentals can produce the whole range of colour, it follows that corresponding
stimulation of the sensations and their resynthesis in the brain tits in with the facts.
2. The various classes of colour blindness which show abnormal types of luminosity-
curve, abnormal colour mixture values, and possibly also a shortening of the spectrum,
are readily explained by supposing one of the sensations to he defective or absent.
For example, cases which show a shortening of the red end of the spectrum are stated
by the theory to have a deficient red sensation. The luminosity curve calculated on
this basis is found to fit closely the curve found by experiment in these cases of colour
blindness. The hypothesis would appear therefore to be able to fully explain the
various cases which fall in this class. Certain objections have however been advanced
which it would be well to examine, (a) That it does not explain why the red blind and
the green blind state that the ends of the spectrum as they see them are yellow and
blue, whereas it w ould be expected that they would say green and blue if red blind, arid
red and blue if green blind. An explanation of this behaviour can be readily obtained
by examining the forms of the red and green sensation curves, Fig. 299, for in both red
and green blindness a yellow light is that which stimulates the remaining sensation most
strongly, without at the same time involving the blue. In both types of case therefore
both red and green are regarded as being but degraded yellow.-., and the spectrum is
therefore named accordingly, {b) That the hypothesis does not explain why these
same cases call white white, instead of bluish green or purple.
This is explained by the fact that a colour-blind person will call white what his
fellows who have normal colour vision call white, because he has learned his colour names
from them. In the same way a green-blind person will not, call the leaves of a tree by
a wrong colour, although he will readily err if a piece of paper of the same colour as a
leaf be handed to him.
The various types of colour blind which have normal luminosity curves cannot
be explained by the hypothesis without some further elaboration. As I have indicated
however they fit in well with the supposition that it is not the eye but the higher centres
which are at fault. The impulses which travel up the optic nerve are in every way
normal; the error occurs in their interpretation. This would appear to be a reasonable
explanation which fits in with the other postulates of the hypothesis. It has been
advanced by Edridge Green as part of another hypothesis of colour vision, which will
be given later.
3. Contrast, after images, and allied phenomena have not been adequately dealt
with. Helmholtz regarded contrast as an error of judgment, but Hering showed con-
clusively that such could not be the case. McDougall's hypothesis, which is to a large
extent founded on that of Young, will be found to add the features that are required
for the explanation of after images and contrast.
HERING'S HYPOTHESIS states that there are in the retina three substances
which are all the time tending to dissociate into their components. They are however
either replaced or built up again from substances in the blood, as quickly as they are
destroyed. There is therefore equilibrium between anabohsm and catabolism, when
the eye is unstimulated, and while this is the case no nerve impulses travel to the brain.
Now each of these substances is dissociated by one of the following colours, red, yellow,
white ; and is built up when green, blue or black fall on the retina. Thus one substance
will break up when red light falls on it, and will recombine when green does. There
is thus a red-green, a yellow-blue, and a wliite-black substance. When a coloured
light falls on the retina these three substances are broken down or are built up in varying
amounts and corresponding impressions sent to the brain. Tested by experiment this
view is found to acquit itself as follows : —
(1) The results of colour mixture are readily explained, with the possible exception
of the formation of grey, by the simultaneous anabohsm and catabolism of one and the
same substance.
586 PHYSIOLOGY
(2) Contrast, alter images and adaptation arc readily explained as follows: —
While a stimulus Calls on the retina, the three visual substances which were previously
in equilibrium with their breakdown products, are caused to take up a iww position
of equilibrium. On cessation of the stimulus however there is a return to the old
position, and therefore the impulses sent to the brain are those which correspond to a
sensation of an opposite character, thus causing a negative after image. Contrast is
explained by supposing that anabolism in one area is accompanied by a stimulus
to catabolism in the same area, but the effect is not sharply limited but tends to spread
for a short distal in' over surrounding areas, and thus causes a change in their equilibrium
point which is of an opposite nature to that of the stimulus which originates them. Thus
blue light falling on a part of the retina causes anabolism in that area, which is followed
by an increased tendency to catabolism. This process affects the surrounding area, pro-
ducing the same change and therefore the same sensation as would a yellow image.
Adaptation is explained as the taking up of a new equilibrium point, for one or all
of the three substances.
(3) ( 'olour blindness is explained as follows : Total colour blindness by the presence
of the black-white substances only. Red-green blindness by the deficiency of this
substance, and yellow-blue blindness in a similar way. Bui we find by experiment that
there are two classes of red -green blindness, namely those which are red deficient.
and those which are green. The Hering hypothesis is incapable of explaining theii
causation in its present form.
EDRIDGE GREEN'S HYPOTHESIS states that the function of the rods is to
secrete visual purple. This pigment under the action of light stimulates the ends of the
cones and causes them to send impulses to the brain which vary according to the
wavelength of the light and its intensity. The rods are on this view merely secretory
organs, and take no other part in vision. The impulses having reached the brain go
first to a light perceiving centre, and then to another especially developed for the
appreciation of colour. In this colour centre there arc three separate mechanisms, which
correspond roughly with the red, green and blue fundamental colours, but which may
respond to other frequencies than those to which they approximately correspond.
Suppose, for example, that a monochromatic yellow light is falling on the retina, then
it is absorbed l>y the visual purple, and thus stimulates the ends of the cones. These
then send up the optic nerve impulses which have a mean frequency corresponding
to yellow light, but at the same time contains impulses of other frequencies on either
side, to a degree which depends on their closeness with the mean. For example in
the above case, beside impulses of frequency of yellow light there are also some which
correspond to green and red. These impulses having reached the colour centre stiinii
late the red and green mechanisms respectively, while those corresponding to the yellow
also stimulate these same mechanisms, but in proportion to the energy which each
receives. This view may now be examined in the light of experiment.
(1) The results of colour mixture would appear to he explained by it with the excep-
tion that the mechanisms in the colour centre must have very definite mean frequencies,
for otherwise mixed colours will not be able to match the whole of the spectral range.
(2) Simultaneous contrast and after images are explained by Edridge Green in a
way which 1 find difficult to understand ; it would therefore be best not to attempt to
discuss it.
(3) Colour blindness was initially explained as being due to defective appreciation
in the colour perceiving centre. The shortening of the red end of the spectrum would
be due not to the inability of the retina to react to the stimulus, but to fault on the part
of the colour centre when receiving the nerve impulses. A different explanation has
been offered by Houston, who has recently elaborated the hypothesis. He states
that colour blindness is due to the excessive reaction on the part of the retinal
apparatus, which causes the energy of the stimulus to be spread over too wide a range
of frequencies. If such were the case one would expect a low appreciation of colour,
as is found in a number of examples of colour blindness, hut there would he difficulty
THEORIES OF COLOUR VISION 587
in finding an explanation of these cases which show an inability to respond to a part
of the spectrum. Although there does not seem to be any special difficulty in bo
modifying this hypothesis that it fits in with all the varieties of colour blindness, yel
it would seem that this would cause it only to be more and more like the theory of Young,
with tin's important difference, that according to Young's theory the three substances
by which light is selectively absorbed, according as its wavelength corresponds to the
icd, green or blue part of the spectrum, is in the retina, whereas the three mechanisms
required by Edridge (liven are in the brain. Changing their situation would not appear
to have added to our knowledge of them, but would on the other hand appear to add
greatly to our difficulties, for it is impossible to understand how impulses of the enor-
mous frequency of light could be transmitted intact up the optic nerves, as Edridge
Green requires.
McDOUGALL'S HYPOTHESIS is not antagonistic to Young's theory, as the two
previous views have been, but adds valuable suggestions as to the causation of contrast
and after image phenomena, points to which the original theory gave little or no atten-
tion. MoDougall also accepts the duplicity theory. He commences by slating that
there are four centres for the two eyes, namely red. green, blue and white (the mechanism
of which is the rods), and that these centres are distinct and have no anatomical iden-
tity. Between these centres there is antagonism, the red centre of one eye against the
green and blue centres of the other and also to a less extent against those of itself.
In this way one can explain not only binocular, but also monocular rivalry. Contrast
is explained in a somewhat similar manner ; thus if the object looked at consists of a
red area on a grey field, the red stimulus inhibits the appreciation of red in the surround-
ing field, and therefore causes it to have a blue-green colour, a deduction which is
confirmed by experiment. After images are dealt with in a somewhat similar manner.
With the evidence that has accumulated up to the present before us, there appears
to be more in favour of Young's hypothesis than is to be found for its rivals. Further
tli. in that, it is not at present advisable to go.
SECTION XII
BINOCULAR VISION
Binocular vision may be defined as the co-ordinated employment of two
separate visual organs in order to produce a single mental inopression. The
advantages of binocular as opposed to monocular vision are : —
1. Optical defects of one eye are less important, since they are masked
by the well-defined images of the other eye.
2. Defective vision in parts of the visual fields of both eyes is hidden so
long as the defects do not affect the same parts of both fields. Thus the blind
spots do not obtrude themselves under ordinary circumstances, because the
corresponding field of the other eye contains normal retina.
3. The combined fields of the two eyes are larger than either alone because,
while the features restrict the nasal halves of the fields of both eyes, the
combined field contains the unrestricted temporal areas of both retinae.
4. Binocular vision under certain circumstances provides a very accurate
perception of depth, size and distance, which is called stereoscopic vision.
In order that there should be binocular vision the following conditions
should be complied with : —
1. The fields of the two eyes must overlap. Animals in which the ej e
axes are parallel have the greatest overlap, and therefore possess the
eompletest binocular vision.
2. Approximately similar images must be formed on the retina?, because
if this condition is not satisfied, antagonism between the images will occur,
as described above, and first one image and then the other will he presented
to consciousness.
3. The retinae must possess physiologically corresponding points in
order that similar images formed on them may produce one conscious
impression.
4. The external eye muscles must so adjust the visual axes that the centres
of the fields of the two eyes coincide with the images of one and the same
object. This adjustment is called fixation. It is sometimes described as
the intersection of the visual axes at the point fixated.
5. The oblique muscles must rotate the eyes about their axes until
corresponding retinal points occupy corresponding meridians.
The rotation adjustment is necessary because otherwise identical points
of the retinae might not correspond, even when the centres did, so that one
image would appear tilted at an angle with the other. Fixation is partly
a voluntary act and partly a reflex process. The former is shown by the
fact that the eyes may be directed towards an imaginary object a short
588
BINOCULAK VISION 589
distance from the face, so that the eye axes are strongly converging and the
accommodation correctly adjusted to the same plane. The presence of a
reflex phase is well shown by the fact that no effort of the will is required
to sustain fixation on an object in which we are interested, and also by those
cases in which when once an object has been fixated, there is found to be
considerable mental difficulty in turning the gaze elsewhere. Rotation fixa-
tion on the other hand appears to be entirely reflex. In order that fixation
should be obtained when the gaze is directed in different directions, it is
necessary that there should be close association between the corresponding
muscles of the two eyes. This is at all events assisted by the anatomical
arrangement of the 3rd, 4th and 6th cranial nerve nuclei which has been
described previously (see page 496).
Not only are the corresponding nuclei on the two sides connected by
transverse fibres so that e.g. either the superior recti or the inferior recti
move together, but the external rectus nucleus of one side is joined to the
internal rectus nucleus of the other by the dorsal longitudinal bundle, so
that the eyes deviate together to right and left. Similar connections are
to be found between the nuclei of the superior and inferior obliques. The
relations of these nuclei to the cerebral cortex have been ascertained by elec-
trical stimulation. It has been found that stimulation of the median third of
the limb of the angular gyrus on either side causes both eyes to be turned
to the opposite side. The right gyrus therefore connects with the nuclei
of the right internal rectus (3rd) and the left external rectus (6th).
Since both these nuclei are on the left, the fibres from the gyri must cross
in order to reach their corresponding nuclei : this they do at the level of the
anterior corpora quadragemina. The angular gyri are connected to both
the frontal and occipital parts of the cortex, so that voluntary movements
of the eyes, and also movements under the action of light, can be carried out.
Experimental stimulation of the semicircular canals is found to cause
conjugate deviations of the eyes. But stimulation of the canals is effected
naturally by a rotation of the head, as will be described later. The conjugate
deviation of the eyes would appear to be initiated in order that the gaze
might remain stationary on external objects in spite of the head move
incuts.
The way in which involuntary fixation is brought about may be described
as follows : — when an image falls on the periphery of the retina an impulse
reaches the oculo-motor nuclei in the manner described above. Thus,
suppose the image to come from the right, it will fall initially on the left
halves of both retinae, and impulses will therefore travel to the left occipital
cortex. From here they will pass to the left angular gyrus, causing impulses
to travel to the left internal and the right external recti. Both eyes arc
therefore directed to the right, the movement being such as to bring the
image on the fovea. But as the fovea is approached, the Lmpre kn sent to
consciousness becomes increasingly distinct, owing to the higher acuity of
the fovea. If the fovea is passed the image begins to become indistinct
again, and therefore the movement of the eyes is checked as soon as the image
590 PHYSIOLOGY
has reached the fovea. In this way fixation is effected. If the acuity of
the fovea is reduced by disease or by working in a bad light, the definition
of the image does not sharply improve as the fovea is reached, and therefore
the movement of the eyes is not checked until the image has reached the.
periphery again. But here the degradation of the image calls for the re-
verse process, which again causes the image to pass over the fovea. Repeated
oscillations of the eyes therefore occur, which are called nystagmus. The
condition is met with in the day blind, since cone vision is defective, in
persons whose visual acuity has been lowered by working in a dull light, e.g.
miners, and in cases of poisoning by tobacco and alcohol.
THE HOROPTER. Theory shows that, even when fixation is properly
effected so that corresponding retinal points occupy the same meridians,
images formed on the retinae do not necessarily fall on corresponding points.
For this to be the case, it is necessary also that the objects from which those
images are formed should occupy certain definite positions in relationship
with one another. For example, if an object 10 feet from the eye is fixated,
the images of other objects on either side will fall only on corresponding
points if these lie on a circle of 5 feet radius, the centre of which lies between
the observer and the object fixated. For calculation shows that oidy then are
the images formed on the two retime the same distance from the centre.
The form of the curve which is called the horopter is found to change with
the different directions of the gaze. When the gaze is directed to a point
on the floor it is stated that the horopter almost corresponds with the plane
of the floor.
MONOCULAR DEPTH PERCEPTION. The perception of depth
with the single eye is found to depend on a number of different factors which
as a rule operate together :--
1. The apparent size of objects, the dimensions of which are known.
Thus the size of a man being approximately known, his distance away is
known from the size of the image which is formed on the retina. The further
away he is the smaller his image will appear.
2. The. colour of an object being known, the effect of distance in modifying
that colour is used in depth perception. Thus trees which, when near, look
yellow-green, when seen at a distance through an intervening layer of haze
appear blue-green or even blue. This fact is made use of by artists for
expressing distance.
3. The partial obstruction of a distant plane by objects nearer to the
observer.
4. The shadows which one plane, casts upon another.
5. The intensity of the light which is reflected by the object frequently
varies with its shape and position. For example, the shape of a solid sphere
can be accurately inferred from the distribution of intensity over its face.
6. By perspective, which may be defined as the geometrical arrangement
of lines in the image formed on the retina. Thus the lines of a tennis ccurt
seen diagonally from one side are all found to converge to one or other of
two points on the horizon.
BINOCULAR VISION 591
7. By the intersection of objects with the horizontal plane. Thus the
positions of trees in a field may be inferred with some accuracy, if the positions
of the roots of the trees in relationship with the boundaries of the field be
observed.
8. By parallax, that is the rate of movement of objects in relationship
with one another. Thus if a middle plane be looked at, it will be noticed
that objects in a plane behind appear to move in the same direction as the
observer, while those in a plane in front appear to move the opposite way.
Even when we are standing still, we are all the time making involuntary
movements which cause the development of parallax. This process is prob-
ably one of the most important in producing the monocular effect of
depth.
9. By the effort of accommodation required to sharply focus an object,
lu man the accommodation is found by experiment to give little or no percep-
tion of depth, possibly because the function is involuntary. It is thought
that in birds, in which the ciliary muscles are striated and are under voluntary
control, the accommodation may give valuable information of distance.
All the above factors operate together to produce an appreciation of
distance which as a result of experience reaches a very high order, and with
the exception of the last two, are used by the artist to produce the effect of
solidity and realness. Any good picture shows us that the result can be very
convincing.
STEREOSCOPIC VISION is the binocular perception of depth. It
consists of all the factors which operate in the case of each eye separately,
and in addition uses :
I. The convergence ol the eye axes which is necessary in order in cause
images of near objects to form on the fovea simultaneously.
"2. The dissimilarity between the images which are formed on the two
retina-.
That convergence has very little effect on the perception of distance
can he proved by placing weak prisms, either base in or base out, in front of
the eyes and in this way changing the convergence of the eye axes without
changing any other condition. It is found that the apparent positions of
objects are unaffected.
That there is dissimilarity between the images formed on the retina can
be easily proved by experiment. Thus if the gaze be directed towards a
distant point, and the finger be held a short distance from the nose, the finger
appears to be to the right of the distant point with the right eve and to I he
left with the left. If two photographs be taken of the same scene, but with
the camera, for the second photograroh, three inches to one side of its posit ion
for the first, it is found that, when the two negatives are placed so that
objects on the horizon correspond, there is a lateral difference of position
in the case of all other objects situated nearer to the camera. Measurement
shows that the nearer the object the greater the difference in position.
this is the case it is clear that only images in one plane can be formed on
corresponding retinal points ; images in all other planes must fall points
592
PHYSIOLOGY
Fig. .'41 >< >. The eyes are directed t" the point 6. A thread hung obliquely at a
under these circumstances gives rise to the images shown in the upper figures
— i.e. two images which do not lie on corresponding points. Nevertheless the
thread is seen as single.
which are discrepant. Two questions therefore
arise: (1) do we. see such objects doubled?
(2) if we see a single image only, is it because
one of the images is displaced from conscious
ness by the antagonism of the other ? An
answer is given by the following experiment : —
a Brewster's stereoscope is taken, the optical
arrangement for which is shown in Fig. 302. At
Yy
Fig. 30i. To show the
difference in the images of m
truncated pyramid as given
by the right and left eyes.
B and B two similar lantern slides are placed which show- a view of any
distant objects. On looking through the instrument at the point S the direc-
tions of the rays are changed so that the images of
the slides are seen to overlap one another. By shift- §
ing one of the slides the images may be made to fall
on corresponding points of the retinae, and they then / \
form a single combined picture. In front of these
slides are now placed another pair of slides which
show the photograph of an index mark. If the
indices are adjusted so that they occupy correspond-
ing positions in relationship with the objects on the
slides below them, on looking into the instrument
it will be seen that these marks appear to lie in the
same plane as the distant objects placed on the
slides below them. If one of the index marks
be moved towards the axis of the instrument, it
will be seen on looking into the eyepieces, that the
indices now appear to lie in a. plane considerably in
Fig. 302. Brewster's
BINOCULAB VISION 593
front of their previous position, in fact that the closer they are placed to-
gether, the nearer do they appear to the observer. But the indices do not
show double images, unless they are moved a considerable distance to-
gether, and then the effect of distance ceases. If one of the index slides
be removed and the other be moved towards and away from the axis of
the instrument, the index is not found to shift its plane towards or
away from the instrument. This shows that for position to be appreciated
both images must be presented to consciousness simultaneously without
appearing double.
THE ACUITY OF STEREOSCOPIC VISION has been investigated in such a
way that other factors which normally assist distance perception were excluded. Two
methods have been used : (1) to adjust the position of a thread which lies between and
parallel with two other threads until they all appear at the same distance from .the
observer ; (2) to observe the fall of small coloured bodies of unknown size, and then to
state the position of the line of fall in relationship with a fixation mark. The former
method at 2 metres distance shows an average error of 1-5 mm., the latter method at
the same distance an error of 40 mm. The difference between the results of the two
methods is considerable ; but it should be noted that in the fall method the object
is seen only for -02 sec. If in the thread method the threads be placed horizontal it
is found that the appreciation of distance is greatly impaired. The greatest acuity
is found when the threads are vertical. If however the head is turned so that the line
joining the two eyes is vertical, the greatest acuity is found when the threads are
horizontal. This would be expected if the appreciation of distance is greatest when the
parallax of the objects at the two eyes is greatest. Experiment shows that the recog-
nition of position in relationship with a definite fixation mark is much more accurate
than recognition of absolute distance in which there is no point of reference. Thus it
is well known how inaccurate the estimation of the distance of a single source of light
at night may be.
HYPOTHESES OF DEPTH PERCEPTION. Javal's view was that the move-
ments of the eye muscles, which are necessary in order to direct the gaze from objects
in one plane to those in the next, caused impulses to travel to the brain which are
interpreted in terms of distance. This view was ruled out by the fact that images
which are formed on the retina for a short length of time only ('02 sec), are able to
be perceived in relief.
HERING'S HYPOTHESIS was that it is the formation of similar images on points
of the retinae that do not correspond which causes distance perception. If the
disparation is crossed the object appears nearer than the fixation mark by an amount
wlu'ch depends on the amount of the disparation. If on the other hand the disparation.
is uncrossed the object is recognised as being further away. Hering supposed further
that crossed disparation acts as a stimulus to convergence and accommodation, while
uncrossed produces the reverse effect. We may now inquire how this hypothesis
fits in with the facts. To commence with, if depth depends on disparatii >n it is clear that,
when we perceive objects lying in different planes, we must subconsciously group them
according as they fall on corresponding retinal points, or on points which are discrepant
by one, two, three or more cone widths, and whether the discrepancy is crossed or
uncrossed. The amount of the discrepancy must be some whole number of cone widths,
because it is clearly impossible to stimulate half a cone with one impression and tin-
other half of the same cone with a different one and obtain two distinct sensations. It
is clear that space must be divided so far as stereoscopic vision is concerned
into a number of concentric shells, the centres of which correspond with the position
of the observer. Now the thickness of these shells can be readily calculated : at 1 i
they are found to be 2 mm. thick, at 10 metres 200 mm. thick, and at 100 metres 17
metres thick. If we are looking at a fixation mark 10 metres away, objects
38
594 PHYSIOLOGY
100 mm. nearer to and 100 mm. further from the observer will lie in the thickness of
one and the same shell, and will therefore appear the same distance from the observer.
Objects between 100 and 300 mm. nearer to the observer will lie in the shell correspond-
ing to one cone discrepancy, and will therefore be appreciated as being at a different
distance from the observer, appearing nearer if crossed, and further if uncrossed. The
same reasoning applies to objects at other distances. If this calculation is correct
it should be necessary to place objects more than 100 mm. from a fixation mark, which
is itself placed at 10 metres, in order that a difference in the distance from the observer
should be appreciated. Greet! found by experiment that -,', , tli the distance of the
fixation mark was necessary (i.e. 200 mm.), the observations being instantaneous ones.
If time be allowed for prolonged observation, greater accuracy in the appreciation
of distance is obtainable, because different points of fixation can be used. Suppose,
for example, that two objects 20 mm. apart be examined at a distance of 10 metres,
under instantaneous observation they will appear identical as described above ; but if
the examination be made more carefully, it will be found that, on fixating a point a mean
distance of 100 mm. away from the objects, the distance between the two is suddenly
appreciated because the demarcation between two shells now falls between them. It
is in this way that the accuracy of extended observation becomes greater than that
obtainable with instantaneous. The limit reached by experiment is stated to corre-
spond to a displacement at the retina corresponding to the ,V,th diameter of a cone.
The corresponding values for the acuity of stereoscopic vision would be i J iT th those
given above, namely -2 mm. at 1 metre, - 20 mm. at 10 metres, and 1 -7 mm. at 100 metres.
Hering's view would therefore appear to agree well with the results of experiment. It
remains to consider the type of cortical mechanism that would be necessary
for the estimation of the discrepancy between the images. One type may be briefly
described as follows : — To a number of parallel planes in the left side of the cortex are
connected the terminal ends of the nerve fibres from the left halves of the two
retinas. At the middle plane fibres from exactly corresponding retinal points are
connected together. At planes which lie superficially to the middle plane are connected
other terminations from the same fibres but with a crossed lateral discrepancy of one
cone in the 1st plane, two cones in the 2nd plane, three cones in the 3rd plane, etc. At
planes which lie deep to the middle one, other terminations from the same fibres are
connected but with an uncrossed lateral discrepancy of one, two, three, etc., cones as the
case may be. On looking at a fixation mark on a uniform background therefore, a
series of impressions of the mark will be formed on all these planes, but in the central
one only will they exactly agree, for in all the others the lateral discrepancy will cause
the impressions to be duplicated. In all these other planes there will thus be antago-
nism, first one image and then the other predominating. When these images are com-
bined in consciousness, the stable image from the central plane will suppress the unstable
ones from all the other planes, the result being a single picture of the fixation mark.
If there are in front of the fixation mark other objects lying in planes at different
distances from the observer, the impulses sent up by the cones to the cortical plan
will not correspond at the central plane, because their images no longer fall on corre-
sponding points, but they will correspond in the superficial planes where the discrepancy
of their images agrees with the discrepancy of the nerve connections. These other
planes will therefore predominate according as each contains the identical images,
and when they are combined in consciousness these planes will suppress all
the others. Since each cortical plane represents a certain lateral discrepancy, it
must also represent a certain distance from the fixation mark. If consciousness recog-
nises the plane in which stable image is formed, it also must apjireciate the distance
of the object lying in that plane from the fixation mark. This would not seem any
more difficult than the localisation of a touch on the skin. So far as we are able to judge
there is nothing inherently impossible in the arrangement of the hypothetical cortical
mechanism which has been outlined above, and therefore Hering's theory would appear
to be very plausible.
PART III
HEARING
PAGES
Section 1. — Properties of sound .......... 595
,, 2. — Structure of Auditory Apparatus ....... 600
„ 3. — Auditory Sensations . ........ 611
SECTION 1
PROPERTIES OF SOUND
Sound is propagated by waves consisting of alternate compressions
and rarefactions which travel through the medium. Any medium
which has the properties of elasticit}' and mass can conduct sound ; thus
solids, liquids and gases are all efficient conductors. Since sound is a form
of wave motion it exhibits many of the properties which are found in the
case of light, namely Reflection, Refraction, Diffraction, etc. But-
owing to the long wavelengths of sound waves compared with those of
light, the effects of diffraction are relatively of greater importance. Therefore
sound does not form sharp shadows, such as light does, and is found to bend
round obstacles and to be conducted down speaking tubes, etc., in a way that
would be impossible if sound were of shorter wavelength.
SOURCES OF SOUND are so well known to us that the fundamental
property of a source of sound tends to be forgotten, namely that, to
produce sound, motion has to be initiated in a sound conductor
which has a velocity the same or greater than that of the trans-
mission of sound. Thus when a book is closed with a snap, the book
becomes a source of sound when the velocity at which the air is
squeezed from between its pages is equal to the velocity of sound in air. A
stick stirred in water becomes a source when the ripples (eddies) it produces
have the necessary velocity to cause a wave motion. Sounds have been
divided arbitrarily into two classes, namely tones and noises ; the former
produce pleasant and the latter unpleasant (harsh, grating, screeching, etc.)
sensations. Between the two extremes fall the sounds of everyday life.
Thus music as a rule consists of tones, but may be found to consist of chords
which examined singly could be grouped as noises. And so at the other
end of the scale, when we strike a single stick with a hammer the eft
that of a noise. If however we take a series of sticks of different lengths
and strike them in succession, it will be noticed that the sound produced by
595
596 PHYSIOLOGY
each stick corresponds to a distinct note, and tunes may be played on such
a collection of sticks.
SOUND ANALYSIS can be performed in a number of ways ; possibly the
simplest method is to record the excursions of a flexible diaphragm on a rota-
ting wax cylinder, as in the phonograph. When thus recorded, sound waves
are found to have a regular sequence when they consist of tones and an
irregular sequence when they are noises. Sources of sound which produce
the former therefore vibrate in a regular manner (for example the limbs of
a tuning-fork, or the air in an organ pipe), while those which produce the latter
vibrate irregularly (e.g. a cart over cobbles).
INTENSITY AND PITCH. In a similar manner loudness or intensity
is found to depend on amplitude (as in the case of light), while pitch depends
on the wavelength, short waves having a high, long waves a low pitch. This
can be proved in other ways : thus, if a violin string be bowed forcibly the ex-
cursion of its string at each vibration is greater than when it is bowed gently,
and the amplitude of the corresponding alternating waves of sound varies
in proportion to that of the vibrating body by which they are started. By
attaching a pointed slip of paper to the end of a tuning-fork and so record-
ing its vibrations on a blackened surface, it is easy to see the connection
which exists between the amplitude of vibrations and the loudness of the
sound produced by the vibrating fork.
That the pitch of a tone depends on tba frequency of the vibrations, is
shown by means of the syren and the klaxon. As the speed of rotation
increases, and therefore also the number of impulses imparted to the air
per second, so the note appears to us to be rising. Since sounds of high
and low pitch travel with the same speed, the distance between the
waves decrease as the number of impulses per second increases.
LIMITS OF PITCH. The ear is unable to perceive tones the pitch
of which falls above or below certain fairly well-defined limits. If
the number of vibrations is less than about thirty per second no musical
tone is produced, the individual vibrations being perceived as a series of
pulses in the surrounding air, and it is only when we increase the number
to about forty per second that we are able to appreciate the pitch of the
note produced. As the number of vibrations per second is increased the
note rises steadily without break till we arrive at 40,000 to 50,000 vibrations
per second. Above this number of vibrations the human ear is incapable
of perceiving any note at all, though it is probable that small animals can
perceive notes still higher in the scale. In music neither the lowest nor
the highest tones are used. The lowest tone of large organs, that
of the sixty-four foot pipe, is 1 6 vibrations per second, and one can hardly
speak of its effect as that of a musical tone. The highest notes employed
in music are «4 and c5 with 3520 and 4224 vibrations per second on the
piano, and d5 with 4752 vibrations on the piccolo flute. In music therefore
we only employ between 40 and 4700 vibrations per second, i.e. about
seven octaves.
SOUND AUGMENTORS. Experiment shows that the intensity of the
PROPERTIES OF SOUND 597
tone produced by a sound source can be considerably increased by the use
of sound augrnentors. These are called resonators, sounding boards or
trumpets according to the form they take or the sound source (musical
instrument) to which they are applied. If from any string instrument
(e.g. violin) the box be removed, the tones generated are found to be
greatly reduced in intensity. The function of these sound amplifiers appears
to be to transmit the vibrations of the source (e.g. the stretched wire) to the
greatest possible volume of air, i.e. to turn into sound as much of the kinetic
energy of the vibrating wire as possible. In the case of the trumpet or horn,
there is in addition the effect of increasing the volume of sound in some ch< isen
direction at the expense of that in others. This effect is well illustrated in
the gramophone. In most musical instruments the amplifier must be
capable of responding to a large range of tones indifferently, and the more
perfectly it can do this the better is the instrument. Such perfection is diffi-
cult to obtain, and more usually it is found that in spite of all care one note
is accentuated more than others, e.g. ' the wolf note ' of the violin. Sound
amplifiers for the reed stops of the organ are on the contrary made as sharply
selective as possible, in order that of the many tones emitted by the vibrating
reed, the chosen one shall alone be augmented. This form of amplifier is
called a resonator, although the term is strictly speaking applicable to other
classes of sound amplifier, e.g. the sounding board. This power of
augmenting one chosen tone has great value, because in a musical chord it is
possible at once to detect the presence of any particular tone, by ascertaining
whether its resonator responds when the chord is sounded. For such analysis
the resonators of Helmholtz are generally employed. These are hollow
vessels open at one end and haying a tube at the other to which the ear may
be applied. A series of graduated sizes are used, each of which has a definite
period of vibration (pitch).
TIMBRE OR QUALITY. When the same note is sounded on different
instruments, i.e. tuning-fork, violin, piano, trumpet, human voice, every
person, whether he has an educated musical ear or not, can say at once what
kind of instrument is being used. This fact shows that the sound wave pro-
duced by these instruments must differ, altogether apart from any differences
in amplitude or in number of vibrations per second, and if the sound waves
produced by these instruments be recorded an actual difference is found in
the shape of the curve.
If a stretched wire be plucked so as to set it into transverse vibrations it
will give out a certain note, dependent on its length, its thickness, and the
tension to which it is subjected. If its length be halved it will give out a
note which is of double the number of vibrations per second. If only one-
third of the wire be set into vibrations the sound wave produced will have
three times the number of vibrations of that of the whole string. When the
string is free to vibrate as a whole the segments of it tend to vibrate even
while the whole string is vibrating. If therefore we take the note given out
by the whole string, the ' fundamental tone' as corresponding to 132 vibra-
tions per second, there will also be a series of notes superadded to the fimda-
598 PHYSIOLOGY
mental tone with vibrations per second in the ratio of] , 2, 3, 4, 5, and 6, etc.
Thus if the fundamental tone be c, the overtones, or harmonics, will be
produced as is shown below :
-a
12 3 4 5 6 7 8 9 10
Vibrations per Second
132 2x132 3x132 4x132 5x132 6x122 7x132 8x132 9x132 10x132
Nearly all musical instruments, as well as the apparatus for producing
the human voice, resemble a stretched wire in giving out overtones in addi-
tion to the fundamental tones, and the difference in the quality of various
instruments is chiefly determined by the varying predominance of the
different overtones. In some the higher overtones may be most marked,
in others only the lower overtones. The tuning-fork is practically the
only instrument the note of which is pure, i.e. free from harmonics or over-
tones. It must be remembered that these different tones arrive at the
external ear simultaneously. We do not have some particles of air vibrating
at one rate and other particles at another rate, but all the simple vibrations
of which each component tone is composed are combined together to form a
compound wave, the shape of which differs according to the constituent
vibrations of which it is made up, and to the time relationship (phase) between
them.
Thus in the diagram (Fig. 303) the wave shown by the. continuous line
Fig. 303. d, a compound sound wave, which may be analysed into a, the
fundamental tone, and b and c, the first and second overtones. (Hensen.)
is compounded of the series of simple vibrations represented by the different
dotted lines. The component fundamental overtones and harmonics can
be readily identified in a tone experimentally by employing the series of
resonators described above. By practice it is possible to train the ear to
recognise strong overtones without the use of resonators.
PROPERTIES OF SOUND 599
THE ORGAN OF HEARING
From a knowledge of the fundamental properties of sound it is possible
to infer the probable features of the organ of hearing. In its simplest variety
the organ would take the form of a sounding board or diajuhragm which would
be set into vibration by the incident sound waves. The vibrations of this
plate would be identified by touch cells similar to those found in he skin.
which would be so placed that the diaphragm during its motion should come
into contact with them. Such an apparatus would respond to and estimate
the total intensity of sound. To identify the pitch a series of resonators
woidd be required, each of which would be sharply tuned to one of a series
of tones. Of the many types of resonator that could be employed a series
of stretched wires would appear to be the simplest and most compact. The
receiving apparatus would therefore take the form of a harp with a touch
cell and its respective nerve attached in close approximation to every
chord.
In order that such a mechanism may be formed of organic material
and be kept nourished during life, it is necessary that it be immersed in a
liquid similar to that which bathes the eye media. The sound waves must
therefore be transmitted from the air to this fluid. In order that this may
occur it is necessary that the sound waves reach the apparatus either (1)
through the walls of the chamber containing the apparatus, i.e. bone conduc-
tion, or (2) through a membrane separating the liquid from the air, or (3) •
by means of suitable levers which would impart to the liquid the vibration
of an external diaphragm. The advantage of the latter method would
be that the intensity of sound reaching the apparatus could be considerably
increased. This desirable result could be still further achieved by concen-
trating the sound waves on to the diaphragm by means of a trumpet and by
causing the trumpet to be adjustable in different directions. The position
of the source of sound could then be ascertained.
Such an organ of hearing would therefore consist of three different parts :
(1) the horn or trumpet with its adjusting muscles, called the external ear ;
(2) the diaphragm and levers for receiving the sound vibrations and for
transmitting them to the internal mechanism, called the middle ear ; and (3)
the internal mechanism consisting of the resonators with their respective
touch cells and nerves called the internal ear.
SECTION II
STRUCTURE OF AUDITORY APPARATUS
EXTERNAL EAR
•
The external ear consists of two parts: (1) that external to the skull
called the pinna and (2) that internal, called the meatus. The pinna in
animals is a horn-shaped structure which is provided with two sets of muscles.
The immediate response to a slight sound is a pricking of the ears by means
of the intrinsic muscles, and the directing of the orifices towards the source of
sound, through the action of the extrinsic muscles. The functions of the
pinna are firstly to ascertain approximately the direction of the source of
sound, and secondly to concentrate the sound waves into the meatus. It
may also be said to have a third function, namely to protect the internal struc-
tures; the stiff hairs with which it is provided must prevent to a considerable
extent the entrance of foreign bodies.
In man the pinna is undergoing retrogression ; not only has it lost its
trumpet shape but also it has become almost entirely immobilised from disuse.
It is improbable therefore in man that pinna has any power of accentu-
ating sound waves ; this is borne out by experiments in which the undulations
are filled with wax, and by cases in which the pinna has been cut off.
The form of the pinna in man may have a .slight influence in the judgment of the
direction from which sounds proceed. It has been noticed that a compound tone
changes slightly in quality as its position in relation to the ear is altered. This is partly
due to the fact that the auricle may reflect a fundamental tone more strongly than
the partial or the converse. According to Rayleigh this difference in quality is deter-
mined chiefly by the fact that diffraction of the sound waves occurs as they pass round
the head to the ear remote from the source of the sound, so that the partial tones reach
the two ears in different degrees of intensity and determine a difference in quality of
the sound as heard by the two ears.
THE EXTERNAL AUDITORY MEATUS in man is about one inch long and
directed forwards, inwards, and slightly upwards. Its general function, other
than as a mere conductor of the sound waves, is to protect the delicate vibrat-
ing membrava li/mpav i which closes its inner end. This it does partly because
of its narrow tubular shape and partly owing to its considerable curvature.
Opening on the skin of the meatus are special sebaceous glands which secrete
a yellow wax (cerumen) with bitter taste and peculiar odour. The wax not
only protects the cuticle of the ear and the membrana tympani from drying
but, together with the hairs at the orifice of the meatus, serves to repel
insects and prevent their entering. By the length of the meatus moreover
the drum is protected from draughts and its temperature is maintained
constant.
600
EXTERNAL EAR
601
Fig. 3(14. Diagrammatic view of auditory organ. (After Schapeb.)
1, auditory nerve ; 2, internal auditory meatus ; 3, utricle ; 5, saccule ; fi, canalis
media of cochlea; 9, vestibule containing perilymph: 12. stapes; 13, fenestra
rotunda; 111. incus; 18, malleus; 17, membrana tympani; Mi, external auditory
meatus; 14, pinna of external ear ; 23, Eustachian tube.
In animals the junction between the pinna and meatus is so fashioned that
1 he orifice can be restricted by means of a constrictor muscle. This permits
the intensity of sound reaching the internal mechanism of the ear to be con-
trolled as light by the iris in the case of the eye.
THE MIDDLE EAR
This consists of a cavity hollowed out of the temporal bone, which com-
municates externally with the meatus, internally by two windows, one circu-
lar and the other oval, with the series of chambers forming the internal car,
below by means of a long duct called the Eustachian canal with the throat.
At the junction with the meatus is a special bony ring to which is attached a
thin diaphragm, the membrana tympani (or drum), which completely closes
the orifice?
THE MEMBRANA TYMPANI. The sound waves which pass down
the external meatus impinge on the drum of the oar ami set this into
vibration. The vibrations are thence transmitted by a chain of
small bones, the auditory ossicles, across the cavity of the tympam
the fluid which bathes the terminations of the auditory nerve in the
internal ear. Since the drum of the ear has to pick up and trai
vibrations of every frequency, and to reproduce accurately in its move-
ment the finest variations of pressure in the course of the wave, it is
602 PHYSIOLOGY
essential that it should be devoid of any periodicity, i.e. a tendency to
vibrate at a certain frequency. If such periodicity were present the ear
would pick out and magnify, to the exclusion of the other overtones,
some particular overtone present in the compound tones reaching the ear.
The perfect aperiodicity of the tympanic membrane is secured by its
structure and attachments. The membrane is composed of a thin
layer of fibrous tissue covered externally with skin and internally by I he
mucous membrane of the tympanum. To its inner surface along its whole
length is attached the handle of the malleus, the first of the auditory ossicles.
This attachment of an elastic membrane to a mass of bone would itself tend
to damp any vibrations of the membrane. By the attachment of the
tendon of the tensor tympani muscle to the inner surface of the handle of the
malleus, the middle of the membrane is drawn inwards, so that it forms a cone
whose walls are convex outwardly. The membrane is built up of circular
and radial fibres, the circular being best marked towards the periphery.
By the dragging inwards of its central part it follows that the tension of its
constituent fibres varies from point to point so that each bit of the membrane
has a different periodicity, and the membrane as a whole be aperiodic.
By exposing the tympanum from above it is possible with a micro-
scope to observe the actual movements of the handle of the malleus when
sound waves fall on the tympanic membrane. The maximum movements at
the apex of the cone may be taken as about '04 mm., but sounds are easily
audible which would produce movements of the tympanic membrane quite
imperceptible under this method of examination.
THE OSSICLES. Stretching across the tympanum, from the membrana
tympani to the outer wall of the internal ear. is a chain of ossicles, which
are named respectively the malleus, the incus, and the stapes. These ossicles
are articulated together, so that a movement inwards of the malleus causes a
movement inwards of the base of the stapes. The malleus, or hammer bone,
consists of a thickened head, from which two processes run, viz. the manu-
brium, which is attached to the tympanic membrane, and the processus
gracilis, by which it is anchored to the walls of the tympanic cavity. By
means of three ligaments it is so fixed that it is capable of rotating only
around a horizontal axis, which passes through the anterior ligament, the
head of the malleus, the body of the incus, and the short process of the incus.
When the manubrium is pushed inwards, the part of the malleus above this
axis must move outwards. The incus, sometimes known as the anvil bone,
is articulated with both the stapes and the malleus, and a ligament passes
from its short process to the posterior wall of the tympanic cavity. The
posterior surface of the rounded head of the malleus fits into the saddle-
shaped cavity on the anterior surface of the incus, while the tip of the long
process of the incus is articulated with the stapes. Movement inwards or
outwards of the head of the malleus causes rotation of the incus round an
axis which passes from the tip of the short process through its body. Thus
when the handle of the malleus moves inwards the greater part of the body of
the incus and of the head of the malleus moves outwards together, while the
MIDDLE EAE 603
long process of the incus moves inwards. The stapes, or stirrup bone, is fixed
in the fenestra ovalis of the internal ear. in the inner surface of the tympanum.
Fig. 305. To show the relations of the malleus and incus to one another. The
shaded area between the two bones shows the articular surfaces which connect
them. The overlapping of the two bones at the lower part of these surfaces
is well shown. It is this arrangement which causes motion to be conveyed
from one to the other.
by the annular ligament. It is placed almost at right angles to the long
process of the incus, and therefore is pressed into the foramen ovale when this
process moves inwards.
THE MUSCLES found in the tympanum are the tensor tympani, which
is attached to the handle of the malleus, and the stapedius attached to the base
of the stapes. The tensor is innervated by a motor branch of the 5th cranial
nerve, and when it is stimulated it draws the handle of the malleus inwards
and so increases the tension of the tympanic membrane. At the same time
the plunger of the stapes is displaced into the oval window, thus putting
compression on the contents of the internal ear. The contraction of the
tensor has been supposed to have a protective function and has been com-
pared to the sphincter pupillae (Helmholtz). Others hold that it modifies
the response to low and medium tones, but even here there is a divergence ol
opinion, because while some hold (I think correctly) that the tensor by its
contraction decreases the natural period of the drum and thus enables
respond to rapid changes of phase and high tones, others have held
opposite view. Observation shows that contraction occurs when sounds
(particularly tones of high pitch) fall on the drum, and that the contrai
is bilateral even if the stimulus be only unilateral. The reflex therefore
travels via the auditory nerve to the motor centre of the 5th nerve.
Since the tensor tympani is uncontracted when no sounds are falling on
604 PHYSIOLOGY
the ear, it allows the drum to go slack and therefore tends to prevent this
membrane from becoming stretched through being continually in tension.
The stapedius muscle is innervated by a twig from the facial. Its function
is problematical. Some say it antagonises the tensor by decreasing the ten-
sion on the drum, others that it reduces the tension on the contents of the
internal ear by reducing the pressure of the stapes on the oval window.
Hartridge's view is that the function of this muscle is to cause the body of
the incus to engage with the spur of the malleus with sufficient force to pre-
vent chattering and lost motion when the vibrations are being transmitted
from one bone to the other.
THE EUSTACHIAN CANAL is a tube about 35 mm. in length which
connects the middle ear with the pharynx. Normally it is kept closed in
order that the respiratory rhythm may not affect the pressure in the tym-
panum, and that the noise set up by the flow of air and the voice may not
be heard. When the canal is closed the middle ear becomes a closed chamber
which appears to increase the response to low tones. Since variations in
barometric pressure would not be communicated to the middle ear if the
canal were always closed, the air pressure on the two sides of the drum would
be found to vary. This is avoided by a periodic opening of the canal which
accompanies the act of swallowing. When the throat is infected the inflam-
mation often spreads to this canal which then becomes blocked either by
mucus or the swelling of its mucous lining. The air in the middle ear is
then gradually absorbed and the difference in air pressure on the two sides
of the drum decreases its response to sound, and the affected ear thus becomes
partially deaf.
Temporary deafness also occurs if the barometric pressure is suddenly
altered by a rapid change of level (as in an aeroplane) or by the application
of external pressure (as in a caisson or submarine). The deafness is however
immediately relieved by swallowing, because the altered pressure is communi-
cated to the other side of the drum through the opening of the Eustachian
canal.
FUNCTIONS OF TYMPANUM. The function of the tympanic
apparatus (consisting of drum, bones and muscles) is to transform
the energy of the aerial vibrations incident on the drum into a series
of mechanical movements of the plunger of the stapes, by which the
pressure within the internal ear is rapidly varied. The evidence may be
summarised as follows. (1) If in man the external ear be made to form a
gas chamber which is connected to a manometric flame, the flame shows
vibration when sound falls on the drum, which could only be caused if the
drum were set into vibration. (2) If the drum be gilded and a beam of light
be caused to fall on it, the extensions of the beam caused by vibrations
of the drum can be recorded photographically, and are found to accompany
the incidence of sound waves. (3) If to the chain of ossicles a light writing
lever be attached, the point of which travels over a rotating smoked drum,
when sounds fall on the drum the vibrations are recorded showing that
the ossicles are set into movement. (4) By opening the middle ear from
MIDDLE EAR 605
above and sprinkling with starch grains the ossicles as they lie within the
movements of the different parts can be readily followed under a low power
microscope. When the drum is set into vibration by sound waves it is readily
seen that the whole chain of ossicles vibrates so as to convey the vibrations
to the plunger in the oval window. Many experimenters have noted the
remarkable way in which the apparatus responds to vibrations varying very
greatly in rate. Tones of low and high pitch appear to be recorded with
equal impartiality and fidelity. Experiment therefore confirms our sensa-
tions which show that the ear responds to vibrations varying from 40 to
40,000 per second. It is stated that the natural period of the ossicles and
drum, owing to their small size, is very much more rapid even than 4 , ,,!,,,„
second, and it is because of this that the system is able to respond faithfully
to the vibrations of longer period used in audition.
Direct observation therefore shows that the ossicles form levers which
together conduct the vibrations from the drum to the filunger of the oval
window. It is necessary to consider the effect of this lever system
on the amplitude and force of the vibration. Motion is applied to the manu-
brium of the malleus and is communicated to the long process of the incus.
The former is one and one-half times the length of the latter and
therefore the stapes moves with two-thirds the amplitude of the drum.
If the levers moved without friction this would be accompanied by an
increase in the force of the vibrations of one and one-half times. But
owing to the air which surrounds the levers and thus damps their vibration
and to the energy required to set them in vibration on account of their mass,
it is probable that the force of the vibrations which reaches the oval window
is not more than half that incident on the manubrium. The drum on the
other hand has an area which is about twenty times that of the oval window,
and the energy incident on the drum and communicated to the
manubrium is that much greater than if the sound waves were incident on
the oval window direct. But owing to the energy absorbed by the levers the
magnification is probably not greater than ten times, that is one- third of the
calculated amount. Two other features of the chain of ossicles should be
mentioned. In the first place it will be observed that the axis, about which
the malleus and incus rotate, passes through the bones, so that the big mass
formed by the articular surfaces is above and the levers below the axis of
rotation, and the ossicles are approximately balanced. Secondly the
articulation between the malleus and incus is saddle-shaped and there is a
spur on the malleus which engages with the body of the incus, so that, when the
tensor tympani muscle relaxes and the malleus travels outwards, the spur
disengages and the incus is therefore not forced to.follow. When on the other
hand the stapedius muscle is in tonic contraction, the spur is in engagement
and vibrations are therefore communicated from one bone to the other. J i
however the force applied is excessive, owing for example to a box on the ear,
then the two bones separate slightly like the limbs of a compass, and the spur
passes the body of the incus without communicating the blow to it. In
this way rupture of the annular seal between the plunger of the stapes and the
oval window is prevented.
606 PHYSIOLOGY
INTERNAL EAR
Within the petrous portion of the temporal bone are two mechanisms
anatomically in close relationship but physiologically entirely separate.
One of these mechanisms, which is called the cochlea, belongs to the auditory
organ ; the other, called the vestibule, consists of a series of organs which con-
cern equilibration and have no connection with hearing.
THE LABYRINTHS lie one within the other ; the outer or osseous
labyrinth is hollowed out of the petrous portion of the temporal bone, and it
conforms roughly with the shape of the membranous labyrinth within it.
Between the two is liquid so that, as in the case of the brain, no constraint
is put by the external wall on the soft structures which it contains. This
liquid is called perilymph. The membranous labyrinth consists of a series
of hollow ducts and sacs which are filled with liquid called the endolymph.
The parts of the membranous labyrinth and the relative positions which
they occupy are shown in Fig. 306. From before backwards they will be
seen to consist of a spiral tube called the cochlea, the saccule, and the utricle
to which are connected the three semicircular canals.
Of these structures the cochlea alone is concerned with hearing, as the
following evidence shows.
(1) Destruction of the utricle and canals causes disturbed equilibration,
nystagmus and vomiting, but no deafness.
(2) Destruction of the cochlea causes deafness but no disturbance of
equilibration.
(3) Fishes, in which no evidence of hearing can be found, possess
utricle, saccule and canals, but no cochlea.
THE COCHLEA is a tube 20 to 30 mm. long which is spirally wound
round a cone of bone called the modiolus, through the centre of which enters
the auditory nerve. From the modiolus a spiral lamina of bone extends
about two-thirds the way across the spiral cochleal canal so as partially to
divide it into two equal portions. From the outer edge of this lamina two
membranes extend to the walls of the canal, so that the latter is divided through-
out its length into three separate ducts. The upper duct is called the scala
vestibuli, the middle duct between the two membranes the scala media,
and the lower the scala tympani. The two membranes dividing
off these ducts are quite different in structure ; whereas the upper, called
Reissner's membrane, is a thin layer of cells only, the lower is of complicated
arrangement and is called the basilar (base) membrane. To the latter is
attached a series of sensitive hair cells, called the organs of Corti,
connected to the fibres of the auditory nerve, which run through the osseous
spiral lamina to the body of the modiolus. To the upper edge of the spiral
lamina is attached a projecting ledge called the lamina tectoria ; this is so
mounted that it projects over but probably does not quite touch the tips of
the hair cells. If however the basilar membrane is displaced upwards,
the hairs touch the membrana tectoria, and the resulting stimuli are com-
municated to the auditory nerve. To prevent damage to the hairs, owing to
excessive motion of the basilar membrane, rods of Corti are placed between
INTERNAL EAR
607
the hair cells in such a way that, when they come in contact with the meni-
brana tectoria, further movement of the basilar membrane is prevt'iitccl.
Fig. 306. The membranous labyrinth.
cm, canalis or scala media of the
cochlea; s,saeeule; a, utricle; sc.semi
circular canals.
Fia. 307. Vertical section through the
cochlea.
The way in which motion is imparted to this membrane by the ossicles
may be described as follows. The osseous labyrinth communicates with the.
middle ear by means of two openings, the oval window and the circular win-
dow. The oval window connects with the upper of the three cochlear canals.
via the vestibular. The upper canal is therefore called the scala vestibuli.
The lower canal connects with the round window only, and since the round
window is fitted with a membrane, the canal gets the name scala tympani
(drum or membrane). Fitting into the oval window is the plunger of the
stapes, and between the two is the annular seal which permits motion of the
plunger without allowing escape of the perilymph from the labyrinth.
Fig. 30S. Vertical section of the first turn of the human cochlea. (G. R)
s.v. scala vestibuli : .«.«, scala tympani ; 1 the organ of Corti and the
basilar membrane form together a series of automatically recording reso-
nators. In the same way that each of the strings of a piano can beset into
vibration by the sounding of a note which corresponds with it in pitch, so
also can the different fibres of the basilar membrane vibrate to a certain
nole. and so cause stimulation of the hair-cells which are attached to it.
Four objections have been made to this hypothesis. (I) That the fibres
of the basilar membrane are so short that they could not respond to the low
notes which the ear is able to hear. The answer to this criticism is that not
only the length but also the tension and weight of a cord determine its vibra-
tion rate. In the case of the basilar membrane the tensions in the fibres are
probably minute, while the weights of the arches of Corti and the hair cells
must make the period ol vibration so much the Longer.
(2) That the separate fibres of the basilar membrane are bound together
so that vibration of the separate fibres would be impossible. This objection
Helmholtz met by calculating that a uniform membrane, in which the tension
was greater from side to sale than longitudinally, would be able to respond in
the manner required.
(3) That the difference in length of the fibres is not sufficiently greal
for the short ones to vibrate to note, of 4000 vibrations per second, while
the long ones vibrate to 10 vibrations per second only. This objection also
fails when we reflect that not only length but also tension and weight di fcer
mine the period of vibration of a stretched cord. However accurately we
cm determine length and weight, by histological examination the method
tells us nothing concerning tension. This objection therefore must fail.
(-1) That if the cochlea depends for its action on the resonance of the basilar
nitres, we should expect a musical note to seem to go on sounding after the
note has actually ceased. Since on the other hand we know from our own
experience that words such as ' utter.' in which there is an interval of silence
between the two "ts," arc quite different from ' udder, ! in which there is no
interval of silence, it follows that the fibres of the basilar membrane have not
been in vibration after the sound ceased, and therefore probably resonan
the basilar membrane is imaginary. If on the other hand we suppo
fibres to be highly damped so that they come to resl at once when the note
ceases, how comes it that they can so readily be se1 in motion so thai in
only three Or four vibrations a note is distinctly heard. The answer is, I
Gil
612 . PHYSIOLOGY
think, bo be obtained from the fact that the cochlea is filled with liquid.
This liquid makes the basilar membrane ' dead beat ' because its move-
ments, when the liquid is still, set up eddies which quickly check the motion
owing to the viscosity of the liquid. On the other hand when a sound
is entering the ear and the fluid is therefore in motion, this movement is the
more rapidly imparted to the basilar membrane because of its continuity,
but even if it consisted of separate fibres it would still be set rapidly into
vibration owing to the viscosity of the liquid. In'this way one can explain
both the rapid response and the rapid damping of the cochlea.
In favour of Helmholtz' theory we have the following evidence :
(1) In boiler- makers' disease we have inability to hear high notes, and
we find that it is the short fibres of the basilar membrane which are degener-
ated.
(2) In experiments in which the ears of animals have been stimulated for
long periods to the same note, subsequent examination has shown the localisa-
tion of degeneration to one part of the organ of Corti. With a high note the
short fibres are affected, with a low note the long.
(3) If one of the ears be fatigued by prolonged stimulation to a constant
note, its response to the same note is found to be inhibited, but notes of slightly
longer or shorter pitch are found to be unaffected. This shows clearly that
the response to a given rate of vibration must affect a certain limited number
of hair cells and nerve fibres only, and is therefore strongly in favour of
Helmholtz' theory.
(4) Animals whose calls have a small range of pitch (e.g. birds) have short
basilar membranes which vary but little in length.
(5) Animals, in which different parts of the cochlea have been destroyed,
appear to give definite evidence for deafness to high notes when the fine
basilar fibres are damaged, and deafness to low notes when the long fibres
have been removed.
(6) Patients are found in whom there are islands of deafness, that is, they
are deaf to a limited part of the musical scale. The Helmholtz theory readily
explains these cases as being due to local disease of certain basilar fibres or
their corresponding hair-cells. Further there are cases in which the two ears
give different notes, a condition called double disharmonic hearing. This is
easily explained by a change in the natural period of the fibres of the basilar
membrane in the diseased ea~, either as the result of stretching or the increased
mass due to inflammation.
(7) McKendrick was able to produce a model of the cochlea with basilar
membrane and organs of Corti. He found that parts of the membrane can
be made to vibrate to a certain pitch and not to others as the Helmholtz
hypothesis requires.
(8) McKendrick calculated that the number of fibres in the auditory nerve,
the number of fibres in the. basilar membrane and the number of hair-cells and
arches of Corti were sufficient to give the total number of different pitches
(about 11,000) in the auditory scale.
It would appear therefore that the evidence in favour "I Helmholtz' hypothesis
THEORIES OF HEARIXC 613
is very convincing. Other theories have been proposed however which will nov
brief consideration.
RUTHERFORDS HYPOTHESIS compares the cochlea to a telephone. In
the same way as the diaphragm of the receiver is set into vibration by the sound waves,
and starts corresponding variations in the strength of the current conducted to the
transmitter, so the vibration of the basilar membrane as a whole causes impulses to
be sent up the auditory nerve which correspond with the air vibrations received by
the ear. Analysis does not take place in the cochlea at all but in the brain. Wrightson,
who has restated this theory and added much detail to it, states that the cerebral
analysis is effected by differences between the time intervals of the points of zero
pressure and of the maximum plus and minus pressures.
The following objections may be stated against the Rutherford-Wrightson hypo-
thesis.
(1) It assumes that the auditory nerve can conduct complicated wave forms, intact
as to pitch and amplitude, at rates up to 40,000 vibrations per second. Rutherford
in this connection pointed to the motor nerves of the bee's wing which are capable
of responding to transmitted impulses at 460 per second. Between 40,000 and 460
is however a big gap which will certainly have to be bridged before this view as to 1 he
transmission of the vibrations intact to the brain can be accepted.
(2) We cannot picture a cerebral apparatus which can analyse these complicated
nerve impulses even if they could reach it, and neither Rutherford nor Wrightson assist
us to do so. The relegation of the powers of analysis to the cerebral cortex is, a1 i In-
present at any rate, equivalent to giving up any attempt to explain the power of analysis
possessed by the organ of hearing.
(3) It would seem that a very much simpler organ than that of the cochlea would
be sufficient to convert sound waves into nerve impulses if no analysis of the stimulus
took place there.
(4) It would be very difficult to explain on this hypothesis the localisation of degene-
ration to certain notes, or the deafness to certain notes which accompanies disease of
part of the organ of Corti.
(5) This hypothesis does not explain why fatigue to one note leaves the response
to all other notes apparently unaffected in intensity.
The objections to this hypothesis are therefore of a formidable character. Much
additional evidence in its favour would be necessary to place it even on a par with
the theory of Helmholtz.
WALLER'S HYPOTHESIS stated that the basilar membrane vibrated in the form
of pressure patterns which are similar to those which may be seen on a vibrating plate.
Ewald who has elaborated this view found by experiment that the patterns take tin-
form of equidistant stationary nodes or ridges, the distance between which varies n it b
the pitch of the note entering the mechanism. The distance between the nodes is
measured by the hair-cells and corresponding impulses are sent to the auditory centre.
The advantage of this hypothesis is that like Helmholtz' it places the analysis of
the sound waves in the cochlea and therefore does not, like Rutherford's hypothesis,
require the transmission by the auditory nerve of rapid impulses or the analysis oi
such impulses by the brain. It is clear however that so far as our present know ledge
goes the evidence is all in favour of Helmholtz' view.
BEATS AND DISSONANCE. The overtones of any sound, at any rate
the lower ones, are at considerable distance from one another on the musical
scale, and therefore differ considerably in the number of vibrations of which
they are composed. If two tuning-forks be sounded, the vibrations of which
differ only by one or two per second, the phenomenon known as ' beats is
produced. This is due to the summation or interference of the waves from the
two tuning-forks. Let us suppose we have, tuning-forks vibrat ing one at 100
(il4 PHYSIOLOGY
and the other at H>| times a second, and I bal i bey begin vibrating together.
At first the waves of compression started by each fork will coincide, so that
the total compression of the air a1 each beal will be the compound effect
of the compression produced by the two forks. The two forks will
reinforce one another. After the lapse of half a second the tuning-forks will
be at different phases of their excursion. The 101 fork will be moving in one
direction while the LOO fork is moving in the other, so that the compression
produced by one fork coincides with the expansion of the air produced by
the moving backwards of the other fork. The sound produced by one fork-
is therefore diminished by the sound produced by the other fork, and the
total sound is less than either of the two forks. At the end of one second,
the phases of the two forks once more corresponding, we shall get the sound
increased in loudness ; thus there is an alternate waxing and waning of the
sound which recurs once a second and is spoken of as a ' beat.'
The number of heats per second may be used to determine the differences
in the vibration frequencies of two forks. Thus two forks vibrating one at
LOO and the other at 1 10 will give ten beats per second. As the number of
heats increases the effect produced on the ear becomes more and more dis-
agreeable, just as the rapid alternation of illumination produced by a flicker-
ing light is disagreeable to the eye. This objectionable character of the
sound is most marked when the beats recur at about thirty-three times per
second ; the individual beats are not then distinguished, but we speak of the
sound as discordant or dissonant.
CONSONANCE. The opposite condition of consonance or harmony in-
volves therefore, in the first place, an absence of beats, i.e. of rhythmic
oscillations of amplitude of sound waves which reach the ear. The con-
stituent tones and overtones must be capable of being combined into a
compound wave of regular amplitude and rhythm. In the most complete
consonance the component notes are identical as concerns at any rate the
greater number of their overtones. The most complete consonance is
attained when the two notes which are sounded together are identical.
Almost as complete is the consonance obtained when a note is sounded
together with its octave. The other consonanl intervals which are employed
in music are as follows ;
1 ; 2 . . . . . . . < Ictave
2:3. Fifth
3:4 Fourth
4:5 Major third
5 : (I . . . . . Minor third
."■ : s . . . . . . . . Minor sixth
3:5. . . . . . . . Major sixth
It will be noticed that in all these consonant combinations the vibration
frequencies of the notes are in proportion to small whole numbers. If we
put down not only the fundamental tones of these notes but also their over-
tones, we shall see that there is considerable identity as regards the latter.
In the case of the octave the two are almost identical, the only difference
CONSONANCE AND DISSONANCE 615
being the ground tone of the lower note, and the identity diminishes as we
pass from the cctave through the thirds to the sixths. The overtones which
are identical are shown by black type :
Fundamental tone Overtone
(1.2. 3. 4. 5. 6. 7. 8. 9. 10
I , 2 4 6 8 10
f 2 . 4 . 6 • 8 . 10 . 12 . 14 . 16 . 18 . 20
1 3 6 !• 12 IS 18
I •'! • 45 54 (>."> 72
f 8 . 10 . 24 . 32 . 40 . 4S . 56 . (14 . 72 . SO
I 15 30 45 60 75 90
Octave 1:2.
Fit t h 2 : 3 .
Fourth 3:4.
Major t liird 4 : 5
Minor third 5 : 6
Major sixth 3 : 5
Second 8:9.
Seventh 8 : 15
In the second and seventh, which are discordant, it is only the eighth
overtones which are identical, while the fundamental tones will, as a rule, be
so close together that beats will be produced of a number calculated to give
dissonance. Since the phenomenon of beats depends on the absolute number
of vibrations per second, they are more easily produced by two notes near
together at the lower end of the scale than at the upper end. Thus the dis-
sonance is quite perceptible in a major third at the lower end of the piano,
but disappears at the upper part, since here the beats produced are so rapid
that they become imperceptible.
The various notes used in music are obtained by employing the consonant
intervals which we have given above. The major chord is composed of the
fundamental tone, the major third and the fifth. If we take ' c ' as the
fundamental tone, the notes of the chord are c, e, g, with vibration fre-
quencies corresponding to 1, -£, :-i, i.e.. 4, 5, 6, the major chord from g is g, b,
(I. i.e. three notes with vibration frequencies corresponding to |, , s \ : ( '.
i.e. 1 . ">, '6. The major chord from the fourth, /. is /. a, c. with the vibration
frequencies *, #-§■, ',.-. i.e. 4. 5, (i. The C major scale is therefore as follows :
c
D
E
F
<;
A
B
C
1
9
5
4
3
5
15
2
Different instruments are tuned to one normal note, i.e. to A with 4 to
vibrations per second (this note varies somewhat in different countries).
Taking this as the normal, the vibration frequencies of the various notes
used in music are given in the following Table :
(116
PHYSIOLOGY
Note?
Vibrations per second
c .
33
66
1 32
264
528
1050
2112
I> .
37-125
74-25
148-5
297
594
1188
2376
E .
4 1 -25
82-5
165
330
660
1320
2640
F .
44
88
176
352
704
1408
2816
G .
49-5
99
198
396
792
1584
3168
A .
55
1 Hi
220
440
880
1760
3520
B .
61-875
123-75
247-5
. 495
990
1980
3960
COMBINATION TONES. If two tuning-forks, with an interval of one-fifth
between them, are sounded together, we may hear a weak lower tone, the
pitch of which is an octave below that of the lower fork. This is known as
a ' combination tone.' The combination tones are divided into two classes :
(1) ' difference tones,' in which the frequency is the difference of the frequen-
cies of the generating tones ; (2) ' summation tones,' which have a pitch
corresponding to the sum of the vibrations of the tone of which they are
composed. By means of appropriate resonators these tones can be rein-
forced, showing that they have an objective existence and are not produced
in the ear itself.
Not only can the ear appreciate differences between different musical
instruments, dependent on the varying overtones present in the sound pro-
duced by each instrument but, when a number of these instruments are
sounded simultaneously, the ear can pick out from the compound sound the
notes due to the individual instrument, and a person with a trained ear can
with ease name notes composing any chord struck on an instrument such as
the piano.
OHM'S LAW. This power of analysis, which is possessed by the ear, or
at any rate by the auditory apparatus, may be stated in the form of the law,
known as Ohm's law, which is as follows :
" Every motion of the air which corresponds to a composite mass of
musical tones is capable of being analysed into a sum of simple pendular vibra-
tions, and to each single vibration corresponds a simple tone, sensible to the
ear and having a pitch determined by the periodic time of the corresponding
motion of the air."
SOUND LOCALIZATION. Experiment shows that man and animals
can appreciate with fair accuracy the direction from which a sound
is coming. There has been considerable speculation as to how this
information is obtained, and although the subject has not been completely
elucidated it appears to have been established that the following factors are
important.
(1) The intensity of the sounds entering the two ears. When a sound is
coming from one side the ear on that side receives the more powerful stimulus.
(2) The relative intensities of the components of high and low pitch vary
with direction, because the notes of long wavelength (low pitch) will be
SOUND LOCALISATION 617
diffracted the more readily round the head to the ear away from the sound,
than will those of short wavelength (high pitch).
(3) The sounds reaching the nearer ear will arrive earlier than those
stimulating the other, because of the time taken to travel round the head.
The nerve impulses from the two ears will not therefore arrive at the same
instant, and by an appreciation of the difference in time the approximate
position of an external object can be gauged.
That this factor is of great importance can be shown by experiment in
the following manner. A stethoscope with two earpieces is fitted in position,
and to its mouthpiece is applied a loud tuning-fork. The tube connecting
the mouthpiece to one of the earpieces has an adjustable U- piece like a
trombone so that the distance travelled by the sound in reaching that ear
can be varied. The other tube has a length which is equal to that of the
others, with the U-piece in its mid position. When a note is sounded and the
U-piece altered, the position of the sound appears to move from one side to
the other according to which ear has the shorter tube.
(-t) The sounds reaching the ears travel not only through the air but also
through the bones of the skull. This can be proved by placing a tuning-fork,
which has been sounded and allowed to fade until its note is inaudible, on
one of the teeth ; the sound will be conveyed by the root of the tooth to bone,
and by bone conduction to the ears. Therefore when a sound enters the
right ear, it will travel by bone conduction to the left, and owing to its rate
of travel being different to that of sound in air, it will reach the left ear at
a different instant to which the sound travelling round the head will reach it.
If one ear is facing the sound, the bone-conducted sound will probably reach
the other ear before the air-conducted does. On the other hand when
both ears are equidistant, it is clear that the air-borne sound will arrive first
at both ears, and the bone- conducted sound very much later. By an
appreciation of the difference in time of the arrival of the two sounds it is
probable that localisation is effected.
(5) In animals, the ability to turn the ears in different directions and so
find the direction of maximum intensity, must be of the utmost possible value
in sound localization.
PART IV
VOICE AND SPEECH
The development of the analytical powers of the auditory apparatus
is so closely connected with that of the faculty of speech that we may
conveniently deal with the latter at this point rather than relegate it to
a chapter on special muscular mechanisms. We may first consider the
mechanism of production of voice, which man shares with many other
animals, before discussing the mechanism of the wholly human faculty
of speech.
Voice is produced in the larynx, a modified portion of the wind-pipe.
by the vibrations of two elastic bands, the vocal cords, which are set into
action by an expiratory current of air from the lungs. In many respects
the larynx resembles a reed instrument, in which a current of air is caused to
vibrate by the vibrations of an elastic tongue. Whereas however the period
of the vibrations in such an instrument, and therefore the note, is deter-
mined by the length of the tube which is attached to the reed and by the
lengths of the reeds themselves, in the larynx the note produced by the blast
of air is modified partly by alterations in the tension of the vocal cord, and
partly by varying the strength of the blast of air.
ANATOMICAL MECHANISM OF THE LARYNX. The essential framework
of the larynx is formed by four cartilages, viz. the cricoid, the thyroid, and the two
arytenoid cartilages. The cricoid cartilage, which lies immediately over the upper-
most ring of the trachea, is shaped like a signet ring, the small narrow part being
directed forwards and the broad plate backwards. The thyroid cartilage consists of
two parts or ate, joined together in front and forming the prominence known as Adam's
apple ; behind, it presents four processes or comua, the superior of which are attached
by ligaments to the hyoid bone, while the inferior comua articulate with the postero-
lateral portion of the cricoid cartilage. By means of this articulation very free move-
ment is permitted between the two cartilages, the general direction of movement being
one of rotation of the cricoid cartilage on the thyroid, round a horizontal axis directly
through the two articular surfaces between the two cartilages, while movements of the
thyroid upon the cricoid are also possible in the upward, downward, forward, and back-
ward directions. The two arytenoid cartilages are pyramidal in shape. By their bases
they articulate at some distance from the middle line with convex articular surfaces
situated in the upper margin of the plate of the cricoid cartilage. The anterior angle
of the base is the vocal process, while the external angle is the muscular process of
the arytenoid. The crico-arytenoid joints permit of two kinds of movements of the
arytenoid cartilages, viz. :
(1) Rotation on their base around their vertical long axis, so that the anterior
vocal process is rotated outwards and the muscular process backwards and inwards
or conversely.
] (2) Sliding movements of the whole arytenoid cartilage either outwards or inwards,
so that their inner margins may be drawn apart or approximated.
618
VOICE AND SPEECH
619
The larynx is covered internally by a mucous membrane continuous with that of
the trachea. It is lined with ciliated epithelium, except over the vocal cords, where
the epithelium is stratified. The two vocal cords, or thyro-arytenoid ligaments, con-
sist of elastic fibres which run from the middle of the inner angle of the thyroid cartilage
to be inserted into the anterior angle of the arytenoid cartilages. Their length in man
is about IE mm., in woman about II mm. The cleft between them is known as the
glottis, or rima ghttidis.
Two ridges of mucous membrane above and
parallel to the vocal cords are the false vocal
cords (Fig. 310). Between the true ami the false
vocal cords on each side is a recess known as the
ventricle of Morgagni. This ventricle permits
the free vibration of the vocal cords. The false
cords take no part in phonation, but help to keep
the true cords moistened by the secretion of the
numerous mucous glands with which they are
provided. The false cords are also used in hold-
ing the breath. For this purpose they function
in a similar manner to the mitral valve of the
heart. It is found that animals who need the
thorax to be fixed in order that they may climb
or strike have well developed false cords. The
position and tension of the vocal cords are
determined by the action of the intrinsic
muscles of the larynx. The part taken by the
various muscles in each movement cannot be
directly ascertained. We can in most cases study
only the direction of the fibres, and judge,
from this direction and consequent isolated
action of the muscles, the part taken by any
given muscle in the production of voice. The
chief muscles (Fig. 311) are as follows:
(1) The crico-thyroid muscle is a short trian-
gular muscle attached below to the cricoid
cartilage and above to the inferior border of the
thyroid cartilage ; the fibres pass from below
upwards and backwards. When this muscle
contracts, the cricoid cartilage is drawn up
under the anterior part of the thyroid cartilage,
so that its broad expansion behind, with the
arytenoid cartilages, is drawn downwards and
backwards, thus putting the vocal colds on the stretch. This muscle is probably the
most important in determining the tension of the vocal cord.
(2) The posterior crico-aryU moid muscle arises from a broad depression on the corre-
sponding half of the posterior surface of the cricoid cartilage. It passes upwards and out-
wards, its fibres converging! to be inserted into the outer angle of the arytenoid cartilage.
These muscles rotate the outer angle of the arytenoid cartilages backwards and inwards.
They thus cause a movement outwards of the anterior angles, so that the glottis is widened.
During every act of inspiration there is a widening of the glottis, which is probabhj
effected by contraction of these muscles. If they are paralysed the vocal cord- are
approximated and tend to come together during inspiration, so that dyspnoea m
produced.
(3) The lateral crico-arytenoid muscle arises from the upper horde) oi the cricoid
cartilage and passes backwards to be inserted into the muscular process ..t tin arytenoid
cartilage. These muscles when they contract pull the muscular process of the arytenoid
Fig. 310. Anterior half of the larynx,
seen from behind. The section on
the right side is somewhat in front
of the left side.
e, epiglottis ; e', cushion of epi-
glottis ; I. thyroid cartilage; 8, s',
ventricle of larynx ; h. great cornu
of hyoid bone ; t n, thyro-arytenoid
muscle: vl, vocal cords Above the
ventricles arc the false vocal cords,
)■. first ring of trachea.
A Thomson.)
620
PHYSIOLOGY
cartilage forwards and downwards, thus approximating the vocal cords at their posterior
ends and antagonising the action of the posterior crico-arytenoid muscles.
(4) The arytenoid muscles consist of transverse fibres, some of which decussate,
uniting the posterior surface of the two arytenoid cartilages. When they contract
they draw the arytenoid cartilages together.
(5) The thyro-arytenoid muscles consist of two portions. The outer fibres rise in
front from the thyroid cartilage and pass backwards to be inserted into the lateral
border and the muscular process of the arytenoid cartilage. Some of the fibres pass
obliquely upwards towards the aryteno-epiglottidean folds. These are often spoken
uf as a separate muscle, the thyro-epiglottidean. By their action they tend to draw
Fig. 311. Muscles of the larynx. (Sappey.)
A, as shown in a view of the larynx from the right side.
1, hyoid bone ; 2, 3, its cornua ; 4, right ala of thyroid cartilage ; 5, posterior part of
the same separated by oblique line from anterior part; 6, 7, superior and inferior tubercles
at ends of oblique line ; 8, upper cornu of thyroid ; 9, thyro-hyoid ligament ; 10, cartilage
triticea ; 11, lower cornu of thyroid, articulating with the cricoid; 12, anterior part of
cricoid; 13, crico-thyroid membrane; 14, crico-thyroid muscle; 15, posterior crico-
arytenoid muscle, partly hidden by thyroid cartilage.
B, as seen in a view of the larynx from behind.
1, posterior crico-arytenoid ; 2, arytenoid muscle ; 3, 4, oblique fibres passing around
the edge of the arytenoid cartilage to join the thyro-arytenoid, and to form the aryteno-
epiglottie, 5.
the arytenoid cartilages forwards and to relax the vocal cords. The upper fibres may
also assist in depressing the epiglottis. The inner fibres are called the mvxcuhis vocalic.
They arise from the lower half of the angle of the thyroid cartilage, and passing back-
wards in the vocal cords are attached to the vocal processes and to the adjacent parts
of the outer surfaces of the arytenoid cartilages. Many fibres do not run the whole
distance, but end in an attachment to some part of the vocal cord. Although their
action must be to draw the arytenoid cartilages forwards, yet, since they are contained
in the vibrating portion of the vocal cords, they cannot by their contraction relax
these cords. It is probable that they play a great part in determining the tension of
the vocal cords after these have been put on the stretch by the action of the crico-thyroid
muscles. They may possibly act as a sort of fine adjustment of the tension, the coarse
adjustment being represented by the crico-thyroids.
VOICE AND SPEECH 62]
THE PRODUCTION OF VOICE
In order to study the changes in the Larynx winch are associated with
voice production we must make use of the Laryngoscope. The principle
of this instrument is very simple. A large concave mirror with a central
aperture is fixed before one eye of the observer, sitting in front of the patienl
or person to be observed. The latter is directed to throw his head slightly
backwards and to open his mouth. In order to keep the tongue out of the
way the patient is made to hold the end of it by means of a towel. The
mirror is then so arranged as to reflect light from a lamp into the cavity
of the mouth. A small mirror fixed in a handle is then warmed, so as to
prevent the condensation of the patient's breath, and passed to the back
of the mouth until it rests upon and slightly raises the base of the uvula.
By this mirror the light reflected into the mouth from the large mirror is
again reflected down on to the larynx, and a reflection of the larynx and
trachea is seen in the mirror. By laryngoscopic examination we can see
the base of the tongue, behind which is the outline of the epiglottis. Behind
this again in the middle line are seen the two vocal cords, white and shining
(Fig. 312). The cords appear to approximate posteriorly; between them
is a narrow chink, the diameter of which varies with each respiration, being
wider during inspiration. On each side of the true vocal cords are seen
the pink false vocal cords. In some cases the rings of the trachea, and even
the bifurcation of the trachea itself (Fig. 312, c), may be seen in the interval
between the vocal cords.
In order that the vocal cords may be set into vibration, they must be put
into a state of tension and the aperture of the glottis narrowed, so as to
afford resistance to the current of air. In the dead larynx it is possible
to produce sounds by forcing air from bellows through the trachea, after
the vocal cords have been put on the stretch by pulling the arytenoid
cartilages backwards. By experimenting on patients on whom tracheotomy
has been performed, it has been found that the pressure of air in the trachea,
necessary to cause production of voice, is, for a tone of ordinary loudness
and pitch, between 140 and 240 mm. of water, and with loud shouting
the pressure rises to as much as 945 mm. of water. This pressure is furnished
by the contraction of the expiratory muscles, i.e. of the abdomen and of the
thorax. Since the pitch of the note produced rises with increasing force
of the blast, while the tension of the cords remains constant, it is evidenl
that, in the act of ' swelling ' on a note, the increased pressure necessary
for the crescendo must be associated with diminishing tension of the cords.
It is the failure to secure this muscular relaxation that so often can
singer to sing sharp when swelling on any given note.
The voice, like the sound produced on any musical instrument, may
vary either in pitch, loudness, or in quality or timbre. The range ol
individual voice is generally about two octaves. The pitch oi tic voice
usually employed is determined chiefly by the length of the vocal cords.
Thus in children the voice is high-pitched. Before, anil at puberty there
622
PHYSIOLOGY
is a considerable development in the size of the larynx in both sexes. This
is especially marked in the male, and accounts for the sudden drop in pitch
(' breaking ') of the voice. In the female the increased size of the larynx
is chiefly perceptible in the increase in fulness and richness of the voice
which occurs at this age. Even when we take all the voices together,
Fig. 312. Three laryngoscopy views of the superior aperture of the larynx and
MiiTuunding parts in different states of the glottis during life. (From Czermak.)
A. the glottis during the emission of a high note in singing. B, in easy or
quiet inhalation of air. C, in the state of widest possible dilatation, as in inhaling
a very deep breath. The diagrams A'. B', C have been added to C'zermak's
figures to show in horizontal sections of the glottis the position of the vocal liga-
ments and arytenoid cartilages in the three several states represented in the other
figures. In all the figures so far as marked, the letters indicate the parts as follows,
viz. : /.the base of the tongue; e, the upper free part of the epiglottis: e', the
tubercle or cushion of the epiglottis ; p h, part of the anterior wall of the pharynx
behind the larynx ; in the margin of the aryteno-efpiglottidean fold »•, the swelling of
the membrane caused by the cuneiform cartilage; s, that of the corniculum ; a,
the tip of the arytenoid cartilages : c u, the true vocal chords or lips of the rima
glottidis ; c v s. the superior or false vocal cords ; between them the ventricle of
the larynx ; in ('. ( r is placed on the anterior wall of the receding trachea, and b
indicates the commencement of the two bronchi beyond the bifurcation, which
may be brought into view in this state of extreme dilatation.
bass, tenor, alto, and soprano, the total range for ordinary individuals does
not exceed three octaves. In singing the voice may be produced in various
ways, i.e. in different registers. Thus we distinguish the chest register, the
middle register, and the head register. The deeper notes of any individual
voice are always produced in the chest register. Observation of the vocal
cord shows that when producing such notes the glottis forms an elongated
slit, all the muscles which close the glottis and increase the tension of the cords
being in action. The vocal cords are relatively thick and broad and can
VOICE AND SPEECH 623
be seen to vibrate over their whole extent. When singing with the head voice,
the vibrations of the cord are apparently confined to their inner margins ;
the aperture of the glottis is wider in front than behind, so that more afr
escapes during phonation by this method than in the production of the
chest voice.
In order to change the pitch of the note the following means are probably
employed in the larynx :
(1) Alteration in the tension of the vocal cords.
(2) Alteration in the length of the part of the vocal cords that is
free to vibrate, which can be accomplished by the approximation of the
arytenoid cartilages to one another, or by their approximation to the thyroid
cartilage.
(3) The alteration in the shape of the vocal cords, which is determined by
the activity of the different portions of the internal thyro-arytenoid muscles.
(4) The varying pressure of the blast of air passing through the glottis.
The loudness of the tone produced is practically proportional to the
force of the blast of air employed. The quality or timbre of the voice
depends not so much on the vocal cords as on the accessory resonating
apparatus, represented by the trachea and chest and by the cavities of the
mouth and nose. The greater part of the education involved in voice training
is directed to the modification of the shape of the mouth cavity, so as to
secure the greatest possible fulness, i.e. richness in overtones, of the tone
produced in the larynx.
THE MECHANISM OF SPEECH
The sounds employed in speech, viz. vowels and consonants, are produced
by modifying the laryngeal tones by changes in the shape of the mouth and
nasal cavities. In whispering sjieech there is no phonation at all, but the
sound is produced by the issue of a blast of air through a narrow opening
between the lips, between the tongue and soft palate, or between the tongue
and the teeth.
VOWEL SOUNDS are continuous, whereas the consonants are pro-
duced by interruptions, more or less complete, of the outflowing
air in different situations. The simple vowel sounds, U, 0, A.
E I, (pronounced as in Italian oo, oh, ah. eh. ee). are tones,
i.e. are produced by a regular series of vibrations. These tones
take, their origin in the mouth cavity, as can be shown easily by the Eaci
that we can whisper these sounds distinctly without any phonation what-
ever. To each of them corresponds one or two distinct notes, the pitch, i.e.
the resonance, of which is regulated by the shape of the cavity in which
they are produced. There has been much controversy as to whether the
pitch of these notes changes at all with the pitch of the voice, or varies
in different individuals. Some said that they did not change, others that
their pitch kept in constant ratio with the pitch of the note sung : if the note
doubled in pitch, so also did that (ot those m the case of E and !) ol the vowel,
Several methods have been employed for investigating this point;
624
PHYSIOLOGY
(1) By recording the vibrations emitted by the voice by means <>f the
manometric flame.
(2) By recording the vibrations by means of a gramophone.
(3) By measuring the intensity of vibration of series of resonators. All
the above methods show that there must be some change, even if it is slight.
(4) By running a gramophone record of a bass voice at an increased speed
so that the notes were those of a treble. If now the pitches of note and
vowels were in constant ratio the quality of the vowels should not change
when the speed is thus increased. Experiment shows that the words are
greatly altered, losing their O's and A's and taking E and I instead.
This shows clearly that change in pitch of the vowels is not nearly
as great as that of the note sung with them. We must conclude therefore
that neither those who say there is no change, nor those who say there is con-
stant ratio, are right, but that the truth lies between the two extremes. The
pronunciation even of the simplest vowel sound differs in different individuals.
For instance, those pronounced by a Londoner differ from those pronounced
by a man from Manchester or from Yorkshire, and the French vowels differ
somewhat in pitch from those employed by the German, and these again from
those employed by the average Englishman.
The characteristic notes were given by Helmholtz as follows :
U = f
= V
A = b u
E = V, V"
1 = £, d lv
TJ
m
m
U O A EI
If the five vowels are whispered loudly, the gradual rise in pitch of the
tone is easily perceptible. We do not in this way however note the lower
component of the sound in the E and I ; this can be brought out by a
single device (Fig. 313). If we place the mouth in the position necessary
to produce these different vowels, and then percuss over the cheek, we
obtain the typical note for each vowel, the air in the mouth cavity being
set into vibration by the percussion. Now shift the linger, which is to be
A (or) U (oo)
Fin. 313. .Shape of the oral cavity in the production of the vowel sounds, .1, U, I.
(Grutzner.)
VOICE AM) SPEECH 625
percussed, so that it lies over the pharynx, just behind the angle of the jaw,
and percuss again. The note will be observed to rise with U, 0, A, and
then fall with E, I. With the three vowels U, 0, A, we have a single
cavity formed by the lips, the palate, and the tongue ; this cavity is longest
and narrowest with U and shortest and most open with A. With E and I
the dorsum of the tongue comes up against the front part of the soft palate,
so that the mouth cavity is divided into two, the anterior short narrow
cavity, and the posterior broader cavity between the soft palate and the
base of the tongue. We therefore have two notes produced, one in each
cavity. The change in shape of the mouth cavity is shown in the figures.
With U and A the cavity seems to be single ; with I the development of
a pharyngeal resonating cavity is well shown. Diphthongs are produced
by changing the form of the mouth cavity from that of one vowel sound to
another, thus AI (the English I) = ah-ee run together and abbreviated.
CONSONANTS are sounds produced by a sudden check being placed in the
course of the expiratory blast of air by closure of some part of the pharynx
or mouth. They are classified into labials, dentals, or gutturals, according
as the check takes place at the lips, between teeth and tongue, or between
back of tongue and soft palate. Each of these again can be divided into
soft and hard consonants as they are accompanied or not with phonation.
Thus when we pronounce D the production of the laryngeal sounds goes on
during the check of the sound produced at the teeth, whereas with T there
is an absolute interruption of phonation during the pronunciation of the
consonant. It is thus practically impossible to make any marked difference
between hard and soft consonants when whispering.
In the production of nasal sounds such as NG the mechanism is the
same as for the production of B, D, G, except that the posterior opening
of the nares is not kept shut by the soft palate, so that part of the sound
comes continually through the nasal passages, when it acquires a peculiar
resonance. These sounds are on this account often spoken of as ' resonants.'
The aspirates are produced by the passage of a simple blast of air through
a narrow opening which may be at the throat as in H, between tongue and
teeth as in TH, or between lips and teeth as in PH or F.
The vibratives, such as R, are formed by placing the tip of the tongue
or the uvula, or the lips, in the path of the blast of air so that they are set
into vibration by the blast. In English the vibrative R employed is entirely
due to the tongue.
The sibilants, which may be voiceless as in ' S ' or accompanied with
phonation as in ' Z,' consist of continuous noises produced by a narrowing
of the path of the air between the tongue and the hard palate. They are
therefore similar in production to the aspirates. In the production of the
sound ' L ' the tongue is applied by its edge to the alveolar process of the
upper jaw, so that the air or voice escapes by two small apertures in the
region of the first molar and between the inner side of the cheek and the
teeth. The acoustic characters of these various consonants are still but
imperfectly studied.
40
PART V
CUTANEOUS SENSATIONS
The skin, being the outermost layer of the body, represents the tissue or
organ by which the organism is brought into relationship with its environ-
ment. In the widest sense of the term the skin is protective. This function
it discharges by virtue not only of its physical properties but also of its rich
endowment with sense organs, by means of which the intracorporeal events
can be correlated with those occurring outside and immediately affecting the
organism.
We are accustomed to distinguish several qualities of sensation among
those having their origin in the skin, the chief of which are the sense of touch,
including that of discrimination, the sense of pain and the sense of tempera-
ture. The very different qualities of sensation included under these three
classes suggest that there may be a special mechanism, or class of mechanism,
for each sense, and a careful investigation of the sensory qualities of the
skin surface bears out this idea. Isolated stimulation of minute areas on the
skin does not excite all the sensations together, but only a sense of touch or
of pain, or a sense of cold or warmth. We are therefore justified in dealing
with each of these sensations separately.
THE TEMPERATURE SENSE
By means of the skin we can appreciate that a body coming
in contact with the skin is either cold or warm. If the body is at
the same temperature as the skin, as a rule no sensation of tempera-
ture is excited. It was formerly thought that the sensations both of heat
and cold were determined by the excitation of one and the same end organ.
Warming of this end, organ would produce a sensation of warmth, while a
diminution of its temperature would produce the sensation of cold. Careful
investigations by Blix and Donaldson of the distribution of the temperature
sense has shown that this opinion cannot be maintained. If a small surface
warmed to a few degrees above the temperature of the skin be moved over
any part of the surface of the body, e.g. the back of the hand, it is found that
the warmth of the instrument is not appreciable equally at all parts of the
surface of the skin. At some points the sensation of warmth will be very
pronounced, but between these points the sensation of warmth may be
entirely wanting and the instrument may be judged to be of the same tem-
perature as the hand itself. In this way a series of ' warm points ' may be
mapped out. On now cooling the instrument a few degrees below the
CUTANEOUS SENSATIONS
627
temperature of the surface of the body and then moving it over the surface in
the same way, it will be found again that the coolness of the instrument is
appreciated only at certain points which can be regarded as ' cold points ' and
as containing the nerve-endings by the excitation of which the sensation of
cold is produced. If the warm points be pricked out in red ink and the
cold points in blue ink, it will be seen that they do not in any way correspond.
A convenient instrument for this purpose is the one invented by Miescher, con-
sisting of two tubes cemented together and communicating at a small flattened extremity,
which is applied to the surface of the skin ; through the tubes water can be led at any
desired temperature, which is read off by a thermometer placed within the tube. Having
mapped out the warm spots it may be shown that they are excitable by means of mechani-
cal or electrical stimuli and that the sensation produced is the same as if they had been
excited by their adequate stimulus, viz. a rise of temperature.
Cold spots. Heat spots.
Fig. 314. Heat and cold spots on part of palm of right hand.
The sensitive points are shaded, the black being more sensitive than the lined,
and these than the dotted parts. The unshaded areas correspond to those parts
where no special sensation was evoked. (Goldscheidek. )
EXACT LOCATION of the spots is rendered difficult by the irradiation
of the sensation produced, so that it is difficult to refer the sensation of
warmth or cold definitely to the point stimulated. An investigation of the
topography of these warm and cold spots shows that the apparatus for the
appreciation of cold is much more extensively distributed over the body than
that for the appreciation of warmth, as is evidenced from the diagram
(Fig. 314) giving the topographic distribution of the cold and warm sense-
organs on the palm of the hand. The temperature sense is best marked in
the following regions of the body : the nipples, chest, nose, the anterior
surface of the upper arm and the anterior surface of the fore-arm, and the
surface of the abdomen. It is much less marked on the exposed parts of the
body, such as the face and hands, and is but slight in the mucous membranes.
Thus it is possible to drink hot fluid, such as tea, at a temperature which
would be painful to the hand, and still more to any other part of the body.
The scalp is also very insensitive to changes of temperature. The acuteness
of the temperature sense varies considerably with the condition of the skin
and with the previous stimulation of the sense organs. Tin- sense i-^ most
acute at about ordinary skin temperature, i.e. between 27° and 32 C. At
this temperature the skin can appreciate a difference of !° C. When the
628 PHYSIOLOGY
skin is very cold or very hot the temperature sense is not nearly so delicate.
This sense presents the phenomenon of adaptation in a marked degree.
It is a familiar experience that, on coming from the external air on a cold day
into a warm room, a sensation of warmth is experienced all over the body.
In a few minutes this sensation wears off. On now leaving the room to go
outside again, the sensation of cold is at once appreciated, to disappear in its
turn after a few minutes. The effect of adaptation is still better shown by
the experiment of taking three basins of water, a, b, and c ; a contains cold
water, b tepid water, c hot water. The left hand is immersed in the cold
water and the right hand in the hot water for a few minutes. On now placing
both hands into the basin of tepid water it feels hot to the left hand and cold
to the right hand. Such experiences as this led Weber to the conclusion
that the essential stimulus for the temperature sense was not the actual
temperature to which the sense organs were subjected, but the fact of a
change of temperature. He imagined that, while the temperature sense-
organs were being warmed, a sensation of warmth was produced, and when
their temperature was being lowered, a sensation of cold. Such a theory
would not however account for the fact that, above a certain tempera-
ture, water may feel warm and the feeling may continue so long as the skin
continues to be stimulated. On a cold day the air may feel cold to the face
and the feeling may last the whole time that the face is exposed. Moreover
we have in the temperature sense conditions which remind one of the after
images which occur in the eye. If a penny be pressed on the
forehead and then removed the sensation of cold lasts some little
time after the penny has been removed. In this case a sensation
of cold is produced although the end organs are being gradually
warmed up after the removal of the penny. In order to account
for these facts Hering, at a time when the differentiation of hot and cold
spots had not yet been effected, suggested that the temperature sense organs
could be regarded as having a zero point at which no sensation was produced.
If their temperature was raised above this point a sensation of warmth was
produced and vice versa. The zero point however was not a fixed one. but
could move upwards to a certain extent on prolonged exposure to high
temperature, or downwards on prolonged exposure to a low temperature.
In the light of the researches of Blix and Goldscheider we should have to
apply Hering's theory of a zero point to each of the temperature end organs
separately.
A cold pencil passed over a warm spot evokes no sensation whatsoever.
If however a pencil considerably warmer than the skin be passed over a cold
spot, this may be excited so that the paradoxical result is produced of a
sensation of cold as the result of stimulation by a warm body. It is a
familiar fact that the immediate effect of entering a hot bath is very much
the same as that of entering a cold bath, viz. a rise of blood pressure and
contraction of the unstriated muscles of the skin and hair follicles with the
production of ' goose skin.' It has been suggested that the distinctive
quality of a sensation of hoi as compared with that of warm is due to the
CUTANEOUS SENSATIONS 629
simultaneous stimulation of warm spots and cold spots. When testing the
distribution of the temperature sense, it is found that the sense of cold is
evoked more promptly than that of warmth. This is interpreted as showing
that the end organs for the warm sense are situated more deeply than those
for coli 1. \\'e have no evidence as to the histological identity of these organs.
THE SENSE OF TOUCH
By means of the sense of touch we arrive at a conclusion as to the qualities,
such as shape, texture, hardness, &c, of the bodies with which the skin
is m contact. In this judgment however, very many other sensations
are involved besides those which can be regarded as strictly tactile. Thus
the hardne:' . of an object signifies its resistance to deformation, besides
its power of deforming the skin surface with which it is in contact ; the
former quality, i.e. of resistance, is one which involves the muscular sen.se.
since we judge of it by the extent to which we can move our muscles without
causing any alteration of the surface of the object.
The tactile sensibility of the skin as a whole, like its temperature sensi-
bility, is due to the presence in it of a number of touch spots, i.e. small
areas which are extremely sensitive, separated by areas almost or entirely
insensitive to pressure. The tactile sensibility of any part is proportional
to the number of such toucli spots present. If the calf of the leg be shaved
and then tested by pressing on it with a fine bristle or hair it will be found
that the minimal stimulation used evokes sensation only at certain definite
points, the ' touch spots.' In a square centimetre of such skin there may
be about fifteen touch spots. On thrusting a fine needle into one of these
spots a sharply localised sensation of pressure is produced unaccompanied
by any painful quality and often described as having a ' shotty ' character,
as of a little hard object embedded in the skin and there pressed upon.
These touch spots are arranged chiefly around the hairs, lying usually
on the side from which the hair slopes. They vary in number according
to the part of the body which is the subject of investigation. Thus the
dorsal surface of the finger contains about seven times as many touch spots
as an equal area between the shoulders. In some regions, such as the
skin over subcutaneous surfaces of bone, as much as one centimetre may
intervene between two neighbouring touch spots. They have no relation
to the warm and cold spots ; they are entirely absent from the cornea, the
glans penis, and the conjunctiva of the upper lid.
RESPONSE TO DIFFERENT STIMULI. The adequate stimulus
for these tactile nerve endings is not so much pressure as deforma-
tion of surface. It appears to matter little whether the surface be
deformed by pulling it or by pushing an instrument into it. The
ineffectiveness of mere pressure is shown by dipping the finger into a
vessel of mercury. The sensation of pressure is noted only at the point
where the finger passes through the surface of the mercury, and this is fche
only part where there is an actual deformation of the skin, due to the sudden
630 PHYSIOLOGY
passage from the pressure of the mercury to the negligible pressure of the
outside air. The tactile apparatus is smarter in its response than any other
of the sense organs. On this account stimuli are still perceived as discrete,
when they are repeated at a rhythm which would result in complete fusion
in the case of any of the other sense organs. Thus if a bristle be attached
to a tuning-fork and allowed to press on the skin, the vibrations of the
fork are perceived by the ear as a continuous sound and by the skin as
a series of discontinuous taps. Faradic currents when applied to the
skin can be perceived as separate when repeated at the rate of L30 per
second. The sensations evoked by placing the finger against the edge of a
cog-wheel do not become continuous until the wheel is revolving at such a
rate that the stimulation on the skin by the serrations occurs at a greater
rate than 500 or 600 per second. The tactile apparatus resembles all the
other skin sense organs in showing adaptation. A stimulus after continuing
for some time may become ineffective. We are usually entirely unaware
of the stimulation of our skin by the pressure of the clothes, and even
an unwonted stimulation, such as that of the mucous membrane of the
mouth by a plate carrying artificial teeth, though almost unbearable during
== 1
I'm:. 315. Hair mounted on a wooden handle, and used
by von Frey for testing tactile sensibility.
the first day, rapidly becomes less, and in a few days it is not perceived
at all.
In order to test the sensitiveness of touch we may use the method in-
troduced by Hensen, viz. the bending of a glass-wool fibre. We can
determine the pressure at which any given fibre will bend, and if we find
by trial the fibre which just evokes sensation when pressed on the skin,
we know exactly the force which we are applying to the skin. Von Frey
employed hairs of different thickness for the same purpose (Fig. 315). The
following represents the minimal excitability of the surface of different
parts of the body when tested in this way.
Tongue and nose ....
2
Lips ......
2-5
Finger-tip and forehead
3
Back of finger ....
5
Palm, arm, thigh ....
7
Fore-arm .....
8
Back of hand ....
12
( lalf, shoulder ....
16
Abdomen .....
26
Outside of thigh ....
26
Shin and sole ....
28
Back of lore arm . . ■ . ■
33
Loins ......
48
CUTANEOUS SENSATIONS 63]
The sensitiveness of the sense organs in the skin is probably much
greater than that of the nerve trunks themselves. Thus Tigerstedt found
that the minimal mechanical stimulus necessary to excite the exposed
nerve amounted to G"2 grm. moving at 140 mm. per second. For the touch
spots von Frey found that 0'2 grm. moving at 0"17 mm. a second is an
adequate stimulus.
In testing the sensibility of any surface it is important to remember
that the hairs themselves form very effective tactile organs. The touch
spots are distributed in greatest profusion around hair follicles, and there
is a rich plexus of nerve fibres round the root of each hair. A slight touch
applied to the hair acts on these as on the long end of a lever, the hair being
pivoted at the surface of the skin, so that pressure on the hair is transmitted,
increased five or more times in force, to the hair follicle and the surrounding
nerve endings. The actual sensibility of any part is therefore much dimin-
ished by removal of the hairs. On 9 sq. mm. of the skin, from which the
hairs had been shaved, the minimal stimulus necessary to evoke a tactile
sensation was found to be 36 mg., whereas on the same surface before it was
shaved 2 mg. was effective.
WEBER'S LAW. The smallest increment or decrement of stimulus
which determines a perceptible difference of sensation must, according
to Weber's law, always bear the same ratio to the whole stimulus. In
measuring such differences it is best to apply the stimulus successively to
the same surface of the skin rather than simultaneously to adjoining areas.
The time interval between two successive stimuli should not be more than
five seconds and the duration of the stimuli should be equal. Weber found
that in the terminal phalanx of the finger the minimal perceptible difference
was about one-thirtieth, but the ratio was not the same for all regions of
the skin nor for all individuals. The following represents the liminal
difference in various skin regions :
Forehead, lips, and cheeks . . . l/30th to l/40th
Back of fore-arm, of leg, and of thigh ; |
back of hand, and first and second ,- 1 /10th to 1 /20th
phalanx of finger, &c. . . .J
All parts of the foot, surface of leg, and
tliigh ...... more than l/10th
THE SPATIAL QUALITY OF TOUCH. DISCRIMINATION. If any
part of the skin be stimulated the subject of the experiment can tell at once
the exact situation of the excited spot. If two points be stimulated simul-
taneously excitation is perceived as double, i.e. as proceeding from two
points, provided the distance between the points exceeds a certain amount,
varying in different parts of the body. The power of discrimination, i.e.
of judging whether a stimulus is single or double, can be tested by arming
the points of a pair of compasses with small pieces of cork and then seeing
how far apart the points must be when pressed on the skin in order that t he
stimulus may be perceived as double. The following Table represents this
distance for various regions of the body :
632 PHYSIOLOGY
Distance in mm.
Skin region. mm.
Tip of tongue ........ 11
2-3
6-8
11-3
31-6
540
67-1
Volar surface of finger tip
Dorsum of third phalanx
Palm of hand .
Back of hand .
Back of neck .
Middle of back, upper arm, and thigl
When touch spots are sought out for stimulation with the points of a
compass, the distance at which the excitation is perceived as double is
much diminished, as is shown by the following Table of distances for the
touch spots in millimetres :
Skin region. Distance of touch spota.
Volar side of finger lips . . . . . til
Palm of hand ....... 0-1
Fore-arm (flexor .side) ...... 0-5
Upper arm ....... 0-6
Back 0-4
The compass points are perceived to lie apart with a special distinctness
when they are applied to touch spots lying on different lines which radiate
from the hair follicles. The figures given in the first Table have no relation
to touch spots, but show the average distance over which an excitation
can be perceived as double.
The delicacy of discrimination of any part is largely associated with
its mobility. Thus in the arm the delicacy increases continuously from
the shoulder to the finger-tip. If the. localising power for touch on the
shoulder be taken as 100, that of the finger tips will be represented by 2582.
In the same way there is a continuous decrease of the distances of discrimina-
tion as we pass along the cheek from the ear to the lip, i.e. from the non-
mobile to the mobile part. The power of discrimination is increased to a
certain extent by practice and largely diminished by fatigue. Any factor
which diminishes the tactile sensibility of the part, such as cold, will also
diminish the power of discrimination.
LOCALIZATION OF TOUCH. The fact that we can localise the
point of stimulation shows that every tactile sensation derived
from the surface of the body, besides the qualities of intensity and
extensity, has also associated with it a characteristic quality de-
pendent on its position. This localised quality of a tactile sensation was
called by Lotze ' local sign.' Among psychologists there has been much
discussion as to how far this ' local sign ' is an inborn attribute of the sensa-
tion of every point on the body surface, or how far it is acquired by ex-
perience and based on memory of movements and muscular impressions.
In the retina we have a sense organ which, like the skin, possesses local
sign, but in far higher degree, the power of discrimination of the retina
being three thousand times as great as that of the most sensitive part of
the skin. Cases of congenital cataract occur in which the subjects have
been blind from birth. By extraction of the cataract we can give such
CUTANEOUS SENSATIONS 633
persons the power of sight. It is found that at first there is no power of
localising visual impressions. The ' local sign ' is developed only in re-
sponse to experience, by comparing simultaneous visual, tactile, and motor
sensations. By analogy we might ascribe the local sign of cutaneous
sensations to a similar causation. Our study of the spinal animal has
indeed given us a physical or histological conception of local sign. We
know that stimulation of any part of the body evokes an appropriate reaction,
the nature of which is determined by the central connections of the entering
nerve fibres. A fibre entering at one segment must therefore come into
relation with a different set of motor cells from those which are set into
action by a fibre entering one segment lower down. Every nerve fibre
from the skin will therefore have an appropriate complex of motor paths
in functional connection with its central endings, and when the activity of
these reflex paths comes to be represented in consciousness, it. is evident
that the sensation derived from each point must differ from that derived
in >in any other point of the skin by virtue of the differing motor events
actually or potentially excited from the two points. In ascribing therefore
' local sign ' to coincident muscular sensations, and to the memory and
experience of past movements, we are giving but an imperfect explanation ;
since the difference between the sensations from different parts, which are
at the bottom of our powers of localisation, has its origin in the structure
of the central nervous system itself and is present from the very beginning
of the evolution of a reactive nervous system.
PROJECTION OF TOUCH. Since the alterations in the surface of the skin
which give rise to tactile sensations are habitually caused by contact with
external objects, we come to regard the sensations themselves, not as
changes in the skin, but as qualities of the object which touch the skin, i.e.
we project the sensation. The projection is however not so great as in
the case of visual sensations. Cutaneous sensations we always consider
as qualities of an object immediately affecting and altering the condition
of ourselves, whereas the visual sensations are referred at once to objects
lying right away from ourselves, so that we are not aware that any change
has taken place in our bodies as a result of the entering of rays of light into
the eye.
It is remarkable to what extent projection of touch sensation may
occur. Thus a surgeon actually lengthens his fingers by using a probe.
When he is probing for dead bone he feels the grating of the bone, not at
his finger-tips, but he projects the sensation to the end of the probe. In
the same way tactile sensations evoked by the contact of bodies with the
insentient endings of hair are referred to the ends of the hairs rather than
to the hair follicles where the nerve impulses actually come into being.
The dependence of local sign on habitual experience is shown by
the various tactile illusions, such as the well-known experiment of Aris-
totle. If with the eyes shut we cross the first and middle fingers and bring
them in this position in contact with a pea, we should at once say that two
peas lay under the fingers. This is especially marked if the pea be rolled
634 PHYSIOLOGY
lid wren the lingers. The two sides of the fingers which come in contact
with the pea usually touch two different objects, and these parts of the
skin would have to be re-educated, i.e. their local sign would have to be
changed in accordance with the changed conditions, before the pea would
be perceived in its true state as single.
THE PAIN SENSE
When the pressure of a hard object on the skin is increased beyond that
necessary to evoke a tactile sensation, at a certain pressure the quality
of sensation changes and it becomes painful. For the evolution of the
race as well as for the preservation of the individual this pain sense is all-
important ; it is the expression in consciousness of the reflexes of self-
preservation which can be evoked in the spinal animal by stimuli which are
nocuous, i.e. calculated to do actual damage to the tissues of the body. Thus
when a sharp point is pressed on the skin the sensation becomes painful just
before the pressure is sufficient to cause penetration. The so-called trophic
lesions which occur in parts devoid of sensation are determined for the
most part by the lack of the pain sense and the consequent failure of the
preservative reflexes of the part. It is remarkable that pain may result
from changes in organs which are devoid of ordinary sensibility. Thus
the intestine may be cut, sewn, or handled without arousing any sensation
whatsoever. A strong contraction of the muscular wall or increased dis-
tension of the gut will however evoke a griping pain. In the same way
the ureters, which are normally devoid of sensation, can give rise to ex-
cruciating agony when they are contracted firmly on a retained calculus.
We are accustomed to distinguish many different qualities of pain,
but on analysis it will be found that these qualities depend on the nature
of the sense organ which is simultaneously stimulated. Thus a burning
pain denotes simultaneous stimulation of the pain sense and of the nerve
endings to the warm spots. A throbbing pain results when the vessels
of the part are dilated and the part is tense with effused lymph, so that
each pulse of the vessels causes an exacerbation of the painful stimulation
and perhaps also stimulation of the tactile end organs.
The sense of pain has often been ascribed to over-maximal stimula-
tion of any form of sensory nerve. Although it is true that over-stimulation
of the auditory or optic nerve by a loud sound or a bright light may be
extremely unpleasant, the sensations evoked do not partake of the characters
of painful sensations such as would be produced by pricking or burning the
skin. Moreover a careful investigation of the sensory points on the skin
brings out the fact that there are besides the tactile and temperature sj>ots,
other spots from which only painful sensations can be evoked. We have
seen already that over-stirnulation of a touch spot does not, as a matter of
fact, cause pain. The pain spots which are distributed among the touch and
temperature spots are insensitive to a low grade of stimulus. As the
strength of the stimulus is increased a point is suddenly reached at which
the sensation evoked is painful. Moreover in parts of the body tactile and
CUTANEOUS SENSATIONS 635
temperature sense are entirely wanting, though painful impressions can be
easily evoked. The best example of this is seen in the cornea, minimal
stimulation of which evokes pain, but nothing which can be regarded as
a tactile sensation. The specific quality of pain sensation is shown more-
over by the fact that in many cases of disease the sense of pain may be
abolished without the sense of touch. Such a patient is said to suffer
from analgesia, but not anaesthesia. When pricked on an analgesic part
the patient can say that he is pricked, but has no objection to any amount
of repetition of the stimulus, since the sensation is entirely devoid of painful
character. In the case of the skin the sense organs concerned in pain
appear to be the free intra-epithehal nerve endings. Pain is found to differ
somewhat from the other skin sensations in being much more uniformly
distributed, more difficult to locate accurately, and more hardy. Thus
while most sense organs are rendered less sensitive by cutting off blood
supply, pain at first reacts more violently.
THE WORK OF HEAD ON CUTANEOUS SENSIBILITY
In a long series of researches on man Head has shown that three different
classes of sensations may be evoked by stimuli applied to the surface of
the body. In order to study the functions of the afferent nerves Head
has investigated not only the condition of patients, the subjects of accidental
division of cutaneous or other nerves, but also (in conjunction with Rivers)
the effects of nerve section on himself. In the first place, it is necessary to
differentiate deep sensibility from cutaneous sensibility proper. After
desensitisation of any given area of the skin it is still possible in this area
to appreciate deep pressure and pain, and the. localisation of the situation
of the pressure is fairly accurately carried out. On the other hand, the
sensations of light touch, as well as of temperature and the pain evoked
by a light pin prick, are absent. The sensations of pressure, as well as of
deep pain or pressure pain, are therefore carried by the nerves of deep
sensibility. These nerves are not the cutaneous nerves, but are derived
from the sensory elements in the muscular nerves. To the fingers, for
instance, they run in the tendons of the muscles. Simultaneous division, as
by a circular-saw cut, of the cutaneous nerves and tendons to the fingers will
abolish deep as well as superficial sensibility. Deep sensibility must there-
fore be classified, anatomically at any rate, with the ' organic sensations '
of muscular effort and of position, which will be dealt with in a subsequent
section.
Cutaneous sensibility proper Head divides into two categories, namely,
protopathic and epicritic sensibility. These two forms of sensibility may
be studied separately on an area of skin, which has been desensitised by
section of its cutaneous nerves, during the process of regeneration of these
nerves.
Prolopathic sensibility returns to the skin at an interval of seven
to twenty-six weeks after the nerve section. At this time it is possible
to appreciate in the area under investigation the sensation of pain, and
036 PHYSIOLOGY
to recognise roughness of an object rubbed on the skin. Localisation
is still somewhat diffuse and inaccurate, so that the sensation evoked by
stimulation of the protopathic area may be referred to some adjoining normal
part of the skin. The temperature sense is also present, but of a low grade.
Thus heat over 38° C. and cold under 24° C. can be appreciated as such,
but the intervening temperatures produce no sensation. Sensations evoked
in the protopathic. area are strongly endowed with what may be termed
' affective ' character. Thus painful stimulation is much more unpleasant
when applied to this area than would a similar stimulation be when applied
to a normal area of skin.
In contradistinction to the deep sensibility which is diffuse, protopathic
sensibilitv is distributed in spots, so that heat and cold spots for instance
may be distinguished as on the normal skin. It is interesting that the
glans penis is normally provided only with protopathic sensibilitv.
E-picriticsensibilit.il docs not return to the desensitised area until
one to two years have elapsed since the division of the nerves. With
its return the affective character of the protopathic sensations at once
disappears and is replaced by an accurate discrimination of the nature and
extent of the stimulus" 1 ; the tactile sense proper, i.e. the appreciation of the
lightest touch applied to the skin and its accurate localisation, belonging
entirely to the epicritic sensations. The power of discriminating the
distance between two points applied to the skin simultaneously is also a
function of the epicritic sensibility.
With the discriminating tactile sense returns also the power of appre-
ciating fine differences of temperature, i.e. differences between 26° and
37° C.
This classification may be summed as follows :
Deep sensibility . . . including [Pressure sense
(.Pressure pain
[ Skin pain
Protopathic sensibility . ,, -: Heat over 38" C.
(characters: high threshold, ^Cold under 24° C.
painful and indefinite)
/Tactile sense proper
Pain localisation
Epicritic sensibility . „ < Discrimination
(characters: accurately local- Heat and cold between
ised, low threshold) V 26° and 37° C.
Head and Thompson have shown that on entering the cord these various
sensations undergo a new grouping. Thus the pain impulses, which arise
in and are carried by the muscular nerves, the nerves of deep sensibility,
unite with those which run in the protopathic system, so that a lesion of the
cord affecting the pain tracts will abolish all forms of pain, whether
arising from the skin or from the underlying tissues. In the same way all
temperature sensations, whether the fine ones of the epicritic system or the
coarser ones of the protopathic system, run together in the cord. If the
CUTANEOUS SENSATIONS
637
heat sense is affected by a lesion of the cord all forms and all degrees of the
sensation are affected in like measure, and the same applies to the sensations
of cold.
The conduction paths of these different sensations in the cord are shown
in Fig. 176 on page 358.
THE HISTOLOGICAL CHARACTER OF THE ELEMENTS
INVOLVED IN CUTANEOUS SENSATIONS
A very large number of different forms of sensory nerve endings have
been described in relation to the skin. Their exact allocation among the
different cutaneous senses presents considerable difficulties.
Fig. 316. Skin end organs and the sensations which they arouse.
As regards touch, two kinds of elements are probably involved. In
the first place, the most sensitive tactile apparatus are the follicles of the
short hairs. Around these follicles we find a sheaf of nerve fibres, some
of which end in the hair papilla and others form a ring near the level of the
openings of the sebaceous glands. The other tactile end organ is Meissner's
corpuscle. The distribution of these in the skin is not however dissimilar
to that of the power of discrimination, with which they may be specially
638 PHYSIOLOGY
connected. Other end-organs which are supposed to be stimulated by
changes of pressure and therefore to be tactile, are the organs of Ruffini
which occur in the papillae of the palm and fingers and, lying more deeply,
the elastic tissue spindles as well as the Golgi corpuscles and the Pacinian
corpuscles in the subcutaneous tissue.
As regards pain, we know that in the cornea, which possesses only
the pain sense, the sensory nerve-endings are in the form of branches of
axis cylinders among the epithelial cells. Similar free nerve endings occur
in the epidermis all over the body, and it is therefore imagined that these
have the special function of subserving the pain sense. We have at present
no evidence as to the histological character of the organs by which the
sensations of heat and cold are aroused.
PAET VI
SENSATIONS OF SMELL AND TASTE
Every living organism shows a susceptibility, i.e. a power of reaction,
to cliemical stimuli. Thus the plasmodium of nryxomycetes, placed on a
strip of filter-paper of which one end is immersed in an infusion of dead
leaves and the other in distilled water, will crawl along the paper towards
the infusion of leaves. If the infusion of dead leaves be replaced by a
weak solution of quinine, the plasmodium will be repelled and will travel
along towards the vessel of water. These movements of attraction and
repulsion are spoken of as positive and negative chemiotaxis respectively.
A similar chemical sensibility accounts for the clustering of aerobic bacteria
towards the surface of a fluid, i.e. where the density of oxygen is greater, or
around chlorophyll-containing algae which are giving off oxygen in the
sunlight. The aggregation of leucocytes round microbes or other foreign
particles in the tissues is also determined by their chemiotactic sensibility.
Chemiotaxis then represents the faculty by means of which these minute
organisms are able to adapt themselves to chemical changes in their environ-
ment and to react to chemical substances at a considerable distance from
themselves. If we could endow these elementary organisms with con-
sciousness and with a sense of their surroundings, we should have to t say
that they became aware of the presence of some harmful or attractive
material at some distance from themselves. The sensation they received
from these distant objects would be therefore a projected sensation.
On the other hand, a chemical sensibility of the body surface or part
of it furnishes the criterion by which particles are accepted and ingested
as food or rejected as useless or harmful. Consciousness in this case would
be of something affecting and in contact with some part of the organism
itself. The sensation would not be projected further than the periphery of
the body.
These two kinds of chemical sense — the projected and the surface
sense — are found throughout almost all classes of the animal kingdom,
and in the higher animals at least are known as the senses of smell and
taste. The former sense in many animals attains a high degree of com-
plexity and is prepotent in determining the behaviour of an animal in
response to the changes in its surroundings. In the elasmobranch li li-
the olfactory lobes form the greater part of the higher brain, and extirpation
of them produces a loss of spontaneity and of delayed reactions similar to
that which can be brought about in higher types by extirpation of the whole
of the cerebral hemispheres.
640
PHYSIOLOGY
The sense of taste, on the other hand, is used only for sampling the nature
of substances taken into the mouth and determining their ingestion or
rejection. It is therefore much simpler in its extent and more susceptible
of analysis.
THE SENSE OF TASTE
The end organs which subserve the function of taste are represented
by the taste buds. These are oval bodies (Fig. 317) embedded in the
stratified epithelium, which occur scattered over the tongue, a few being
also found on the hard palate, the anterior pillars of the fauces, the tonsils,
the back of the pharynx, the larynx, and the inner surface of the cheek.
On the tongue they are found chiefly in the grooves around the circumvallate
papillae of man, and in the grooves of the papillae foliatse of rabbits. A
few are also present on many of the fungiform papillae. They consist
of medullary and cortical parts, the former being composed of columnar
or sustentacular cells, the latter of thin fusiform cells, the taste cells
proper. The nerve fibres concerned with taste end in arborisations among
these taste cells. The peripheral end of the
fusiform cell projects as a delicate process
through the, orifice of the taste bud, so
that it can come in contact with the fluids
contained in the cavity of the mouth. A
sapid substance, to stimulate these organs,
must be in solution ; hence quinine in
powder is almost tasteless, owing to its
slight solubility in neutral or alkaline fluids.
DIFFERENTIATION OF TASTE. The
number of different tastes is very limited.
We distinguish four primitive taste sensa-
tions, viz. sweet, sour, bitter, and salt,
some authors adding to this an alkaline
taste and a metallic taste. Many sub-
stances owe their distinctive character when
taken into the mouth to the fact that they
stimulate not only the taste' nerves but
also the nerve endings of common sensa-
tion. Thus acids, when in weak solution,
have an astringent character besides their
sour taste, and if strong produce a burning sensation. The primitive
taste sensations can affect one another if excited simultaneously.
With weak stimulation one taste may practically annul another. Thus
a dilute solution of sugar is rendered almost tasteless by the addition to
it of a few grains of common salt. If the primitive taste sensations are
more strongly excited we get a mixed sensation, in which the components
can still be distinguished. Thus, adding sugar to lemon juice not only
diminishes its acidity but produces a mixed sensation, the quality of which
Fig. 317. Two taste buds
from the tongue.
e, Stratified epithelium ;
?V opening or pore of taste
bud ; s, gustatory cells ;
st, sustentacular cells.
(KOIJUKEB.)
SENSATIONS OF SMELL AND TASTE 641
is pleasant and in which the components, sour and sweet, can be easily
distinguished. We get no such fusing of sensations as in the eye, where
a sensation of white light may result from stimulation of the retina by
two complementary colours. Stimulation of one kind of taste organ heightens
the sensibility of the other taste organs. Thus after the application of salt,
distilled water may taste sweet.
That these primitive taste sensations are served by different nerve
endings is shown by the following facts :
(a) The tongue is not equally sensitive at all points to all tour tastes.
Thus the back of the tongue is more sensitive to bitter, while the tip and
sides of the tongue react more easily to sweet and sour substances. A differ-
ence may be detected between even the circuni vallate papillae themselves ;
a mixture of quinine and sugar applied to one papilla may excite chiefly
a bitter taste, while with an adjacent papilla a sweet taste may predominate.
(6) By certain drugs we can depress the sensibility of the taste organs,
and we then find that the various tastes are affected to different degrees.
Thus on painting the tongue with cocaine the first effect is a diminution
of tactile and pain sensibility, so that the application of acid evokes a very
sour taste without any of the astringent or stinging sensations normally
aroused by the contact with the acid. After this point the taste sensations
are also abolished. The bitter sensation disappears first, then the sweet,
and then the sour, while the taste of salt appears to remain unaffected. On
the other hand, if the leaves of Gymnema sylvestre be chewed, the sensations
of bitter and sweet are abolished, leaving intact the acid and salt tastes,
and also the general sensibility of the mucous membrane.
TASTE AND CHEMICAL CONSTITUTION. There is no doubt
that the stimulating effect of any chemical substance on the taste
nerves has relation to its chemical constitution. Thus a sour taste
is determined by the presence of H ions ; the alkaline taste by that
of OH ions. The fact that certain acids, e.g. acetic, have a stronger sour
taste than would correspond to their dissociation, i.e. to the number of II
ions present, is due to the fact that these acids penetrate more easily into
the gustatory cells than the mineral acids with a larger dissociation co-
efficient. All the «-amino-acids have a sweet taste. On the other hand,
the polypeptides produced by the combination of these ammo-acids, as
well as the peptones derived from the hydrolysis of proteins, have a bitter
taste. Most of the alcohols and sugars have a sweet taste, while the metallic
derivatives of these substances are bitter. We do not yet u u< lerstand the
law which determines whether any given substance shall have a taste at
all, and what its taste should be.
The nerves of taste are the glossopharyngeal, which supplies the back
part of the tongue, and the lingual branch of the fifth nerve and the chorda
! \ mpani, which supply the front part. All these fibres are probably con-
nected with a continuous column of grey matter in the brain stem, which
represents the splanchnic afferent nucleus of the fifth nerve, the nervus
intermedins, and the glossopharyngeal. Some authors have stated that
41
642
I'lfYSloLOKY
all the taste fibres of the fifth nerve are derived from the glossopharyngeal
by the communication through the tympanic plexus and the chorda tympani
nerve, while Gowers has recorded a case of complete unilateral loss of taste
in which there was a lesion destroying the fifth nerve, the glossopharyngeal
being intact. It seems possible that the actual region of the taste nerve-
may vary, the fibres running to the splanchnic column of grey matter being
contained sometimes in the fifth, sometimes in the glossopharyngeal, and
sometimes in both.
Most of our so-called tastes should rather be designated flavours, and
are dependent, not on the gustatory nerves, but on the sense of smell.
Fig. 318. Diagram showing origin and course of the nerve fibres of taste.
When the olfactory sense is destroyed very little difference is to be perceived
between an onion and an apple. The epicure with a fine palate has really
educated his sense of smell and would be but little satisfied with the simple
sensations derived from his four sets of gustatory end organs.
THE SENSE OF SMELL
The psychical analysis of olfactory sensations is rendered difficult
by the fact that this sense in man plays but a small part in his usual adapta-
tions. We have thus to deal with a sense which is in many respects vestigial.
We see traces of great complexity in its possibilities of performance, but
are baffled in our endeavours to reduce the whole of the phenomena to the
simpler factors of which they are composed. Moreover, like all vestigial func-
tions, the extent to which the sense is developed varies from one individual to
another. Many for instance are unable to appreciate the smell of vanilla,
of hydrocyanic acid, or of violets. On the other hand, in animals such as
the dog, the olfactory sense seems to play a great part in determining
behaviour, and the nervous associations, which are the physiological basis
of ideas, must in these animals be largely connected with olfactory im-
SENSATIONS OF SMELL AND TASTE
643
pressions. Another factor which diminishes the importance of olfactory
sensations in man is the ease with which the sense organ becomes fatigued.
It often happens that the inmates of a room are perfectly comfortable
and may perceive no fault in the ventilation, although a newcomer fr
the outside at once remarks that the air is foul.
THE ORGAN OF SMELL is situated at the upper part of the nasal cavi-
ties. Here the mucous membrane covering the superior and middle turbinate
bones and the corresponding part of the septum is different from that
covering the rest of the nasal passages. Over the lower parts of the nasal
cavities the mucous membrane is of the ordinary respiratory type, and
is composed of ciliated columnar epithelium containing a number of goblet-
cells. In the olfactory part the epithelium is much thicker, of a yellow
colour, and apparently composed of a layer of columnar cells resting on
several layers of nuclei. These nuclei belong to the olfactory cells proper.
true spindle-shaped nerve cells with one process extending towards the
mucus covering the free surface, while the other is continued along channels
in the bone, and through the cribriform plate as one of the non-medullated
olfactory nerve fibres. These nerve fibres dip into the olfactory lobes.
Fig. 319. Antero-posterior section through the nasal fossal. The arrows show
the direction of the air currents during inspiration.
where they terminate by a much-branched arborisation or end basket in
the so-called olfactory glomeruli, in close connection with a similarly
branched dendrite of the large ' mitral ' cells of the olfactory lobe. The
axons from these latter carry the olfactory impulse towards the rest of the
brain. In the connective tissue basis (dermis) of the mucous mem
are a number of small mucous or serous glands (Bowman's glands) whose
office it is to keep the surface of the membrane constantly moist.
644 PHYSIOLOGY
In ordinary respiration the stream of air never passes higher than the
anterior inferior border of the superior turbinate bone, so that it does not
come in contact with the olfactory mucous membrane. The sensations
of smell which are aroused during ordinary respiration depend on diffusion
from the respiratory air into the still air of the upper olfactory portion
of the nasal cavity. The direction of olfactory attention is achieved by
sniffing ; in this act the nostrils are dilated and the direction of the anterior
part of the nasal respiratory chamber altered, so that the stream of entering
air is directed towards the upper olfactory portion of the cavity.
The fact that the air. which enters the nasal cavity during respiration,
does not come into direct relationship with the olfactory epithelium has the
following advantages :
(1) The cold inspired air does not come into contact with and cause
damage to the sensory surface.
(2) Foreign particles carried by the air (including bacteria) do not get
deposited there. The position of the epithelium at the very top of the
nasal cavity is an additional safeguard.
(3) The olfactory epithelium is not dried by the rush of dry air
across it.
(4) Noxious vapours only reach it indirectly and therefore do not cause
permanent damage as they otherwise might.
The fact that we are able to perceive smells when breathing normally
shows that the odorous substance must be diffusible, i.e. gaseous in form.
The amount of substance necessary to excite sensation is extremely minute.
Thus 01 mg. of mercaptan diffused in 230 cubic metres of air is still distinctly
perceptible. In this case a litre of air would contain only "00000004 mg.
of the substance, and the amount actually in contact with the olfactory
epithelium would be still smaller. It is possible however to show the
presence of these odorous substances in air by physical means. Tyndall
pointed out that air containing a small proportion of odorous substances
absorbed radiant heat to a much greater degree than did pure air. Thus
in one experiment air containing patchouli absorbed radiant heat thirty-
two times as strongly as the pure air. Most odorous substances possess
large molecules and have therefore high vapour densities. On this account
the smell tends to hang about objects, the rate of diffusion of the vapour
being only small.
MODE OF ACTION OF SMELLS. Since the endings of the olfac-
tory cells are bathed in fluid, it is evident that the odorous
„ substances must be dissolved by this fluid before they can excite the
olfactory nerve fibres, and in the case of aquatic animals we know
that the projected chemical sense, which we call smell, can be aroused only
by substances in solution. It is difficult to show in man that the nerve
endings can be excited by solutions. Most of the experiments have been
made with solutions which had an injurious effect upon the olfactory
epithelium. According to Aronsohn it is possible to excite sensations
of smell if the nasal cavity be filled with normal saline fluid, containing
SENSATIONS OF SMELL AND TASTE 645
a very small proportion of the odorous substance. To this experiment
ir lias been objected that it is almost impossible to till the nasal cavities
without leaving some air spaces, so that the olfactory sensation obtained
might have been due to stimulation of the olfactory cells in such a space
There is however no a priori reason to deny the probability of Aronsohn's
conclusions.
Many olfactory stimuli owe their peculiar character to the simultaneous
stimulation of other kinds of nerve endings. Thus a pungent smell, as that
of ammonia, chlorine. &c, in-
volves stimulation of the nerves
of common sensibility, i.e. the
fifth nerve, besides stimulation
of the olfactory nerve.
No satisfactory classification
of smells has yet been made.
The following facts tend to show
that there are a number of primi-
j. ., r Fig. 320. Zwaardemaker 8
tive sensations ot smell, as oi olfactometer.
other sensations :
(a) Certain individuals, whose
olfactory sense is in other re-
spects normal, have no power of distinguishing some odours.
(b) The olfactory sense is easily fatigued. If it be fatigued so as to be
absolutely insensitive tor one kind of smell, it is still normally excitable for
other smells.
(c) It is possible by mixing odoriferous substances in certain proportions
to annul their effect on the olfactory organ. Thus 4 grm. of iodoform
in 200 grm. of Peruvian balsam is almost odourless, and the same neutralisa-
tion of odour- i- obtained if the odour of each substance lie allowed to act
separately on each side by tubes inserted into each nostril.
For this purpose we may use the instrument invented by Zwaardemaker called
the olfad eter. 'Phis consists of a porous cylinder into which i- inserted a tubi
The porou ! cj Under is first immersed in the fluid w hose porous qualif ii - are to be tested,
and when it is thoroughly soaked it is taken out. dried outside by a cloth, and inside
hv drawing air through it for a short time. One end ot the bent tube is then insert d
into the cylinder, which it must accurately tit. while the other end is placed in one
nostril. The small wooden screen shown in Fig. 320 serves to shut oil' the snail of the
fluid from the other nostril. When the observer breathes through the bent tube, the amount
of vapour taken up from the cylinder will depend on tin- amount of sum
oil therefore can hi- diminished or increased by pushing the bent tuhe further in. or
by drawing it out. If tin- tube is pushed in so far that the smell is only just perceptible,
ength of the tube maybe mea ured dt ken a thi in al intensity of stimulus
tor the given substances, in it- action on the olfactoi lings This unit was
called by the inventor ot the instrument an ■- this means it is p
to make quantitative estimations of the olfactory sens i one individual and to compare
them with observations made on other individual two such instruments
it is |> .ssihle to present different smells to the two nostrils. sin thi- way
combination effects which can l»- compared to the phenomenon which v
studied in dealing with binocular contrast.
PART VII
SENSATIONS OF MOVEMENT AND POSITION
In studying the phenomena of reflex movements, as presented by the spinal
animal, our attention was drawn to the importance of the afferent impulses
transmitted to the central organ by means of a special system of sense
organs, called by Sherrington the proprioceptive system. These afferent
impressions intervene at a later period in every reflex action than do the
initiating sensory (exteroceptive) impulses. They arise as a result of the
reflex movement itself, and serve to regulate the extent of this movement
as well as the co-ordinated changes in the other muscles of the body.
Whether they be synergic or antagonistic, the abolition of the impulses
arising in this system has an effect similar to that of the destruction of the
governor of an engine. The movements excited by peripheral stimulation
become excessive and conflicting ; there is no longer the give-and-take of
the antagonistic muscles surrounding the joint, and the result is a state of
disorder and inco-ordination, termed ataxy.
Of the proprioceptive impulses a certain proportion reach the cerebral
cortex and arouse states of consciousness which we speak of as sensations of
position, movement, or resistance, and which form the basis of judgments as
to these conditions. In consciousness they are contrasted with the sensa-
tions arising from the other sense organs in the same way as they are in the
subconscious regulation of the motor adaptations of the body. 'All the
senses which we have so far considered give us information of things, i.e. of
a material world which can affect ourselves, but which we conceive of as
existing altogether apart from our sensations of it. Indeed the visual and
auditory sensations we project to distances remote from the body. The
sensations on the other hand, which are aroused through the intermediation
of the proprioceptive system, we refer entirely to ourselves. By them we
receive information of the condition of the material ' me,' i.e. of ourselves
as things apart from the objects which surround us and the changes in which
ordinarily excite our activity.
VOLITIONAL MOVEMENTS. Consciousness we have seen to be
developed in proportion to the differentiation of the educatable associa-
tion centres, which are responsible for our powers of ideation, and
by means of which the different reflex movements which we call
volitional are carried out. guided, augmented, or inhibited, according
to the past experience of the individual. Volitional movement is there-
fore a movement determined by previous neural events, of which a part
646
SENSATIONS OF MOVEMENT AND POSITION 647
at any rate is represented in consciousness as feeling, emotion, or desire.
Where an act is involuntary, i.e. does not need the guidance of experience,
individual or racial, for its performance, the afferent impulses which arouse
it are also, as a rule, devoid of representation in consciousness. Thus we
have no sensation of the passage of a bolus along the oesophagus. The
proprioceptive impulses also only affect consciousness where they are
necessary for the guidance of volitional movement. The tactile and gusta-
tory impressions from the tongue have a very full representation in conscious-
ness. Volition however only interferes for the rejection or acceptance of
the food taken into the mouth, and is not required for the minute direction of
the movements of mastication and deglutition. The muscular sensibility of
the tongue, and therefore our voluntary control of its movement, is extremely
slight, although there must lie a continual flow of afferent impressions from
the tongue to the lingual motor centres to guide the complex movements both
ot mastication and deglutition. In the case of the palate muscles, as of the
oesophagus, muscular sensibility is not highly developed.
It has been suggested that afferent impressions from the muscles can play
only a subordinate part in our sensations of movement, since we are not
aware of the part taken by each individual muscle in any given move-
ment. Such a statement is absurd. We have no objective phenomenal
experience of our muscles. All that we are aware of and can judge of by
our other senses is the movement as a whole, and our sensation of move-
ment is therefore referred to the whole movement and not to the individual
muscles.
The sensations arising in the proprioceptive system can be divided
into two main classes :
(1) The sensation of the relative positions of parts of the body.
(2) The sensations which inform us of the position of the head, with
regard to its surroundings, i.e. with regard to the direction of the pull of
gravity. (It must be remembered that ' downwards ' always means towards
the centre of the earth. ' upwards ' away from the centre of the earth, i.e.
osl the gravitational forces.) This orientation sense depends on the in-
tegrity of a special sense organ contained in the labyrinth of the internal
ear. It is therefore sometimes spoken of as the labyrinthine sense.
THE SENSE OF RELATIVE POSITION, INCLUDING THE
MUSCULAR SENSE
Without using our eyes we are able at any moment to t ill the position of
our limbs. If one arm be moved passively into any position we can without
difficulty move the other arm into an exactly similar position. We thus
know the extent to which we move the limb and the static position attained
as the result of the movement. If the movement is resisted, we are able to
adjust the force of the muscular contrail ion to the resistance, and to form
therefore a fair idea as to the strength of the resistance.
(«) PASSIVE" MOVEMENTS. A large uumbei of differenl sen-.- organs
contribute to the formation of these judgments. In the appreciation of
648 PHYSIOLOGY
passive movement t be chief end organs involved are those in connection with
the joints and their ligaments, though it is probable that the deeper sense
organs in the soft parts around the joints also contribute to the total sensa-
tions. Cutaneous sensations apparently play hut little part in the judgments
of passive movement. It is true that the alternating movements of the hind
limbs, which occur in a spinal animal when it is held up by the hands under
the fore limbs, are started, partly at any rate, by the stretching of the skin
of t he thighs ; but t his effed is one rather of initiation of movement, and can
hardly be regarded as proprioceptive in character.
The strength of the sensation of passive movement depends on the
extent of the movement as well as on the rate with which it is carried out.
The delicacy of perception varies in different joints. Thus in some joints
a movement of 025° per second is appreciated as a movement, while in other
joints the movement must be as extensive as T4° per second. It is more
easily appreciated when the joint surfaces are pressed together than when
thev are pulled apart, showing that the nerve-endings in the joint surfaces
play a part in the origination of the sensations.
(b) THE SENSE OF MOVEMENT (MUSCULAR SENSATION). This term
is applied to those sensations by which we judge of the extent and force of
any active movement which we may have carried out. Many authors have
ascribed an important part in this act of judgment to the so-called ' sense of
innervation,' i.e. a sense of the actual energy which is being discharged
from the motor cells of the central nervous system to the muscles, and have
thought that when we raise a weight we judge of its amount, not by the
degree of stretching of the muscle or pressure on sensory nerves in the muscle,
but by the amount of force we voluntarily put out to raise the weight. The
fact however that we can judge of weights, when the muscles are made to
contract by electrical stimuli and not by voluntary impulses, shows that this
sense is in large part, if net entirely, peripheral. It is however very com-
plex in nature, and is served by a whole array of different end-organs in
the skin, joints, tendons, and muscles. The muscles themselves are known
to be well supplied with afferent nerves. Stimulation of the central end
of a muscular nerve may reflexly excite or inhibit movements of other
muscles. Sherrington has shown that, after section of the motor roots,
over one-third of the fibres in a muscular nerve remain undegenerated,
provmg their connection with the posterior root ganglia. The sensory nerve-
endings in the muscle are represented partly by the tendon nerve endings
and partly by the muscle spindles. The former are richly branched end
arborisations of nerve fibres on the surface of the tendon bundles. The
muscle spindles consist of one or more muscle fibres, often continuous with
normal fibres, enclosed in a sheath composed of several layers of fibrous
tissue with intervening lymph spaces. One or more nerve fibres pierce this
sheath and, after making many spiral turns round the muscle fibres, branch
freely and terminate in little knobs on the surface of the fibres (Figs. 321, 322).
The cross striation of the muscle fibres within the spindle is but faintly
marked. It is evident that the continuity of these sense organs with the
SENSATIONS OF MOVEMENT AND POSITION 649
contracting muscle ensures in the best possible way that the organs should
lie affected by the slightest change of tension of the muscle, and should
Fig. 321. A neuromuscular spindle of the cat. (Botfini.)
c. capsule: pr.e, primary ending; s.e. secondary ending; pl.e, plate ending
(all these are probably sensory in function).
Fig. 322. Part of a muscle spindle more highly magnified.
n, nerve fibres passing to spindle ; a, annular endings "I axis cylinders ; s. spiral
endings ; d. dendritic endings ; sh, connective-tissue sluyth of spindle. (Kcffini.)
transmit information of the state of tension to the central nervous system.
THE PSYCHOLOGICAL SIGNIFICANCE OF SENSATIONS OF MOVE-
MENT. Not only are these organic sensations of importance as affording
us information of the condition of our own bodies as distinct from the objects
in the world around, but they enter into and qualify our judgments derived
from all the sensations which arise in the special sense organs.
When we regard the continuous aimless activity of a healthy baby, we
3ee i hat all ideas of space, of extension, of relative position arc wanting, or at
any rate are not present to guide the movements. Hit by bit muscular
experience is acquired. The child learn- thai a given movement of the right
arm will bring the hand in contact with something which is exciting the left
side of the retina. The surface of the thing, if of sutlicient extension, can
excite tactile sensations in all the fingers of the right hand. By inovin;
finger over the object the tactile sensations are found to be continuous: by
moving the whole hand forwards the thing is found to po extension in
650 PHYSIOLOGY
a direction away from the body, and therefore in the third plane of space.
Thus gradually are acquired not only ideas of extension, distance, and space,
but certain movements are correlated with stimulation of definite regions
of the skin or of the retina. Tactile and retinal impressions therefore acquire
local sign, and power is acquired of moving the limbs to a degree and in a
direction adapted to stimuli arising from any part of the tactile or retinal
surfaces. The child gradually acquires the power of following a bright
object with its eyes, i.e. of contracting the ocular muscles so as to keep
the retinal image of the object on the fovea centralis, and up to adult age
we are still engaged in this balancing of muscular movement against sense
impressions — a balancing in which the muscular sensations are the constant
guide and criterion of success. Only by the muscular sensations are we
informed whether our willed movement has been carried out or not. It
is in virtue of the muscular and allied sensations that we are able to clothe
our visual and tactile sensations with properties of extension, solidity, and
resistance, which create them in consciousness as parts of a material world.
PART VIII
THE LABYRINTHINE SENSATIONS
Throughout almost the whole of the animal kingdom, and in practically
all freely moving metazoa, we find a sense organ which has often been
designated as an auditory organ. This organ, which is situated in the integu-
ment, is in the form of a small sac generally open to the exterior, and lined
by cells provided with hairs and richly supplied with nerves. Resting among
the hairs is a small concretion, generally of carbonate of lime, which is known
as an otolith. These sacs have generally been regarded as auditory in
function, hence the term otolith applied to the concretion. The evidence
for audition, i.e. the power of appreciating vibrations in the elastic medium
surrounding them, is scanty. Thus in fishes this power has been stated to be
absent unless the vibrations are of sufficient amplitude to affect the sense-
organs of the skin* On the other hand, there is evidence that these otolith
organs are connected with equilibration. Section of the nerves going to them
in the crayfish causes disturbance of locomotion. Steinach has succeeded
in the crayfish in replacing the concretion by a small particle of iron. The
animal's behaviour and movements were perfectly normal until it was
brought within a powerful magnetic field. Under the influence of this.
field the effect of gravity on the iron particle was annulled and replaced by a
force of attraction in another direction, and the effect was at once seen as
pronounced disorders of locomotion, the animal swimming in an abnormal
position.
From a sac, such as that present throughout the lower animals, the organ
of hearing in the hi«her vertebrata is developed. Arising as a pit in the
epiblast in the neighbourhood of the hind-brain, the auditor} - sac becomes
shut off from the exterior, and then, by an outgrowth in various directions,
forms the complex membranous labyrinth of the internal ear. This mem-
branous labyrinth, as we have seen, can be divided into two parts, viz. the
canalis media of the cochlea in front, and the saccule, utricle, and semi-
circular canals behind. The canalis media of the cochlea is concerned with
the reception and analysis of sound waves. In the lower vertebrates in
which auditory sensations are wanting the cochlea is absent, and in fishes
is represented merely by a small diverticulum known as the lagena. With
the development of air-breathing vertebrates we see the first signs of a special
organ of hearing. Thus a primitive cochlea is present in the amphibia, and
especially in the anura, and in some of the reptiles as well as in birds it,
acquires a bend and shows the beginning of a spiral arrangement. Only in
the mammals does it attain a degree of development at all comparable with
* Piper, however, has detected an electrical variation in the eighth nen
fishes in response to a sound stimulus.
651
652
PHYSIOLOGY
that found in man. and characterised by the formation of one and a half
to four spiral turns in the cochlea as well as in the canalis media.
This development of auditory functions cannot involve any abrogation
of the important part played by the otolith organ throughout all the lower
classes of the animal kingdom. In man. as in the crayfish, it is the otolith
organ which determines his behaviour in relation to the force of gravity,
and is therefore responsible not only for the maintenance of equilibrium
but also for the sensations which enable him consciously to orientate himself
and to know the position in which he happens to be at any given moment.
With the increasing import-
ance of visual sensations in
determining the behaviour
of the animal, (lose connec-
tions are established be-
tween the central connec-
tions of the nerves running
from the otolith organ and
the parts of the brain con-
cerned with the innervation
of the eye muscles. By
this means the position of
the eyes is constantly adap-
ted to the position of the
head.
The auditory part of the
internal ear has already been
described. That part of the
labyrinth which represents the
primitive otolith organ consists
of a bony framework containing
perilymph, in which is contained
the membranous labyrinth with
the endings of the vestibular
division of the eighth nerve.
The osseous labyrinth consists
of a cavity, the vestibule, into
which open behind the three bony semicircular canals. In the vestibule are con-
tained two little membranous sacs, the utricle and saccule, the cavities of
which are connected by means of the saccus enddymphaticus. Into the utricle
open the three semicircular canals, the three canals having five openings. These semi-
circular canals are arranged in three planes.eaeh of which is at right angles to the other
two, so that in the organ are represented the three planes of space. We may distinguish
on e ne canal can be affected by and trans-
mit the sensation of rotation about one axis in one direction only : and for
complete perception of rotation in any direction about any axis six semi-
circular canals are required in three pairs, each pair having its two canals
parallel (in the same plane), and with their ampullae turned opposite ways.
Each pair would thus be sensitive to any rotation about a line at right angles
to its plane or planes, the one canal being influenced by rotation in the one
direction, the other by rotation in the opposite direction " (Crum Brown).
These reflex movements of head and eyes are the invariable result of move-
ments set up in the endolymph, and occur equally well in the absence of
the cerebral hemispheres. If an animal or man be placed on a turntable
and rotated, his first tendency will be to turn his head and eyes in the opposite
direction to that of rotation in order to preserve fixation. If the rotation
be continued, the endolymph gradually takes up the movement of the sur-
rounding parts of the head, and if the eyes be closed, no movement of head
or eyes is observed. If now the rotation is stopped, the endolymph will tend
to go on moving, and the effect will be the same as if a movement of rotation
were suddenly begun in the opposite direction. Head and eyes will now be
turned, without any voluntary impulse, in the direction of the previous
rotation, and in consciousness there will be an actual sensation of rotation
in the opposite direction. This sensation is in opposition to the sensations
derived from other parts, and hence the feeling of giddiness and the actual
disorders of equilibrium which are its concomitants.
That this feeling of giddiness on rotation is due to impulses started in the
semicircular canals is shown by the fact that, in a large number of deaf-mutes
where these organs are imperfectly developed, it is impossible to produce
giddiness and the associated eye movements by passive rotation.
THE FUNCTION OF THE OTOLITHS
The semicircular canals are, as we have seen, a higher development of
the otolith organ. The primitive part of this organ is represented by the
maculae in the utricle and saccule. It is to these organs that we must
ascribe our powers of appreciating the static position of the head, as well
as, to a slight degree, movements, not of rotation, but in one plane forwards
or 1 uick wards.
A consideration of the structure of the otolith organ shows at once that
the incidence of the weight of the otoliths on the hairs of the macula will vary
according to the position of the head. Thus in the diagram (Fig. 2C0, p. 397)
in a (normal jwsition) the chief weight of the otolith falls on the hairs from
b in c whereas, when the head has been rotated round a right angle so that
the man, for instance, is lying on his right side, the chief weight of the otoliths
will tall on the hairs at c. The nerve-endings stimulated by the weight of the
otoliths will therefore vary according to the position of the head. The cere-
bellum and its associated structures represent a mechanism for the regulation
of the movements of the trunk as a whole and the position of its centre of
gravity in relation to the position of the head.
BOOK III
THE MECHANISMS OF NUTRITION
12
CHAPTER IX
THE EXCHANGES OF MATTER AND ENERGY
IN THE BODY
GENERAL METABOLISM
All the energy which leaves the body as heat 01 work is derived from
processes of oxidation, the carbon, hydrogen, nitrogen, and sulphur of the
art's uniting with oxygen in the body and being eliminated iu the form
of carbon dioxide, water, urea and allied substances, and stdphates. Iu a
starving animal this discharge of energy must be associated with a loss of
body substance. The necessity for taking food is determined by the need of
replacing this loss. The foodstuffs cannot, like the coal or fuel of a steam-
engine, be utilised directly as a source of energy, but must be built up to a
_iee into the structure of the living protoplasm. The total
amount of living material in the body, though maintained fairly constant
in the adult animal, may yet undergo alterations under varying conditions.
and these alterations are naturally more marked in the growing animal. We
have in this chapter to inquire into :
(1) The nature and amount of the sul ch may serve as food-
si art's and are necessary for maintaining the weight of the body constant or
providing for its growth;
The relation between the total amount of material taken up by the
body and the total amount given out ;
(3) The variations iu the total chemical exchanges determined by
variations in the output of energy by the body; and
(4) The significance of the vat iss - of foodstuffs as sour.
energy and in the replacing of tissue was
We have therefore to make balance-sheets of two kinds, namely : (1) an
accurate comparison of the ingests (food and oxygen) aud the egesta (carbon
dioxide, water, urea, el - showing the amouut of potential
energy introduced into the body compared with the amount of energ
free iu the body.
SECTION I
METHODS EMPLOYED IN DETERMINING THE
TOTAL EXCHANGES OF THE BODY
The determination of the material exchanges of the body involves an
accurate comparison of its income and output. The income consists of the
foodstuffs and oxygen. The foodstuffs may be divided into two classes,
namely, (1) the organic foodstuffs, which on oxidation may serve as sources
of energy, and (2) the inorganic foodstuffs, such as salts and water.
The latter class neither add to nor subtract from the total energy of the
organism, but their presence is a necessary condition of all vital processes,
and as they are contained in the various excreta a corresponding amount
must be present in the food hi order to make good this loss.
In spite of the bewildering complexity of the nature of the foods taken
by man, their essential constituents can always be assigned to the three
classes, proteins, fats, and carbohydrates, and any analysis of the food must
give the relative amounts present of these three classes of substances. The
approximate analysis of the foodstuffs presents little difficulty. The '
nitrogen is determined by Kjeldahl's method. The figure thus obtained
is multiplied by the factor 6-25, and the resulting figure is taken to represent
the total protein in the food. Of course such a valuation may give too high
a value when the foodstuff is one that is rich in nitrogenous extractives.
The total fat is determined by extracting the food in a Soxhlet apparatus
with ether. It is advisable to precede this extraction by an extraction with
boiling alcohol. The total ethereal and alcoholic extract obtained is reckoned
as fat. The amount of water is determined by drying the foodstuffs at
110° C, and the amount of inorganic constituents by ashing the dried
remainder. Carbohydrates may be determined directly by boiling the food
with dilute acids in order to convert all its disaccharides and polysaccharides
into hexoses, which are then reckoned as glucose, and estimated by their
copper-reducing power. In most cases however, the total protein, fat, and
ash are subtracted from the dried weight of the food and the remainder is
taken as carbohydrate.
Although the methods for the analysis of foodstuffs are by no means difficult,
the total analysis of the food during a metabolism experiment may become extremely
tedious on account of the very large number of analyses which have to be performed.
The labour is lightened by the fact that nearly all the ordinary foodstuffs have been
subjected to analysis and their average composition published by the Agricultural
Board of the United States. Since however the foods vary in composition, especially
in water content, from time to time, a calculation of the total income of proteins,
660
THE TOTAL EXCHANGES OF THE BODY 661
fats, and carbohydrates from data given by workers in other lands must present a
considerable margin of error. In order to attain greater accuracy, some observers
have made in the form of biscuits or of preserve a complete food which is prepared
in large quantities at the beginning of the experiment and used as the sole diet through-
out the experiment. Pfliiger, for instance, converted the horse-flesh, witli which he
desired to feed his dogs in a metabolism experiment, into sausage meat which was
sealed up in cases and sterilised. The sausage meat having been analysed at the
beginning of the experiment, it was only necessary thereafter to weigh the amount
eaten by the dog in order to know accurately the total amount of protein, fat, and
carbohydrate ingested by the animal. In experiments on man it has been endeavoured
to obtain the same result by limiting the food to a few articles of diet which could
be accurately analysed in each case. The monotony of such a diet tends to interfere
with the success of the experiment, since the subject of the experiment loses his appetite
and his processes of nutrition are not normally carried out. It is usually possible to
steer a middle course between the two extremes of too much and too little variation
of diet, and so to obtain values for the composition of the ingesta wliich cannot differ
very largely from their true composition.
The material output of the body consists of the products of combustion
of the foodstuffs, which are turned out by the various channels of excretion,
namely, the kidneys, the alimentary canal, the lungs, and the skin. These
excreta must therefore be collected and analysed. In addition to the main
sources of excretion, small quantities of material are lost by the shedding
of the cuticle, by the growth and cutting of the hair and nails, and so on. In
most cases the losses in this way are so small that they may be disregarded.
The nitrogen of the foodstuffs and that derived from the disintegration of
the tissues of the body is excreted almost exclusively in the urine, a small
amount being thrown out by the alimentary canal. The total nitrogen must
be therefore determined both in the faeces and in the urine. The nitrogen in
the faeces is derived from two sources. Part represents those nitrogenous
constituents of the tissues which have resisted the digestive processes of the
alimentary canal. There is in addition a certain amount derived from the
intestine itself. During complete starvation faecal masses are formed in the
intestine, and it has been calculated that in a normal individual about one
gramme of nitrogen a day is excreted by the mucous membrane of the gut and
contributes to the formation of the faeces. It is usual therefore to regard
one gramme of the nitrogen of the faeces as belonging to the output of the
body and representing the result of nitrogenous metabolism, while the
balance is taken as belonging to undigested foodstuffs, and is subtracted
from the total nitrogen of the latter in reckoning the real income of the body.
A small amount of nitrogen is also lost by sweat, but this can be disregarded
unless the sweating is profuse, when the loss of nitrogen by this channel may
rise to as much as 4 per cent, of the total nitrogenous output of the body.
Although a trace of ammonia has been described as occurring in the expired
air, the amount is so minute that any loss of nitrogen by the lungs can be
neglected. That the loss both by lungs and skin under ordinary circum-
stances can be disregarded is shown by the fact that it is possible to account
directly for the whole nitrogen of the body by a comparison of the compo-
sition of the food with that of the urine and faeces. If. lor instance, an animal
is kept on a sufficient diet wliich contains a, perfectly regular amount of
662
PHYSIOLOGY
nitrogen, after a few days a condition known as nitrogenous equilibriumia set
up, i.e. the total nitrogen of fares and urine is exactly equal to the total
nitrogen of the food. The same thing applies to the alphur, as is shown
in the following Table (quoted by Tigerstedt) :
Days of Nitrogen
experiment oi food
Nitrogen Percent,
excrel ed differ mce
Sulphur
3ted
Sulphur
excreted
1-7 . . j 154-81
8-17 . . 213-72
153-02 - 0-51
213-2G - 0-21
12-77
12-79
In order to express the nitrogenous metabolism in terms of protein,
we use the factor employed in estimating the amount of protein in the
food, i. e. we multiply the total nitrogen of the excreta by 6-25. This will
give the total protein which has been broken down during the period of the
experiment. Much more important from the energy standpoint is the deter-
mination of the total processes of oxidation of the body, information on
which is given by a comparison of the oxygen intake with the output of
Fig. 327. HaklanePembrey respiration apparatus,
c, chamber for animal; M, gas meter.
carbon dioxide and water. The estimation of these substances presents
much greater difficulties than the investigation of the nitrogenous exchange
and involves the use of some form of respiration apparatus.
The following are the chief methods which have been employed for this purpose :
I. THE METHOD OF HALDANE. This method is extremely convenient when
dealing with the gaseous exchanges of small animals, such as mice, rats, guinea-pigs
or rabbits. The animal is placed in the chamber c, which may be simply a wide-
mouthed bottle (Fig. 327). This chamber is supplied with a thermometer, and can
be kept at any desired temperature by immersion either in warm or cold water. On
the inlet side of the bottle is a series of tubes or bottles, some of which contain
sulphuric acid and pumice-stone, while the others contain soda lime. On the outlet
side of the vessel is a corresponding series of vessels for the absorption of water and of
carbon dioxide. On the further side of these vessels is a gas meter. During an ex-
periment air is sucked through the whole apparatus by means of an aspirator or a water
pump, the amount of air passing through the apparatus being measured by the meter.
The animal is thus supplied with pure air freed from water vapour and from carbon
dioxide. Any water or carbon dioxide produced by the -animal is absorbed by the
vessels interposed in the course of the outgoing air. These vessels are weighed at the
beginning of the experiment and at the end, and the difference in weights will there-
fore give the amounts of carbon dioxide and water which have been discharged by
the animal.
The intake of oxygen by the animal is determined indirectly. Since it gives off
THE TOTAL EXCHANGES OF THE BODY 663
only carbon dioxide and water, and absorbs only oxygen during its stay in the chamber,
the loss of weight of the animal during its stay in the chamber, subtracted from the
total amount of carbon dioxide plus water it gives off, will represent the amount of
oxygen absorbed.
The advantage of this apparatus is that it can be fitted up in any laboratory, and
is accurate for the purposes to which it is applied. It is not however appropriate
for long-continued experiments or for experiments on larger animals or on man
himself. Most of the data with regard to the respiratory exchange under various
circumstances have therefore been obtained by one of the following methods.
II. THE METHOD OF REGNAULT AND REISE-T. The principle of this method
consists in placing the animal th.at is to be the subject of investigation in a closed
chamber containing a given volume of air. The carbon dioxide produced by the animal
is absorbed by means of caustic alkali, and the oxygen consumed by the animal is made
good by allowing oxygen to flow into the chamber from a gasometer. The inflow of
oxygen is regulated so as to keep the pressure of air in the chamber constant. At
the end of the experiment the alkali is titrated and the amount of carbon dioxide
absorbed thus determined. The air in the chamber is also analysed so as to be certain
that it contains an excess neither of carbon dioxide nor of oxygen. The amount of
oxygen absorbed by the animal is known already, the oxygen which has been allowed
to flow in having been measured.
A modification of this method has
been devised by Benedict and is espe-
cially applicable to clinical purposes.
In this method the individual who is
the subject of the experiment breathes
through a nose-piece into a wide metal
tube, the mouth being kept closed.
The metal tube forms part of a closed
system through which a current of air
is maintained by means of a pump. In
the course of the current of air are. inter-
posed vessels for the absorption of
carbon dioxide and of water, and the
volume of gas in the system is main- Fig. 32S. Air circuit in Benedict's respiration
tained constant by admitting oxygen apparatus.
to it in proportion as the oxygen of
the system is used up in respiration. In Fig. 32S is given a diagrammatic
scheme of the air circuit, and in Fig. 329 a diagram of the arrangement of the whole
respiration apparatus, showing the nose-piece for breathing, the tension equaliser,
the air-purifying apparatus, and the oxygen cylinder. The tension equaliser, a, is
attached to the ventilating pipe near the point of entrance of the air into the lungs.
It consists of a pan with a rubber diaphragm (which may be conveniently made from
a lady's bathing-cap). As the air is drawn into the lungs the rubber diaphragm sinks.
to rise again with expiration. The respiratory movements can thus proceed without
altering appreciably the pressure within the closed system of tubes. By the admission
of oxygen the supply of oxygen is adjusted so as to keep t he bag from becoming either
too much distended or too much flattened. As the air leaves the lungs and passes
into the constantly moving current of air, it is carried along by the pump and flows
through two Wolff's bottles containing strong sulphuric acid and pumice for the remova 1
of water vapour. It then passes through a brass cylinder, c, filled with soda lime
for the absorption of carbon dioxide. From here it passes again through sulphuric
acid in a Kipp generator for the absorption of water given off by the soda lime. Since
the air so deprived of moisture would be uncomfortable to breathe, it is then carried
through another Kipp generator containing water with a trace of sodium carbonate
for the neutralisation of any acid fumes which may be given off by t bi sulphuric acid.
It then passes back to the tube from which the subject is breathing. In this way it is
possible to determine very accurately the amount of oxygen used up and the amount
664
PHYSIOLOGY
of carbon dioxide given off in the course of an experiment lasting one to I luce hours
or longer. The oxygen consumption is measured by weighing the cylinder of this
gas, chosen small for this purpose, before and after the experiment.
III. PETTENKOFER'S METHOD. In the apparatus designed by Pettenkofer
the animal or man was placed in a chamber through which a constant current of fresh
air was passed. The amount of air passing through the chamber was measured by
means of a meter. Throughout the experiment continuous samples both of the air
entering the chamber and of the air leaving the chamber were taken. The analyses
of these samples served to show the composition of the whole air entering and leaving
the chamber, and therefore the changes in the air caused by the presence of the animal.
The advantage of this apparatus is that an adequate ventilation can be kept up, and
the apparatus can be built of any size. In the apjiaratus of Tigerstedt built on this
plan the'eharnber had a capacity of 100-6 cubic metres, and was, in fact, a small room.
A small respiratory apparatus has been built by Atwater.
IV. ZUNTZ AND GEPPERT'S
l\lj?| (~~~~\ METHODS. For many purposes the
*g* ' methods'devised by Zuntz and Geppert
present many advantages, especially
when it is desired to'take the respiratory
exchanges in man or any animal during
a limited period of time. The subject of
the experiment has his nostrils clamped
and breathes into and out of a face-
piece. This face-piece is provided with
valves either of aluminium or of animal
membrane, which serve to separate the
in-going from the out-going current
of air. In the course of the out-going
current is placed a very delicate gas
meter which presents practically no
resistance to the air current. A branch
from the efflux tube passes to a gas
analysis apparatus. By an ingenious
method it is arranged that an abquot
part of the whole of the out-going air is
drawn off into this apparatus, so that
the experiment can be interrupted at
any time, and the analysis of this sample
will give the average composition of the
expired air, and therefore, on multipli-
cation by the total gas passing through
the gas meter, the total output of
carbon dioxide during the course of the
observation. One advantage of this method is that the apparatus is portable, and can
be applied to the investigation of the respiratory exchanges of patients in hospitals
or of man or animals while they are walking about. It has been used, for instance,
by Zuntz and his pupils in an interesting series of researches on the gaseous metabolism
of men at high altitudes.
V. THE DOUGLAS BAG. By far the most convenient method for estimating
the respiratory exchanges of man under varying conditions is the use of the Douglas
Bag. Li this method the subject for experiment breathes through a mouthpiece
provided with valves into a bag of about 100 litre capacity. The valves are so arranged
that he inspires from the external air and expires into the bag. After from two to
ten minutes the bag is removed, the time being accurately noted. The amount of
air expired during this time is measured by emptying the bag through a gas meter.
A sample of its contents is analysed and the oxygen and f :0 2 in it determined. Since
the composition of the external air is known, the analysis and measurement of the
Fig. 329. Arrangement of apparatus in
Benedict's method for determination of
respiratory exchange.
N, tubes inserted into nostrils of patient ;
A, tension equaliser; c, cylinder contain-
ing soda lime for adsorbing C0 2 .
THE TOTAL EXCHANGES OF THE BODY
605
expired air gives the respiratory metabolism during (lie time of the observation.
The bag is carried on the back of the individual, so that it does not interfere with his
movements. This method has been used for determining the metabolism of soldiers
in training, of munition workers, etc.
By means of one or more of these methods we may arrive at a correct
idea of the total income and output of an individual for periods of many
days. The following details by Tigerstedt may serve as an example of the
results obtained in such an experiment. The experiment lasted two days.
The subject was a man of twenty-six years of age, weighing about 65 kilos,
who had previously taken no food for five days. The following Tables
represent his material income and output.
Corrugated
Side tube for
sampling (with dtp)
Fig. 330. Douglas' Big for determining respiratory exchange in man.
Total Income
Total
amount
N.
• Water
i
£
Fat
Of
Ash
<
Bread .
373
7-3
36
337
46
4
278
9
Butter
388
0-4
37
.■;;, i
3
337
4
7
—
Cheese
110
4-3
56
60
27
35
—
5
—
Salt meat
26
1-1
16
10
9
—
2
—
Milk .
2313
11-3
2047
266
71
85
95
16
—
Broth .
658
11-8
580
78
74
—
—
9
Beer
1413
1-2
1273
77
8
—
67
3
."id
Beef steal;
7(10
20-6
533
167
129
33
7
Potatoes
152
Oil
359
93
1
82
5
Water .
2:!.'!r>
59-3
2335
371
I!I7
525
61
59
Totals .
8773
831-6
72::.
1439
066
PHYSIOLOGY
Total Output
Total
a: i
N.
c.
Water Solids
Protein Fat
Carbo-
hydrate
Asli
21
15
Respiration .
Urine .
Fteces .
2701
2564
455
41-5
4-8
453-0
32-5
43-8
2248 —
2490 —
363 91-6
30 20
27
Totals . . 5720
46-3
529-3
510] 91-6
30 20
27
36
As we should expect in a man who had previously fasted five days, this
balance-sheet shows a marked retention of the food taken in, i. e. a marked
excess of income over output. Thus of the nitrogen ingested, 13 grrn., which
is equivalent to 81-3 grm. of protein, was retained; of the carbon, 302 grm.
was retained. Of this 302 grm., 42-7 grm. would be contained in the 81-3
grm. of protein, so that the rest of the carbon, namely, 259-6 grm., was
probably laid down in the form of fat. This would correspond to 339 grm.
of fat. Of the salts contained in the ash of the food, 25 grm. were retained
in the body. The carbon and nitrogen reappearing in the excreta serve as
an index of the amount of metabolism of the foodstuffs which had occurred
during the two days. In order to supply the energy requirements of the
body during the time of the experiment, 498 grm. of carbohydrate, 59 grm.
of alcohol, and 138 grm. of fat had been completely oxidised. The amount
of protein used up during this time can be obtained by multiplying the
nitrogen of the urine plus 1 grm. of nitrogen of the faeces by the factor 6-25,
and is found to amount to 271-9 grm.
THE ENERGY BALANCE-SHEET OF THE BODY
The energy income of the body is measured by the potential energy of the
foodstuffs, i. e. the amount of energy which can be evolved, either as heat,
work, or in any other form, by the oxidation of the foodstuffs to the end-
products which occur in the body. Since it is convenient to have a uniform
method of expressing the total potential energy of a foodstuff, we generally
express it in calories, and speak of the heat-value of a foodstuff. The
heat value of any given food is the amount of large Calories 1 which it
evolves on complete combustion with oxygen, and is determined by burning
a weighed quantity of the dried foodstuff in oxygen in the bomb calorimeter.
The following heat values have been obtained for different foodstuffs :
Substance
Lean meat
Lard
Butter .
Grape sugar
Cane sugar
Starch .
Heat value
5-656 (or 5-345 Rubner)
!)-423
9-231
3-692
4-116
4191
1 A calorie is the amount of heat necessary to raise a gramme of water from 15° C.
to 16° C. A large Caloric (printed with a capital C) is the heat required to raise a kilo-
gramme of water from 15° C. to 16° C, and is therefore equal to 1000 small calories
THE TOTAL EXCHANGES OF THE BODY 667
In the case of some foodstuffs it is necessary to draw a distinction
between the absolute heat value and the physiological heat value. Since
carbohydrates and fats undergo complete oxidation in the body to carbonic
acid and water, their physiological heat values, i. e. the values of these food-
stuffs to the organism, are identical with their absolute heat values. Pro-
teins however do not undergo complete oxidation. When they are oxidised
in the bomb calorimeter the nitrogen is set free in a gaseous form. In the
animal body no nitrogen is eliminated in the gaseous form, the whole of it
being excreted as nrea and allied substances still endowed*with a considerable
store of potential energy, which can be set free when their oxidation is com-
pleted in a calorimeter. In order to determine the physiological heat value
(if protein, we must subtract from its absolute heat value the heat value of
the excretory products in the form of which it leaves the body. The
physiological heat value of proteins has been determined by Eubner in the
following way : A dog was fed with the same protein which had served for
the determination of the absolute heat value. AYhile the dog was receiving
this food its urine was collected, dried, and its heat value determined by
combustion in the calorimeter. It was found that for each gramme of
protein which had undergone disintegration in the body an amount of urine
was passed corresponding to a heat value of 1-0945 Calories. The heat value
of the faeces formed under the same diet was 0-1854 Calorie for each gramme
of protein. Eubner further reckoned that a certain amount of heat would
be required for the solution of the proteins and of the urea, and reckoned
this at 0-05 Calorie. The reduced or physiological heat value of protein is
therefore equal to 5-345 - (1-0945 + 0-1854 + 0-05) = 4-015 Calories.
A determination of the heat values of the various foodstuffs shows
minute differences between individual members of the same class. Since it
is impossible to reckon out accurately the relative amounts of the different
kinds of protein, carbohydrate, etc., contained in each diet, Eubner has
calculated the average physiological heat values of the three classes of food-
stuffs. These figures have been universally adopted, and are as follows :
1 grin, protein = 4-1 Calories
1 grm. fat = 9-3 „
] grin, carbohydrate = 4-1 ,,
These figures are accurate only for a diet containing the normal pro-
portion of vegetable to animal foods — 60 to 40. The heat value of vegetable
protein is. as a rule, less than that of animal protein. It has been pointed
out that these figures are rather too low for the food as ingested and too
high if taken to represent food as digested. Taking the normal mixture
of foods used in civilised countries, the following figures give more accurately
(he energy available from any given diet (allowing for the loss in digestion) :
Carbohydrates Proteins Fats
4 Calories per gramme 4 Calories per gramme 8-9 Calories per gramme
Careful experiments have shown that just as there is no loss of matter
in the body, so also the sum of the energies put out by the body is equal to
the sum of the energy obtained by the oxidation of the tissues and of the
068
PTTYSIOLOCiY
foodstuffs in the body during the same time. In an earlier chapter I have
quoted the results of an experiment by Rubner on a dog, which demonstrated
this equivalence, as proving the important fact that the fundamental
doctrine of the Conservation of Energy applies to the organised as to the
inanimate world. Similar results have been arrived at by Atwater in a
series of experiments with a special calorimeter on man. It may be sufficient
heTe to give the figures from one such experiment :
a
b
c
d
c
f
g
h
'
Date
Culs.
( als.
(ills.
Cals.
Cals.
Cals.
Cals.
Cals,
,
Dec. 9-10
2519
IK)
142
-85
+ 3
2349
2414
+ 65
+2-8
10-11
2519
110
133
-25
-44
2345
2386
+41
+ 1-7
11-12
2519
110
132
-21
-93
2391
2413
+ 22
+0-9
12-13
2519
110
133
-14
-55
2345
2375
+ 30
+ 13
Total 4 days
10,076
440
540
-145
-189
9430
9588
+ 158
Average one day
2519
110
135
-36
-47
2357
2397
+40
+ 1-7
a
a
•s
S +
3 °
•a —
6 +
If-
+|
SS
+|
3
-a
&
3
S
3
.3
|
l~+
•3
c
It
•3 S
It
-
5 ■
Sfe
l S
h' 5 -
§■§-
■3
■3 £**
iS ° M
If we take into account the great difficulties of such an experiment, we
cannot but be impressed with the closeness of agreement between the total
output of energy reckoned as heat and measured by the warming of a given
volume of water and the total income of energy as estimated from the
chemical reactions involved in the metabolic changes which had taken
place during four days of the experiment. The important result which
comes out in such experiments is that the foodstuffs produce the same
amount of energy when oxidised in the body as when burnt to the same
end products outside the body, so that it becomes easy in any given research
to sum accurately the energy income of the body.
The Atwater calorimeter has been improved to such an extent by Bene-
dict and his fellow-workers that it has practically replaced all other forms
for physiological purposes. It consists of a room or chamber with double
non-conducting walls. All round the inner wall of the room are fitted coils
of pipes through which a stream of water flows. The pipes are fitted with
discs so as to take up rapidly heat produced in the room. The current of
water is accurately adjusted so as to maintain the temperature of the inner
wall constant. As the inner wall and outer wall are kept at the same tem-
perature, no heat is lost to the exterior, the whole of the heat produced by
THE TOTAL EXCHANGES Of THE BODY
669
the animal or individual in the chamber being communicated to the water
passing through the chamber. The temperatures of the entering and leav-
ing water are taken by accurate thermometers reading to a hundredth or a
thousandth of a degree Centigrade. Knowing the amount of water that has
passed through in a given time and the difference in temperature during the
same time, it is easy to calculate the amount of heat given off by the animal
under investigation. It is generally convenient to maintain a constant
difference of temperature between the entering and leaving water by appro-
priate adjustment of the amount of water passing through the apparatus.
The equality of temperature between the inner and outer casing is recorded
Oxygen enters .'
Flu. 331. Diagram to show the principle of the Atwater-Benedict calorimeter.
(After Halliburton.)
by electric themio couples, any difference of temperature being at once
compensated by electrically warming the cooler part. The chamber con-
tains a bicycle or other arrangement for the performance of mechanical
work. It is adequately ventilated by a current of air passing through an
apparatus similar to that of Benedict, described on p. 663. It is thus
possible to estimate simultaneously the total heat production of an individual
as well as the respiratory changes, including both carbon dioxide output
and oxygen intake. The general principle of the calorimeter is shown in
the diagram (Fig. 331). The calorimeter is also supplied with bed, table,
chair, etc., and food can be introduced through a double window so that
an experiment may be continued over two or three days on one and the
same individual.
SECTION II
METABOLISM DURING STARVATION
It will tend to simplify our task if we deal first with the results of the
experiments which have been made on the metabolic exchanges of animals
during starvation, i. e. during a period when the whole energy involved in
the maintenance of the movements of respiration and circulation, and in
the maintenance of the body temperature, etc., is derived from the animal's
own tissues. It must be remembered that the tissues of an animal comprise
two distinct classes. In the first class must be placed the living machinery
of the body, generally composed of proteins or their near allies. In the
second class are the fatty tissues of the body, which form no part of the
ordinary machinery, but function simply as a storehouse of material which
can be utilised for the production of energy. In addition to the store of fat
there is, in a well-fed animal, a certain reserve of carbohydrate in the form
of glycogen, deposited in the liver and the muscles. This store of glycogen
is drawn upon to a large extent at the beginning of a period of starvation.
The total amount of glycogen present at any time is generally so small in
comparison with the fat of the body that it cannot provide the energy
necessary for the maintenance of life during prolonged inanition, although
it plays an important part during the first one or two days of a period of
starvation.
Contrary to general belief, the condition of an animal which is completely
deprived of food is not a painful one. For this statement we have not only
such evidence as can be derived from inspection of animals placed in this
condition, but also evidence derived from men who have voluntarily or
involuntarily been deprived of food for considerable periods. Especially
instructive in this connection are the cases of the so-called professional
' fasting men,' two of whom, Succi and Cetti, have been subjected to com-
plete metabolic investigation during the period of their starvation. During
the first day or two there is a craving for food at meal-times. This how-
ever passes off, and during the later portions of the experiment even the
desire for food may be entirely absent. As might be expected, the restric-
tion of food is followed by a diminution in the amount of water required
by the animal. The essential characteristic of the state of inanition is an
ever-increasing weakness, accompanied by a strong disinclination to under-
take any mental or physical exertion whatsoever. The animal passes its time
in a state of sleep or semi-stupor. In the case of Succi, who fasted for thirty
days, considerable muscular exertion was undertaken on the twelfth and
on the twenty-third day of starvation without any appreciable ill-effects.
A strong effort of the will must have been necessary in his case to overcome
the automatic instinct to preservation of life by the utmost economy in the
expenditure of energy. The pulse rate and the body temperature remain
670
METABOLISM DURING STARVATION
671
nearly normal until a few days before death, which is ushered hi by an
increase in the somnolent condition of the animal and by a gradual slowing
of respiration and fall of temperature. The urine is naturally diminished
with diminution in the output of urea and in the amoiuit of water consumed.
Some faeces are formed, and may be voided during or at the close of the
starvation period. In Succi their amoimt varied from 9-5 to 22 grm. a day
and contained from 0-3 to 1-0 grm. nitrogen. On microscopic examination
they consisted of an amorphous material enclosing a number of crystals of
fatty acids.
During the whole of the starvation period, energy is being used up in the
body for the maintenance of its temperature and the vital movements of
respiration and circulation. Since this energy is derived from the destruc-
tion and oxidation of the tissues of the body, there must be a steady loss
of body weight. In experiments on man the daily loss of weight during the
first ten days amounts to between 1 and 1-5 per cent, of the original total
weight. This loss of weight does not affect all parts of the body alike. It
might be imagined that, since the loss of weight is determined by the using
up of the tissues of the body for the production of energy, those organs
which are most active should show also the greatest loss of weight. The
very reverse of this is the case, as will be seen from the following Table :
Percentage Loss of
Weight of Different .Organs and Tissues during
Starvation. (Voit. )
o^si»& •s-sgxsr
Fat
07 —
Spleen
67 63
Liver
5 1 57
Testes .
Hi
Muscles
31 30
Blood .
27 18
Kidneys
20 21
Skin and hairs
21
—
Intestine
18
—
Lungs .
18
19
Pancre.i
17
—
Heart .
3
— .
Brain and spil
;.l cord
3
Those organs of the body which are most necessary for the maintenance
of life, the brain, the heart, the respiratory muscles, such as the diaphragm,
undergo very little loss of weight. Of the other tissues the fat, which is a
mere reserve to prov de for such contingencies, is drawn upon first, and
during starvation 97 per cent, of the total fat of the body may be consumed.
The nitrogen needs of the body during starvation seem to be supplied chiefly
at the expense of the muscles and glands, which waste to a very marked
de S»
•■g o
— .3
o-°5
3
J 1
ft 1
-3 -3
|o|o"
SooS so,
3.~'3.~5
■3 s '3 M
p,^ a, —
o o
8 &
5 o
732
PHYSIOLOGY
method from ' Witte's peptone,' a commercial preparation containing
proteoses and peptones.
The following careful analysis of the constituents of protoalbumose and
heteroalbumose (or protoproteose and heteroproteose) respectively shows
that the different proteoses really correspond to different groupings of the
amino-acids making up the original protein molecule :
Results of the Complete Hydrolysis of Hetero- and Protoalbumose
Heteroalbumose
Protoalbumose
Glutaminic acid .....
9-51
0-63
Leucine .
305
5-79
Isoleucine
2-96
1-62
Valine
3-54
0-76
Alanine .
3-39
2-50
Valin,e-alanine mixtu
"e
1-86
000
Proline .
4-27
4-96
Phenylalanine .
2-45
4-35
Aspartic acid .
.
4-73
2-98
Glycocoll
0-15
1-44
Tyrosine
3-48
4-58
Arginine .
7-30
7-72
Histidine
3-90
2-77
Lysine
8-90
8-40
Cystine .
1-36
0-68
Ammonia
1 1-28
0-92
The results obtained by Pick by hydrolysis of these different bodies show
that, in the breakdown of protein by gastric juice, there is really a division
of the complex molecule into smaller molecules, which are qualitatively
different. Thus of the fractions which he obtained, some contain the
greater part of the sulphur originally present in the protein molecule, another
contains the greater part of the carbohydrate group, while others are free
altogether from the tryptophane group which is responsible for Hopkins'
reaction obtainable in the original protein.
Proceeding from primary through secondary albumoses to peptones, there
is probably a continuous diminution in the size of the molecule. During
the time which gastric juice has to exert its influence, a maximum, say, of
twelve- hours, the breakdown of proteins never passes beyond the albumose
and peptone stage, and it is in this form that the proteins of the food pass on
through the pyloric orifice into the small intestine.
ACTION ON THE CONNECTIVE TISSUES AND OTHER
FOODSTUFFS ALLIED TO PROTEINS
Collagen. The connective tissues are made up chiefly of white fibres
more or less modified, which consist of collagen. This substance forms the
main basis of areolar tissue, of white fibrous tissue, and of bone. On
DIGESTION IN THE STOMACH 733
prolonged boiling, it is converted into gelatin. The gastric juice dissolves
collagen, converting it, probably through the stage of gelatin, into gelatoses
and gelatin peptones, bearing the same relation to the original substance
as is borne by the proteoses and peptones to the proteins. On account of
this action, adipose tissue (which consists of protoplasmic cells distended
with fat and bound together by connective tissue) is broken up into its
constituent cells. The protoplasmic pellicle is dissolved, and the fat floats
freely in the gastric juice.
Elastin, which also occurs in varying amounts as the chief constituent
of the elastic fibres of connective tissues, is slowly acted upon by gastric
juice. Under the conditions of natural digestion however, it may be
regarded as indigestible.
Mucin, which forms a considerable proportion of the ground substance
of connective tissues, is converted by gastric juice into peptone-like sub-
stances, and into reducing bodies probably allied to glycosamine.
The nucleo-PROTEins, the chief constituents of cells, and therefore
ingested in large amounts with foodstuffs such as sweetbreads, are first
dissolved by the acid of the gastric juice, and are then broken up into two
moieties. The protein half is converted into proteoses and peptones, while
the nuclein moiety is precipitated in an insoluble form.
On phospho-proteins gastric juice acts in a somewhat similar manner.
The protein of milk, caseinogen, undergoes special changes in the stomach.
The first effect of gastric juice, even in neutral medium, is to convert the
caseinogen into an insoluble casein. This action is generally ascribed to the
presence of a distinct ferment of the gastric juice, named rennin, or rennet
ferment. But, according to some authorities, it is due directly to the pepsin,
i. e. rennin and pepsin are identical. For the conversion of caseinogen into
the solid clot of casein the presence of lime salts is necessary. The addition
of rennet to an oxalated milk apparently produces no effect, but clotting
ensues if a soluble linie salt, such as calcium chloride, is then added to the
mixture. Under the action of the acid gastric juice the solid clot of casein
is dissolved, but a precipitate is left containing a small proportion of the
original phosphorus of the caseinogen. This precipitate is sometimes
spoken of as para-nuclein, or pseudo-nuclein. It does not yield purine
bases on hydrolysis with acids, but contains phosphoric acid in organic com-
bination. By prolonged digestion with strong gastric juice it is possible to
dissolve the whole of this precipitate. It is therefore thought that, in the
clotting of milk, the caseinogen under the action of the rennet first undergoes
a conversion into a soluble casein, or perhaps a splitting into a soluble casein
and some other protein. The soluble casein then, under the influence of
the hme salts, forms an insoluble casein, which is precipitated and causes the
solidification of the milk. In the absence of lime salts, the conversion or
splitting of caseinogen takes place, but the second stage of the process cannot
occur until the hme salts are added.
734 PHYSIOLOGY
THE EFFECT OF GASTRIC JUICE ON CARBOHYDRATES
On account of the fact that cane sugar undergoes inversion into equal
molecules of glucose and fructose in the stomach, it has been sometimes
thought that gastric juice contains a ferment, invertase. It seems however
that the inversion which takes place in the stomach can be completely
accounted for by the action of hydrochloric acid present, and that there is
no need to assume the presence of a special ferment.
In the same way inulin. the variety of starch which gives rise to the
laevorotatory sugar, fructose, on hydrolysis, and is found in dahlia tubers and
certain other reserve structures of plants, is converted by the acid of gastric
juice into fructose. The inulin is therefore completely utilised in the
alimentary canal of animals, although there is no definite ferment inulase
provided for its hydrolysis.
THE EFFECT OF GASTRIC JUICE ON FATS
The chief action of this juice on fats is the solution of their connective
tissue framework and protoplasmic envelopes, so as to set the fat free in
the gastric contents. After a fatty meal it. is found moreover that a
considerable proportion of the fat in the stomach has undergone hydrolysis
and conversion into free fatty acid. In this hydrolysis two factors are
involved, viz. (1) the action of the warm dilute hydrochloric acid; (2) the
action of a special fat-splitting ferment or lipase, which is secreted by the walls
of the stomach, and acts especially at the beginning of gastric digestion
before the contents have attained a high degree of acidity. The action of
this ferment is marked only if the fat be present in a finely divided form,
e. g. as in yolk of egg. The chief digestion of fat takes place in the next
segment of the alimentary canal, namely, in the duodenum.
THE SECRETION OF GASTRIC JUICE
Pawlow has shown that, if an animal provided with gastric and oesophageal
fistulse be given food when hungry, it will eat with avidity, and since the
food cannot reach the stomach and so satisfy its hunger, it will continue to
eat for two or three hours. Five minutes after the beginning of this sham
feeding, gastric juice begins to drop from the fistulous opening ; and in this
way large quantities of juice, free from any admixture with other substances,
can be easily obtained. By this means we obtain a secretion of gastric juice,
which is excited by the presence of food in the mouth. This method does not
however enable us to determine whether the character of the juice will be
altered in any way by the changes which the food undergoes in the stomach
itself. In order to form an idea of the normal course of secretion of gastric
juice, when food is taken into the stomach in the ordinary way, Pawlow has
devised another procedure. A small diverticulum representing about one-
tenth of the whole stomach is made at the cardiac or pyloric end, in direct
muscular and nervous continuity with the rest of the stomach, but shut off
from the main part of the viscus by a diaphragm of mucous membrane. The
method in which this operation is carried out will be evident by reference to
DIGESTION IN THE STOMACH
735
the diagram (Fig. 348). In a dog treated in this way it is found that the
amount of juice secreted by the small stomach bears always the same ratio
to the amount secreted by the large stomach, while the digestive power of the
juice obtained from the small stomach is equal to that obtained from the
larsre. This is shown in the folio wins; Table : 1
Secretion from Gastric Fistula after Sham Meal
Hours
Small stomach
Large stomach
Quantity
Strength *
Quantity
Strength
1
2
3
7-0 c.c.
4-7 c.c.
1-1 C.C.
5-88 mm.
5-75 mm.
5-5 mm.
68-25 c.c.
41-5 c.c.
140 c.c.
5-5 mm.
5-5 mm.
5-38 mm.
Total.
13-4 c.c.
-
123-75 c.c.
ITig. 348. Diagram to show Pawlow's method of making a cul-de-sac of tho
cardiac end of the stomach, with vascular and nerve supply intact.
In A tho line of the incision into the gastric wall is shown. B represents
the operation as completed.
In A: 0, oesophagus; R.v, L.v, right and left vagus nerves; P, pylorus;
6", cardiac portion of stomach; A, B, line of incision.
In B : V, main portion of stomach; S, cardiac cul-de-sac; A, abdominal
wall; e, c, mucous membrane reflected to form diaphragm between the two
cavities.
In this case a fistulous opening had been established into the large
stomach, so that the juice could be obtained simultaneously from both
sections of this organ. Secretion was excited by a sham meal, in which the
food taken by the animal was not allowed to reach the stomach, but dropped
out of an opening in the neck. It will be seen that the secretions in the two
sections of the stomach run parallel to one another, while there is an almost
1 Puwlow, Tlie Work of the Digestive Glands (translated by Sir W. H. Thompson,
M.D.). p. 80.
a The strength of the juice was determined by measuring the number of millimetres
of coagulated egg-white (in Mett's tubes) which were digested in eight hours.
736
PHYSIOLOGY
exact equivalence between the strengths of the juices obtained from each
section. We may therefore regard the secretion obtained from the small
stomach as a sample of that produced by the large, and from the changes in
this small stomach judge of the effects occurring in the whole organ. By
this method it is possible to study the effects of a normal meal in which the
food is swallowed, or of a sham meal in which the food is merely masticated
in the mouth, or of a meal in which the food is directly introduced into an
opening into the large stomach.
The method which we must adopt for the collection of gastric juice shows
that we have to do, in the first place, with a reflex nervous mechanism,
since an active secretion is excited by the presence of food in the mouth and
by its mastication. Moreover a secretion, which is at least as vigorous as that
produced by a sham meal, can be evoked by merely arousing in the dog the
idea of a meal. If the animal be hungry, it is sufficient to show it the food to
produce a secretion. In the experiment from which the following Table is
taken, the dog was continually excited by showing it meat during a period
of an hour and a half. At the end of this time the animal, which had an
oesophageal fistula, was given a sham meal. It will be observed that the
psychical secretion obtaiued during the first period of the experiment was
rather greater than the secretion produced by the introduction of food into
the mouth.
Psychical Secretion of Gastric Jdice (Pawlow)
Time
8 minutes
4
4
10
10
Quantity
10 c.c.
10 „
10 „
10 „
10 „
io „
10 „
10 „
3 „
Sham Feeding
Time
17 minutes
9 „
8 „
Quantity
10 c.c.
10 „
10 „
The afferent ".hannels for this reflex may be therefore either the afferent
nerves from the mouth or, when the idea of food is involved, any of the nerves
of special sense, such as sight, smell, or hearing, through which these ideas
are called forth. The efferent channels can be only one of two nerves, viz.
the vagus and the sympathetic, since these are the only two which are
distributed to the stomach. That it is the former of these nerves which is
involved is shown by the fact, recorded by Pawlow, that psychical secretion,
as well as the results of a sham meal, is entirely abolished by division of both
DIGESTION IN THE STOMACH 737
vagi. On this account division of both vagi may give rise to entire absence of
gastric digestion, and death of the animal may ensue from inanition, or from
poisoning by the products of decomposition of food in the stomach, even
when care has been taken to avoid injury to the pulmonary and tracheal
branches of these nerves.
The converse experiment of exciting secretion by direct stimulation of the vagus
presents greater difficulties. Stimulation of the vagus in the neck causes stoppage
of the heart, and consequent anaemia of the mucous membrane of the stomach. More-
over the stomach seems to be much more. susceptible than the salivary glands to the
action of poisons, such as anaesthetics. Its activity is also easily affected by inhibitory
impulses arising in the central nervous system as the result of either painful impressions
or emotional states of the animal. In order to avoid these disturbing factors Pawlow
proceeded as follows : An animal with fistula? of oesophagus and stomach had one
vagus nerve divided. A thread was attached to the peripheral end of the cut vagus
and allowed to hang out through the wound. Four days after the operation the vagus
was drawn out of the wound by carefully pulling on the thread, so as not to hurt or
frighten the animal in any way, and its peripheral end stimulated by means of induc-
tion shocks. No effect was produced on the heart, owing to the degeneration of the
cardio-inhibitory fibres, which is well known to occur within this period after section.
Five minutes after the commencement of the stimulation the first drop of gastric juice
appeared from the gastric cannula, and a steady secretion of juice was obtained with
continuation of the stimulation. This experiment furnishes the decisive and final
evidence that the secretory nerves to the stomach run in the two vagi. There is one
marked difference however between the action of these nerves and the action of the
chorda tympani nerve on the submaxillary gland, namely, the great length of the
latent period before gastric secretion begins. The length of this latent period has
not yet been satisfactorily explained. It cannot be due to delay occurring between
the vagus fibres and the local nervous mechanism in the stomach. It may be that
the chemical changes finally resulting in secretion require a longer period for their
accomplishment than is the case in the salivary gland. Physiologically there is indeed
no special need for a rapid secretion of gastric juice, whereas in the mouth it is essential
that the introduction of food should be immediately followed by the production of
saliva, for the tasting and testing of the food and for its subsequent mastication or
rejection.
These experiments show conclusively that an important— probably the
most important — part of the gastric secretion is determined by a nervous
mechanism. This nervous secretion does not however account for the whole
of the gastric juice obtained as the result of a meal. If an animal provided
with two gastric fistulse, one into a diverticulum and the other into the
main stomach, has both its vagi divided, it is found that the introduction of
meat into the large stomach is followed, after a period of twenty to forty -five
minutes, by the appearance of a secretion of gastric juice from the small
stomach. Moreover, when an animal is given a normal meal and is allowed
to swallow the food after mastication, the total amount of gastric juice
obtained is greater than that produced by the sham feeding alone and the
flow is of longer duration. In fact, we may say that the gastric juice secreted
in response to a normal meal consists of two parts, viz. (1) a large amount,
the secretion of which begins within five minutes of the taking of the food
and is determined by the reflex nervous mechanism described above ; and
(2) a smaller portion, the secretion of which is excited by the presence of the
17
738
PHYSIOLOGY
food in the stomach. This combined character of the gastric juice produced
by a normal meal is shown in the following Table (Pawlow) :
Secretion of Gasteic Juice
Hours
Normal meal.
200 grm. meat into
stomach
150 grm. meat direct
Into stomach
Sham meal
Sum of two
last ex-
periments
Quantity
c.c.
Strength
mm.
Quantity
c.c.
Strength
2-5
2-75
3-75
3-75
Quantity
c.c.
Strength
mm.
G-4
5-3
5-75
Quantity
c.c.
12-7
12-3
7-0
5-0
1
3
4
12-4
13-5
7-5
4-2
5-43
3-63
3-5
312
50
7-8.
6-4
50
7-7
4-5
0-6
In the first column is given the result of a normal meal on the secretion
from the gastric diverticulum. In the second column are given the amount
and digestive power of the juice which is excited by the direct introduction of
150 grm. of meat into the large stomach of the animal, care being taken not
to excite in any way the nervous reflex mechanism. In the third column
are given the amount and digestive power of the juice which is evoked by a
sham meal of 200 grm. of meat. In the fourth column is given the sum of
the last two experiments. It will be seen that the total effect of the sham
meal plus the direct introduction of meat into the stomach is almost identical
with the secretion obtained when the food is taken in a normal way and
allowed to pass through the oesophagus into the stomach.
The second phase of the gastric secretion cannot be ascribed to the inter-
vention of the reflex vagal mechanism. Since it occurs after cutting off the
stomach from its connections with the central nervous system, it must have
its causation in the gastric walls themselves. That it cannot be due to
mechanical stimulation is shown by the fact, previously mentioned, that
it is impossible by local stimulation of the mucous membrane, by rubbing,
by introduction of sand, or any other method, to evoke a secretion. Moreover
it is not produced by all sorts of food. The introduction of white of egg, of
starch, or of bread into the stomach causes no secretion. On the. other hand,
if bread be mixed with gastric juice and allowed to digest for some time, the
introduction of the semi-digested mixture into the stomach evokes a secre-
tion. We have already seen that meat produces a secretion; still more
potent than meat however is a decoction of meat, or bouillon, or Liebig's
extract of meat, or certain preparations of peptone. Pure albumoses and
peptones have no effect, so that the exciting mechanism must be some
chemical substances present in meat, and produced in various other foods
under the action of the first gastric juice secreted in response to_ nervous
stimuli. Popielski has shown that this secretion occurs after complete
severance of the stomach from the central nervous system, as well as after
destruction of the sympathetic nervous plexuses of the abdomen. Since
DIGESTION IN THE STOMACH 739
the injection of bouillon directly into the circulation has no effect, this author
concludes that the second phase of secretion is determined by the stimulation
of the local nerve plexus, and that we have here, in short, a peripheral reflex
action, the centres of which are situated in the walls of the stomach
itself. There is yet another possible explanation for this second phase of
secretion. Although the peptogenic substances, those substances which
evoke gastric secretion on introduction into the stomach, have no effect on
the gastric glands when injected directly into the blood stream, it is possible
that they may have an influence on the cells which line the cavity of the
stomach, and that they may produce, in these cells, some other substance
which is absorbed into the blood and acts as a specific excitant of the gastric
glands. A process of this nature is known to occur in the next segment of
the alimentary canal, viz. the duodenum, where it determines the secretion
of the pancreatic juice and the bile.
Edkins has carried out a series of experiments to determine whether such
a chemical mechanism may not also account for the secretion of gastric juice,
which is excited by the introduction of substances into the stomach. Edkins'
experiments were carried out in the following way : The animal, dog or cat,
having been anaesthetised, the abdominal cavity was opened, and a ligature
passed round the lower end of the oesophagus so as to occlude the cardiac
orifice and effectually crush the two vagus nerves. A glass tube was then
introduced through an opening in the abdomen into the pyloric part of the
stomach, and fixed in this position by a ligature tied tightly round the
pylorus. The glass tube was connected by means of a rubber tube with a
reservoir containing normal salt solution at the temperature of the body.
By means of this reservoir, a certain amount of fluid was introduced into the
stomach and kept there at a constant pressure ; the quantity of fluid intro-
duced vaiied from 30 to 50 c.c. It has been shown by Edkins, as well as by
von Mering, that no absorption of water or saline fluid occurs in the stomach.
It is therefore possible to recover the whole of the fluid an hour after it has
been introduced, by simply lowering the reservoir below the level of the
animal's body. If secretion of gastric juice has occurred into the cavity of
the stomach, the fluid will be increased in amount and will contain hydro-
chloric acid as well as pepsin. In a series of control observations Edkins
showed that the mere introduction of this fluid into the stomach caused
no secretion of gastric juice, the fluid removed at the end of an hour having
the same bulk and the same neutral reaction as the fluid which had been
injected. Edkins then tried the influence of injecting substances into the
blood stream. The injection of peptone, of acid, of broth, or of dextrin into
the blood stream produced no secretion of gastric juice. If however in the
course of the hour during which the fluid was allowed to remain in the
stomach, a decoction made by boiling pyloric mucous membrane with acid,
or with water, or with peptones was introduced in small quantities every ten
minutes into the jugular vein, the fluid removed at the end of the hour was
found to be distinctly acid in its reaction and to possess proteolytic properties.
The injection of these substances had therefore caused the secretion of a
740 PHYSIOLOGY
certain amount of gastric juice containing both hydrochloric acid and
pepsin. In order to produce this positive effect, it was necessary to employ
pyloric mucous membrane, extracts made by infusing or boiling cardiac
mucous membrane with any of these substances being without effect.
Edkins concludes therefore that the secondary secretion of gastric juice is
determined, not, as Pawlow and Popielski imagined, by a local stimulation
of the reflex nervous apparatus in the gastric wall, but by a chemical
mechanism. The first products of digestion act on the pyloric mucous
membrane, and produce in tbis membrane a substance which is absorbed into
the blood stream, and carried to all the glands of the stomach, where it acts
as a specific excitant of their secretory activity. This substance may be
called the gastric secretin or gastric hormone. It is noteworthy that it is
produced in that portion of the stomach where the process of absorption is
most pronounced.
The normal gastric secretion is therefore due to the co-operation of two
factors. The first and most important is the nervous secretion, determined
through the vagus nerves by stimulation of the mucous membrane of the
mouth, or by the arousing of appetite in the higher parts of the brain. The
second factor, which provides for the continued secretion of gastric juice
long after the mental effects of a meal have disappeared, is chemical, and
depends on the production in the pyloric mucous membrane of a specific
substance or hormone, which acts as a chemical messenger to all parts of the
stomach, being absorbed into the blood and thence exciting the activity of
the various secreting cells in the gastric glands. It is still a moot point
whether this gastric hormone is formed only in the pyloric mucous membrane,
or whether it may not be also produced in the lower sections of the gut.
Popielski has stated that the introduction of bouillon into the small intestine
excites a secretion of gastric juice in animals, even after extirpation of the
abdominal sympathetic plexuses and division of both vagi. On the other
hand, introduction of the same substance into the large intestine has no
influence on gastric secretion. Popielski ascribes this secretion again to a
local reflex ; but it is more probable that the mechanism in this case is the
same as that involved in the secretion which is excited by the presence of
semi-digested food in the stomach itself.
Pawlow has shown that the second phase of the gastric secretion is largely
influenced by the character of the contents of the stomach. Thus the inges-
tion of large quantities of oil diminishes considerably the amount of gastric
juice secreted, and Pawlow has suggested the administration of oil or oily
foods as a possible remedy in cases where the production of gastric juice,
and especially of hydrochloric acid, is in excess. It has long been imagined
that the secretion of gastric juice was stimulated by the taking of alkalies.
This idea has been shown by Pawlow to be erroneous. Whereas the forma-
tion of gastric juice is increased by the administration of acids, especially
after a meal, it is largely diminished by the administration of alkalies such
as sodium bicarbonate. In fact, sodium bicarbonate diminishes the activity
of the digestive glands throughout the alimentary tract, and ca-u be used as
DIGESTION IN THE STOMACH 741
a means of diminishing the secretion of gastric juice as well as of pancreatic
juice.
A further important question has been propounded by Pawlow, namely,
whether there is any alteration in the constitution and amount of gastric
juice with variations in the character of the food. So far as concerns, the
first phase of secretion, the psychical or ' appetite ' juice, this observer has
shown that, whatever the previous diet of the animal, the juice always has
the same characters, the same digestive power, and the same percentage
of hydrochloric acid. He finds, however, that in the case of the second, or
what we may call ' chemical ' secretion, i. e. that produced by local changes
in the stomach, there is considerable variation in the nature of the juice.
Whereas the secretion of juice is greatest in amount after a meal of meat,
the digestive power of the juice is greatest after one of bread, and Pawlow
regards these differences in the juice as determined by the variations in the
stimulus applied to the gastric mucous membrane. It is doubtful however
whether these results justify us in ascribing a number of specific sensibilities
to the gastric mucous membrane. We have seen that the psychical juice
depends merely on appetite, and therefore will be greater in amount the more
welcome the food is to the animal. On the other hand, the juice secreted in
the second phase must vary according to the quantity of gastric hormone
produced in the pyloric mucous membrane, and therefore with the nature
and amount of the substances produced in the preliminary digestion of the
gastric contents by .means of the psychic juice. The amount of juice may
vary also with the salts contained in the food, according to their alkaline or
acid character, and the percentage of pepsin in the juice may vary with the
intensity of stimulus as well as with the quantity of fluid available for the
formation of the gastric juice. These factors will co-operate in determining
the characters of the whole juice secreted after any given meal, and it seems
possible to explain the variations, observed on such different diets as meat
and bread, without having recourse to the difficult assumption of a specific
sensibility of the gastric mucous membrane to such inert substances as
dextrin or e, 13 D, twelfth and thirteenth dorsal
ganglia; 3 L, third lumbar ganglion; G.Sp.N, L.Sp.N, great and small
splanchnic nerves; S.G, left semilunar and superior mesenteric ganglia;
I).A, dorsal aorta.
which was placed there has been neutralised by the secretion of pancreatic
juice and succus entericus. AVe have probably in the walls of the alimentary
canal a local nervous mechanism for the movements of the pyloric sphincter.
This may be played upon by impulses starting either in the stomach or in
the duodenum, probably by the contact of acid with the mucous membrane.
Increasing acidity on the side of the stomach causes relaxation of the orifice,
whereas acidity on the duodenal side causes contraction of the pyloric
746 PHYSIOLOGY
sphincter. The exact parts played in this mechanism by the local
system and by the central nervous system respectively have not yet been
thoroughly made out, though there is no doubt that these movements may
proceed independently of any connection with the central nervous system.
Stimulation of the peripheral end of the vagus nerves may exercise vary-
ing effects on the gastric wall as well as on its sphincters. In the normal
animal stimulation of the peripheral end of the vagus as a rule causes strong
contractions of the oesophagus as well as of the cardiac sphincter. After
the administration of atropine, stimulation of the same nerve will occasion
dilatation of the cardiac sphincter. On both cardiac and pyloric portions of
the stomach the vagus exercises inhibitory as well as augmentor effects. So
far as concerns the musculature of the fundus or body of the stomach, the
most usual result is an inhibition during stimulation of the vagus succeeded
by an augmented tonus immediately the stimulus is removed. If the vagus
be excited a number of times, the tonus of the muscular wall augments with
each stimulus. On the pyloric portion stimulation of the vagus also causes
inhibition, followed by contraction. The inhibition may however be very
short and in rare cases altogether absent, so that during the excitation this
inhibition is followed by a series of large rhythmic contractions. The pre-
vailing motor effect of the vagus therefore is in the fundus increased tonus,
in the pyloric portion augmented peristaltic waves. On the pylorus itself
we may obtain from vagal stimulation either increased or diminished con-
traction. The conditions under which each of these may be evoked have not
yet been definitely ascertained. Whether the splanchnic nerve, i. e. the
sympathetic system, has a direct influence on the movements of the stomach
has been disputed. According to Page May any effect produced by stimula-
tion of this nerve, generally consisting in diminished motor activity, is
probably due to the simultaneous influence on the vascular supply to the
organ ; the blood vessels being constricted, an artificial anaemia is produced
which in itself is sufficient to account for diminished activity. Other
observers regard the splanchnic as having an influence on the stomach similar
to its action on the intestine, and regard it as the chief inhibitory nerve to
this organ. It is possible that the extent to which the stomach is brought
under the control of the sympathetic system may vary in different species of
animals.
Cannon has shown that the 'pangs of hunger' are associated with and probably
due to rhythmic contractions of the stomach wall, which come on about meal time,
especially if this be delayed.
VOMITING
Expulsion of the stomach contents may occur as a result of over-
distension of this organ, of the presence of irritating material in its contents,
or from abnormal conditions of the brain. It is generally preceded by a
feeling of nausea, which is associated with salivation. The large quantities
of saliva swallowed still further distend the stomach and assist the opening
of the cardiac orifice. In the act of vomiting itself the first event is a deep
inspiration. The glottis is then closed, and this is followed by a strong
THE MOVEMENTS OF THE STOMACH 747
contraction of the diaphragm and of the abdominal muscles. At the same
time the cardiac orifice is relaxed. By means of X-rays it may be seen that
at this time a strong contraction occurs at the incisura angularis, dividing
the stomach into two separate portions. The dilated body of the stomach
is pressed between the abdominal muscles and the diaphragm, so that its
contents are expelled through the relaxed oesophagus and out through the
mouth. As vomiting proceeds the stomach contracts down on the remaining
contents, but the main factor in the expulsion is the contraction of the
abdominal muscles and diaphragm. In fact, vomiting may be excited in an
animal in which the stomach has been replaced by a bladder.
NERVOUS MECHANISM OF VOMITING
Normally the action of vomiting is reflex. It can be excited by tickling
the back of the throat, when the afferent nerves are the trigeninal and the
glossopharyngeal, or by irritation of the stomach through the afferent fibres
of the vagus. But it may be excited from almost any of the abdominal
viscera, e. g. uterus, kidney, intestines, etc. It may also be excited reflexly
through the labyrinth or through the eyes, as in vomiting of sea-sickness,
and is a marked symptom in many cases of disease of the cerebrum and
cerebellum. The efferent impulses are carried by the vagi to the stomach,
by the phrenics to the diaphragm, and by the various spinal nerves to the
abdominal muscles. There are also inhibitory impulses descending the vagi
to the oesophagus and cardiac sphincter. The reflex act depends on the
integrity of the medulla, so that a ' vomiting centre ' is sometimes said to
be situated in the medulla.
Drugs may produce vomiting either by irritating the stomach, e.g.
mustard and water, zinc sulphate, ipecacuanha, or by direct action on the
medullary centres, e.g. tartar emetic, apomorphine, etc.
INTESTINAL DIGESTION
The products of gastric digestion, after being worked up in the pyloric
half of the stomach, are passed at intervals into the first part of the duo-
denum. Here they meet the secretions of three glands, namely, the pancreas,
the liver, and the tubular glands of the intestine. La addition to these must
be mentioned the secretion of Brunner's glands, which are situated at the
very beginning of the duodenum. The glands of Brunner extend only over
about half to one and a half inches in the carnivora, such as the dog or cat,
but in the herbivora they may be found occupying the upper six inches of
the intestine. The secretion of these various juices is practically simul-
taneous and is aroused by the very act of entry of the acid chyme into the
duodenum. Although they co-operate in their action on the foodstuffs, it
will be convenient to deal separately with each, both as regards their action
and the mechanism of their secretion.
SECTION V
THE PANCREATIC JUICE
Pore pancreatic juice can be obtained either from an animal with a perma-
nent fistula or from one with a temporary fistula by the injection of secretin
into the animal's veins. A flow of pancreatic juice may also be produced
by the administration of pilocarpine. This drug acts however as a poison
on many tissues of the body, not confining its action to the pancreas or
even to the secreting glands. It is not to be wondered at therefore that the
pancreatic juice obtained by its injection differs in quality from that obtained
by the more natural method of injection of secretin. The average com-
position of pancreatic juice is shown in the Table on p. 749.
It is a clear or slightly opalescent fluid, strongly alkaline from the presence
N N
of sodium carbonate, its alkalinity varying between — and — Na 2 C0 3 . It is
therefore about as alkaline as gastric juice is acid, and it will be found that
equal quantities of gastric juice and pancreatic juice, when added together,
practically neutralise one another. The proteins of the juice may be roughly
divided into three groups, a small amount of nucleo -protein precipitated
on acidification, a protein coagulating at 55° C, and another at about 75° C.
The juice tends to become poorer in proteins and richer in alkali as secre-
748
THE PANCREATIC JUICE
749
A
B
c
Alkalinity :
(a)
(b)
Number of c.c. NaOH equal to I
10
ll'-T
12-4
5-5
10 c.c. juice . . . . )
J. ".. in terms of Na in 100 c.c.
Total solids in 100 c.c. . . \
0-2921
1-6 \
1-5G J
0-2852
2-25
0-2587
„ (
0-116o
6-38
6-10
Total proteins in 100 c.c.
0-5
—
—
4-8
(
Ash in 100 c.c j
1-00 |
0-92 |
100
1-00
1-3
Chlorides in 100 c.c. .
0-280S 1
0-2966 I
—
—
ii 2695
Total nitrogen ....
—
—
0-735
A. Secretin juice from three dogs. Sp. gr. 1014.
B. Secretin juice, specimen collected at beginning (a), and at end (6).
C. Pilocarpine juice.
tion proceeds. The concentrated juice obtained by injection of pilocarpine,
which may contain as much as 6 per cent, total solids, is always considerably
less alkaline than the more dilute juice got by injection of secretin. The
most interesting and important constituents of the juice are its ferments
or precursors of ferments. The juice on arrival in the intestine has, or
develops, an effect on all three classes of foodstuffs, namely, proteins, fats,
and carbohydrates, due to the presence of distinct ferments, viz. trypsin,
steapsin or lipase, and amylopsin.
/
ACTION ON PROTEINS
Although the digestive action of pancreatic juice on proteins was pointed
nut- by Corvisart, little attention was paid to this effect either by Claude
Bernard or subsequent authorities, until Kiilme subjected the action of
extracts of the gland to a thorough investigation. The neglect of this
action by Claude Bernard mast be ascribed to the fact that he worked with
pancreatic juice. It has been shown more recently that pancreatic juice as
secreted is free from proteolytic effects, and that for the development of this
power it is necessary that some change should be brought about in the juice
itself, namely, a conversion of trypsinogen into trypsin. This change under
normal circumstances is brought about directly the juice enters the gut, by
the action of a substance — enterokinase — contained in the succus entericus.
The pancreatic juice thereby acquires a proteolytic activity superior to that
of any other digestive juice, so that the proteins of the food undergo a very
thorough disintegration. The different constituents of the protein molecule
show a varying resistance to the action of trypsin. The greater part of the
molecule is rapidly broken down into its proximate constituents, namely,
amino-acids, and the same change is undergone by the proteoses and pep-
tones resulting from the gastric digestion of proteins. Within a few minutes
therefore after the chyme has reached the small intestine, a certain amount
750 PHYSIOLOGY
of ammo-acids will have been formed. Some of the groups present a
resistance to disintegration. After tryptic digestion for a few hours, the
mixture will be found still to contain a considerable quantity of peptone,
which in consequence of its resistance to further alteration was designated by
Kiilme ' antipeptone.' The autipeptone of Kiihne certainly included some
of the diamino-acids, which at that time had not been isolated. There is
always a part however which gives the biuret reaction and is only slightly
broken down after the prolonged action of trypsin. Even when the trypsin
has acted for weeks and the biuret reaction has entirely disappeared, the
mixture will be found to contain, in addition to the separate amino-acids,
some members of the polypeptide class, composed of two or more molecules
of amino-acid united together. One of these polypeptides has been isolated
by Fischer and Abderhalden from the products of tryptic digestion of the
protein of silk, and has been found to contain glycine, alanine, and proline.
The stages in tryptic digestion, e.g. of fibrin, may be set out as follows :
(1) After one hour's digestion — soluble coagulable protein, deutero-
albumose, peptone, amino-acids, with a small amount of alkali metaprotein
produced by the action of the alkali of the juice.
(2) After digestion for one day — deutero-albumose, ' antipeptone,'
a mil i u-acids, polypeptides.
(3) After digestion for one month — amino-acids, polypeptides.
Among the amino-acids tyrosine is one of the first to be split off, and this
substance, with leucine, was among the earliest known products of pancreatic
digestion. The action of trypsin is thus seen to resemble very closely the
action of boiling concentrated hydrochloric acid. Like the latter it attacks
the protein molecule at the — CO— NH — coupling, introducing water at
this point and therefore breaking up the polypeptide groupings into simple
amino-acids. Why it always leaves a certain remnant of the polypeptides
unattached is not at present explained. The investigation of its action on
the polypeptides has shown that very minute differences in the grouping
of the molecule may determine whether or not the molecule is attacked by
trypsin. Apparently it will only attack such molecules as are present in
the naturally occurring proteins. Thus under the action of trypsin the
following polypeptides undergo hydrolytic dissociation : alanyl glycine,
alanyl alanine, alanyl leucine A; while the closely similar polypeptides,
glycyl alanine, glycyl glycine, alanyl leucine B are left untouched.
CONDITIONS OF TRYPTIC ACTIVITY
Since the pancreatic juice is strongly alkaline, it might be expected that
trypsin would be most effective in an alkaline medium. It must be remem-
bered however that the alkaline juice, when secreted, meets the correspond-
ingly acid contents discharged from the stomach, and that the resulting
mixture is practically neutral. This neutrality exists throughout the small
intestine, the reaction of the contents of the gut being similar to that of a
fluid containing alkali which has been saturated by the passage of carbonic
THE PANCREATIC JUICE 751
acid, viz. alkaline to such indicators as methyl orange, and acid to such
indicators as phenolphthalein. On investigating the action of trypsin out-
side the body, it is found that, at any rate as concerns its earlier stages, t his
ferment is more active in the presence of sodium carbonate. It is usual to
make up an artificial digestive mixture by dissolving commercial trypsin in
0-2 to 0-3 per cent, sodium carbonate. The optimum amount of sodium
carbonate depends on the strength of the solution in trypsin : the more
trypsin present the higher is the optimum amount of sodium carbonate. It
is stated that, although an alkaline reaction is more advantageous for the
earlier stages of tryptic activity, the later stages take place best in a neutral
medium. This result is probably due to the fact that trypsin in alkaline
medium is extremely unstable so that, when prolonged digestions are carried
out, the trypsin would be rapidly destroyed if the medium were strongly
alkaline. The destructibility of trypsin, as well as its action, is largely
affected by the presence of proteins or their digestion products in solution.
Eayliss has adduced evidence to show that, when trypsin acts upon protein,
it enters into some form of combination with the protein molecule. This
combination protects the trypsin from the destructive action of alkali. The
velocity of the reaction, which takes place under the influence of trypsin,
gradually diminishes, owing probably to a combination of the trypsin with
the products of digestion, e.g. with the peptones or amino-acids, and its
consequent removal from the sphere of action. If by any means the amino-
acids be removed the action of the trypsin is renewed. Destruction of the
ferment occurs in the intestine itself. If the intestinal contents be collected
by means of a fistula at the lower end of the ileum, they show little or no
proteolytic activity. Trypsin is therefore an extremely active ferment,
which carries out its function of protein hydrolysis at the upper part of the
gut and is destroyed before reaching the lower end.
THE ACTIVATION OF PANCREATIC JUICE
It was observed by Kuhne that extracts of the fresh pancreas did not
develop their full activity for some considerable time, the development
being aided by preliminary treatment with a weak acid. When a pancreatic
fistula is made according to Pawlow's • method, the juice obtained always
presents some proteolytic activity. It was shown by Pawlow and Chepo-
walnikoff that the development of the activity of the juice was due to the
action of a constituent of the succus entericus which they named enterokinase,
and it has since been found that, if care be taken to avoid contact of the
juice with the mucous membrane surrounding the orifice of the duct, it is,
when secreted, entirely inactive. The enterokinase acts like a ferment
on a body, trypsinogen, present in the juice as secreted, converting this into
trypsin. Pawlow therefore called this body the ' ferment of ferments.'
This view of the action of enterokinase has been challenged, especially by Delczenne,
according to whom there is an actual combination between the enterokinase and (lie
trypsinogen, trypsin itself being a mixture or combination of the two bodies. He
compared the reaction to that of the hemolysins, which, as is well known, involve in
752 PHYSIOLOGY
their action the co-operation of two bodies, the amboceptor and the complement.
If (liis were correct, there should always be a proportionality between the quantities
of trypsinogen and enterokinase respectively which are necessary to form trypsin. It
lias been shown by Bayliss and Starling that this proportionality is not present. The
smallest quantity of enterokinase is sufficient to activate any amount of trypsinogen
if sufficient time be allowed. The effect of increasing or diminishing the amount of
enterokinase is not to alter the total amount of trypsin finally produced, but merely
the time taken for its production. This behaviour characterises a ferment, and we may
therefore conclude that the view originally put forward by Pawlow is correct, namely,
that trypsin is produced from trypsinogen under the action of a ferment, enterokinase.
If pancreatic juice be allowed to stand, even with the addition of toluol to prevent
bacterial infection, it gradually acquires a certain degree of activity. If however
sochum fluoride be used as an antiseptic, the juice remains permanently inactive. The
spontaneous activation of the juice may be hastened by neutralisation. The most
potent means next to enterokinase is the addition of lime salts. If a few drops of
10 per cent, calciiun chloride solution be added to fresh pancreatic juice, the calcium
being in such a quantity as to suffice to combine with all the carbonate present in the
juice, complete activation of the juice occurs within a couple of days, no further increase
in its digestive powers being obtained on subsequent addition of enterokinase. It has
been suggested that the action of calcium is in some way to assist in the production
of an enterokinase from some precursor of this body already present in the juice.
According to Mellanby, the calcium acts simply by neutralising the juice and thus
allowing minute traces of enterokinase already present in the juice to exert their effect.
It is not likely that this calcium activation plays any part in the normal processes
of digestion, since for its completion it needs twelve to sixteen hours, whereas the
enterokinase present in the succus entericus will effect the activation of the juice within
a few minutes.
THE ACTION OF PANCREATIC JUICE ON MILK
On the addition of pancreatic juice to milk a clot is produced which
speedily redissolves. If re-solution takes place too rapidly the production
of a formed clot may be missed. In every case however, on heating the
milk a few minutes after the addition of the trypsin, a clot is obtained. How
far this action is to be ascribed to the proteolytic ferment trypsin, or how
far it is due to the presence of a free rennet-like ferment in the juice, is not
yet definitely settled. Since the rennet action is parallel to the proteolytic
activity of the juice, it is probable that we must regard the clotting of milk
as the first stage in its proteolysis.
THE ACTION OF PANCREATIC JUICE ON CARBOHYDRATES
The pancreatic juice, as well as fresh extracts of the pancreas itself,
contains a strong amylolytic ferment, diastase, amylase, or amylopsin. If
a few drops of pancreatic juice be added to a 1 per cent, solution of boiled
starch, within a few seconds the solution clears, and in half a minute, on the
addition of iodine, a red colour is obtained, showing the presence of erythro-
dextrin. At the end of a few minutes no colour is produced with iodine,
and the solution contains maltose. The stages in the hydrolysis of starch
brought about with pancreatic juice are exactly similar to those effected
by ptyalin. If the juice be neutralised, the process of hydrolysis goes on
to the formation of dextrose or glucose. This further conversion is due to
the presence in the juice of a second ferment — maltase — which converts
THE PANCREATIC JUICE 753
the disaccharide maltose into the monosaccharide glucose. The juice in
the gut is therefore able to effect the further digestion of the products of
salivary digestion. On the other disaccharides pancreatic juice is without
effect. It contains no invertase, nor does it, in spite of certain statements
to the contrary, ever contain lactase. It has therefore no effect on either
cane sugar or milk sugar.
' THE ACTION OF PANCREATIC JUICE ON FATS
Fresh pancreatic juice contains a strong lipase or fat-splitting ferment, by
means of which, in the presence of water, neutral fats, e. g. the triglycerides
of palmitic, stearic, and oleic acids, are broken up into glycerin and the
corresponding fatty acids. This ferment is active either in alkaline, neutral,
or very slightly acid reaction. If the reaction be alkaline, the fatty acids
produced by the lipolysis combine with the alkali present with the formation
of soaps. The ferment may be obtained from extracts of the fresh gland,
but is rapidly destroyed if active trypsin be present. It is also contained in
some of the dried commercial preparations of trypsin. It is apparently
insoluble in distilled water, and is therefore found in the residue after extract-
ing these commercial preparations with water. It is easily soluble in glycerin.
The velocity with which iipolysis occurs is much increased (four to five times)
by the addition of bile. This adjuvant action of bile is not destroyed by
boiling, and is due entirely to the bile salts. These act in two ways. In
the first place, by their physical qualities they diminish the surface tension
between water and oil, so enabling a closer contact to be effected between
the watery solution contained in the juice and the oil which is presented
to it. Moreover they may aid in the solution of the ferment itself. In the
second place, bile salts have a solvent action on soaps as well as on fatty
acids in slightly acid medium. Bile may be regarded therefore as a favour-
able excipient or medium for the interaction of the lipase and the neutral
fats. The lipase of pancreatic juice will also hydrolyse the esters of the
fatty acids, such as ethyl butyrate or monobutyrin. On the phosphorised
fats or phosphatides, such as lecithin, its action is still a subject of doubt.
According to certain authors extracts of the pancreas have the power of
splitting off choline from lecithin. It is not known whether the same
property is present in pancreatic juice itself, or whether any other dissocia-
tions are brought about in the complex molecule of lecithin under the action
of this digestive fluid.
THE SECRETION OF PANCREATIC JUICE
In order to study the relation of the secretion of pancreatic juice to the
other processes of digestion, observations must be carried out on an animal
with a permanent pancreatic fistula.
Such a fistula was established by Claude Bernard by bringing the duct of the pancreas
to the surface and inserting into it a lead or silver tube. The arrangement was
unsatisfactory, since after a few days the tube dropped out and the natural course of
the duct from pancreas to intestine was restored. In order to avoid the disadvantages
48
754 PHYSIOLOGY
of this proceeding Heidenhain and Pawlow independently devised another method
to enable us to determine the causes of pancreatic secretion. The pancreas in most
cases possesses two ducts, the upper one opening along with the bile duct, the lower one
a short way down. The relative sizes ot these two ducts vary in different animals,
the lower one being larger in the dog, while in man and the eat the upper one is larger.
In order to establish a pancreatic fistula in a dog, a small quadrilateral piece of the
duodenal wall is exsected, having the papilla of the lower duct opening in the middle
of its mucous surface. The integrity of the gut is restored by suturing in a single line
of stitches the margins of the wound in the duodenum, and the exsected piece is brought
to the surface and stitched in the middle of the abdominal wound. The greater part
of the pancreatic secretion will escape by the fistula, and can be collected either by the
insertion of a cannula into the duct or by attaching a glass funnel below its orifice.
Great care has to be taken in the after treatment of such animals. The pancreatic
juice, which flows over the papilla, acquires in so doing strong proteolytic powers,
and tends therefore to dissolve and irritate the adjacent abdominal wall. This can be
prevented by taking care to collect all the juice, and to allow none to flow away over
the surface of the body. Another drawback is that the continual loss of pancreatic
juice in many cases seriously affects the animal's health. This may be obviated to a
certain extent by keeping the animal on a milk diet with the addition of sodium bicar-
bonate to replace the loss of this salt by the juice. With great care Pawlow has succeeded
in keeping such animals in a perfectly healthy condition.
In the fasting condition there is, as a rule, no secretion of juice, though
the escape of a few drops may be observed at long intervals. If a meal be
administered to the animal, a flow of juice begins in one to one and a half
minutes. From this time there is a steady, slow rise of the rate of secre-
tion, which lasts for two to three hours, and then gradually diminishes. The
greatest increase in flow is observed at the time when the first portions of
digested food escape from the stomach into the duodenum. The secretion
must therefore be determined in some way by the entry of this food into
the duodenum. By experiments on dogs possessing a gastric as well as a
pancreatic fistula, it has been shown that the introduction of acid, e. g.
0-4 per cent. HC1, into the stomach evokes, as soon as it passes into the
duodenum, a rapid flow of pancreatic juice. A similar, but smaller, effect
is produced by the passage of oil from the stomach into the duodenum.
The. introduction of alkalies is without effect. Weak acids are also effective
exciters of secretion if they be introduced directly into the duodenum itself
or into a loop of small intestine. The effect gradually diminishes as the
loop which is chosen comes nearer to the csecum, and as a rule the injection
of dilute acid into the lower foot or eighteen inches of ileum is without effect
on the pancreas. The striking resemblance between the secretion thus
evoked and that produced in the salivary glands by injection of acid into
the mouth suggests that we have here to do with a reflex of the same kind
as that which affects the sab vary glands. In the search for the channels
of this reflex Heidenhain showed that stimulation of the medulla oblongata
occasionally produced a flow of pancreatic juice. He was unable however
to obtain any secretion on stimulation of the vagus nerve. The pancreas
receives fibres from the vagi as well as from the splanchnic nerves (sym-
pathetic system). According to Pawlow the ill success of Heidenhain's
experiments was due to the fact that in any operation a gland is played
upon by reflex impulses partly of an inhibitory, partly of a secretory nature,
THE PANCREATIC JUICE 755
in which the inhibitory predominate, and by the further fact that the
pancreas is extremely susceptible to alterations in its blood supply, so that
any stimulation of the vagus which caused inhibition of the heart would
ipso facto prevent the effect of simultaneous excitation of secretory fibres
from making its appearance. Pawlow noticed that if in an animal with a
permanent fistula the vagus on one side were cut and left for four days in
order to allow the cardio-inhibitory fibres to degenerate, repeated stimula-
tion of the peripheral end of the nerve evoked a flow of pancreatic juice.
He obtained the same results by stimulating this nerve below the point at
which it had given off its cardio-inhibitory fibres, in animals in which the
reflex inhibitions from the operation itself were prevented by total section
of the medulla. Under certain circumstances he obtained also secretion
on stimulation of the splanchnic nerves, and therefore concluded that these
two nerves — splanchuics and vagi — were the efferent channels in the reflex
secretion set up by the introduction of the acid into the duodenum. It
was shown later however independently both by Popielski, a pupil of
Pawlow, and by Wertheimer, that the injection of acid into a loop of small
intestine was followed by secretion of juice even after section of both vagi
and destruction of the sympathetic ganglia at the back of the abdominal
cavity. On repeating these experiments Bayliss and Starling found that a
secretion of juice was produced even when the acid was introduced into a
loop of the small intestine entirely freed from any possible nervous connec-
tions with the rest of the body. It was evident therefore that the stimulus
or message from the intestine to the pancreas which causes the secretion of
the latter must be carried, not by the nervous system, but by the blood
stream. Since the injection of acid into the portal vein was without effect
on the pancreas, it was concluded that something must be produced in the
epithelial cells of the gut under the influence of acid, and that this product
of the epithelial cells was absorbed in the blood stream and was the active
agent in exciting the pancreas. On pounding up some scrapings of the
intestinal mucous membrane with dilute hydrochloric acid and filtering, and
injecting the filtrate, a copious flow of pancreatic juice was produced. This
chemical messenger or hormone from the intestine to the pancreas is called
1 secretin,' or ' pancreatic secretin ' to distinguish it from possible other
members of the same class. It is produced in the mucous membrane from
a precursor — pro-secretin. The latter has not been isolated, but that it is
present in the mucous membrane is shown by the fact that secretin can be
extracted by the action of acids from mucous membrane which has been
killed by heat or by the prolonged action of alcohol.
Secretin itself is not a ferment. In order to prepare it the mucous
membrane is groimd up with sand, boiled wath 04 per cent, hydrochloric
acid, and then neutralised while boiling by the cautious addition of sodium
hydrate. The coagulable proteins are in this way precipitated, and the
filtered solution contains the secretin. It is not precipitated by the ordinary
alkaline reagents, and diffuses slowly through animal membranes Though
stable in acid solutions, it is very rapidly destroyed in alkaline or neutral
756 PHYSIOLOGY
solutions, especially under the influence of bacteria. It is apparently
oxidised with extreme ease. A similar, or more probably the same, body
may be produced from intestinal mucous membrane by treating this with
solutions of soap.
Li this secreting mechanism we have a very striking example of a
correlation between the activities of two different portions of the body effected
by chemical means. The strongly acid chyme enters the first part of the
duodenum. Immediately a certain amount of secretin is produced by
the acid in the cells of the mucous membrane. The secretin is carried by
the blood stream to the cells of the pancreas and excites there the secretion
of strongly alkaline pancreatic juice. As soon as sufficient juice has been
secreted to neutralise the acid chyme, the formation of secretin and there-
fore the further secretion of pancreatic juice, comes to an end. If the stomach
still contains food, the process is however renewed, in virtue of the local
reflex mechanism which we have just studied regulating the opening and
closure of the pylorus. So long as the contents of the duodenum are acid,
the pylorus remains firmly closed. As soon as these are neutralised, the
pylorus relaxes and allows the entrance of a further portion of acid chyme.
Thus the formation of secretin proceeds afresh, and the whole chain of
processes goes on until the stomach is empty and all its contents have
passed into the intestine.
In view of the efficacy of this chemical reflex mechanism, the question
arises whether the results first obtained by Pawlow were really due in some
way to the formation of secretin. Stimulation of the vagus may cause
contraction of the stomach, opening or closing of the pylorus, and it seems
possible that under its action there might have been an escape of acid gastric
contents into the intestine, and therefore the formation of secretin, which
would suffice to arouse the pancreatic secretion. Later experiments by this
observer, in which the escape of any gastric contents was effectively pre-
vented by ligature of the pylorus while the stomach itself contained an
alkaline solution, have shown that even with these precautions a flow of juice
may be obtained on stimulation of the vagus nerve. The flow however
is very small in comparison with that obtained by injection of secretin, and
one must conclude that, although the nervous system may play a small
part in the excitation of the activity of this gland, the main factor involved
is the chemical mechanism which has just been described.
The amount of pancreatic juice obtained after a meal varies with the
nature of the latter. The Table on p. 757 represents the results obtained on
an animal fed with 600 c.c. of milk, 250 grm. of bread, and 100 grm. of meat
respectively.
The differences between these results seem largely determined by the
duration of gastric digestion, and therefore the amount of acid secreted
in the stomach and passed on to the duodenum. It was suggested by
Walther that, apart from this quantitative adaptation, there was a qualitative
alteration in the constitution of the juice according to the nature of the
food ingested, that, e.g., excess of protein causes an increase of the trypsin,
THE PANCREATIC JUICE
757
while excess of carbohydrate would cause an increase in the amylase of the
juice. Later researches have failed to confirm this view. Apparently when
the pancreas is excited to secrete, it turns oat its various ferments in constant
proportion, depending on the amounts of these already present and stored
up in the gland.
Secretion of Pancreatic Juice (Walther)
Hours after meal
600 c.c. milk
250 grm. bread
100 grm. meat
1
8-5 c.c.
36-5 c.c.
38-75 c.c.
2
7-6 c.c.
50-2 c.c.
44-6 c.c.
3
14-6 c.c.
20-9 c.c.
304 c.c.
4
11-2 c.c.
14-1 c.c.
16-9 c.c.
5
3-2 c.c.
16-4 c.c.
0-8 c.c.
6
1-0 c.c.
12-7 c.c.
—
7
—
J0-7 c.c.
—
S
—
6-9 c.c.
—
THE STRUCTURAL CHANGES IN THE PANCREAS
ACCOMPANYING SECRETION
The ease with which secretin may be prepared and used to arouse the
activity of the pancreas has rendered it possible to study more closely the
changes which in this gland accompany activity. Kuhne and Sheridan
Lea succeeded in observing the gland of the rabbit in a living state under the
Fio. 352. A terminal lobulo of the pancreas of the rabbit. (Kuhne and
Sheridan Lea.)
a, in resting condition; B, after active socretion.
microscope. They noted that activity, excited by pilocarpine, was asso-
ciated with a discharge of granules, a clearing up of the cells, and a diminu-
tion in size and the appearance of a lumen to the gland alveoli (Fig. 352).
A normal resting gland is of an opaque, yellowish-white colour and of firm
consistence. On section it is seen to consist of numerous secreting alveoli
which open into narrow intercalary tubules, and these in their turn into wide
collecting tubules. The lining epithelium of the intercalated tubules is
often continued into the secreting part, where they he internal to the secret-
ing cells, as the so-called centro-acinar cells. The secreting cells themselves
758
PHYSIOLOGY
present two well-marked zones, a narrow peripheral zone in which the
nucleus is embedded, which is strongly basophile, and a central part which
is turned towards the lumen, occupying two-thirds or three-quarters of the
cell, and is closely packed with highly refractive gramiles strongly acidophile
and presumably containing or composed of the precursors of the various
constituents of the pancreatic juice (Fig. 353). If the activity of the gland
be aroused by injection of secretin and the injection be continued until the
Fig. 353. Alveoli of dog's pancreas. (Babkin, Rubaschkin and Sawitsch.)
a, resting ; B, after moderate secretion with discharge of granules.
rate of secretion evoked by each injection diminishes considerabty, i. e. the
gland shows signs of fatigue, marked changes are observed both macro-
«;ally and under the microscope. The gland is now pink and trans-
t in appearance, moist and soft in consistence. On section the lumen
3h alveolus is enlarged, the cells are shrunken, and the granules are
found to he only along the border of the cell turned towards the lumen, the
rest of the cell, which is much reduced in size, being made up of the
basophile protoplasm. Similar effects are observed after long continued
stimulation of the vagus (Fig. 353 B).
V
SECTION VI
LIVER AND BILE
The liver, the largest gland in the body, is, like the other glands associated
with the alimentary tract, formed in the embryo by an outgrowth of the
hypoblast lining the alimentary canal. At first it resembles in structure
other secreting glands, such as the pancreas, being composed of branch
tubules which pour their secretion into a common duct. In the adult
however, the relation of the hver cells to the ducts is entirely subordinated
to their relation to the blood vessels of the liver, and it requires special
histological methods to make out the relations between the liver cells and
the bile ducts. The hver, on section, is seen to be divided oft into lobules
composed of columns of polygonal cells, radiating from the centre like the
spokes of a cart-wheel. The portal vein, which drains the blood from the
alimentary canal, breaks up into branches which he at the periphery of
the lobules, forming the interlobular veins, and send off numberless capillaries
which pass inwards between the columns of cells to join the intralobular vein
lying at the centre of the lobule. From the intralobular the blood passes
by the large sublobular vein into the hepatic veins and inferior vena cava.
In an injected specimen it is easy to see that every liver cell is comiected
with at least one blood capillary, and the liver thus forms a blood gland,
lying as it does at the gate of entrance of blood from the alimentary canal
into the general circulation. The portal vein conveys only venous bloo^l
to the liver. In order to supply oxygen to the working hver cells, 1
organ receives a second supply of arterial blood by the hepatic artery derr
from the cceliac branch of the aorta. The branch of the hepatic artery runs
with the branches of the portal vein in the connective tissue pf Glisson's
capsule surrounding the lobules, and breaks up into capillaries which are. in
free communication with the capillaries derived from the portal system
and pour their blood finally into the hepatic vein.
As might be expected from its structure, the secretory functions of the
hver represent but a small proportion of its activities in the body. The
liver is, in fact, the greatest chemical factory of the body, receiving by
the portal vein the products of digestion as they are absorbed from the
alimentary canal. It converts these into other substances, breaking them
down or building them up according to the needs of the body as a whole.
Thus, when carbohydrates are being absorbed in quantity, it converts the
glucose contained in the portal blood into glycogen which it stores up,
769
blood
2lW
7G0
PHYSIOLOGY
reconverting the latter into glucose and letting it loose into the circulation
when this substance is required by the body tissues. In the complete
absence of carbohydrate from the food, the liver may, as we shall see later,
actually convert the products of protein digestion into sugar. In the same
way the liver plays an important part in the metabolism of proteins and
of fats, so that its functions will have to be dealt with in the various chapters
concerned with the fate of the different foodstuffs and different constituents
of the animal body. In this chapter we are merely concerned with its action
as a secreting gland. The fact that its secretion is in so many animals
poured into the intestine by an orifice common to it and the pancreatic juice
suggests that these two fluids co-operate in their actions on the ingested
foodstuffs, and points to a direct use of the bile in the processes of digestion.
In addition to this function, the bile must also be regarded as an excretion,
representing as it does the channel by which the products of disintegration
of haemoglobin — the red colouring-matter of the blood — are got rid of from
the organism. As an excretion the production of bile must be continuous
and related, not to the processes of digestion, but to the intensity of destruc-
tion of the red corpuscles. On the other hand, bile as a digestive fluid is
needed in the gut only during the period that digestion is going on. The
exigencies of the body therefore require a continuous excretion of bile by the
liver, but a discontinuous entry of this fluid into the small intestine. This
discontinuity in the entry of a continuous secretion into the intestine is
secured, in the majority of animals, by the existence of the gall bladder, a
diverticulum from the bile ducts, in which all bile, secreted during the
intervals between the periods of digestive activity, is stored up. In the
horse, where the gall bladder is absent, its place is taken to some extent by
the great size of the bile ducts. Moreover in such an animal the process of
digestion is much more continuous in character than it is in carnivora.
Since the bile accumulates in the gall bladder during the whole time that
digestion is not going on, and is only poured into the gut during digestion,
ia^a fasting animal the gall bladder is distended, whereas in an animal
^Kb hours after a meal the gall bladder is practically empty.
^^T>uring the period that the bile remains in the gall bladder it under-
goes certain changes, as is shown by comparison of the composition of bile
obtained fr,om the gall bladder with that obtained from a fistula of the
bile duct.
Analyses of Bile (Human)
From a biliary fistula (Yco and Herroun) in 100 parts
Mucin and pigments . . 0-148
Sodium taurocholate
Sodium glycocholate
Cholesteriu .
Lecithin
Fats .
Inorganic salts
Water .
From the gall bladder (Hoppe-Peyler) in 100 pnrts
Mucin 1-29
0-055 Sodium taurocholate
0-87
0-165 Sodium glycocholate
303
Soaps
1-39
0038 Cholesterin
0-35
Lecithin
053
0-840 Pats .
0-73
98-7
THE LIVER AND BILE 761
During its stay in the bladder the bile is concentrated by the loss of
water and by the addition to it of mucin or nucleo-albumen, derived from
the cells lining the bladder. Of the other constituents of bile, the pigments
must be regarded simply as waste products, and an index to the disintegra-
tion of haemoglobin. Their mode of origin will be discussed in dealing with
the history of the red blood corpuscles. They pass into the intestine and
are there converted by the processes of bacterial reduction into stercobilin,
which is excreted for the most part with the faeces, a small proportion being
absorbed into the blood vessels and turned out in a more or less altered
condition as the pigments of the urine. From the point of view of digestion,
the important constituents of bile are the bile salts, with the lecithin and
cholesterin held in solution by these salts. The time relations of the secre-
tion, as well as of the flow of bile into the intestine in connection with the
processes of digestion, can be learnt from animals in which the bile is
conducted to the outside of the body by means of a permanent fistula.
For this purpose Pawlow has devised the following operation : In the dog the
abdomen is opened, and the common bile duct sought as it passes through the intestinal
wall. The orifice of the duct, with a piece of the surrounding mucous membrane,
is cut out of the wall of the intestine, and the aperture thus made sutured. The
excised portion of mucous membrane, with the opening of the duct, is then sewn on to
the surface of the duodenum, and the loop of duodenum at this point is stitched into
the abdominal wound. After healing, the natural orifice of the bile duct is thus made
to open on the surface of the abdomen.
In an animal treated in this way the flow of bile from the fistula is found
to run parallel to the pancreatic secretion. Although smaller in amount, it
rises and falls with the latter. Thus a meal of meat produces a large flow of
bile, a meal of carbohydrates only a small flow. Moreover, beginning almost
immediately after taking food, it attains its maximum with the pancreatic
juice in the third hour and then rapidly declines.
In the production of this flow of bile two factors may be involved : (1) the
emptying of the gall bladder; (2) an increased secretion of the bile. In
order to determine the relative importance to be ascribed to each factor,
we must compare the results obtained on an animal possessing a Pawlow
fistula with those obtained on an animal provided with a fistulous opening
into the gall bladder, the common bile duct in the latter having been ligatured
to ensure that the total secretion of bile passes out by the fistula. In such
animals we find, as we should expect, that the secretion of bile is a con-
tinuous process, but that, synchronously with the great outpouring of bile
into the intestine during the third hour after a meal, there is an increased
secretion of tins fluid. The passage therefore of the semi-digested food
from the stomach into the duodenum causes not only a slow contraction
and emptying of the gall bladder but also an increased secretion of bile by
the liver. What is the mechanism involved in the production of these two
effects ? The muscular wall of the gall bladder, as has been shown by Dale,
is under the control of nerves derived both from the vagus and from the
sympathetic, the former conveying motor and the latter inhibitory impulses.
It is usual to suppose that the entry of acid chyme into the duodenum
7G2 PHYSIOLOGY
provokes reflexly the concentration of the gall bladder, but the exact paths
and steps in this reflex act have not yet been fully determined. The increased
secretion of bile, which is produced by the passage of the acid chyme through
the pylorus, can be also evoked by the introduction of acid, such as 0-4 per
cent. HC1, into the duodenum, and occurs even after division of all con-
nection between the liver and the central nervous system. Since the
presence of bile is necessary for the full development of the activities of the
pancreatic juice, and its secretion is initiated by the same sort of stimulus,
i. e. acid applied to the mucous membrane of the gut, the question naturally
arises whether the mechanism for the secretion of bile may not be identical
with that for the secretion of pancreatic juice. In order to decide this
point we must make a temporary biliary fistula by inserting a cannula into
the hepatic duct. A solution of secretin is then prepared from an animal's
intestine. In making this solution we must be careful to avoid any con-
tamination by bile salts, which may possibly be adherent to the mucous
membrane of the gut and would in themselves, on injection, evoke an increased
secretion of bile. It is therefore better to extract the pounded mucous
membrane with boiling absolute alcohol, until this fluid, evaporated into
a small bulk, shows no trace of bile salts. The dried and powdered gut is
then boiled with dilute acid. On injecting the solution of secretin so obtained
into the animal's veins, an increased flow of bile is at once produced. In
one experiment, for instance, the injection into the veins of 5 c.c. of a solu-
tion of secretin, prepared in this way, increased the secretion of bile by the
liver from twenty-seven drops in fifteen minutes to fifty-four drops in
fifteen minutes. The rate of secretion was therefore doubled. We may
conclude that the mechanism, by which the increased secretion of bile is
produced at the time when this fluid is required in the intestine, is identical
with that for the secretion of pancreatic juice, and that in each case one
and the sam^ substance — secretin — is formed by the action of the acid on
the cells of the mucous membrane and, on absorption into the blood stream,
excites both the fiver and the pancreas to increased activity.
THE DIGESTIVE FUNCTIONS OF THE BILE
Bile contains a weak amylolytic ferment. Its uses in digestion are
dependent however, not on the presence of this ferment, but on the peculiar
action of the bile salts on the fermentative powers of the pancreatic juice.
It was shown long ago by Williams and Martin that the amylolytic power
of pancreatic extracts is doubled by the addition of bile or of bile salts.
Pawlow has stated that the same holds good of the proteolytic power of this
juice. Most important however is the part played by the bile in the diges-
tion and absorption of fats. The fat-splitting action of pancreatic juice is
trebled by the addition of bile, whether boiled or unboiled. This quickening
action of the bile probably depends, like its function in the absorption of
fats, on the peculiar physical properties of the bile salts, with those of the
lecithin and cholesterin which they hold in solution. Not only does such
a solution diminish the surface tension between watery and oily fluids, so
THE LIVER AND BILE 763
promoting the closer approach of the lipase of the pancreatic juice to the
fats on which it is to act, but it has also the power of dissolving fatty acids
and soaps, including even the insoluble calcium and magnesium soaps.
It is probable that it aids also in holding in solution, and bringing in con-
tact with the fat, the lipase of the pancreatic juice. It has been shown by
Nicloux that the lipase contained in oily seeds, such as those of the castor
plant, is insoluble in water, but soluble in fatty media. The dried ferment
obtained from the pancreas in many cases yields no lipase to water, but
gives a strongly lipolytic solution when extracted with glycerin. The
digestive function of bile therefore lies in its power of serving as a vehicle
for the suspension and solution of the interacting fats, fatty acids, and
fat-splitting ferment. This vehicular function plays an important part
in the absorption of fats. These pass through the striated basilar mem-
brane bounding the intestinal side of the epithelium, not, as was formerly
thought, in a fine state of suspension (an emulsion), but dissolved in the
bile in the form of fatty acids or soaps and glycerin. On the arrival of
these products of digestion in the epithelial cells, a process of resynthesis
is set up. Droplets of neutral fat make their appearance in the cells, whence
they are passed gradually into the central lacteal of the villus and so into
the lymphatics of the mesentery and into the thoracic duct. The bile
salts thus released from their function as carriers are absorbed by the blood
circulating through the capillaries of the villi, and carried by the portal
vein to the liver. On arrival they are once more taken up by the liver
cells and turned out into the bile. Owing to the fact of their ready excre-
tion by the liveT cells, bile salts are the most reliable cholagogues with
which we are acquainted . By this circulation of bile between liver and intes-
tine, the synthetic work of the liver in the production of the bile salts is
reduced to a minimum, and it has only to replace such of the bile salts as
undergo destruction in the alimentary canal under the influence of micro-
organisms, and are lost to the organism by passing out in the faeces as a
gummy amorphous substance known as dyslysin. Further investigation is
still wanted as to the exact method in which secretin acts on the liver cells,
and especially as to whether it actually excites in them the manufacture of
fresh bile salts, or whether it simply hastens the excretion of such bile salts
as have been formed by the spontaneous activity of the liver cells or have
arrived at them after absorption from the alimentary canal. Such questions
can be decided only by studying the action of secretin on animals possessing
a permanent biliary fistula.
The eSect of various diets on the secretion of bile has been studied by Barbera.
He finds that, whereas the secretion of bile is greatest on a meat diet, it is somewhat
less on a diet of fat, and is insignificant on a purely carbohydrate diet. That is to say,
l In- secretioD of bile is greatest on those diets the digestion of which is attended by the
passage of a large amount of acid chyme or of oil into the duodenum. Oil is almost
as efficacious as acid in promoting the production of secretin in the living duodenum,
the production in this case being probably determined by the formation of soap from
the oil and the direct action of the soap on the prosecretin in the epithelial cells of
the gut.
*s
SECTION VII
THE INTESTINAL JUICE
For the development of one of its most important properties, namely, that
of proteolysis, the pancreatic juice is dependent on the co-operation of the
intestinal juice or succus entericus. Besides this activating power on the
pancreatic juice, the intestinal juice has numerous other— functions to
discharge in the digestion of the foodstuffs. In spite of the great similarity
which obtains between the microscopic structure of the wall of the gut at
different levels from duodenum to ileocolic valve, functionally there are many
differences between the upper, middle, and lower portions of the gut.
Speaking generally, we may say that, whereas the processes of secretion are
better marked in the upper portions of the gut, the processes of absorption
predominate in the lower sections, i. e. in the ileum. Much of the divergence
in the statements which have been made with regard to the factors determin-
ing secretion and absorption in the small intestine is due to the failure to
appreciate this great difference between the activity of the mucous membrane
at various levels.
The process of secretion in the small intestine may be studied by isolating loops by
means of ligatures, and determining the amount of secretion formed in these loops in
the course of a few hours' experiment on an anaesthetised animal. Better results
however may be obtained by establishing permanent fistulse. These fistulas are of
two kinds. Thiry's original method of establishing a fistula consisted in cutting out
a loop of intestine, and restoring the continuity of the gut by suturing the two ends
from which the loop had been severed. The upper end of the loop itself is closed and
the lower end is sutured into the abdominal wound. For some purposes it is better
to make a Thiry-Vella fistula. In this case the continuity of the gut is restored as in
the simple Thiry fistula, but both ends of the excised loop are left open and brought
into the abdominal wound. In such a fistula it is easy to introduce substances into
the upper end and determine the flow of juice from the lower end, the constant empty-
ing of the loop being provided for by the peristaltic contractions of its muscular coat.
In animals with intestinal fistulae a number of different conditions have
been found to give rise to a flow of succus entericus, and so far no qualitative
difference has been recorded between the upper and lower ends of the gut.
A condition which will cause a free flow of juice from a fistula high up in the
intestine will generally cause a scanty flow from a fistula made from the
ileum. In all cases it is found that a flow of juice is produced in consequence
of a meal. If a dog with a fistula, which has been starved for twenty-four
hours, be given a meal of meat, a flow of juice may begin within the next
7G4
THE INTESTINAL 5 JUICE 765
ten minutes. The flow remains very slight for about two hours and then
suddenly increases in amount during the third hour, corresponding thus
very nearly to the flow of pancreatic juice excited by the same means. In
this post-prandial secretion of juice it is not probable that the nervous system
takes any very large share, though its intervention in the secretion has not
been excluded by direct experiment.
There are certain facts which seem indeed to speak for an action of the central
nervous system on the process of intestinal secretion, not in the direction of augmenta-
tion, but in the direction of inhibition of secretion. Thus it has been observed, on
many occasions, that extirpation of the nerve plexuses of the abdomen or section of
the splanchnic nerves causes a condition of diarrhoea which may last for two or three
days. This condition might be determined either by an increased motor activity of
the gut, or by removal of inhibitory impulses normally arriving at the intestinal glands.
Such a view receives support from an experiment first performed by Moreau. The
abdomen of a dog is opened under an anaesthetic, and three contiguous loops of small
intestine are separated by means of ligatures from the rest of the gut. The middle
loop is then denervated by destruction of all the nerve fibres lying on its blood vessels,
as they course through the mesentery, care being taken not to injure the blood vessels
themselves. The loops are then replaced in the abdomen and the animal left from
four to sixteen hours. On killing the animal at the end of this time, it is often found
that the middle loop, i. e. the denervated loop, is distended with fluid having all the
properties of ordinary intestinal juice, whereas the other two loops are empty. A
series of comparative experiments by Mendel and by Falloise have shown that the
secretion begins about four hours after the operation, increases for about twelve hours,
and then rapidly declines, so that at the end of two days all three loops will be found
empty. This has often been interpreted as due to the removal of inhibitory impulses
passing from the central nervous system to the local secretory mechanism, and we have
no direct evidence which can be adduced against such a view. It is possible however
that the hyperemia of the gut, which is produced by the process of denervation,
may be sufficient to account for the increased formation of intestinal juice, since the
hyperemia will tend to pass off as the vessels recover a local tone.
It is not possible to explain the flow of intestinal juice which follows a
meal by any assumption of nervous impulses transmitted through the local
nerve plexuses of the gut, since these have been divided in the making
of the fistula. If we exclude a nervous reflex action by the long paths,
namely, through the spinal cord and the sympathetic or vagus nerves, the
flow which attends the passage of food into the first part of the duodenum
must be excited by the formation of some chemical messenger. As to the
existence of such a chemical messenger or hormone for the intestinal secretion
there can be no doubt, bat the evidence as to its precise nature is at present
conflicting. It is stated by Pawlow that the most effective stimulus to the
flow of succus entericus is the presence of pancreatic juice in the loop of
gut. No evidence has yet been brought forward that injection of pancreatic
juice into the blood stream will cause any flow of intestinal juice. On the
other hand, Delezenne and Frouin have shown that, in animals provided
with a permanent fistula involving the duodenum or upper part of the
jejunum, intravenous injection of secretin always causes a secretion of
intestinal juice. In the upper part of the gut therefore, the simultaneous
presence of the three juices necessary for complete duodenal digestion, is
ensured by one and the same mechanism, namely, by the simultaneous
766 PHYSIOLOGY
activity of the secretin, produced in the intestinal cells by the action of the
acid chyme, on pancreas, liver, and intestinal glands. A further chemical
mechanism for the arousing of intestinal secretion has been described
by Frouin. According to this observer, the flow of juice can be excited by
intravenous injection of intestinal juice itself. Since this juice is alkaline
and does not produce any effect on the pancreas, it must be free from pan-
creatic secretin. It would seem therefore that the flow of juice in the upper
part of the gut, excited by the pancreatic secretin, causes also a production of
a different secretin or hormone, which can be absorbed from the lumen of the
gut, travel by the blood stream to other segments of the small intestine, and
there excite a secretion in preparation for the on-coming food. Further
experiments are however necessary on this point.
The glands of the small intestine can also be excited by direct mechanical
stimulation of the mucous membrane. The easiest method of exciting a
flow of intestinal juice from a permanent fistula is to introduce into the
intestine a rubber tube. The presence of the solid object in the gut causes
a secretion, and within a few minutes drops of juice can be obtained from
the free end of the tube. The object of such a sensibility to mechanical
stimuli is obvious; it is of the highest importance that the onward passage
of any solid object, especially if it .be indigestible, shall be aided by the
further secretion of juice in the portions of gut which are immediately
stimulated. This mechanical stimulation probably acts on the tubular
glands of the intestine through the intermediation of the local nervous
system, the plexus of Meissner. It is stated by Pawlow that a juice obtained
by mechanical stimulation differs from that produced by the introduction of
pancreatic juice into the loop in containing little or no enterokinase, so that
the pancreatic juice excites the secretion of the substance which is necessary
for its own activation.
CHARACTERS OF INTESTINAL JUICE
The intestinal juice obtained from a permanent fistula has a specific
gravity of about 1010. It is generally turbid from the presence in it of
migrated leucocytes and disintegrated epithelial cells. It contains about
1-5 per cent, total solids, of which 0-8 per cent, are inorganic and consist
chiefly of sodium carbonate and sodium chloride. It is markedly alkaline in
reaction, but less so than the pancreatic juice. The organic matter, besides
a small amount of serum albumin and serum globulin, includes a number of
ferments, all of which are adapted to complete the processes of digestion
of the foodstuffs commenced in the stomach and duodenum. Of these
ferments two are concerned in proteolysis. Enterokinase we have already
studied in detail. Possessing itself no action on proteins, its presence is
necessary for the development of the full proteolytic powers of the pancreatic
juice. In addition to this ferment another ferment has been described by
Cohnheim under the name ' erepsin.' Erepsin or some similar ferment is
present in the fresh pancreatic juice and in almost all tissues of the body. It
THE INTESTINAL JUICE 767
i.s distinguished by the fact that, although it has no power of digesting coagu-
lated protein or gelatin, and only slowly dissolves caseinogen and fibrin, it
has a rapid hydrolytic effect on the first products of proteolysis, converting
alburnoses and peptones into amino- and diamino-acids — their ultimate
cleavage products.
The other ferments of the intestinal juice are connected with the digestion
of carbohydrates. In all mammals the intestinal jaice is found to contain
inverlase, which transforms cane sugar into glucose and lsevulose or fructose,
and maltose, which converts maltose into glucose. In mammals the
intestinal mucous membrane also contains lactase, i. e. a ferment converting
milk sugar into galactose and glucose. Such a ferment can be extracted
from the mucous membrane of all young animals, but may be very slight or
even absent in the intestines of older animals, when it is no longer needed for
the ordinary processes of nutrition. By means of these three ferments,
coming as they do after the digestion of the starches by the amylase of the
saliva and pancreatic juice, it is provided that all the carbohydrate food of
the animal is transformed into a hexose, in which form alone carbohydrate
can be taken up and assimilated by the cells of the body. The seat of origin
of these various ferments has been the subject of special investigations by
Falloise. Whereas secretin can be obtained from the whole thickness of the
mucous membrane, and is probably therefore contained in the form of
prosecretin in the epithelial cells covering the villi as well as in those lining
the follicles of Lieberkiihn, a superficial scraping of the mucous membrane,
which removes only the epithelial cells covering the villi with the adherent
mucus and intestinal secretion, gives a much more active solution of entero-
kinase than a deeper scraping. The most active solutions of enterokinase
are however to be obtained from the fluid found in the cavity of the intestine
after the injection of secretin. It seems therefore that enterokinase is not
present as such in the epithelial cells, but is first produced in the process of
secretion and formation of the intestinal juice. The other ferments, namely,
erepsin, maltose, inverlase, and lactase, probably pre-exist as such in the
epithelial cells, especially in those lining the tubular glands of the gut, since
pounded mucous membrane in water yields a solution of these ferments which
is generally more powerful in its action than the succus entericus itself. So
great is the difference, in fact, that many physiologists have suggested that
the chief action of these ferments occurs, not in the lumen of the gut, but in
the passage of the foodstuffs through the epithelial cells of the small intestine
on their way to the blood vessels.
SECTION VIII
FUNCTIONS OF THE LARGE INTESTINE
Grkat differences are found in the structure of the large intestine of different
animals, differences which depend, not on the zoological position of the
animal, but entirely on the nature of its food. In the carnivora the large
intestine is short and narrow and possesses little or no caecum. In herbivora
the large intestine is well developed with sacculated walls, and the caecum — -
i. e. that part of the large gut distal to the opening of the ileum into the
colon— is very large. Man occupies a somewhat intermediate position be-
tween these two classes. The differences between the total length of the
alimentary canal in various animals are largely determined by the varying
development of the large intestine. The relation of these differences to the
diet is seen if we compare the length of the intestine with the length of the
animal. Thus in the cat the intestine is three times the length of the animal,
in the dog from four to six times, in man from seven to eight times, in the
pig fourteen times, and in the sheep twenty-seven times. The great develop-
ment of the large intestine in vegetable feeders is due to the fact that, in this
class of food, all the nutritious material is enclosed in cells surrounded by
cellulose walls. In order that the foodstuffs — e.g. proteins, starch, etc. — •
may be dissolved by the digestive juices and absorbed by the wall of the
gut, these cellulose walls must be disintegrated. In none of the higher verte-
brates do we find any cellulose-digesting ferment, cytase, produced in the
alimentary canal. The cellulose has therefore to be dissolved either by the
agency of bacteria or by means of cellulose-dissolving ferments which may be
present in the vegetable cells themselves. Thus in ruminants the masses of
grass and hay are first received into the paimch, where they are kept warm
and moist with saliva. In the paunch opportunity is thus given for the
development of huge numbers of micro-organisms which can dissolve cellu-
lose. From time to time portions of the sodden mass are returned to
the mouth, chewed and then swallowed again to be subjected to the action
of the proper digestive juices. In the horse and rabbit the chief part of the
digestion of the cellulose occurs in the C33cum. Even after abstinence from
food for some time the caecum is still found to contain food material. In the
caecum, under the action of bacteria, the cellulose is dissolved and the cells
are opened up so as to allow their contents to escape. The products of
digestion of cellulose include a number of organic acids, chiefly of the lower
fatty acid series, as well as methane, carbon dioxide, and hydrogen. In the
paunch the acids accumulate so that fermentation occurs in an acid medium,
768
FUNCTIONS OF THE LARGE INTESTINE 769
whereas in the caecum the acids are neutralised by the secretion of alkalies
and the reaction remains practically neutral. The products of digestion
of cellulose, as well as the contents of the vegetable cells set free by the
solution of the cell walls, are gradually absorbed by the walls of the large gut.
In carnivora the large intestine has very unimportant functions to discharge
in digestion and absorption. The proteins of meat are practically entirely
absorbed by the time that the food has arrived at the ileocolic valve, and the
same applies to fat. In man the importance of the large intestine will vary
with the nature of his food. Under the conditions of civilised life the food
material is almost entirely absorbed by the time that it reaches the lower end
of the ileum. If however a large quantity of vegetable food be taken, such
as fruit or green vegetables, or cereals roughly prepared and coarsely ground,
a considerable amount of material may reach the large intestine unabsorbed.
A certain proportion of this may undergo absorption in the large intestine,
while the rest will pass oat with the faeces, increasing their bulk.
It is hardly possible to speak of a secretion by the mucous membrane
of the large intestine. In herbivora alkaline carbonates are secreted to
neutralise the acids produced in the bacterial fermentation of the food, but
the processes of absorption and secretion keeping pace, there is no accumu-
lation of the products of secretion in the intestine. A section of the mucous
membrane shows a number of simple tubular glands. The greater number of
the cells liniug these glands are typical ' goblet ' cells and contain plugs of
mucin. The secretion of mucus not only aids the passage of the faeces
along the gut, but probably impedes the propagation of the bacteria which
are present in countless numbers in the faeces. This may account for the
fact that although bacteria are so numerous in the faeces, it is difficult to
cultivate any large numbers, most of them being dead.
As an absorbing organ the large intestine of man is of little importance.
From observations on fistulae in man it has been calculated that about 500
c.c. of water pass the ileocolic valve in the twenty-four hours. Of these about
400 c.c. undergo absorption in the large intestine. The absorption of any
of the food substances by this part of the gut is much slower than that which
takes place on introduction by the mouth. Feeding by nutrient enemata
is thus always very inadequate. In some cases after the introduction of
large enemata into the large intestine, a certain amount may escape back-
wards into the ileum and may there undergo absorption. The isolated large
intestine of man is able to absorb only about 6 grm. of dextrose per
hour and about 80 c.c. of water. If egg albumin or caseinogen solutions
be introduced by the rectum, no absorption can be detected after several
hoars. In observations extending over a considerable time, some disappear-
ance has been observed of proteins and emulsified fats, as well as of boiled
starch. This was due however to the action of bacteria on these substances,
and was probably of very little value for the nourishment of the individual.
Feeding by nutrient enemata is thus merely a method of slow starvation.
If it is employed it should be limited to administration of water, salines,
or solutions of glucose.
49
770 PHYSIOLOGY
The chief value of the large intestine in carnivora and in civilised man
would seem to be as an excretory organ, since it plays an important part in
the excretion of lime, magnesium, iron, and phosphates. Lime salts are
excreted partly with the faeces, partly in the urine. The path taken by the
lirne under different conditions varies with the character of the other con-
stituents of the food. If phosphates are present in large quantities, the
greater part of the lime will be excreted by the large intestine and escape
with the faeces as insoluble calcium phosphate. If acids be administered,
such as hydrochloric acid, the amount of lime in the urine will increase, that
in the faeces will diminish. Thus in herbivora normally only about 3 to 6
per cent, of the lime is excreted with the urine, whereas in carnivora with
an acid urine the proportion leaving the body by this channel rises to
27 per cent. The excretion of magnesium is determined by very similar
conditions. Its phosphates are somewhat more soluble than those of lime.
In man about 50 per cent, of the magnesium leaving the body is contained in
the urine, whereas the amount of lime in the faeces is ten to twenty times
as much as. that contained in the urine. It must be remembered that the
whole of this difference is not due to excretion of lime into the gut, since a
certain proportion of this substance may be precipitated as an insoluble
phosphate or carbonate in the upper part of the small intestine and pass
through the gut without undergoing absorption.
The absorption of iron takes place in the duodenum and upper part of
the jejunum. Only 1 or 2 milligrammes appear in the urine, all the rest
being excreted in the large gut and appearing in the faeces, chiefly as sulphide
of iron.
Of the acid radicals phosphates may pass out either with the urine or with
the faeces, the exact path taken being determined by the relative amount of
calcium and alkaline metals present in the food. If there is an excess of
calcium most of the phosphates will leave with the faeces.
The large intestine is the main channel of excretiou for certain substances
which cannot be regarded as normal constituents of the food, e. g. the heavy
metals, such as bismuth and mercury. If bismuth be administered sub-
cutaneously, the faeces will be found to contain this substance, and the wall
of the large intestine will be stained black from a deposit of sulphide of
bismuth. This deposit stops short at the ileocolic valve. The excretion
of mercury by the wall of the large intestine may account for the frequent
presence of ulceration of + his part of the gut in cases of poisoning by mercury.
SECTION IX
MOVEMENTS OF THE INTESTINES
The movements of the intestines can be investigated either by observation
of the exposed gut, or by the shadow method introduced by Cannon, in which
the nature of the movements is judged from the shadows of food containing
bismuth which are thrown on a sensitive screen by means of the Rontgen
rays. These movements have been the subject of experimental investigation
for many years, but with varying results. The great discrepancy which
obtained between the statements of earlier observers is due to the fact that
they failed to exclude the many disturbing impulses which can play on any
segment of the gut, either reflexly through the central nervous system, or
from other parts of the alimentary canal itself through the local nervous
system. In order to observe the normal movements of the gut, it is neces-
sary to exclude the disturbing influences due to reflexes through the central
nervous system, either by extirpation of the whole of the nerve plexuses in
the abdomen, or by division of the splanchnic nerves, or by destruction of the
lower part of the spinal cord from about the middle dorsal region. If the
abdomen of an animal, which has been treated in this way, be opened in a
bath of warm normal salt solution, so as to exclude the disturbing influence
of drying and cooling of the gut, the small intestine will be seen to present
two kinds of movements. In the first place, all the coils of gut undergo
swaying movements from side to side — the so-called pendular movements.
( lareful observation of any coil will show that these movements are attended
with slight waves of contraction passing rapidly over the surface. If a
rubber balloon, filled with air and connected with a tambour, be inserted
into any part of the gut, it will reveal the existence of rhythmic contractions
of the circular muscle repeated from twelve to thirteen times per minute.
By means of a special piece of apparatus (the ' enterograph ') it is possible
without opening the gut to record the movements of either circular or
Longitudinal muscular coats; and it is then found that both coats present
rhythmic contractions at the same rate, the two coats at any point con-
tracting synchronously. When the contractions are recorded by means of a
balloon, the constriction which accompanies each contraction is seen to
be most marked at the middle of the balloon, i. e. at the point of greatest
tension, and the amplitude of the contractions is augmented by increasing
the tension on the walls of the gut. These movements are unaffected by
the direct application of drags such as nicotine or cocaine, which we might
771
772 PHYSIOLOGY
expect to paralyse any local nervous structures in the wall of the gut.
Bayliss and Starling concluded that these rhythmic contractions were
myogenic, 1 that they were propagated from muscle fibre to muscle fibre, and
that they coursed down the gut at the rate of about 5 cm. per second. Since
however they may apparently arise at any portion of the gut which is subject
to any special tension, it is not easy to be certain that a contraction recorded
at any point is really propagated from a point two or three inches higher up.
These contractions must cause a thorough mixing of the contents of the gut
with the digestive fluids. On examining under the Rontgen rays the
intestines of a cat which has taken a large meal of bread and milk mixed with
bismuth some hours previously, a length of gut may be seen in which the
food contents form a continuous column. Suddenly movements occur in this
i v - — — -~^j
' CD CD CD CD CD M '
FlG. 354. Diagram of the ' segmentation ' (pendular) movements of the intestines as
observed by the Rontgen rays, after administration of bismuth. (Cannon.)
I. A continuous column, intestinal movements being absent. 2. The column
broken up into segments. 3. Five seconds later, each segment divided into two,
the halves joining the corresponding halves of adjacent segments. 4. Condition
(2) repeated five seconds later.
column, which is split into a number of equal segments. Within a few
seconds each of these segments is halved, the corresponding halves of adja-
sent segments uniting. Again contractions recur in the original positions,
dividing the newly formed segments of contents and re-forming the segments
in the same position as they had at first (Fig. 354). If the contraction is a
continuous propagated wave, it is evidently reinforced at regular intervals
down the gut, so as to divide the column of food into a number of spherical
or oval segments. The points of greatest tension immediately become the
points which are midway between the spots where the first contractions
were most pronounced. The second contractions therefore start at these
points of greatest tension, and divide the first formed segments into two parts,
which join with the corresponding halves of the neighbouring segments. In
this way every particle of food is brought successively into intimate contact
with the intestinal wall. These movements have not a translatory effect, and
1 Magnus has shown that strips of the longitudinal coat, pulled off from the small
intestine of the cat, may continue to beat regularly in oxygenated Ringer's solution. He
stated that these contractions occurred only if portions of Auerbach's plexus were still
adherent to the muscle fibres, and concluded therefore that the rhythmic, like the
peristaltic, contractions were neurogenic. Gun and Underhill however have obtained
well-marked rhythmic contractions from strips of muscle entirely free from any remains
of the nerve plexus, thus confirming the view enunciated above.
MOVEMENTS OF THE INTESTINES 773
a column of food may remain at the same level in the gut for a considerable
time.
The onward progress of the food is caused by a true peristaltic contrac-
tion, i. e. one which involves contraction of the gut above the food mass and
relaxation of the gut below. If a balloon be inserted in the lumen of the.
exposed gut, it will be found that pinching the gut above the balloon causes
an immediate relaxation of the muscular wall in the neighbourhood of the
balloon. This inhibitory influence of the local stimulus may extend as
much as two feet down the intestine towards the ileocaecal valve. On the
other hand, pinching the gut half an inch below the situation of the balloon
causes a strong continued contraction to occur at the balloon itself (Fig. 355).
Fig. 355. Intestinal contraptions (balloon method). In this dog all the abdominal
ganglia had been excised, and both vagi cut. Showing propagated effects of
mechanical stimulation above and below the balloon.
(1) pinch above, (2) pinch below, (3) pinch below balloon.
Stimulation at any portion of the gut causes contraction above the point of
stimulus and relaxation below the point of stimulus (the ' law of the intes-
tines '). The same effect is produced by introduction of a bolus of food,
especially if it be large or have a direct irritating effect on the wall of the gut
(Fig. 356). In this case the contraction above and the inhibition below
cause an onward movement of the bolus, which travels slowly down the
whole length of the gut until it passes through the ileocaecal opening into
the large intestine. The peristaltic contraction involves the co-operation of
a nervous system. Whereas in the oesophagus it is the central nervous
system which is involved, the peristaltic contractions in the small intestine
occur after severance of all connection with the brain and spinal cord. On
the other hand, they aTe absolutely abolished by painting the intestine with
nicotine or with cocaine. They must therefore be ascribed to the local
nervous system contained in Auerbach's plexus, which we can regard
as a lowly organised nervous system with practically one reaction,
namely, that formulated above as the 'law of the intestines.' An anti-
peristalsis is never observed in the small intestine. Mall has shown that,
if a short length of gut be cut out and reinserted in the opposite diredion, a
species of partial obstruction results, in consequence of the fact that the peri-
staltic waves, started above the point of operation, cannot travel downwards
774 PHYSIOLOGY
over the reversed length of gut. The intestine above this point therefore
becomes dilated. If however the reactions of the local nervous system
be paralysed or inhibited, a reflux of intestinal contents is quite possible, since
the contractions excited at any spot by local stimulation (if the muscle have
the effect of driving the food either upwards or down wards ; the direction of
movement of tke food will be that of least resistance.
The movements of the small intestine, are also subject to the central
nervous system. Stimulation of the vagus has the effect of producing an
initial inhibition of the whole small intestine, followed by increased irrita-
bility and increased contractions (Fig. 357). On the other hand, stimulation
of the splanchnic nerves causes complete relaxation of both coats of the small
gut (Fig. 358). It seems that the splanchnics normally exercise a tonic
Fie:. 356. Passage of bolus. Contractions of longitudinal coat (enterograph). The
bolus (of soap and cotton-wool) was inserted into the intestine four inches above the
recorded spot at A. The figures below the tracing indicate the distance of the middle
of the bolus from the recording levers. As the bolus arrives two inches above the
levers, there is cessation of the rhythmic contractions and inhibition of the tone of
the muscle. This is followed, as the bolus is forced past, by a strong contraction in
the rear of the bolus.
inhibitory influence on the intestinal movements, which can be increased by
all manner of peripheral stimuli. On this account it is often impossible to
obtain any movements in the exposed intestine so long as these remain in
connection with the central nervous system through the splanchnic nerves.
The relaxed condition of the gut which obtains in many abdominal affections
is probably also reflex in origin, and is due to reflex inhibition through the
splanchnic nerves.
As a result of the two sets of movements described above, the food is
thoroughly mixed with the digestive juices, and the greater part of the
products of digestion are brought into contact with the intestinal wall and
absorbed. What is left — a proportion varying in different animals according
to the nature of the food — is passed on by occasional peristaltic contractions
through the lower end of the ileum into the colon, or large intestine. The
lowest two centimetres of the ileum present a distinct thickening of the
circular muscular coat, forming the ileocolic sphincter. This sphincter relaxes
in front of a peristaltic wave and so allows the passage of food into the colon.
On the other hand, it contracts as a rule against any regurgitation which
might be caused by contractions in the colon. Although thus falling into
line with the rest of the muscular coat as concerns its reaction to stimuli
MOVEMENTS OF THE INTESTINES 775
arising in the gut above or below, it presents a marked contrast to the rest of
the gut in its relation to the central nervous system. It is unaffected by
stimulation of the vagus. Stimulation of the splanchnic however, which
Fig. 357. Effect of stimulation of right vagus on intestinal contractions.
Fig. 358. Excitation of both splanchnic nerves. Balloon method. Intestine
returned to abdomen.
causes complete relaxation of the lower part of the ileum with the rest of the
small intestine, produces a strong contraction of the muscle fibres forming the
ileocolic sphincter (Elliott).
MOVEMENTS OF THE LARGE INTESTINE
By means of the occasional peristaltic contractions, accompanied by
relaxation of the ileocolic sphincter, the contents of the small intestine
are gradually transferred into the large. In man these contents are
considerable in bulk, are semi-fluid, and probably fill the ascending as well
as the transverse colon.
776 PHYSIOLOGY
The large intestine is supplied with nerves from the central nervous
system. These run partly in the sympathetic system along the colonic
and inferior mesenteric nerves, partly in the pelvic visceral nerves or nervi
erigentes, which come off from the sacral cord and pass direct to the pelvic
viscera. In addition it possesses a local nervous system, presenting the
same structure as that found in the small intestine. The movements of the
large intestine differ considerably in various animals, as has been shown by
Elliott, according to the nature of the food and the part played by this
portion of the gut in the processes of absorption. In the dog absorp-
tion is almost complete at the ileocolic valve, whereas in the herbivora a very
large part of the processes of digestion and absorption occurs in the colon and
csecum. Man takes an intermediate position as regards his large intestine
between these two groups of animals. Elliott and Barclay Smith divide
the large intestine into four parts, according to their functions, viz. the
csecum, and the proximal, intermediate, and distal portions of the colon.
Of these the dog possesses practically only the distal colon. We may take
Elliott's account of the movements as they probably occur in man. They
agree very closely with those observed by Cannon under normal circum-
stances in the cat by means of the Kontgen rays. The food as it passes from
the ileum first fills up the proximal colon. The effect of this distension is to
cause a contraction of the muscular wall at the junction between the ascend-
ing and transverse colon. This contraction travels slowly over the tube
in a backward direction towards the cascum, and is quickly succeeded by
another, so that the colon may present at the same time several of these
advancing waves. These waves are spoken of as anti-peristaltic; but as
they do not involve also an advancing wave of inhibition, they must not
be regarded as representing the exact antithesis of a peristaltic wave, as we
have defined it. The effect of these waves is to force the food up into the
csecum, regurgitation into the ileum being prevented partly by the obliquity
of the opening, partly by the tonic contraction of the ileocolic sphincter.
As the whole of the contents cannot escape into the caecum, a certain portion
will slip back in the axis of the tube, so that these movements have the same
effect, as the similar contractions in the pyloric end of the stomach, causing a
thorough churning up of the contents and its close contact with the intestinal
wall. The movements are rendered still more effective by the sacculation of
the walls of this part of the large intestine. The distension of the csecum
paused by this anti-peristalsis excites occasionally a true co-ordinated
peristaltic wave which, starting in the csecum, drives the food down the
intestine into the transverse part. These waves die away before they reach
the end of the colon, and the food is driven back again by waves of anti-
peristalsis. Occasionally more food escapes through the ileocolic sphincter
from the ileum, so that the whole ascending and transverse colon may be filled
with the mass undergoing a constant kneading and mixing process. The
result of this process is the absorption of the greater part of the water of the
intestinal contents, as well as of any nutrient material ; and the drier part of
the intestinal mass collects towards the splenic flexure, where it may be
MOVEMENTS OF THE INTESTINES 777
separated by transverse waves of constriction from the more fluid parts
which are being driven to and fro in the proximal and intermediate portions.
By means of occasional peristaltic waves these hard masses are driven into
the distal part of the colorr. The distal colon must be regarded as a place
for the storage of the faeces and as the organ of defsecation. In the transverse
colon, in the descending and iliac colon, the anti-peristaltic movements and
consequent churning of the contents are probably slight. These therefore
represent the intermediate colon, with propulsive peristalsis as its chief
activity. The descending colon is never distended, and Elliott therefore
Fia. 359. Skiagram to show normal position of colon in man, and the position attained
by its contents at different periods after a meal containing bismuth. The bismuth
meal was taken at 8 a.m. The timos of arrival at different leveLs are marked on tho
colon. (Hertz. )
regards it as a transferring segment of exaggerated irritability. The
storage of the waste matter takes place chiefly in the sigmoid flexure.
This with the rectum represents the distal portion of the colon. The dis-
tinguishing feature of the distal colon is its complete subordination to the
spinal centres. It probably remains inactive until an increasing distension
excites reflexly through the pelvic visceral nerves a complete evacuation of
this portion of the gut. Stimulation of these nerves in an animal, such as the
cat, produces a rapid shortening of the distal part of the colon, due to
contraction of the recto-coccygeus and longitudinal fibres of the gut, followed
after some seconds by a contraction of the circular coat. This originates
at the lower limit of the area of anti-peristalsis, i. e. probably at the upper end
of the sigmoid flexure, and spreading rapidly downwards empties the whole
of this segment of the gut. In man the emptying of the rectum itself is
largely assisted by the contractions of the voluntary muscles of the
abdominal walls and pelvic floor.
The last section of the rectum is emptied at the close of the act, by a
778 PHYSIOLOGY
forcible contraction of the levator ani and the other perineal muscles, and
I his contraction also serves to restore the everted mucous membrane.
The carrying out of this reflex act is dependent on the integrity of a certain
part of the lumbar spinal cord. If this 'centre' be destroyed, the tonic
contraction of the sphincter muscles disappears. This centre may be either
excited to increased action, or be inhibited by peripheral stimulation of
various nerves or by emotion such as fear. Application of warmth to the
region of the anus causes reflex relaxation of the sphincter; application of
cold increases its tonic contraction.
In man, as Hertz has shown by the skiagraphic method, the pelvic
colon becomes filled with faeces from below upwards, the rectum remaining
empty till just before defalcation. In individuals whose bowels are opened
regularly every morning after breakfast, the entry of faeces into the rectum
gives rise to a sensation of fulness and acts as the call to defalcation. If
no response be made, the desire to defaecate passes away, since the rectum
relaxes and the faecal mass no longer exercises pressure on its wall. ' Hertz
has shown that the minimal pressxire required to produce the call to defaecate
varies from 30 to 40 mm. Hg., according to the length of the gut which is the
seat of distension.
SECTION X
THE ABSORPTION OF THE FOODSTUFFS
THE ABSORPTION OF WATER AND SALTS
The intake of water and probably of salts by the alimentary canal, in
accordance with the requirements of the organism as a whole, seems to
be regulated almost entirely by the central nervous system, the higher parts
of this system, viz. those concerned with appetite, being particularly
involved in the process. Thus in man any large loss of fluid to the body,
as by sweating, diarrhoea, haemorrhage, gives rise to an intense thirst that
has its natural reaction in increased intake of water by the mouth. On the
other hand, the property possessed by the alimentary canal of absorbing
water and weak saline fluids contained in its interior is veiy little influenced
by the state of depletion, or otherwise, of the water depot's of the body.
It is practically impossible, however large the quantities of fluid ingested,
to evoke the production of fluid motions, the greater part of the ingested
fluid being absorbed on its way through the alimentary canal. Thus a
man may keep himself in perfect health and maintain the water content of
his body constant whether he take one litre or six litres of water daily.
The whole process of regulation , apart from that determined by appetite, is
carried out at the other end of the cycle, viz. by the kidneys. As concerns
absorption of water there is no chemical solidarity between the alimentary
surface and the rest of the body. Whenever water is presented to this
surface it is absorbed and passes into the circulation.
The absorption of water in the stomach may be regarded as nil.
Although from this viscus alcohol and possibly peptone and sugar may
be absorbed to a slight extent, water or saline fluids introduced into it
are passed through the pylorus either without change or increased by the
secretion of fluid from the gastric glands. In no case is there a diminution
of fluid in the stomach.
The chief absorption of water occurs in the small intestine. It is on
this account that the salient features of cases of dilatation of the stomach
with stenosis, absolute or relative, of the pyloric orifice can be nearly all
referred to the starvation of the body in water, and can be often relieved
by the administration of water either subcutaneously or by the rectum, i. e.
by the channels through which absorption is still possible. The introduction
of water into the stomach simply increases the dilatation, but does not
relieve the intense thirst of the patient. Water that has been swallowed
779
780
PHYSIOLOGY
to quench thirst has first to be passed from the stomach into the small
intestine before it can be absorbed and relieve the needs of the tissues. The
intestinal contents at tin- ileocaecal valve contain relatively nearly as much
water as they do at the upper part of the jejunum. Their absolute bulk is
however much smaller, so that only a small proportion of the water that
has been taken in by the mouth remains to be absorbed in the large gut—
an amount probably much less than that which has been added to the
contents of the small intestine in the form of secretion by the stomach,
liver, pancreas, and intestinal tubules.
The main problem before us is therefore the mechanism of absorption
of water and saline fluids by the villi of the small intestine. By means
i lentra] lactea I
- Submucosa
Lymphatic plexus
Circular muscle
Lymphatic plexus
Longitudinal muscle
300. Diagrammatic section through wall of small intestine to show vascular and
lymphatic arrangements of mucous membrane. (After Mall.)
of these structures the absorbing surface of the intestine is largely increased.
It has been calculated that each square milhmetre of intestine represents
an absorbing surface of 3 to 12 mm. 2 Each villus (Fig. 360) consists of a
framework of reticular tissue containing many leucocytes in its meshes,
separated from the lumen of the gut by a continuous layer of columnar
epithelial cells. These cells rest on an incomplete basement membrane aud
present on the side turned towards the lumen of the gut a striated border.
The villus offers two channels by means of which material, which has passed
through the epithelium, may be carried into the general circulation. In
the centre of the villus is the central lacteal, a club-shaped vessel bounded
by a complete layer of delicate endothelial cells. This leads into a plexus
of lymphatics placed superficially to the muscularis mucosa?. From the
superficial plexus communicating branches pass vertically to a correspond-
ing plexus lying in the submucosa. The central lacteal and the superficial
plexus are free from valves, which however are present in abundance
in the deeper plexus, so that fluid can pass easily from the lacteal to the
THE ABSORPTION OF THE FOODSTUFFS 781
deeper plexus, but not in the reverse direction. From the muscularis
mucosa unstriated muscle fibres pass up through the villus to be attached
partly to the other surface of the central lacteal, partly by expanded
extremities to the basement membrane covering the surface of the villus.
Contraction of these muscle fibres will tend to empty the central lacteal
into the deep plexus of lymphatics and may also cause an expulsion of
the contents of the spaces of the retiform tissue of the villus into the central
lacteal. The alimentary canal represents one of the few localities where a
formation of lymph is constantly proceeding, even in a condition of com-
plete rest. On placing a cannula in the thoracic duct of a dog an outflow of
lymph is obtained which may vary in different animals between 1 c.c. and
10 c.c. in the ten minutes. The greater part of this lymph is derived from
the alimentary canal, so that any of the intestinal contents which have
made their way into the spaces of the villus might be entrained in this
lymph current and carried away with it into the thoracic duct and so into
the general blood system.
The other possible channel of absorption is by the capillary blood
vessels of the villus. Each villus is supplied with blood from one or two
arterioles which break up into a rich plexus of capillaries lying close under
the basement membrane of the villus. The return blood is collected into
one or two veins, which join the radicles of the portal vein in the submucosa
and in the mesentery. In these capillaries the blood is circulating rapidly,
so that a considerable amount of material may pass into them from the
spaces of the villus within, say, one hour without altering appreciably the
percentage composition of the blood. On the other hand, it must be remem-
bered that the blood in these vessels is at a high pressure, probably not less
than 30 mm. Hg., so that any absorption into the blood stream must occur
against this pressure. It is probable therefore that, in explaining any
absorption by the blood vessels, we shall have to place out of court any
possibility of the passage occurring in consequence of hydrostatic differences
of pressure, i. e. by a process of filtration'.
When salt solutions are introduced into the small intestine, they are
rapidly absorbed without the production of any corresponding increase in
the rate of lymph flow from the thoracic duct. On the other hand, the
absorption of large amounts of fluid may cause an actual diminution of
the solids of the plasma, so that we are justified in regarding the capillary
network of blood vessels at the surface of the villi as solely responsible for
the absorption.
What are the forces which cause this transference of fluid and dissolved
substances from one side to the other of the membrane composed of epithelial
cells plus capillary endothelium ? Like other cells, those of the intestinal
epithelium are bounded on their free surface by a ' lipoid ' membrane,
i. e. one containing some complex of lecithin and cholesterin and permeable
only by such substances as are soluble in lipoids. On the other hand, the
cement substance between the cells may be of a different character and
possibly permeable to water-soluble substances. The question has been
7«2 PHYSIOLOGY
propounded whether the greater part of the substances, which enter the
blood plasma from the gut, pass between the cells or through the cells. Water
could of course pass in either way. Most of the inorganic salts such as
sodium chloride, as well as the very important constituents of the food,
the sugars, are insoluble in lipoids and would have to pass between the
cells. When the question is investigated by the use of dyestuffs, soluble
or insoluble in lipoids, it is found that the lipoid-soluble dyestuffs, such
as neutral red or tohiidin blue, pass into the cells, whereas the dyestuffs
which are insoluble in such substances pass into the intercellular spaces.
Too much stress however must not be laid on these experiments. All these
dyestuffs are abnormal so far as the body is concerned. We cannot imagine
that, at any time in the course of evolution of the properties of the intestinal
epithelium, the cells were ever presented with or had to discriminate between
different dyestuffs. The fact that absorption of these dyestuffs is deter-
mined by the physical conditions of the cell membrane is no proof that the
absorption of the normal food constituents is determined in the same way.
In fact, it is quite legitimate to assume that the lipoid membrane or limit ing
layer round every cell has as its main office, not the regulation of the access
of foodstuffs to the cell, but its protection from any of the foodstuffs which
it does not require for its metabolism. If it were not for such a membrane
the assimilation of a salt would be determined entirely by its concentration
in the immediate surroundings of the cell, whereas we know that assimila-
tion by any living organism, whether uni- or multi-cellular, is regulated
in the first place by the activity of the organism itself. According to this
activity and the needs thereby induced, the uptake of food material may
be large or small whatever its concentration in the surrounding medium.
It would indeed be strange that the whole absorbing surface of the intestine
should be covered by a membrane, of which the greater part was useless
for the absorption of the common foodstuffs, as would be the case if these
could only penetrate the membrane by the narrow chinks between the
cells. It seems more probable that the absorption of the different food-
stuffs, and probably also of the normal salts of the body, is effected by
the cells themselves, in accordance with their nutritional needs, and this
view is strengthened when we come to examine into the absorption even
of normal saline solutions. If 50 c.c. of normal sodium chloride solution
be introduced into a loop of intestine, it is absorbed steadily, so that at
the end of an hour not more than about 20 c.c. may be recoverable. The
absolute amounts absorbed differ in various experiments, but are fairly
uniform for repeated observations on one and the same animal. The
absorption of such a solution could be ascribed to the osmotic pressure of
the colloids in the blood plasma or lymph within the spaces of the villi.
If, instead of using isotonic solutions, hypertonic solutions are employed,
e. g. a 2 or 3 per cent. NaCl solution, absorption still takes place, but may
be preceded by an interval in which there is an actual increase of the fluid
contained in the gut. Here again we might ascribe the absorption to the
physical factors present, were it not that absorption is found to commence
THE ABSORPTION OF THE FOODSTUFFS 783
before the fluid in the gut has attained isotonicity with the blood. In fact,
employing a 1-5 per cent, salt solution, absorption may occur from the
very beginning of the experiment. If such a solution is passed through
the epithelial membrane into the blood plasma with a smaller tonicity,
it is evident that work must be done in the process, work which can only
be furnished by the cells of the epithelium. When sugar solutions are
employed they behave in somewhat similar fashion to sodium chloride
solutions, provided that the sugar is one of the absorbable hesoses, both
sugar and water being rapidly absorbed. It is important to note that
dextrose is absorbed from the gut almost as rapidly as sodium chloride, and
quite as rapidly as sodium iodide, although its diffusibility is very consider-
ably less than either of these salts. Moreover, great differences are found
between the rate at which different sugars are absorbed, differences which
are not referable to the diffusibility of the sugars in question. Thus the
monosaccharides glucose, fructose, galactose are absorbed with double
the rapidity of solutions of cane sugar and maltose, and it seems that, in
the absence of hydrolytic splitting of the disaccharides, absorption from the
gut would be entirely abolished. Lactose disappears from the intestine
much more slowly than either of the other two disaccharides, so that large
doses may give rise to a laxative effect. In animals devoid of lactase, the
lactose-splitting ferment, in their intestinal epithelium milk sugar is apparently
not absorbed at all.
The most cogent argument, perhaps, in favour of an active intervention
of the cells of the gut in the process of absorption is furnished by the study
of the absorption of blood serum. It has been shown that if an animaFs
own serum be introduced into a loop of its intestine the serum undergoes
absorption. This absorption affects the water and salts more than the
protein, so that the percentage of the proteins in the fluid remaining in the
intestine is increased. Finally however the whole of the serum is absorbed.
In this case the fluid within the gut is identical with the fluid within the
blood vessels. There are no differences in concentration, quality of salts,
or osmotic pressure of proteins. Nevertheless water passes through the
cells of the gut from their inner to their outer sides, entraining with it the
salts of the serum and a certain proportion of the indiffusible proteins. It
is impossible to explain this result as due to the digestion of the proteins
and their conversion into diffusible products, since the intestinal loops
were washed free of any trypsin that they contained, and serum has itself
' a strong antitryptic action which would prevent its being attacked by a
solution of trypsin.
The active intervention of the cells in the absorption of salt solutions
and serum can be abolished by any means which diminishes or destroys
their vitality, such as the addition of sodium fluoride to the fluid to be
absorbed, or destruction of the epithelium by previous temporary occlusion
of the blood vessels supplying the loop of intestine.
We must conclude that, when a fluid is introduced into the intestine, an
active transference of water from the lumen into the blood stream is effected
784 PHYSIOLOGY
by the intermediation of forces having their origin in the metabolism of the
cells themselves. This work of absorption of the cells may be aided or
hindered according to the physical conditions present. If these act against
the cells, e.g. if the fluid be hypertonic, the absorption is effected more
slowly, while with hypotonic solutions the physical conditions concur with
the vital activity of the cells in bringing about a very rapid transference of
fluid from the gut into the blood vessels. Among these physical conditions
we must reckon the nature of the salts present in the solution. If these
can pass easily into and through the cells, e.g. ammonium salts, sodium
chloride, absorption is carried out rapidly. If on the other hand the salts
in the intestinal contents are but shghtly diffusible or have very little power
of penetrating into the cells, the absorption of water by the cells causes an
increased concentration of the salts, and therefore an increased osmotic
pressure which offers a resistance to any further absorption; and the
process comes to an end when the absorptive power of the cells is exactly
balanced by the increased osmotic pressure, or attraction for water, of the
intestinal contents.
Cushny and Wallace, as the result of their experiments on the relative absorbability
of salt solutions from the gut, divide the salts into, four main classes as follows :
I
II
Ill
IV
Sodium chloride,
Ethyl sulphate,
Sulphate, phosphate,
Oxalate,
bromide, iodide,
nitrate, lactate, sali-
ferrocyanide, capry-
fluoride.
formate, acetate,
cylate, phthalate.
late, malonate, succi-
propionate, butyrate,
nate, malate, citrate,
valerianate, caprate.
tartrate.
Of these the first class contains those salts which are absorbed with great ease
from the intestine. The second group of salts are absorbed with somewhat greater
difficulty. The third group are absorbed so slowly, i. e. the salts retain the water in
which they are dissolved so long that they increase peristalsis and act as laxatives or
purgatives. The members of the fourth class are not absorbed at all. It is evident
that this classification is independent of the diffusibility of the salts. Sodium acetate
has a much smaller dissociation value and a lower diffusibility than sodium chloride
or iodide, and yet is absorbed at approximately the same rate as these two salts. There
is however, as Cushny pointed out, one physical or chemical character which apparently
determines the non-absorbability (relative or absolute) of the members of the tliird
and fourth classes. All these salts form insoluble compounds with calcium. This
common character is not an explanation of the permeability of the cell wall, but is
simply a general statement of one of the conditions which affect the power of the cells
to take up salts from their solutions, this power being absent in the case of salts which
furnish an insoluble calcium compound.
THE ABSORPTION OF FATS
Fats administered to an animal in excess of its diurnal requirements
are stored up in the body in the form in which they are administered. Each
cell of the body probably possesses in itself the mechanism for the utilisation
of these neutral fats, and for effecting in them the various changes involved
in the successive stages of their disintegration and oxidation through which
they are finally converted to C0 2 and water. The problem therefore of fat
THE ABSORPTION OF THE FOODSTUFFS 785
absorption is ultimately one of the simplest with which we have to deal,
and involves merely the transference of the neutral fat of the food to the
circulating fluids in such a form that it can be carried by them to the place
where it is required for the metabolism of the body or where it may be
stored up as a reserve substance.
The processes of digestion of fat result in the production of glycerin and
fatty acids, if the reaction be neutral or slightly acid. If the reaction of the
gut be alkaline, the alkali will combine with the fatty acids to produce soaps.
Analyses of the contents of the gut after a fatty meal show that the greater
proportion of the fats are present as a mixture of fatty acids and soaps, the
amount of these substances as compared with unchanged fat increasing as we
descend the gut.
In studying the absorption of fats the investigator is able to take advantage of tho
fact that the micro-chemical detection of this substance is usually very easy. Globules
of fats or fatty acids containing any proportion of the unsaturated fatty acids have
the property of reducing osmic acid, and therefore of being stained black by this reagent.
Practically all the fats which occur in the food or in the cells of the body contain oleic
acid or the glyeende of this acid in association with palmitic or stearic acid, and therefore
give the typical micro-ohemical fat reactions. In many cases it is useful to employ the
specific stains for fats, such as Sudan red or alkanna red. It is important to remember
that the intensity of the fat reaction given by a cell is only an expression of the fat or
fatty acid contained in a free state in the cell, and is no criterion of the total amount of
fat which may be present. Thus a normal heart muscle in section gives only a diffuse
light brown coloration with osmic acid. After poisoning by phosphorus or by diphtheria
toxin, every muscle cell may be found studded with minute black granules of fat.
Chemical analysis shows however that the normal heart muscle contains as much fat
as the degenerated muscle. Our micro-chemical methods will therefore throw no light
on the amount of fat which is actually in combination with the cell protoplasm.
If an animal be examined a few hours after the administration of a
meal rich in fats, the lymphatics of the intestine are seen to be distended
with a milky fluid — chyle — and the same fluid is found filling the cistema
lymphatica magna and the thoracic duct. The lymph from the thoracic
duct will also be niilky, and chemical analysis shows that the opacity is due
to the presence of minute granules of neutral fat. The fat in such chyle
may amount to over 6 per cent., so that in a moderate-sized dog 12 grammes
of fat may be carried in the course of au hour from the intestine to the blood
by this means. This great access of fat to the blood during fat absorption
introduces corresponding changes in the blood.- The plasma itself becomes
milky, and if the blood be allowed to clot, the serum expressed from the clot
is also milky. On standing, a layer of fat globules hke cream may rise
to the surface of the serum. Fat is found in a free state in this finely divided
condition in the blood plasma so long as it is being absorbed in the intestine.
During starvation it disappears entirely, the serum becoming perfectly clear.
Thus part, at any rate, of the fat which is absorbed from the gut is carried
thence by the lymphatic channels in the form of neutral fat to the blood
stream, by which it is distributed to the various tissues of the body, gradually
leaving the blood stream in a manner which at present has not been deter-
mined. Not all the fat which is absorbed takes this path by wav of the
50
786 l'liYSIOLocY
lymphatics and the thoracic duct. Ligature of the thoracic duct, if effective,
certainly impedes the absorption of fat, but does not abolish it. If the
thoracic duel lymph be collected during the absorption of a given quantity of
fat from the intestine, not more than 60 per cent, of the fat which has disap-
peared from the gut can be recovered from the lymph. What happens to
the remainder we do not know. Apparently it does not reach the blood
in a finely divided condition. If the thoracic duct be ligatured, the per-
centage of fat in the blood rapidly falls to a minimum which remains
constant, even during starvation. If now fat be administered, although a
considerable proportion of it may be absorbed, the percentage of fat in the
•»•
•• •
Fig. 361. Columnar epithelium from small intestine of frog stained with osmic
acid to show fat absorption.
A, five hours after a meal of olive oil; B, three hours later. It should be noticed
that the fat globules first formed grow in size in the course of digestion, pointing
to a gradual deposition of fat on the globules from solution in the protoplasm.
(Schafer. )
blood is not raised. If therefore the fat is absorbed directly into the blood,
it cannot be in the particulate condition, and it must be in such small
quantities at a time that it is at once removed from the blood by the tissues
through which this fluid flows. It is difficult to imagine that any large
proportion of this lost fraction of the fat is absorbed into the blood stream
in the form of soaps, since, as Munk has shown, soaps injected into the
blood stream act as poisons and give rise to a great fall of blood pressure,
incoagulability of the blood, and a condition of coma. We must therefore
leave out of account for the present the mechanism of absorption of this lost
fraction and endeavour to trace the course of the absorption of that part of
the fat which makes its way into the lymphatics.
Microscopic examination of a section of the villus during fat absorption
shows that the absorption occurs for the most part through the epithelial
cells. These are found closely packed with fat granules (Fig. 361) which,
small at the beginning of the process of absorption, rapidly enlarge till they
occupy the greater part of the cell lying between the nucleus and the basilar
striated border. Most observers are agreed that no fat -globules are to be
seen within the border itself.
T1IF ABSORPTION OF THF FOODSTUFFS
787
According to Alt liianii tlie fat granules found in the cells during absorption are them-
selves produced by a transformation of fuchsinophile granules which are present in the
cell even during the fasting condition. At an early stage the small fat granules can be
stained so as to show a distinct fuchsinophile envelope. Altmann interprets this appear-
ance as showing that the epithelial cells take up the fat in a dissolved form, probably
in a hydrolysed condition, and that a process of synthesis then occurs in the granules
leading to the formation and accumulation of fat. When the process of absorption is
proceeding actively, the meshes of the villus contain a number of free fat granules, and
the leucocytes in these meshes are generally found also full of these granules. According
*-'
•V-At,
Flu. 362. A. Vertical section through intestinal epithelium of a rat during fat
absorption, b. Horizontal section through deeper parts o£ the cells, showing
exi ration of fine fat globules into the intercellular clefts. (Reutek.)
to Sehafer an important function in the transfer of the granules from epithelial cells
to central lacteal was performed by the leucocytes. These were supposed to take up
the fat granules extruded by the epithelial cells at the base of the villi, to wander into
the central lacteal where they broke down, furnishing in this way the molecular basis
of the chyle as well as its protein constituents. This view was strongly combated by
Heidenhain, who pointed out that many of the granules staining darkly with osmic
acid were not necessarily fat, and that the number of leucocytes within the villi were
hardly sufficient to account for the amount of material observed. According to Beuter
the epithelial cells take up fat in a dissolved condition through the striated border,
and deposit it as granules of neutral fat in the inner portion of the protoplasm. From
here the fat is passed on by the protoplasm by the side of the nucleus and extruded in
the form of very fine granules in the deeper parts of the inter-epithelial clefts, winch
thus function as true excretory channels for the epithelial cells (Fig. 362).
It is probable that the muscular mechanism of absorption described
many years ago by Brlicke plays an important part in the absorption of fats,
but it is difficult to furnish any experimental proof of the manner in which
this mechanism works. Repeated contractions of the muscle fibres of the
villus would tend to empty the spaces into the central lacteal, and this in its
turn into the submucous plexus of lymphatics, so that the lymph in the
.•spaces is constantly renewed and passes laden with absorbed fat particles into
the valved lymphatics of the mesentery.
788 PHYSIOLOGY
It was long considered that the fats were taken up by the ephithelial cells
from the intestine as line particles of neutral fat, the chief use of the pan-
creatic juice being to aid the formation of an emulsion of fat in the intestines.
There seems to be little doubt that this was an error, and that the fats are
absorbed, dissolved in the bile, either as soap or as fatty acid . The arguments
for this view can be shortly .summarised as follows :
(1) Although the bile does not dissolve neutral fats, it has a strong solvent
action on fatty acids, on soaps, and even on the insoluble calcium soaps.
This solvent power is greatest in the case of oleic acid, of which bile can dis-
solve 19 per cent. It is very small in the case of pure stearic acid, but the
solubility of the latter acid is largely increased if it be associated as usual with
oleic acid. Moore has shown that this solvent action is chiefly conditioned
by the bile salts, aided by the lecithin and cholesterin also present in the bile,
a solution of lecithin and cholesterin in bile salts having a greater solvent
power than the salts alone.
(2) The presence of bile in the intestine is essential for the normal
absorption of fat. If the bile be cut off by occlusion of the bile ducts or by
the establishment of a biliary fistula, the utilisation of fat sinks from about
98 per cent, to about 40 per cent., the unabsorbed fat appearing in the
fasces. This large undigested residue of fat hinders also the absorption of
the other foodstuffs by covering them with an insoluble layer, so that
nutrition as a whole may suffer considerably.
(3) Absorption ma) r also be interfered with by ligature of the pancreatic
duct. This result is probably due to the absence of the fat-splitting ferments
of the pancreatic juice from the intestine. If the fseces be analysed it is found
that a very large proportion of the fat has been split into fatty acids in the
course of its passage through the alimentary canal. This lipolysis has how-
ever been carried out by the agency of micro-organisms, i.e. in the lower
segments of the gut where the greater part of the bile has been already
reabsorbed into the portal circulation. If fat, in a finely divided form such
as cream or milk, be given to animals deprived of their pancreas, a certain
proportion of it is absorbed. Under these conditions a considerable degree
of lipolysis may occur in the stomach itself, so that the fats would be already
hvdrolysed when they came in contact with the bile in the duodenum.
(4) It was shown by Schiff, by means of his amphibolic fistula, that the
bile which is poured into the gut undergoes a circulation, being re-absorbed
from the low r er parts of the digestive tube, carried to the liver by the portal
vein, and re-secreted in the bile. The same quantity of bile salts may
therefore be used over and over again as a vehicle for the transfer of the fatty
acids and soaps from the lumen of the gut into the epithelial cells.
(5) Substances which are physically almost identical with fats, e.g.
petroleum or paraffin, are not absorbed even when introduced into the intes-
tine in the finest possible emulsion. If neutral fat be melted with a soft
paraffin and the resulting mixture made into a fine emulsion and administered,
it is found that the intestine rejects the paraffin, but takes up the neutral
fat. This result can be explained only by assuming that the fat in the
THE ABSORPTION OF THE FOODSTUFFS 789
particles has been actually dissolved out by the digestive juices and has
been absorbed in a state of solution.
We may sum up the processes involved in digestion and absorption of
fat as follows : Neutral fat is hydrolysed into fatty acid and glycerin under
the action of the gastric juice, the pancreatic juice, and the succus entericus,
the effect of the gastric juice being however extremely limited unless the
fat be presented to it in a finely divided condition. The lipolytic action of
the pancreatic juice and succus entericus is largely aided and increased by the
simultaneous presence of bile which, in virtue of the bile salts and lecithin
and cholesterin it contains, enables the pancreatic juice to enter into close
relation with the fat, and dissolves the products of the activity of the ferment,
so that this can attack renewed portions of the neutral fat. As a result
of this lipo lysis there are formed glycerin, which is soluble in water, and
fatty acids or soaps, according as the reaction of the medium is acid or
alkaline. The alkaline soaps are soluble in water, the soaps of magnesium
and calcium are soluble in bile, free fatty acids are soluble in bile acids. The
fat is thus reduced to a condition in which it is soluble in the intestinal
contents whatever their reaction. In this state of solution its constituents
are taken up by the cells of the intestinal mucosa. Within the cells a
process of synthesis takes place, the soaps being split and the fatty acids thus
set free or absorbed, being combined with glycerin with the elimination of
water. to form neutral fat, which appears as fine granules in the cell .proto-
plasm. By an active process of excretion these granules are extruded in a
somewhat more finely divided form into the intercellular clefts and into the
spaces of the villus, whence by the contractions of the musculature of the.
villus they are forced with the lymph transuding from the capillary blood-
vessels into the central lacteal, and thence along the mesenteric lymphatics
to the thoracic duct. This description would apply to about 60 per cent, of
the fat which is absorbed. It is probable that all the fat which is absorbed
is taken up in a dissolved condition, but whether the remaining 40 per cent,
enters the blood stream , or is utilised and broken down in the tissues of the
intestinal wall itself, we have no means of judging. Under normal circum-
stances the utilisation of fat is almost complete. By the time the intestinal
contents have arrived at the lower end of the ileum 95 per cent, of the fat
has been absorbed. Removal of the whole large intestine was found by
Vaughan Harley not to affect fat absorption in the dog.
THE ABSORPTION OF CARBOHYDRATES
As a result of the action of the various digestive juices, all the carbo-
hydrate constituents of the normal diet of man are reduced to the state of
monosaccharides. The absorption of these digestive products may take
place at any part of the alimentary canal, the greatest part in the act of
absorption being taken by the small intestine. By the time that the food
has arrived at the ileocsecal valve, practically the whole of the carbohydrate
constituents of the food have been absorbed. All experimenters are agreed
that the carbohydrates pass into the body by w r ay of the vessels of the portal
790 PHYSIOLOGY
system. The lymph Erom the thoracic duct contains no more sugar than
docs tlic arterial blood taken 'it the same time, whereas several observers have
obtained an increased percentage of sugar in the portal blood during the
absorption of a big carbohydrate meal.
Of the carbohydrates of the food. some, like starch, dextrin, glycogen, are
colloidal and indifmsible; others, such as the disaccharides, cane sugar, milk ■
sugar, and maltose, are soluble and diffusible ; and the products of the action
of digestive ferments on these two classes, namely the monosaccharides,
mannose, fructose, glucose and galactose, are also soluble and diffusible. The
problem as to the mechanism involved in the passage of these substances
across the intestinal wall into the blood vessels has been already dealt with
in treating of the absorption of water and salts. The most striking fact is the
relative impermeability of the intestinal wall to the disaccharides as compared
with the monosaccharides. The intestinal wall is apparently able to take
up in any quantity only such sugars as can be utilised by the cells of the
organism. For this purpose the disaccharides are useless ; cane sugar or
lactose introduced into the blood vessels or subcutaneously is excreted quan-
titatively in the urine and, as might be expected, does not increase in any
way the glycogen of the liver. When maltose is injected in the same manner,
a certain proportion of it is utilised owing to the fact that the blood and
fluids of the body contain a ferment, maltase, capable of converting the
disaccharide into the monosaccharide, glucose. The absorption of- these
disaccharides occurs therefore much more slowly from the intestine than does
the absorption of monosaccharides, the process of absorption being always
preceded by and waiting for the process of hydrolysis. Thus huge doses
of cane sugar may be taken without causing the appearance of cane sugar
in the blood or urine. It has been found that sugar does not appear in the
urine until as much as 320 grm. of cane sugar have been ingested, whereas
any quantity of glucose over 100 grm. may give rise to glycosuria. Lactose
is absorbed still more slowly and, in animals whose intestine is free from the
ferment lactase, is not absorbed; large doses of lactose in such animals
therefore give rise to diarrhoea. The behaviour of the intestinal wall to
the non-assimilable sugars of artificial origin has not yet been sufficiently
investigated. It would be interesting to inquire whether the rate of absorp-
tion of the different sugars is in any way determined by their stereomeric
configuration, whether, for instance, ^-glucose would be absorbed as rapidly
as the ordinary rf-glucose.
THE ABSORPTION OF PROTEINS
In very few departments of physiology has there been so great a revo-
lution in our ideas as in that relating to protein absorption, especially as to
the form in which it is absorbed from the alimentary canal, and its fate after
absorption. As to the channel by which it obtains entry into the circulation,
practical agreement reigns that it is absorbed by the blood vessels. Almost
every physiologist who has occupied himself with the investigation of the
lymph flow from the thoracic duct has been impressed by the fact that the
THE ABSORPTION OF THE FOODSTUFFS 791
variations in the amount of lymph to be obtained in this way bear no
relation to the condition of the animal as regards the state of digestion. Nor
do we find any appreciable increase in the amount of lymph flow or in the.
amount of proteins contained in this lymph during digestion. The small
increase observed by Asher and Barbara would be sufficiently accounted for
by the increased blood supply to the intestines during digestion, and is
insufficient to accoimt for the absorption of any appreciable quantity of the
protein which is being taken up from the alimentary canal. Moreover it was
shown by Schmidt Mulheim that the absorption of proteins was not inter-
fered with as the result of ligature of the thoracic duct and that, after this
duct had been ligatured, the ingestion of proteins was followed at the usual
interval by the increased output of urea, which is the invariable concomitant
of protein absorption and assimilation. We must therefore conclude that
the products of protein digestion are taken up by the epithelial cells and
passed on by these into the blood vessels.
During the absorption of a protein meal changes have been described by various
observers in the structures of the villus. In nearly every case there is marked increase
in the number of mitotic figures in the epithelium lining the follicles of Lieberkiihn.
According to Hofmeister there is during absorption an increase in the number of
leucocytes in the villi, and this observer ascribed an important function to these
cells in the absorption of protein. Heidenhain showed that this increase of
leucocytes was not constant in all animals, and bore no relation to the amount of
absorption that was taking place, and was quite inadequate to account for the total
absorption that was carried on. On the other hand, several observers have described
changes in the epithelium as the result of protein digestion. According to Reuter the
epithelial cells become swollen, their protoplasm stains less deeply, and at their basal
ends the cells' limits disappear, the protoplasm being apparently distended with hyaline
coagulable material (Fig. 363). Reuter regards this appearance as a direct expression
of the taking up of proteins in a dissolved form and their conversion near the bases
of the cells into coagulable proteins ; but further evidence on this subject is necessary
before we can attach much importance to such an interpretation of the appearances
observed.
Under the influence of the gastric juice the proteins of the food are
resolved during their stay in the stomach into albumoses and peptones. In
the small intestine the process of hydration is carried further, the trypsin of
the pancreatic juice carrying the proteins through the stage of secondary
albumoses and peptones, and converting them into a mixture of amino-acids
and polypeptides. The same end-products result from the action of the
erepsin of the intestinal wall on the albumoses and peptones produced by
gastric digestion. The digestive juices finally reduce the proteins therefore
to a mixture of amino-acids, with a certain remainder of polypeptides con-
sisting of two or three of the amino-acids associated together, which do not
undergo further disintegration under the action of the intestinal ferments.
The final products give no biuret test. The first question we have to decide
is to what extent the proteins are reduced to their ultimate hydration pro-
line! s before absorption. We have evidence that protein may be absorbed
by the small intestine without having undergone any hydration whatsoever.
The absorption of serum protein has been discussed already in dealing with
the mechanism of absorption of salt solutions from the gut. In a series of
792
PTIYSIOLOfJY
experiments made by Friedlander, the absorptions of various proteins were
compared after their introduction into loops of the .small intestine which had
been washed free from ferment. During a period of three hours this author
found that 21 per cent, of the proteins of egg white or of blood serum were
absorbed. During the same period, of alkali albumin which had been intro-
duced into the loops, 69 per cent, was absorbed. On the other hand, when
Fig. 3G3. Figures (from Eetjter) showing changes in intestinal epithelium
induced by absorption of protein.
I, epithelium of fasting rat; II, initial stage; III, later stage of protein
absorption.
syntonin and casein were introduced into the intestine, no absorption what-
ever was observed. As to the condition in which such unchanged protein
reaches the blood stream, our knowledge is still imperfect. Foreign proteins,
such as egg albumin, or the serum of other species introduced into the blood
stream, may cause poisonous effects and give rise to albuminuria, to lowering
of blood pressure, or to alteration of the coagulability of the blood. If
injected in small quantities they excite, as a reaction on the part of the
organism, the production in the blood serum of a precipitin, and the presence
of the precipitin may be looked upon therefore as a test by which we may
decide whether these proteins have passed through the intestinal wall
unchanged. In most cases it is found that, however abundant the amount
of protein administered in the soluble form, none of it appears in the urine,
THE ABSORPTION OF THE FOODSTUFFS 793
nor is any precipitin formation aroused. Ascoli has however observed such
events occasionally to follow the administration of large doses of egg white,
and it has been. shown that there is a difference in the behaviour of animals to
the introduction of soluble protein into their alimentary canal, according as
they are new born or are more than a few days old. It seems that during the
first few days of fife the cellular lining of the alimentary canal is permeable
to foreign proteins, whereas later on any protein which is taken up unchanged
from the gut does not arrive in the same unchanged condition in the blood
stream.
The absorption however of unchanged proteins can play but a small
part in the assimilation of protein as a whole. Animals very rarely take
coagulable proteins in a condition in which they will arrive at the small
intestine in a state of solution unchanged. Even in the camivora the living
tissues taken into the stomach will undergo coagulation by the acid, and will
then be dissolved by the gastric juice. In man practically all the proteins of
the food are either insoluble or are rendered insoluble by the process of
cooking. For absorption to take place it is therefore necessary that this
insoluble or coagulated protein should be brought into solution, and this
process is accomplished, together wath hydration, by means of the ferments
of the gastric and pancreatic juices.
This process of solution has long been regarded as the cluef object of the digestive
ferments. Although both Kuhne and Schmidt Miilheim were aware of the production
of aniino-acids such as leucine and tyrosine as the result of digestion, they regarded
their production as evidence of a waste of material. Proteoses and peptones are soluble,
diffusible, and rapidly absorbed from the alimentary canal, and there is no doubt that
a large proportion of the products of protein digestion are taken up by the absorbing
membrane in this form. For many years physiologists were occupied with the problem
as to the fate of these peptones and proteoses after their entrance into the mucous
membrane. They do not pass as such into the blood. The injection of small quantities
of proteose and peptone into the blood gives rise to the excretion of these substances by
the kidneys ; injection of larger quantities has pronounced poisonous effects, which were
first studied by Schmidt Miilheim and Fano. If samples of blood be taken either from
the portal vein or from the general circulation after a heavy protein meal, no trace
either of proteose or of peptone is to be found in the blood. The observations of Hof-
meister and others to the contrary depend on the fact that these observers employed a
method for the separation of coagulable protein, as an antecedent to the testing for
proteoses, which was in itself capable of producing small traces of these substances.
Hofmeister showed that during the absorption of a protein meal the mucous membrane
either of the stomach or of the intestine, if rapidly killed by plunging into boiling water
directly it was taken from the animal, always contained a considerable amount of
peptone, and similar observations were made by Neumeister. If however the mucous
membrane was kept warm for half an hour after removal from the body, the peptone
disappeared. Salvioli, under Ludwig's guidance, introduced peptone into a loop of
gut which was kept alive by passing defibrinated blood through its vessels. At the
end of some hours the loop was found to contain a certain amount of coagulable protein,
but no trace of peptone, nor was any trace of the latter substance found in t lie blood
which had been passed through the vessels. These observations were interpreted as
pointing to a regeneration in the intestinal wall of coagulable protein from the proteose
and peptone taken up from the gut, and opinions were divided whether the most
important part of tins regeneration was to be ascribed to the leucocytes of the villi
(Hofmeister) or to the epithelial cells of the mucous membrane itself.
It is evident that such a conclusion was not justified by the experiments. All that
794 PHYSIOLOGY
these experiments showed was thai the proteoses and peptones disappeared, i. e. were
converted into something which did not give the biuret test. The discovery of the
ferment erepsin bj I lohnheim led I his observer to repeat the experiments of Hofmeistei
and Neumeister with a view to testing the conclusions drawn by these physiologists.
Cohnheim found that, although it was perfectly true thai proteose and peptone disap-
peared when intestinal mucous membrane ;i m I peptone were placed together in the
presence of either blood or of Binger's fluid, this disappearance was due, not to a regener-
ation of coagnlablc protein, but to the fact that the erepsin of the mucous membrane
carried the process of hydrolysis a step further, converting the proteoses and peptones
into t he ultimate crystalline products of protein hydrolysis. Similar observations were
made by Kutscher and Seemann, who showed that at any time after a protein meal these
end-products, especially leucine, tyrosine, lysine, and arginine, were to be found in the
contents of the small intestine. A repetition of Salvioli's experiment by Cathcart and
I.e. it lies deprived this also of much of its significance. It was found that the artificial
circulation, although sufficient to maintain the activity of the muscular wall of the
intestine, as evidenced by the peristaltic movements, was insufficient to keep the mucous
membrane alive. After one hour's experiment the loop contained a mass of epithelial
cells mixed with the products of the action of erepsin on the introduced peptone solution.
In no case was there any diminution in the amount of uncoagulable nitrogen, i. e. there
was no formation of coagulable protein, while the processes of absorption had been
brought by the desquamation entirely to a standstill.
All the evidence shows that protein, however introduced, whether as
coagulated protein or as albvtmose and peptone, undergoes complete
hydrolysis either in the gut or in the wall of the gut before entering the
blood stream. It should thus be possible to feed an animal on a diet in
which the necessary protein had been replaced by the corresponding amount
of ultimate products of protein hydrolysis, i. e. by a mixture which would
give no biuret reaction.
Sufh a possibility w\as formerly negatived on theoretical grounds by Kiihne and by
Bunge. It was thought by these observers either that the animal body lacked the
power of synthesis of proteins from these crystalline products (hydration products), or
that any complete hydration occurring in the intestine would involve such a loss of
energy to the body as to be unteleological. Neither of these theoretical objections is
justified in fact. We know from the researches of Fischer and others that, although the
different proteins in our food present a marvellous qualitative similitude, in that all of
them yield on'hydrolysis the same kinds of amino-acids, there are great differences in
the relative amounts of these amino-acids contained in different proteins. Thus in
gelatin, glycine is contained in considerable quantities, but is absent in many of the other
proteins. C'aseinogen is distinguished by the large amount of leucine that it yields,
while gliadin, the chief protein of wheat flour, contains very large amounts of glutamic
acid. It is difficult to imagine how, for instance, muscle protein could be formed from
wheat protein, a process continually occurring in the growing animal, unless we assumed
that the protein molecule is first entirely taken to pieces, and that its constituent mole-
cules are then selected by the growing cells of the body and built up in the order and
proportions which are characteristic of muscle protein. Moreover, when we measure
the amount of energy change involved in the hydrolysis of the proteins, we find it is
relatively small. There is not a loss of 5 per cent, of the total energy available — i. e. the
heat of combustion of the products of pancreatic digestion would differ from that of
the original protein submitted to digestion by less than 5 per cent. The energy of the
protein as evolved in the body lies, not in the coupling of the amino-acids with one
another, or indeed in the coupling of the nitrogen to the carbon but, like that of the
other foodstuffs, in the carbon itself, and is derived from the combustion of the carbon
of the molecule under the influence of the oxidising processes of the body into carbon
dioxide.
THE ABSORPTION OF THE FOODSTUFFS 795
The experimental decision of this question was first attempted by 0. Loewi,
who found that it was possible to keep a dog in a state of nitrogenous
equilibrium on a diet containing fat, starch, and a pancreatic digest of
protein which contained no substances giving the biuret test. These
results have been confirmed for carnivora by Henderson, by Liithje, by
Abderhalden and Rona, and by Henri ques and Hansen. According to
Abderhalden, it is possible to keep an animal alive when the nitrogen in his
food is represented entirely by the end-products of pancreatic digestion.
The same result cannot be attained by the administration of the products
of acid hydrolysis of protein, but this may be due either to the racemisation of
the ammo-acids under the action of the strong acid, or to the fact that the acid
splits up certain polypeptide groupings which are still contained in the trypsin
digest, and which possibly cannot be synthetised by the cells of the body.
We are justified therefore in concluding that while a certain small
proportion of the proteins of the food may be absorbed \mchanged, a much
larger proportion is taken up as proteoses and peptones or as amino-acids.
The proteoses and peptones are however rapidly changed in the mucous
membrane itself into amino-acids, which we may regard as the form in
which practically all the protein of the body is presented to the absorbing
mechanisms of the alimentary canal for absorption and for passing on
into the circulating fluids.
THE FATE OF THE AMINO-ACIDS AFTER ABSORPTION BY THE
INTESTINAL EPITHELIUM. During a condition of starvation the normal
protein requirements of the body, or rather of the active tissues, are met
at the expense of the less active tissues. The protein characteristic of any
tissue can be taken down, removed to another part of the body, and built
up into the protein characteristic of some other active tissue. It is difficult
to conceive that such a transference and transformation could occur in any
other way than by a more or less thorough disintegration of the protein
molecule at one place and its synthesis at the other, and we know from the
researches of Hedin and others that every tissue contains intracellular
ferments which are capable of effecting the disintegration of the protein
molecule, and are responsible for the autolytic degeneration of tissues after
death. If therefore the normal interchange of protein between the tissues
is accomplished, as we know it to be in plants, by the disintegration of the
proteins into their constituent amino-acids and their subsequent reintegra-
' tion. there is no a priori reason to believe that the blood carries the proteins
from the alimentary canal to the tissues in any other form than that of
amino-acids. The experimental proof of this conclusion was hardly possible
before the invention of a reliable method for the detection of small quantities
of amino-acids in the blood and tissues. This is rendered possible by van
Slyke's method in which, after the separation of coagulable proteins by
alcohol, the amino-acids are determined by measuring the nitrogen evolved
on addition of nitrous acid. Van Slyke has shown that the blood always
contains a certain amount of amino-acids even during fasting. After a
796 PHYSIOLOGY
protein meal there is a considerable increase in the amount of ammo-acids.
Thus Hie blood of fasting animals coirl ains from 3- 1 i o 5-1 milligrams amino-
acid nitrogen per Juo c.c. Blood taken after food contains 8-6 to 10-2
milligrams amino-acid nitrogen per 100 c.c. of blood. The question of the
fate of ammo-acids thus absorbed from the intestine to the blood is decided
by an estimation of the amino-acid content of the different tissues after
the injection of amino-acids into the blood. Van Slyke Jms found that
after the injection of amino-acids only a certain proportion is excreted
with the urine, and that the rest of the amino-acids rapidly disappears
from the blood and is taken up by the tissues without undergoing any
immediate chemical change, though in the case of certain tissues, such
as the muscles, a definite saturation point exists which sets the limit to the
amount of amino-acids that can be absorbed. On the other hand, the
capacity of the internal organs, and especially of the liver, for the absorption
of amino-acids is much greater.
It is worthy of note however that the absorption of amino-acids by the
tissues from the blood is never complete, i. e. the amino-acids of the blood
must be in a state of equilibrium with those of the tissues, although the con-
centration in the latter may be much greater than in the former. If several
hours be allowed to elapse after the injection of amino-acids before the
analysis of the tissue is undertaken, it is found that the amino-acid nitrogen
content of the liver may have returned to normal, although the concentration
in the muscles has suffered no appreciable fall. Since we have evidence
that the circulation of amino-acids through the liver gives rise in this organ
to the formation of urea, we must conclude that this organ is especially
responsible for the breakdown of the products of protein digestion which are
not directly required for replacing tissue waste. This breakdown must
involve a process of deamination. We may therefore conclude that the
amino-acids normally produced by a protein digestion are absorbed without
further change into the blood stream. They then circulate throughout the
body, a certain proportion of them being built up in each tissue into the
proteins characteristic of that tissue in order to replace the waste caused by
wear and tear. The rest, probably the major part of the protein, is taken up
by the liver, where it imdergoes deamination, the nitrogen moiety being
rapidly converted into urea and excreted by the kidneys, while the non-
nitrogenous moiety is carried to the working tissues to which it serves as a
ready and immediate source of energy.
The fact that not only the blood but also the tissues contain amino-acids,'
even after complete starvation for some days, shows that these substances
are intermediate steps not only in the synthesis but in the breaking down of
body proteins. Free amino-acids are thus the protein currency of the body,
just as glucose is the carbohydrate currency. In the fasting body we must
regard the processes of autolysis as the main source of the amino-acids found
in the tissues, and it is by autolysis that the proteins of the resting tissues are
made available in starvation for those whose continued working is essential
for the maintenance of life. The fact that high protein feeding does not
THE ABSORPTION OF THE FOODSTUFFS 797
appreciably increase the amiiio-acid content of the tissues, shows that any
storage of nitrogen in the organism must take place, not in the form of
amino-acids, but as body protein.
It was formerly thought that the deaniination of amino-acids occurred on a large
scale in the wall of the alimentary canal, on the grounds that a larger amount of
ammonia was present in the portal blood than in the arterial blood. It seems probable
however that the source of this excess of ammonia is to be found in intestinal bacterial
changes, and that the major portion of the amino-acids is actually absorbed unchanged.
The view of Abdcrhalden that the amino-acids are synthetised in the intestinal wall
to serum proteins, and absorbed in that form into the blood stream, need here only
be mentioned, since it lacks experimental support.
THE ACTUAL COURSE OF DIGESTION
In a recent series of papers London describes the course of digestion of meals of
various characters in dogs winch had been provided with fistula? in one of the following
places : (a) gastric fistula (into the fundus of the stomach); (b) pyloric fistula (on the
duodenal side of the pylorus); (c) duodenal fistula (about one foot below the pylorus);
(f an aromatic compound, i.e. forming a side-chain of the benzene ring,
!t is protected from complete oxidation by the stability of this ring. The
oxidation of the fatty side-chain may proceed to a certain degree, so that
SOfi PHYSIOLOGY
intermediate products of metabolism may be excreted still attached to the
benzene i«icleus. In the a-amino-acida the point where disintegration
first occurs is the a-group. Deamination Knoop finds most usually asso-
ciated with oxidation. The primary product is therefore an a-keto-acid.
Further oxidation affects the CO group, so that carbon dioxide is eliminated
and the next lower acid in the fatty acid series is produced. Thus from
alanine the body would produce pyruvic acid, CH,.CO.COOH, and this
on further oxidation would form acetic acid, CH 3 .COOH, and carbon dioxide.
On the other hand, these keto-acids may undergo reduction to an oxy-acid, or
even a step further, to a fatty acid, though the conditions which determine
whether oxidation or reduction shall take place have not yet been fully
studied.
This loss of nitrogen diminishes little, if at all, the energy value of the
amino-aeids of the body. The following table shows the heat equivalents
of some of the amino-acids and their corresponding fat and oxy-acids :
_ , . Calories
Substance per grm. molecule
Leucine ..... 855
Isobutylacetio acid
Alanine
Propionic acid
Lactic acid .
Pyruvic acid
837
389
367
329
not determined
These heat equivalents represent the heat evolved on the total oxidation
of the substances in question. In the case of the amino-acids, part of the
molecule is not oxidised, the nitrogen leaving the body not as free nitrogen
but as urea. To obtain the total possible heat value of an amino-aoid to
the body, we must subtract from its heat equivalent half the heat equivalent
of urea, (an amino-acid contains 1 atom of nitrogen, while urea contains
2 atoms, so that one molecule of urea is produced from 2 molecules of an
amino-acid.) The heat equivalent of urea being 80, the physiological
heat equivalent of leucine will be not 855 but 815, while the physiological
heat equivalent of alanine will be 349, as against 329 for lactic acid. Thus
even in the case of the smallest molecule, the loss of energy attendant on
simple deamination and conversion into the corresponding oxy-acid amounts
to little more than 5 per cent., and the proportion will be much smaller in
the case of the larger molecules. We are accustomed to regard the urea
excretion as an index to protein metabolism. In truth it is an index only
of the deamination of the protein constituents, and it tells us nothing what-
ever about the fate of that part of the protein, the non-nitrogenous part,
which contains 95 per cent, or more of the total energy of the protein food.
The rise in the rate of excretion of urea after a protein meal was regarded
both by Voit and Pfliiger as a sign that the cells of the body prefer to use
protein for all their requirements, if this substance were available. We
see now that the rapid output of urea after a protein meal affords no basis
PROTEIN METABOLISM 807
for this view, but is rather a sign that the body, after satisfying its modest
needs for the repair of its tissue waste, has no need for the rest of the nitro-
genous content in its food, and that this must be got rid of before the really
valuable part, the energy-giving part, of the protein molecule, is admitted
into the metabolic cycle of the cells.
The important problem in the energy metabolism of protein is thus not
the origin of the urea, but the fate and nature of the substances that are
left after deamination. We have seen that the protein when taken as a
food, more than either of the other two foodstuffs, causes a direct augmenta-
tion of the respiratory exchanges of the body. Thus in one experiment by
Rubner, an animal previously starved received on one day 574 Calories
protein, on another day 54-2 Calories fat, and on the third day 57 Calories
carbohydrates per kilo, body weight. During hunger the total metabolism
per kilo, body weight amounted to 37-5 Calories ; with meat ; to 46 Calories ;
with fat, to 39-4 Calories ; with carbohydrates, to 39-4 Calories. Compared
with the metabolism during starvation the rise per cent, with protein was
24-3, and with fat and carbohydrates 5-1. This surplus output of energy
resulting from the administration of protein cannot be ascribed to increased
work thrown on the digestive organs; There is no evidence that this is
greater in the case of proteins than it would be with carbohydrates or fats ;
and even if the capacity of these organs be strained to their utmost by
administration of large quantities of bones, the increase in the C0 2 output
which results is not so great as that following a large protein meal. It
might be concluded that the CHO moiety of the protein undergoes oxidation
more rapidly than either glucose or the ordinary fats of the diet, and that
its metabolism is dependent rather on the quantity presented to the organism
than on the actual needs of the cells of the body. The work of Lusk points
however to the earlier view of Voit as being correct, according to which
protein food acts as a stimulant to all the metabolic processes of the body.
Lusk has shown that this specific dynamic action of protein is possessed
also by certain of the amino-acids resulting from its decomposition, but not
by all. Thus while glycine and alanine exert a well marked specific dynamic
action, glutamic acid, leucine and tyrosine exert little or no effect upon
heat production. The question then arises whether this increased heat
production resulting from the ingestion of glycine is due to the rapid dis-
integration and oxidation of the glycine molecule itself, or is due to a direct
stimulating action upon the body cells. The question was decided by giving
glycine to an animal which had been rendered diabetic by the injection of
the phlorhizine. Under these circumstances glycine is converted quanti-
tatively into glucose, which is excreted in the urine, so that the CHO moiety
of the glycine molecule undergoes no oxidation in the body. Notwith-
standing this fact glycine produces the same augmentation of metabolism in
the phlorhizir.ised animal as it would in a normal animal. The same results
were obtained with alanine, so that it. must be concluded that the specific
dynamic action of protein is due to the quality possessed by certain of the
amino-acids of stimulating the cells of the body and raising their rate of
808 PHYSIOLOGY
metabolism. But it is not the amiiio-acids themselves that are the stimu-
lants. This is shown by the fact that when amino-acids are built up
to form new tissues, as in the baby or in the animal recovering from
starvation, they exert no specific dynamic action. This action only
occurs when the amino-acids undergo deamination, and must therefore be
the result of the products of this deaminalion. Lusk suggests that in
the case of glycine and alanine, the stimulating substances may be
glycollic and lactic acids, but there is no direct proof of this suggestion.
We know in fact very little of the nature of the substances that are left
after deamination. Since they contain only the elements carbon, hydro-
gen, oxygen, one would expect to find that they could replace either
fat or carbohydrate. So far as concerns the production of energy this
is true. Moreover, as we shall see in dealing with the metabolism of
carbohydrates, we have definite evidence that part of this non-nitrogenous
moiety of the protein molecule may be converted into sugar or glycogen.
Thus, of the amino-acids formed by the digestion of proteins, glycine, alanine,
aspartic acid and glutamic acid can be converted quantitatively under appro-
priate circumstances into glucose. On the other hand, leucine, phenylala-
nine and tyrosine yield no glucose, even in the diabetic animal, but may
in the liver undergo conversion into aceto-acetic acid, which is a stage in
the oxidative disintegration of fats. In spite of this latter fact we have
no evidence that fat may be formed from this part of the protein molecule ;
at any rate, no fat which can be stored in the body and give rise to the
production of adipose tissue. The reason why the CHO remainder of the
protein molecule is so prone to oxidation and does not. like an excess of
carbohydrates, undergo conversion into fats in the body, we shall have to
consider in greater detail in dealing with the fate of this latter class of sub-
stances. We need however considerably more evidence as to the extent
to which deamination occurs and as to its conditions and end-products
before we can hope to determine the cause for the rapid breakdown of these
end-products in the body.
The Synthesis of Amino- Acids
Many though not all of the processes in the body are reversible. If
the body can effect deamination of an ammo-acid, there seems no reason
why it should not carry out the reverse change and synthesise an amino-acid
from its corresponding fatty or oxy-acid and ammonia. Knoop has shown
that, given a right molecular grouping, the fatty acid residue may in the
body react with ammonia to form an amino-acid. The proof of this fact
was facilitated by the discovery that the next higher homologue of phenyl-
alanine, namely, phenyl-a-amino-butyric acid, when administered to an
animal, was excreted in large quantities in the urine as an ether-soluble
acetyl derivative, which was easity isolated in a state of purity. If then this
amino-acid were formed in the body, one might expect to find it without
difficulty in the urine. Knoop found that the administration of either
phenyl-a-keto-butyric acid or phenyl-a-oxybutyric acid led to the excretion
PROTEIN METABOLISM 809
of the corresponding ainino-acid in the urine. Since keto-acids occur as the
ordinary products of the breakdown of amino-acids and also as the inter-
mediate products of oxidation of oxy-acids, e. g. lactic acid, it is evident that
the animal body can assimilate ammonia and form amino-acids, provided
only that it is supplied with the proper non-nitrogenous acids. These latter
need not be derived from proteins at all but, like lactic acid, be a result of
carbohydrate metabolism. Thus, if the fitting non-nitrogenous food be given
{e.g. oxy-fatty acids, or carbohydrates, from which these bodies may be
formed), part of the nitrogen set free by protein disintegration might be
recombined with the formation of amino-fatty acids without giving rise to
urea or appearing in any way in the nitrogen balance-sheet of the body.
This possibility enjoins the necessity of caution in interpreting the results of
metabolism experiments where the nitrogen excreted is taken to represent
the total protein metabolism of the body.
Are the Amino-acids interconvertible ?
Although the animal organism is apparently capable of synthetising
amino-acids from ammonia and the corresponding keto- or oxy-fatty acid,
it is unable to convert one amino-acid into another. On this account many
proteins are inadequate as food substances since they do not contain the
necessary amino-acid groups. Life cannot be supported on such bodies as
zein or gelatin, which are lacking in the tryptophane and tyrosine groups.
The failure in these cases is not, as has been generally supposed, owing to
an inability to assimilate, i. e. synthetise, nitrogen as ammonia, but to the
fact that in the animal the apparatus is wanting for the manufacture of some
of the oxy-fatty acids and other radicals which form the non-nitrogenous
part of the amino-acids. This view receives confirmation from the fact that
the simplest of the amino-fatty acids, namely, glycine, can be easily manu-
factured in the body, acetic acid being one of the latest stages in the oxidation
of most carbohydrates and fats. It has been shown that alanine too can
be easily manufactured by the body, by the animation of the three carbon
acids or oxy-acids derived from the breakdown of glucose or glycogen.
The Excretion of Ammonia
A large proportion of the urea appearing in the urine after a protein
meal is exogenous and is derived by a rapid separation of ammonia from the
proteins or their disintegration products almost immediately after their
absorption. The greater part of the ammonia is converted in the liver into
urea, which is excreted by the kidney. A certain small proportion of the
nitrogen in the urine is generally turned out in the form of ammonia. This
proportion is not increased by the administration of ammonium carbonate.
If ammonium chloride be given to a starving rabbit, it appears in the urine
unchanged, and so increases the proportion of ammonia hi this fluid. If
however the ammonium chloride be administered at the same time as the
animal is receiving its ordinary vegetable diet, there is no increase in the
ammonia in the urine, the whole of the ammonium chloride being converted
810 PHYSIOLOGY
into urea. The factor, which determines the proportion of ammonia in the.
urine, is the relative proportion of acids and bases which have to he eliminated
from t he body. The normal reaction of urine, though acid as regards certain
indicators, can be regarded as neutral since it contains no free acids, the
' acidity ' being due to the presence in solution of such substances as acid
sodium phosphate. If the fixed alkalies in the food are sufficient to combine
with the whole of the acids excreted from the. body, then the ammonia will be
completely converted into urea and eliminated as such. If however a dose
of mineral acid be administered to an animal, this must be excreted in com-
bination with a base. If the fixed alkalies available do not suffice for this
purpose, the neutralisation of the acid is effected by coupling with ammonia.
The ammonia of the urine is therefore an index to the amount of acids which
are excreted. These acids may be introduced directly with the food, as when
mineral acids are administered by the mouth, or may be the product of
abnormal metabolic processes occurring in the body. Thus under certain
circumstances, e. g. in complete carbohydrate starvation, there is a failure
in the last stages of the oxidation of fats, and oxy-fatty acids, viz. oxybutyric
acid and aceto-acetic acid, are produced in the body in large quantities,
but cannot undergo further disintegration. The alkalescence (electrical
neutrality) of the fluid media of the body is a necessary condition for the
continuance of the life of the cells and especially of the normal processes
of oxidation. It is therefore essential for -the preservation of life that the
acids thus formed and accumulating as a result of the impaired oxidative
processes should be neutralised, carried to the kidneys, and excreted by them
in combination with some base. When these acids are produced in large
quantities, the alkalies of the food and of the tissues do not suffice for their
neutralisation. Ammonia, which is a constant intermediate stage in the
production of urea, is then utilised for this purpose and the acids appear in the
urine in combination with ammonia. The ammonia of the urine therefore
gives valuable information, not as to the total nitrogenous exchanges of the
body, but as to the formation of acids in abnormal quantities during the
processes of metabolism.
The Fate of Arginine.
There is one other method in which urea may be formed by a rapid
alteration of the proteins taken in with the food. Nearly all the ordinary
proteins contain arginine as an integral part of their molecule. This sub-
stance can be regarded as formed by a coupling of guanidine with amino-
valerianic acid and as analogous to the most prominent extractive of muscle,
namely, creatine, which is methyl guanidine acetic acid. On heating either
of these substances with baryta water, it undergoes hydrolysis and is decom-
posed with the formation of urea and, in the case of arginine, a-<5-diamino-
valerianic acid ; in the case of creatine, methyl amino-acetic acid or sarco-
sine. It has been shown by Dakin and Kossel that the same change may be
effected under the agency of a ferment, arginase, which is contained in
extracts of the intestinal wall or of the liver. We have every reason to
PROTEIN METABOLISM 811
believe therefore that a certain small proportion of the urea, which appears
in the urine after the ingestion of protein, is due to this hydrolytic splitting
of the arginine contained in the protein molecule. The other moiety of the
arginine, namely, the diamino-valerianic acid, probably undergoes the same
changes as the other amino-acids, such proportion of it as is not required for
the building up of the tissues of the body being deaminised and giving rise to
urea and some CHO group in the manner already discussed.
THE ENDOGENOUS OR TISSUE METABOLISM OF PROTEINS
On comparing the output of the various nitrogenous excreta given in
Folin's Tables quoted above (p. 802), we see that on a low protein diet, when
the exogenous or energy metabolism of this foodstuff is reduced to a mini-
mum, the only substance which does not undergo simultaneous diminution
is the creatinine. Whereas on an ordinary diet free from meat, it accounts
only for about 3 per cent, of the total nitrogen output, on the low diet
it forms as much as 17 per cent. The conclusion at once suggests itself that
creatinine, more than all the other constituents of the urine, must be regarded
as an index of the tissue metabolism of protein. Let us see what facts can
be adduced in favour of this view.
Creatinine has the formula :
NH = C.N(CH 3 ).CH,
I I "
NH CO
and may be regarded as derived by a process of dehydration from creatine
(methyl guanidine acetic acid).
NH = C.N(CH 3 ).CH 2 COOH
NH 2
It may be formed from tliis latter substance by boiling for three hours with
strong hydrochloric acid. Creatine has long been known as the most
abundant nitrogenous extractive in the body. It exists in relatively large
quantities in muscle; and in meat extracts, such as Liebig's, it occurs to the
extent of 10 or 12 per cent. It has been calculated that the body of a man
at any time contains about 90 grm. of this substance. On boiling creatine
with baryta water, it undergoes hydrolysis with the formation of urea and
sarcosinc or methyl glycine.
CH 3
CH3
*C.N.CH,COOH + H 2 =
NH./
NH 2 \
>co-
NH/
1
|- HN.CH 2 COOH
Creatine
Urea
Methyl slycuie •
Owing to the ease with which this formation of urea from creatine may be
brought about outside the body, it was natural that this substance should
be regarded as an important precursor of the urea in the urine. The view
812 PHYSIOLOGY
was held till recently however, on the ground of experiments by Voit, that
creatine administered in the food appeared in its entirety as creatinine in the
urine, so that if creatine were liberated from the muscles in their normal
processes of metabolism, it would pass to the kidneys and be excreted as
creatinine without undergoing further decomposition. On this account too,
the creatinine in the urine was regarded as derived almost exclusively from
the creatinine taken in with the food. The analyses given in Folin's Tables
show that in one respect at any rate this view was incorrect. Creatinine is
excreted in considerable quantities even when the man is on a creatine-free
diet, or even when his food is almost free from protein. It has been found
moreover by Folin that creatine administered by the mouth may disappear
in the body. This is especially the case if the animal or man is on an
insufficient protein diet, but there is no evidence of a corresponding increase
in urea formation. If a larger amount be given, creatine appears as such in
the urine. In most cases a certain minute proportion escapes and causes an
increase in the quantity of creatinine. Under abnormal circumstances, e.g.
during illness, when the physiological activities of the body are lowered, a
portion of the creatine may be found in the urine in an unchanged con-
dition. If creatinine is to be regarded in any way as the index of tissue
metabolism, its amount ought to vary with the extent of this metabolism.
Thus it should be increased when there is an exaggeration of the disintegrative
processes in the tissues, and should be diminished when the nutritive changes
in these tissues, especially in the muscles, are reduced to a minimum. The
end-products of tissue metabolism therefore should be increased under the
following conditions :
(1) Increased motor activity involving increased wear and tear of the
muscular tissues.
(2) In fevers, especially in those where there is severe toxaemia and rapid
wasting of the muscles of the body.
On the other hand, it should be diminished where the activity of the
muscular tissue is reduced to a minimum, as under the influence of sleep or
soporifics, or where the bulk of the muscular tissue is reduced as well as its
activity, as in cases of widespread muscular atrophy and paralysis. The
excretion of creatinine has been investigated under these various conditions
by van Hoogenhuyze and Verploegb, and their results bear out the view
expressed above as to the intimate relation of creatinine with the tissue
metabolism of protein.
During protein starvation the uric acid output, though diminished, does
not show a change which is at all proportional to that shown by the urea.
This substance also might therefore represent an end-product of tissue
metabolism. Since however uric acid is an outcome of the metabolism of
a special group of bodies, the nucleins and purine bases, we shall have to
devote a complete section to its consideration.
Although the urea is diminished in protein starvation, it still remains the
most abundant nitrogenous constituent of the urine. We are therefore not
justified in excluding this substance from the products of tissue metabolism.
PROTEIN METABOLISM 813
If any creatine undergoes complete oxidation in the body during protein
starvation, a certain proportion of the urea might be derived in this way.
We shall see later that uric acid may possibly also undergo further oxidation
with the formation of urea. Even during complete protein starvation, some
of the urea which is turned out may be the expression of a utilisation of pro-
tein through deamination for the energy needs of the body. The active cells
are bathed everywhere with a tissue fluid in which proteins form a prepon-
derating constituent, and it is possible that, even in the times of greatest
protein need, these cells utilise the proteins of their surrounding medium,
though in a reduced degree, for the production of energy. In this case the
active cell would initiate the utilisation by throwing off that part of the
protein molecule, namely, NH 2 , which is useless to the cell as a source of
energy, so that deamination would be carried out in the working tissues, and
not, as in the rapid formation of urea after a heavy meal, in the liver.
SULPHUR
Sulphur occurs in the urine in three forms, namely, as ordinary inorganic
sulphates, as ethereal sulphates (indoxyl- and skatoxyl-sulphates), and in an
unoxidised condition often termed neutral sulphur. There is no doubt that
part of the latter consists of cystine, part of sulphocyanates, and in some
animals mercaptan compounds. The excretion of the inorganic sulphates
rises pari passu with that of the urea, so that very soon after the throwing
off of the NH 2 group, there must be also a removal and oxidation of the greater
part of the sulphur contained in the cystine group of the protein molecule.
So far as regards the metabolism of the body as a whole, the ethereal sul-
phates may be classed with the inorganic sulphates. They are excreted in
varying quantity according to the extent of the decomposition processes which
are occurring in the intestine. Under the influence of these processes the
tryptophane, produced in the pancreatic digestion of proteins, is converted
into indol and skatol. These two substances, after absorption, are deprived of
their poisonous qualities by oxidation and conjugation with sulphuric acid
to form the indoxyl- and skatoxyl-sulphates of the urine, both of which are
innocuous. If the processes of putrefaction are increased, as in intestinal
obstruction, the relative amount of sulphate appearing in the conjugated
form is also increased. On administration of phenol a large proportion of
the sulphate appears in the urine conjugated with phenol or with products of
its oxidation. If the normal putrefactive processes, which go on in the
intestine, are abolished by the administration of intestinal antiseptics such
as naphthalene or calomel, the ethereal sulphates practically disappear
from the urine. We cannot therefore regard the absence or diminution of
the ethereal sulphates during protein starvation as throwing any light on the
endogenous protein metabolism. On the other hand, the fact that the
neutral sulphur undergoes no decrease suggests that this part of the sulphur
nut put of the organism may be connected with tissue metabohsm. Further
observations on the output of neutral sulphur during fever or wasting diseases
are necessary before a definite conclusion can be arrived at on this point.
814 PHYSIOLOGY
THE FATE OF THE AROMATIC AND OTHER CYCLIC
GROUPS IN THE PROTEIN MOLECULE
A typical protein such as can be utilised as a complete foodstuff con-
tains, in addition to the aniino-acids of the fatty series, a number of other
nitrogenous derivatives of cyclic compounds, including benzene, indol, pyrrol,
and iminazol. Substances such as gelatin, from which some of these
groupings are absent, cannot, as we have seen, entirely replace protein in the
food. So far we are acquainted with three compounds of the aromatic
series among the products of disintegration of the protein molecule. These
are tyrosine, phenylalanine, and tryptophane. Since these substances are
also contained in the protein constituents of the tissues, we may assume
that, after they have been set free by the digestive hydrolysis of proteins, they
are absorbed and built up again with the other aniino-acids in appropriate
groupings. Like these they are susceptible of complete oxidation in the
body, so that they can contribute to the supply of energy. Any one of these
substances, administered with the food or subcutaneously, is entirely
destroyed, with the production of urea, carbon dioxide, and water. In this
respect they present a marked contrast to almost all other compounds of
the aromatic series. In these we find that the benzene ring is extremely
stable, so that, although changes may occur in its side-chains, the benzene
ring itself appears intact in the urine, and is not broken up in the body.
Thus benzoic acid, benzylalcohol, and phenyl propionic acid, when
administered, are passed in the urine as hippuric acid (benzoyl glycine).
Indol and skatol, which are closely allied to tryptophane, undergo oxida-
tion in the body without further modification and appear in the urine as'
conjugated aromatic sulphates.
Some fight is thrown on the conditions of breakdown of these aromatic
bodies by the study of a rare disorder in metabolism, which may occur in
certain families and is known as alcaptonuria. In this condition, which is
congenital and lasts throughout life, the urine darkens considerably when
made alkaline and exposed to tfie air. It has the power of reducing Fehling's
solution, so that the presence of sugar might be suspected. On analysis
the peculiarities of the urine are found to be due to the presence in it of a
substance known as homogentisic acid. Tins is dioxyphenyl acetic acid.
CH 2 COOH
The amount of this substance in the urine bears a constant ratio to the
nitrogen excreted. It does not disappear during starvation, and is much
increased on a large protein diet. It must therefore be derived from the
disintegration of proteins both exogenous and endogenous. If tyrosine or
phenylalanine be administered to patients affected with this disorder, both
substances are quantitatively converted into homogentisic acid. The ratio
PROTEIN METABOLISM 815
of this acid to the total nitrogen indicates that the whole of the tyrosine and
phenylalanine of the protein molecule, whether set free in the alimentary
canal or hi the tissue metabolism, is converted into homogentisic acid. It
is not possible to conceive of the direct conversion of
OH
HO
/ \
tyrosine I into homogentisic acid
CHjCOOH
CHo.CHNHj.COOH
The tyrosine must first be reduced to phenylalanine
OKj.CHNHj.COOH
and then tins substance must undergo oxidation into homogentisic acid.
Since phenyl lactic acid and phenyl pyruvic acid, but not phenyl acetic
acid, are also converted hi alcaptonuric patients to homogentisic acid, it
has been suggested that these two substances form stages in the conversion of
phenylalanine into homogentisic acid. Thus
./\ /\
HO
OH
\/ \/
CH 2 0HOH.COOH CHgCO.COOH CH 2 COOH
Plieuyl lactic Phenyl pyruvic Homogentisic
It is further thought that under normal circumstances the phenyl deriva-
tives, tyrosiue and phenylalanine, are oxidised to homogentisic acid as in the
alcaptonuric patient. In the normal individual however, the introduction of
two hydroxyl groups into the benzene ring leads to some process, perhaps
of a ferment character, which breaks up the ring. This ferment is absent
in the alcaptonuric, so that the transformation of the phenyl derivatives
stops short at the stage of homogentisic acid (Garrod). The eminently
specific character of this process is shown by the fact that, although these
various substances undergo complete oxidation in the body, a slight modifi-
cation in the chain of the processes renders the change impossible. Thus
if the side group in phenyl lactic or phenyl pyruvic acid be converted to
acetic acid before the introduction of the two OH groups into the phenyl
ring, the phenyl acetic acid thus produced is incapable of undergoing further
oxidation. Tyrosine in the intestine undergoes deamination to form
oxyphenyl propionic acid and oxyphenyl acetic acid. These cannot be
further oxidised, but appear in the urine as such or, after conversion into
kresol or phenol, as sulphuric acid esters.
Somewhat similar conditions apply to the oxidation of tryptophane.
816 PHYSIOLOGY
This body is an indol derivative and consists of a benzene ring and a pyrrol
ring having two of their carbon atoms in common. Its formula
/ CH \
HC C C.CH,CHNH 2 .COUH
I II II
HC C CH
i. e. it is indol amino-propionic acid. It undergoes, like tyrosine, complete
oxidation in the body. On the other hand, a very slight alteration in the
molecule renders it incapable of this change. Thus the tryptophane, set
free by the tryptic digestion of proteins under the influence of the putre-
factive bacteria of the intestine, may undergo deamination and reduction
with the production of indol propionic acid, and this by oxidation may be
converted to indol acetic acid. The latter substance by decarboxylation may
be converted into skatol or, by oxidation nearer the chain and further loss
of carbon dioxide, into indol. Of these products of bacterial change, indol
acetic acid may be found in the urine, and indol and skatol are oxidised to
the corresponding phenols and pass into the urine conjugated either with
sulphuric acid or with glycuronic acid.
Apart from these putrefactive changes due to bacteria, no indol derivatives
pass into the urine. The amount of the indol and skatol esters serves
therefore as an index of bacterial decomposition in the alimentary canal,
but gives no clue to the total tryptophane metabolism of the body. If
putrefaction be prevented by the administration of calomel or other intestinal
antiseptic, these esters may entirely disappear from the urine. On the other
hand, the partial obstruction to the onward passage of food, caused by
dividing the small intestine in two places a few inches apart and replacing
the intervening length of intestine the wrong way round, causes the indican
excretion to be increased twenty or thirty fold. Subcutaneous injection
of tryptophane in rabbits does not increase the indoxyl and skatoxyl
sulphates (urinary indican) in the urine, whereas a considerable increase is
brought about by subcutaneous injection of indol.
The pyrrol ring which occurs in proteins as proline and oxyproline (i. e.
pyrrolidine carboxylic acid and oxypyrrolidine carboxylic acid) appears to
undergo complete disintegration in the body. The steps in this conversion
are unknown, though it is possible that the ring may be unlinked so as to
produce from the pyrrol ring amino-valerianic acid, which would then under-
go the process of deamination with which we are already familiar. This ring
is of interest since it appears to take an important part in the building up
oi the molecule of hsematin, the essential prosthetic group of the haemoglobin
molecule.
Another ring grouping, iminazol, occurs in histidine, which is iminazol
a -amino-propionic acid. This too undergoes complete oxidation in the
body. It is important to bear in mind that this ring may be produced
synthetically by very simple means, i. e. by the action of zinc oxide and
PROTEIN METABOLISM 817
ammonia on glucose, which results in a rich yield of methyl iminazol (v.
p. 115). The same grouping is found in creatinine, as is seen by comparing
the formula; :
,CH 3 /CH 3
H,C— N( HC— Nf
o'c-NH XC-^
Creatinine Methyl-iniinazol
and it is possible that this may furnish a clue to the mode of formation of
creatinine in muscle. Creatine has generally been regarded as the primary
product of muscular metabolism, but it is possible that the ring-grouping is
the original one and that creatine is produced by hydrolysis occurring in this
ring.
The iminazol group is at present chiefly interesting in that it contributes
to the formation of the complex ring compounds known as the purines. Since
the purine metabolism is closely connected with the question of the origin
of uric acid, we may consider these questions together.
SECTION II
NUCLEIN OR PURINE METABOLISM
In an undifferentiated cell the proteins, as such, form but a small part, the
mass of the cell being composed of conjugated proteins. The nucleo-proteins
are especially abundant constituents of nuclei, and therefore occur to a
greater or less extent in all the ordinary animal foods, eggs and milk excepted.
Just as the metabolism of proteins is the metabolism of the ammo-acids, so
the metabolism of the nucleo-proteins and nucleins is essentially comprised
in the history of its main constituents, i. e. the purines.
The nucleo-proteins themselves are bodies of very varying composition.
If any cellular tissue such as thymus or liver be extracted with water or salt
solution, a fluid is obtained from which a precipitate can be thrown down
by the addition of acid. This precipitate as a rule is soluble in excess of
acid or in alkalies. If subjected to gastric digestion it undergoes solution,
leaving behind a residue of nuclein which is rich in phosphorus. The amount
of this residue varies with the strength of the artificial gastric juice employed,
so that the method cannot be looked upon as in any way quantitative,
and the question arises whether the original nucleo-protein is to be regarded
as an association or a combination of nuclein with ordinary protein. The
most convenient source for the preparation of nucleins is from the heads of
fish spermatozoa. All nucleins are associations or compounds of nucleic acids
with proteins belonging to the class of protamines or histones. The nucleins
of fish spermatozoa contain protamine as one of their constituents. On
separating off the protamine, nucleic acids can be isolated. These acids
have been named either according to their source or according to the purine
base which is their most prominent constituent. Only from inosinic acid, the
nucleic acid of muscle, has it been found possible to prepare crystalline deriva-
tives, so that in all other cases it is difficult to decide whether we are dealing
with chemical individuals or with mixtures.
On hydrolysing any of the nucleic acids by heating with strong mineral
acid, they are broken down into a series of bodies belonging to the following
four groups : (1) phosphoric acid, (2) purine bases, (3) pyrimidine bases,
(1) a carbohydrate. The chief purine bases obtained from the hydrolysis
of nucleic acid are guanine and adenine.
Hypoxanthine and xanthine are often obtained as products of decom-
position of nucleic acid, but are generally formed by the deamination and
oxidation of guanine and adenine. Fischer has shown that all these bodies
818
NUCLEIN OR PURINE METABOLISM 819
are derivatives of a base purine. They contain a central chain of three
carbon atoms to which is attached on each side a urea group, so that they
may be regarded as diureides. Purine itself has the formula
N=CH
I I
HC C— NH
N— 0— N^
Purino
The relation of the purine bases obtained from disintegration of nucleic acid
to purine itself has been given on p. 100. From these formulae we see that
adenine and hypoxanthine are related to one another, adenine being
6-aminopurine, while hypoxanthine is 6-oxypurine. In the same way
guanine and xanthine are related, guanine being 2-amino-6-oxypurine,
while xanthine is 2-6-dioxypurine. The investigation of the relationships
of these bases was of interest to physiologists since it brought to light the
close relation which they have to uric acid, a substance which has been
known as a constituent of urine and urinary calculi for a long time, having
been discovered in 1776 by Scheele. Uric acid is 2-6-8-trioxypurine and
has the formula
HN— CO
i io C— NH V .
! | || >co
HN— C— NH/
Uric acid = 2-6-S-trioxypurino
The pyrimidine bases, which are also obtained from the hydrolysis of
nucleic acid, are derived from a pyrimidine nucleus which is, so to speak,
/N
half a purine nucleus, consisting of a G( chain joined to a 3-carbon chain.
Three pyrimidine bases have been isolated from the decomposition products
of nuclein, namely, thymine, cytosine, and uracil.
After separation of the purine and pyrimidine bases and phosphoric acid,
a substance is left over which gives the reactions of a carbohydrate.
This carbohydrate differs in different nucleic acids. In plant nucleic acid, as well
;is in guanylic acid from the pancreas and inosinic acid from muscle, the carbohydrate
is a pentose, d-ribose. Most nucleic acids of animal origin yield Iscvulinic acid on
hydrolysis and must therefore contain a hexose.
FORMATION OF NUCLEINS IN THE BODY
In the case of the proteins we saw reason to believe that in the higher
animals at any rate, there was no power of converting one amino-acid into
another (with the exception of the lowest members of the series, namely,
glycine and alanine), and that on this account the food had to contain
representatives of every amino-acid (or perhaps of the corresponding oxy-
820 PHYSIOLOGY
fatty acid) necessary to the building up of the tissue proteins. The nucleins,
on the other hand, can certainly be synthetised by the animal. This is
shown by the fact that the hens' egg before incubation contains practically
no nuclein or purine bases. During incubation tissues are formed, and
there is a rapid increase in the number of nuclei, so that the chick just
before it is hatched contains a considerable amount of nuclein from which
purine bases can be extracted. This nuclein must have been formed by a
synthesis from the phospho-proteins and phosphatides (phosphorised fats)
which form so important a constituent of the egg-yolk, and in the same way
the purines must have been formed by a process of synthesis. This syn-
thesis may occur by a conjugation of two urea molecules with the 3-carbon
chain which is so prominent a feature in the proximate principles of the
body {e.g. in lactic acid, alanine, and all the compound amino-acids of
which alanine is a constituent). Methyliminazol, representing one-half of
the purine ring, can be formed simply by allowing ammonia and glucose to
stand in contact with zinc hydroxide. The power of synthesis of purines
possessed by the body must complicate the question of their fate after
ingestion, since it is evident either that they can be destroyed and excreted
in some other form or that the products of their destruction may be built
up into fresh purine or nuclein molecules. In the same way, in the growing
child there is a rapid increase in the nuclein of the body, although the only
food ingested is milk, which contains but an insignificant amount of nuclein.
»
FATE OF NUCLEINS IN THE BODY
Nucleins and nucleic acids are dissolved by the pancreatic juice, but no
digestion of the nucleic acid occurs in the alimentary tract other than by
the action of micro-organisms. We must assume therefore that the nucleic
acid is taken up by the cells of the intestinal wall unchanged.
Ingestion of nucleic acid is, in man, followed by an increased excretion of
uric acid in the urine, so that we regard this substance as the end-product
of nuclein metabolism in the body. It is evident that the uric acid of the
' urine may be derived either from the nucleins of the food or from the
nucleins of the tissues of the body, the uric acid in these two cases being
spoken of as exogenous and endogenous respectively. By digestion of
nucleic acids with animal tissues or extracts of animal tissues under varying
conditions, it is possible to bring about all the changes involved in the
conversion of the purine bases contamed in them into uric acid. In the
intestinal wall, or after absorption into other tissues of the body, the nucleic
acid is subjected to hydrolytic changes by the agency of ferments which
may be classed as nucleases. These are however of different kinds, the
phosphonuclease splitting off the phosphoric acid and leaving the nucleo-
sides, w T hile the purine nucleases, which are more effective in a slightly
alkaline medium, split off the purines, leaving the phosphoric acid com-
bined with the carbohydrate. The purines set free in this way undergo
further changes. The hypoxanthin derived from inosinic acid is converted
under the action of an oxidase first into xanthine and then into uric acid.
NUCLEIN OR PURINE METABOLISM
821
This was one of the earliest facts discovered in the metabolism of purines.
Horbaczewski showed that, if spleen pulp be digested with blood for some time, it is
possible to extract a considerable amount of xanthine from the mixture. If however
oxygen be bubbled through the fluid, the xanthine disappears, its place being taken
by uric acid.
From the more complex nucleic acids the amino-purines, adenine and
guanine, are set free. These first undergo deamination under the action
of special ferments, adenase and guanase, and are thus converted into
hypoxanthine and xanthine respectively. These bodies subsequently,
under the action of oxidases, may be converted into uric acid.
All these changes occur in the living body, though not necessarily in the order just
set out. Thus when the pyrimidine derivatives are administered to dogs, they pass
out unchanged. If however free nucleic acid be administered to the animal, no trace
of these derivatives can be found in the urine, so that they must have undergone com-
plete oxidation. In the same way the dog's liver is able to deaminise completely
the adenine group of nucleic acid, converting it into hypoxanthine, but is without
effect on free adenine. It is evident therefore that the various ferments which have
been described act partly on the whole nucleoside molecule, partly on the products
of its decomposition, and that the results of the action of the body ferments are not
the same in the two cases.
If we make this reservation, namely, that the constituent parts of the nucleic, acid
molecule may undergo changes while still bound to the other parts, we may represent
diagrammatically the formation of uric acid from nucleic acid as follows :
Ferments
Nuclease
Deaminase
Hydrolysis
Oxidase
Oxidase
Oxidase
(Uricase)
or
Nuclease
Nucleio acid
Phosphoric acid Guanosine Adenosine Uridine Cytidine
Xanthosine Inosine Fate unknown
I I
Xanthine Hypoxanthine
' , I
Xanthine
I
Uric acid
Allantoin (in dogs)
Nucleic acid
I
4 Mononucleotides
Purine nuclease
Pentose-phosphoric acid Guanine Adenine Pyrimidine bases
Deaminase
(Guanase and adenase)
< taddase
Oxidase
Xanthine Hypoxanthine
r I
Xanthine
_J
Uric acid
822 PHYSIOLOGY
The question arises whether the uric acid excreted by a man represents
the whole of the nucleins which have been destroyed in the body. Although
complete equivalence has been found between the amount of hypoxanthine
ingested and the amount of uric acid excreted, the same equivalence has
not been established in the case of nucleic acid, and the important question
arises whether uric acid once formed is stable or whether it may undergo
further changes before being excreted. In many animals, such as the dog,
the amount of uric acid in the urine is only minute, the chief purine
derivative in this fluid being allantoin. Allantoin is formed when uric
acid is oxidised with potassium permanganate, the following changes
taking place :
NH— CO NH— CO
II. II
CO C— NH + O + H 2 = CO NH 2 + C0 2
| || >C0 >co
NH— C— NH' NH— CH— NH
The same transformation can be effected by extracts made from the
liver of the dog and probably of other animals. The ferment carrying out
this change is known as uricase. No such ferment is found in human liver
or any human organs, and, according to Jones and others, uric acid once
formed in the human organism is not further oxidised. The small trace
of allantoin which may occur in human urine is directly derived from the
food. Modern research does not confirm the idea which was formerly
held that a portion of the uric acid formed might undergo further oxidation
in man with the production of urea.
On the other hand it is important to bear in mind the possibility that
some of the uric acid which occurs in human urine may be formed by a
process of synthesis. We have seen already that in the bird the greater
part of the uric acid is formed not from purines at all but by a process of
synthesis from lactic acid and ammonia, and though we have no evidence
of a similar change occurring in the mammal, we are not able definitely to
exclude its possibility.
EXCRETION OF URIC ACID
The complexity of these various processes in man renders it a difficult
task to form a clear idea of the origin of the urinary uric acid and of the
conditions which determine the variations in the amount excreted at
different times. Under ordinary circumstances a man excretes about half
a gramme of uric acid per day. In addition the urine contains a small
amount of purine bases, the ratio of these bases to the uric acid being
generally about 1 : 6. From 10,000 litres of human urine Kriiger and
Salomon succeeded in isolating the following purine bases :
Xanthine .... 10-1 grin.
Hypoxanthine . . 8-5 „
Adenine . . . - . 3-5 „
NUCLEIN OR PURINE METABOLISM
823
The same urine would probably have contained about 500 grm. of uric
acid. As we should expect, the amount of uric acid in the urine varies with
the diet. The following Tables from Bunge give the composition of the
urine secreted (1) on a mixed diet, (2) on a diet mainly composed of meat,
(3) on a diet mainly composed of bread :
Twenty-four hours Mixed
Meat
Bread
Quantity c.c. .
1500
1672
1920
Urea
Uric acid
grm.
33
•55
67
1-3
20
•25
Ammonia
•9
21
•9
Creatinine
•77
•9
•4
Hippuric acid .
Sulphates
Sodium chloride
•4
2
16-5
4-6
7-5
1-2
• 8-2
Phosphates
Potassium
316
2-5
3-4
3-3
1-6
1-3
Calcium, m
ignesi
um, i
n on, colo
iring matter,
jases, ferments.
An attempt has been made to arrive at the amount of uric acid produced
endogenously, i. e. from the breakdown of the tissues, from a study of the
quantity of uric acid in the urine under varying conditions of food. During
starvation, when the man is living on his own tissues, one might expect the
uric acid to be increased in consequence of disintegration of the tissues.
It has been suggested that the amount of the endogenous uric acid in the
urine would be obtained by an analysis of the urine from patients taking
a diet free from purine bases, but containing sufficient nitrogen to maintain
nitrogenous equilibrium. It is impossible however to arrive at any
constant figure for the endogenous uric acid. Even in the entire absence
of purine derivatives from the diet, the amount of uric acid increases with
the total nitrogenous metabolism. This fact is well shown in the Tables
by Folin (already quoted) of the composition of the urine on a low and a
high protein diet respectively. Although in each case care was taken to
exclude purine-containing bodies from the food, the output of uric acid
on the high nitrogenous diet was double as much as on the low diet. All
we can say is that uric acid is constantly being derived from the tissue
disintegration, but that it varies under different conditions of nutrition as
well as under different conditions of activity of the body.
There are two maiii conditions which give rise to a marked increase in
the output of endogenous uric acid. These are (1) severe muscular activity,
(2) febrile states accompanied by increased nitrogenous metabolism. Since
both these conditions are associated with an increased breakdown of muscle
substance, we may regard the uric acid as derived especially from the
hypoxanthine or its precursors, such as inosinic acid, contained in the
muscle.
824
1MIVSI0L0GY
The foods which are especially effective in causing increase in the
exogenous uric acid are those rich in nuclein, such as sweetbreads or liver
and those rich in hypoxanthine <>r its precursors, such as meat or meat
extract.
When these foods are taken, or when nucleic acid itself is administered, a con-
dition of leucocytosis is generally produced, the number of leucocytes in the blood
being increased as much as three times. It has been suggested that the uric acid is
actually formed by a disintegration of the newly formed leucocytes and not by a direct
x
_ L
/ 5 ys "V ^
5 "17- \ "-•
- N i **•■ \
-—'^h?*—- — te ~s--
i" - %
' \
- V
'' i I I T +
Fig. 366. Curves showing the hourly excretion of uric acid and urea after a singlo
meal. (Hopkins.) The continuous line = uric acid output; the dotted
line = urea output.
conversion of the purines of the food. It is quite possible, as suggested by Schittenhelm,
that the leucocytes play a part in the transference of the nucleins from the intestine
to the circulation. But the absence of any absolute proportionality between the degree
of leucocytosis and the amount of uric acid excreted points to the probability of a direct
conversion of the purines of the food into uric acid.
URIC ACID IN GOUT
Gout is a condition in which deposits of urate of soda occur in the cartilages of the
joints, the great toe joint being the seat of predilection for this disorder. The deposit
is generally associated with an acute inflammation of the joint. In normal individuals
the amount of uric acid in the blood is too small to be detected. Uric acid is readily
excreted by the healthy kidneys. If the production of uric aeid be largely increased
by the administration in large quantities of foodstuffs rich in purines, it becomes
possible to demonstrate the actual presence of uric acid in the blood. In gout there
is constantly an increased amount of uric acid in the blood, probably in the form of
sodium urate, even when the patient is on a purine-free diet, so that gout may be re-
garded, from one point of view at any rate, as a uricaemia of endogenous origin. On
the other hand, the output of uric acid in the urine is not increased, and may in fact
be somewhat smaller than normal. It might be thought that the presence of uric
acid in the blood must therefore be due to diminished power of excretion of this sub-
stance by the kidneys. This view is difficult to reconcile with the fact that, if uric
acid be injected subcutaneously into gouty subjects, it is stated to be excreted in the
urine exactly in the same way and as rapidly as in normal persons. It has been
suggested that gout consists essentially in a disturbance in the various fermentative
mechanisms which are responsible for the changes undergone by the purines, so that
NUCLEIN OR PURINE METABOLISM 825
there is an increased amount not only of uric acid itself but of various intermediate
products in its formation from the purine bases of the food and of the tissues. The
deposit of the uric acid in the joint cartilages, characteristic of acute gout, appears to be
simply a crystallisation of urate of soda from a supersaturated solution of this substance
in the blood. The whole question of the pathology of gout and of the disordered
metabolism, which may precede or intervene between actual acute attacks of the disease,
is in need of further investigation. Especially is it important to determine the influence
on this condition not only of the nucleins and proteins of the food, but of the other
constituents such as carbohydrates and fats. Speaking broadly, gout is a disease
of the well-to-do, of the person who, while pursuing a sedentary or no occupation, is
not limited in his food-supply. It is almost unknown in the labouring class, where
hard manual work is combined with a bare sufficiency of food. It seems therefore
that it is not so much the supply of purines in the diet which must be controlled as the
general conditions of nutrition, which determine the fermentative changes in the purines
either of the food or tissues under normal conditions of metabolism.
SECTION III
THE HISTORY OF FAT IN THE BODY
Fat is found in the body in various situations. In a fat animal the largest
amount occurs in the panniculus adiposus in the subcutaneous tissues.
Large quantities are also found surrounding the abdominal organs and
between the layers of the mesentery and great omentum. In this adipose
tissue the fat is enclosed within and distends connective-tissue cells, the
protoplasm of which is reduced to a thin pellicle round the fat globule.
Fat is also found in the form of granules in more highly specialised cells,
such as the secreting cells of the liver or the muscle cells. The condition
of these cells is often spoken of as fatty infiltration, or fatty degeneration,
according to the circumstances which are responsible for bringing about
the deposition of fat. We shall have to discuss later on how far we are
justified in assuming any real distinction between these two processes.
From the physiological standpoint the most important intracellular depot
of fat is in the liver. If this organ be deprived of glycogen and fat by
starvation, a fatty meal gives rise to a great deposition of fat in its cells.
There is apparently an antagonism between the processes which lead on
the one hand to the deposition of glycogen and on the other to the deposition
of fat. Thus an excessive carbohydrate diet, which induces great deposition
of fat in the subcutaneous tissues, causes only the formation of glycogen
in the liver. The glycogen must be got rid of before it is possible to cause
the deposition of fat. On this account, the normal content in fat of the
livers of different animals varies with their ordinary diet. Fishes, e. g. the
cod, which take but little carbohydrate in their food, have generally a very
large quantity of fat in their livers. Herbivorous animals, as a rule, have
practically no fat in the liver.
Fat also occurs in certain secretions, e.g. the milk and the sebum, its
function in the latter case being mainly protective.
Besides the visible deposit of fat found in adipose tissue and in other
situations, a large amount of fat is always present built up into the proto-
plasm of the cells in such a condition that its presence cannot be detected
by histological means. The presence or absence of visible fatty globules
affords very little clue to the total quantity of fat in the cells. Thus in one
case the heart nmscle, which had undergone extreme fatty degeneration
and was loaded with fat globules, contained 19 per cent, of its dried weight
of fat. A heart muscle taken from a normal animal at the same time,
presenting no visible fat globules, contained 17 per cent, of fat.
826
THE HISTORY OF FAT IN THE BODY 827
COMPOSITION OF FAT
The fats occur generally in the form of triglycerides of various fatty
acids. In adipose tissue the acids are chiefly stearic, palmitic, and oleic,
the consistency of the fat depending on the relative amount present of
triolein, with its low melting-point. In certain animals the glycerides of
more unsaturated fatty acids occur. Thus lard contains about 10 per
cent, of fats belonging to the linoleic series. The fats of cows' milk, though
consisting chiefly of the three above-mentioned, include also the esters of
butyric and caproic acids in fair amounts, and traces of the intermediate
acids, caprylic, capric, lauric, and myristic acids.
The ' fat ' extracted from the tissues (e. g. heart muscle) includes a %
considerable amount of ' phosphatides ' (lecithins, etc.). It also contains
a much larger proportion of unsaturated fatty acids of the linoleic and even
lower series, so that its ' iodine value ' is generally found relatively high
(120 as compared with 40 to 60 in adipose tissue).
FUNCTIONS OF FAT
First and foremost must be mentioned the significance of fat as a reserve
food store. The power of the organism to store up reserve carbohydrate is
strictly limited. The liver of man can probably not accommodate more
than 150 grm. of glycogen, and assuming that the muscles of the body may
contain an equal amount, 300 grm. represents the extreme limit of storage
of carbohydrates in the body. On the other hand, in most animals there
is practically no limit to the amount of fat which can be laid down, and
over-feeding, whether with carbohydrates or fats, leads to the deposition
of fat. This fat does not enter into the normal metabolism of the body,
but is available for use whenever the needs of the body are increased above
its income.
As to the part taken by fat, especially the hidden fat of the working
cells, in the chemical processes 'which deternune the life of the cell, our
knowledge is still very scanty. Fats enter into the constitution of the
complex bodies, lecithin and myelin, which form important constituents of
the limiting membrane of every living cell. As constituents of the mem-
brane itself, fatty substances therefore have a protective action, and also
regulate the passage of substances into the cell across the membranes.
The presence of lecithin as an integral constituent of all protoplasm,
and of the first products of disintegration of protoplasm, suggests that
this substance may play a part in the normal transformations which occur
within the cell, and may represent, so to speak, the currency into which
fat is transformed in order to participate in the vital processes, and that
it is in this form that the energy of fat is utilised for the needs of the cell.
ORIGIN OF FAT IN THE BODY
Fat formation is the result of an excess of iilcome over expenditure.
As soon as the latter exceeds the former the fat store is drawn upon, so that
828 PHYSIOLOGY
adipose tissue is the one which presents the greatest loss during starvation.
As much as 97 per cent, of the total fat of the body may disappear during
this process. We have therefore to consider what part is played by each
class of foodstuffs in the formation of fat. Can this substance be formed
from all three classes of foodstuffs \
FORMATION FROM THE FAT OF THE FOOD. Experiment has
shown that the composition of the fat of any animal is by no means constant
and can be varied within wide limits by alterations in the nature of the
fat presented in the food. This dependence of the composition of the fat
on the fats of the food is shown strikingly in an experiment performed by
Lebedeff. Two dogs, after a preliminary period of starvation, were fed,
one on a diet containing a large proportion of linseed oil, and the other on
a diet containing much mutton suet. After some weeks, when the animals
had put on a large amount of fat, they were killed, and it was found that
whereas the fat of the dog which had been fed on mutton suet was solid
at 50° O, that of the dog fed on oil was still fluid at 0° C. It has been
shown moreover that, by feeding animals with fatty acids not usually found
in the body, these are laid down in the adipose tissue. Thus colza oil
contains a glyceride of erucic acid, and an animal, as Muuk has shown,
fed on colza oil lays on fat in which erucic acid is present. The same
physiologist has observed that, after the administration of various fatty
acids to a man with a chylous fistula, the glycerides of the corresponding
fatty acids made their appearance in the chyle, whether these fatty acids
were those normal to man or consisted of substances, such as erucic acid,
not generally found in human fat. One must conclude therefore that the
fats taken with the food, if not immediately required for the energy needs
of the body, are laid down without change in the adipose tissues, as well
as in the cells of the body. The mechanisms involved in the translation of
fat from the alimentary canal to the tissues are of the simplest possible
description and involve only changes of hydrolysis and dehydrolysis. The
fats are hydrolysed in the gut and are resynthetised to a certain extent
in their passage into the epithelium. In the chyle and blood they probably
wander chiefly as neutral fats, to be rehydrolysed for their passage into
the cells of the body, which they may enter either in the form of soaps or
possibly as fatty acids dissolved in some of the constituents of protoplasm.
FORMATION OF FAT FROM CARBOHYDRATES. It has long been
the experience of farmers that animals might be fattened on a diet in which
carbohydrates predominate. The chemical difficulty involved in the trans-
formation of carbohydrates into fats has often led to a doubting attitude
on the part of chemists towards this transformation. Voit put forward
the view that, when fats are formed in the body as a result of an excessive
carbohydrate diet, they are formed, not directly by a transformation of
carbohydrate, but from the proteins of the food, the role of the carbohydrates
of the food being simply to protect the proteins from disintegration and
oxidation, so that thej whole of their carbon can be utilised for the
formation of fat.
THE HISTORY OF FAT IN THE BODY 829
Definite evidence has however been brought forward, especially by
Lawes and Gilbert, for the transformation of carbohydrates into fats. In
these experiments two young pigs ten weeks old of the same litter, with
approximately equal weights, were taken. One was killed and the fat
and total nitrogen in the body estimated. From the amount of nitrogen
the maximum possible quantity of proteins present was calculated. The
second was fed on barley for four months. The barley was measured and
analysed, as well as the amount of undigested fat and protein that passed
through the animal. At the end of the four months the second animal
was killed and analysed. It was found that the animal contained 1-56
kilos, more protein and 8-6 kilos, more fat. It had taken up with the food
7-49 kilos, more protein and 0-66 kilo. fat. If we subtract the protein added
to the body (1-56) from that taken up with the food (7-49), there is a
remainder of 5-93 kilos, which might possibly have given rise to fat. But
7-9 kilos, of fat had been added in the body — a far larger amount than
could possibly have arisen from the maximum amount of protein left over
for the purpose. At least 5 kilos, of fat in this experiment must have been
derived from the direct conversion of the carbohydrates of the food. We
must conclude that fat can be formed directly from carbohydrates, although
how and where this conversion takes place is at present quite unknown.
The fats formed on a carbohydrate diet are deposited chiefly in the sub-
cutaneous tissue. For the reasons already given the liver is found free from
fat under these conditions. In the fat formed from carbohydrate the two
saturated acids, palmitic and stearic acid, predominate. On this account
tii<- fat has a firm consistencv and a high melting-point. The fats of low
melting-point, such as olein, are absorbed more readily from the intestine
than those of high' melting-point. Where the fat of the body is chiefly
derived from the fat of the food, it tends to be of the more fluid acids and
contains a larger percentage of olein.
Although it is impossible to trace out all the steps in the process of
conversion of sugar into fatty acid, we are acquainted with certain reactions
which may throw some light on the nature of the changes involved. If
we compare the formula of dextrose with that of the corresponding fatty
acid, caproic acid,
(H.j CH,OH
I I
CH., CHOH
I " I
OH, CHOH
I " I
CH 2 CHOH
I " I
CH„ OHOH
COOH CHO
we see that the conversion involves a considerable loss of oxygen. In
order to convert three molecules of glucose, C 6 H 12 6 , into one molecule
830 PHYSIOLOGY
of stearic acid, C 18 H 38 2 , it is necessary to split off 1G atoms of oxygen.
That this setting free of oxygen actually occurs in the transformation of
carbohydrate into fat is shown by the study of the respiratory exchanges of
animals which are rapidly laying on a store of fat at the expense of a carbo-
hydrate food. Thus the marmot, towards the end of summer, eats large
quantities of carbohydrate food and very rapidly lays on a thick layer of
subcutaneous fat to last it during the winter. If glucose were entirely
oxidised in the bud}', the amount of oxygen absorbed would be exactly
equal to the amount of carbon dioxide evolved. Thus
r 2 H 12°6 + 60 2 = CC0 2 + 6H 2°-
In this case the respiratory quotient would be
6C0 2 = 2
60 2
If however oxygen is being set free by the conversion of part of the
carbohydrate into fat, this oxygen will be available for the oxidation of
other portions of the carbohydrate. The animal will not need to take in
so much oxygen from outside for the production of the same amount of
carbon dioxide, and the carbon dioxide output of the animal will therefore
be greater than its oxygen intake. Pembrey has shown that under these
conditions the respiratory quotient may be as high as 1>5. We cannot
assume however that the process of conversion of glucose into fatty acids
takes place by this simple process of deoxidation. The change is probably
a more complex one, and occurs in separate stages. Glucose easily breaks
up under the action of ferments into two molecules of lactic acid, and
lactic acid can be equally easily converted into aldehyde and formic acid,
thus :
C 6 Hj,O e = 2C' 3 H 6 3 lactic acid, and
CH 3 "
I CH 3 H
CHOH= | + |
| CHO COOH
COOH
Now aldehydes possess a marked tendency to combine with other
molecules of itself or other substances, i. e. to undergo polymerisation.
Thus from two molecules of aldehyde we get one molecule of aldol,
CH 3
I
CH 3 CHOH
2 | = |
CHO CH,
I
CHO
which by a simple transposition of oxygen would give butyric acid, or by
oxidation would give /3-oxybutyric acid, a substance which occurs during
various abnormal conditions of metabolism.
The fats occurring in the body, e. g. in milk, include only the fatty acids
THE HISTORY OF FAT IN THE BODY 831
wit b an even number of carbon atoms (v. p. 117).' We may probably assume
from this fact that the building up, as well as the breaking down, of fatty
acids occurs by two carbon atoms at a time. Although heating aldehyde
or aldol with potash or any other polymerising agent gives rise to a mixture
of many substances, it is probable that under the catalytic agencies at the
disposal of the living cell these synthetic changes are directed entirely in
one direction, so that from butyric acid we shall have hexoic, caprylic,
capric acid, and so on. The process would seem to take place more easily
through pyruvic acid, as described on p. 119. Why the process comes to
ai i end with the formation of the 16 and 18 carbon atoms it is difficult to
see. 1 Possibly with the formation of acids whose rnelting-point is higher
than that of the body temperature, a certain stability is imparted to them
which prevents their further circulation and ready synthesis to the still
higher acids.
With regard to the glycerine which is a necessary constituent of the
neutral fats laid down in the body, there is no difficulty in accounting for
its formation from the carbohydrates. By a simple splitting of glucose,
we may obtain two molecules of glyceraldehyde,
CH,OH
CHOH
I
CHOH
I
CHOH
I
CHOH
I
CHO
which by reduction is readily converted into the corresponding alcohol
glycerine, CH 2 OH.CHOH.CH 2 OH.
We may conclude then that fats are formed by the body with ease
from carbohydrates, and that in all probability this change involves a
building up of the fatty acid from the lower members by the successive
addition of a group containing two atoms of carbon. The whole change,
as Leathes has shown (v. p. 118), is an exothermic one. For the formation
of one molecule of palmitic acid, four molecules of glucose would be required,
and 12-5 per cent, of the total energy of the glucose would be set free as
heat.
THE FORMATION OF FAT FROM PROTEINS. Among the decom-
position products of proteins, the amino-derivatives of the fatty acids take
a prominent part. Of these some may be converted into carbohydrate in
the body, while others such as leucine and tyrosine may give rise to aceto-
acetic acid. It seems therefore that these latter might in their turn be
built up by the process we have just discussed into the higher members
1 From the fats extracted from the kidney Dunham has isolated carnaubic acid,
CvfH. a Oo.
CH 2 OH
I
= 2 CHOH
I
CHO
832 PHYSIOLOGY
of the series. For many years, as a result of the investigations of Voit,
the proteins were indeed regarded as the chief, if not the sole, source of
the fats of the body, and it needed the energetic assaults of Pfliiger on this
doctrine in 1891, before it could be clearly examined by physiologists.
Let us see what are the grounds for assuming a formation of fat from
protein. In the first place, there is a well-known experiment by Voit.
A dog was fed with large quantities of. lean meat for a considerable time.
Voit found that the whole of the nitrogen of the intake was excreted, but
that a certain percentage of carbon was retained in the body, and that
the percentage of this carbon was greater than could be accounted for by
the deposition of glycogen in the liver and muscles. He therefore assumed
that it must have been laid down as fat. Pfliiger showed that these con-
clusions were not justified by Voit's results, and were really based on the
fact that too high a figure had been assumed for the carbon of the meat.
Whereas Voit found that the animal had laid on 56 grm. of fat during
one day of the experiment, a recalculation of the same results by Pfliiger
shows that the animal could not have put on more than 3-9 grm. of fat,
an amount which might quite well be accounted for by the fat and glycogen
present in the meat. Pfliiger has shown moreover that an animal may
be fed in any quantities for weeks on the leanest meat that it is possible
to procure, without putting on any fat at all ; and, as we have seen, increasing
the ration of protein increases simply the nitrogenous and general
metabolism of the body.
Although therefore we must assume that the healthy body does not
normally form fat from protein, there are' certain pathological conditions
which seem at first to tell in favour of such a conversion. Thus during
certain diseases, such as diphtheria, pernicious anaemia, and as the result
of poisoning by phosphorus, the majority of the organs of the body undergo
acute fatty degeneration. The fiver may be enlarged. All its cells are
studded with fat granules which are apparently formed by a change in
the protoplasm of the cells. This change was long interpreted as due to
a direct conversion of protein into fat. More exact analyses have shown
that during fatty degeneration the total fat in the body is not increased.
Thus one observer took 124 pairs of frogs and poisoned one of each pair
with phosphorus. The animals were then killed, and the whole of them
analysed. The difference in the content of fat between the' poisoned and
unpoisoned animals fell within the limits of experimental error, so that
there had been no increase in the fat of the body as the result of the poison-
ing. In some of these cases the liver is actually enlarged, but this
deposition of fat in the cells is due to the immigration of the fat from other
parts of the body and not to conversion of the protein of the cells. This
is shown by the facts that the composition of the fat in the degenerated
liver varies according to the composition of the fat in the rest of the body,
and that, if abnormal fats are given with the food, such as erucic acid or
iodine fats, these are found in the fat extracted from the fiver. In fatty
degeneration two processes are at work : one is the immigration of fats
THE HISTORY OF FAT IN THE BODY 833
from other parts of the body ; the second, and probably the more important
one, is a change in the relation of the fat to the protoplasm of the cell.
It was long stated that the fat of milk was not increased by feeding with
fats, but only by feeding with proteins. More recent researches have given
contrary results. The dependence of the composition of milk fat on the
composition of the fat present in the body or administered in the food is
shown by the fact that cows fed on oilcake may produce a butter which
is useless for commercial purposes owing to its low melting-point. In one
experiment, when a cow was fed on linseed oil, the iodine number of the
milk fat rose from 30, its normal figure, to 704. After the introduction
of iodine fat subcutaneously, iodine fats are found in the milk. In another
experiment a bitch, which had been fed with mutton suet and had deposited
in its tissues a fat of liigh melting-point, produced a milk the iodine number
of which was the same as that of the mutton suet. In this case the fat
of the milk had evidently been derived from the tissues, since during the
lactation the animal was being fed on meat which was poor in fat. The
same dependence of fatty secretion on diet has been found in geese, where
the composition of the oil secretion of the feather glands has been altered
by giving unusual fats, such as sesame oil, with the food.
We must conclude that the protein of the food does not give rise to
fat in the body. A nearer consideration of the composition of the proteins,
taken in connection with our discussion as to the mechanism by means of
which the fat is built up in the body, might help to account for this fact.
The fatty acids formed by the disintegration of proteins are chiefly the
lower acids of the series, such as acetic and propionic, which would undergo
rapid oxidation in the body. Butyric acid has not yet been found among
the products of disintegration of the proteins, and the 6-carbon acid,
derived from leucine, is not the normal acid, but is a branched chain, viz.
isobutyl-acetic acid.
THE UTILISATION OF FATS IN THE BODY
The constant presence of fat, and bodies allied to fat, in protoplasm,
from whatever source obtained, suggests that these substances can enter
directly into the chemical changes on which the life of the cell depends
and that they play an essential part in vital phenomena. The direct
utilisation of fat for the needs of the body is also indicated by the results
of experiments on man and the lower animals. After a few days' starva-
tion the body may be regarded as practically free from stored carbohydrate.
The sole source of the energy which is evolved under these circumstances
must be fats and proteins, and it is possible to determine by an estimation
of the nitrogen output the exact fraction of the total energy evolved which
is to be ascribed to protein metabolism. Thus in the case of Cetti, the
professional faster, it was found that the nitrogenous metabolism per unit
of body weight remained fairly constant between the fifth and tenth days
of starvation, and corresponded to an average of 1 gnn. of protein per
kilo body weight daily. In order to convert this amount of protein into
53
834
PHYSIOLOGY
urea, carbonic acid, sulphuric acid, and water, nearly 2 gnu. of oxygen
would be required in the twenty-four hours, i. e. about 1 c.c. per minute.
Cetti's total oxygen consumption was at the rate of 5 c.c. per kilo per
minute, so that four-fifths of the oxygen absorbed was required for the
oxidation of non-nitrogenous substances, and these, as we have seen,
could only have been fats. Li animals with a large store of fat the pro-
portion of the energy obtained at the cost of the fats may be still greater.
In dogs Rubner and Voit reckoned that only 10 to 16 per cent, of the total
energy was derived from proteins, the rest, i. e. 84 to 90 per cent., being
obtained from the oxidation of fats.
The oxidation of fats supplies energy not only for the production of
heat but also for the performance of mechanical work, and it seems probable
that the utilisation of the fat occurs in the muscular tissues themselves.
Fat is found as a normal constituent of all muscle fibres, and the amount
of this substance is greater in proportion to the activity of the muscles
concerned. Thus the ever-active heart muscle, and the red muscles of
the diaphragm, contain larger amounts of fat than the pale voluntary
muscles which have to undertake only short periods of activity. In the
human heart muscle 15 per cent, of the solids are soluble in ether, and
more than one-half of the ether extract is composed of fat, and is suffi-
cient to supply the energy of the contracting heart for six or seven hours'
work.
The degree to which the muscles during contraction call upon each
class of foodstuffs may be judged from the respiratory quotient. If the
body has previously supplied the greater part of its needs at the expense
of fats, it will continue to do so during muscular work. This is well shown
in the following Table, in which the oxygen consumption and respiratory
quotient are compared in a man resting and working on three different
diets, one principally fat, one principally carbohydrate, and the other
principally protein :
Resting
Working
kg. m.
of work
done
Per kg. m. of work
Diet
principally c.c. oxy-
gen used
per min.
Eesp.
quo-
tient
c.c. oxygen
used per
Eesp.
quo-
tient
c.c.
oxygen
used
Cal.
Tat . . . 319
Carbohydrate . 277
Protein . .306
0-72
0-90
0-80
1029
1029
1127
0-72
0-90
0-80
354
346
345
201
217
2-38
9-39
10-41
11-35
__,
We may conclude then that the tissues of the body are able to obtain
their energy by the direct utilisation of the fats which they contain. The
changes in the fat molecules, which are involved in the utilisation of their
energy, are still to be determined. The energy of fat is available only on
its oxidation. The transformation of fats into fatty acids or glycerine,
or the synthesis of fats from aldehydes or from carbohydrates, which we
THE HISTORY OF FAT IN THE BODY 835
have discussed in the previous section, do not involve any large changes
of energy. Weight for weight, butyric acid with its 4 carbon atoms has
practically the same heat value as stearic acid with its 18 carbon atoms,
or stearine with its 57 carbon atoms. We have therefore to determine
what changes the great fat molecule undergoes before it is brought into a
condition in which it may undergo oxidation and set free the energy required
for the purposes of the body. The general tendency of metabolic research
of recent years is to show that the living cell is in a position to effect all
changes which do not involve a' large evolution or absorption of energy in
either direction. In the plant cell, at any rate, the fatty acids may be
converted into ammo-acids, or the latter may be deaminised, as occurs
in the liver, into fatty or oxyacids. Dextrose may pass into maltose and
starch, or starch may be converted into maltose or dextrose. If therefore
fats are constantly being made from carbohydrates, or from the lower
molecules such as aldehyde, by a process of repeated addition of a group
containing two carbon atoms, it seems possible that the same change might
go on in a reverse direction when fats are broken down previous to
oxidation.
In the germination of oily seeds the utilisation of the fat is preceded
by the splitting of the higher fatty acids into acids of lower molecular
weight. Although we cannot trace out in the animal body the stages in
the breakdown of a large fatty acid, such as stearic acid, we can, by a certain
artifice much used in metabolic experimentation, bring forward evidence
in favour of the view that the breakdown, like the building up of fats,
occurs by two carbon atoms at a time. When, in the process of breaking
down, a fat finally arrives at the four- or two-carbon stage, it is quickly
oxidised and is therefore not traceable in the excretions or in the fluids of
the body. This end stage may however be preserved from oxidation
by hanging it, so to speak, on to an aromatic ring. If acetic acid or ethyl
alcohol be administered in small quantities, it is entirely oxidised. If
however these bodies be attached to a benzene ring and be administered
as a phenacetic acid or phenylethyl alcohol, they are excreted in the oxidised
form of phenaceturic acid, which is simply a combination of phenacetic
acid with glycine. In the same way benzoic acid and benzyl alcohol are
excreted in the form of hippuric acid, thus :
C 6 H B .COOH + NH 2 .CH 2 .COOH = C 6 H 5 .CO.NH.CH 2 .COOH + H 2
Benzoic acid Glycine Hippuric acid
Phenacetic acid, C 6 H 5 .CH 2 COOH, is excreted as C 6 H 5 .CH 2 .-
CO.NH.CHoCOOH. In each case the fatty side-chain is protected from
further oxidation by its attachment to the benzene ring and by the tacking
on of the glycine molecule.
With phenylpropionic acid two carbon atoms of the side-chain are
oxidised, and the remaining benzoic acid excreted as hippuric acid. Phenyl-
butyric acid undergoes a similar change : two carbon atoms are oxidised
away, leaving phenylacetic acid, which is excreted as phenylaceturic acid.
836 PHYSIOLOGY
If phenyl valerianic acid be given, four carbon atoms are oxidised away
and benzoic acid is left, and appears in the urine as hippuric acid. In
each case the oxidation of the side-chain occurs by two carbon atoms at
a time, and it seems probable that a similar change will occur in the ordinary
fatty acid, the last stages, in the absence of any protective ring compound,
being oxidised like the earlier groups and therefore not detectable in the
excretions.
Evidence in the same direction is afforded by certain cases in which
the oxidative power of the body for fats is inadequate, either by reason of
morbid changes in the oxidative powers of the body, or as the result of
what we may call an overstrain of the fat -oxidising powers. Such a con-
dition is found in the acetonuria of acute acidosis, such as occurs in the
end stages of diabetes. The oxybutyric and diacetic acids occurring in
the urine in this condition were formerly thought to be derived from the
carbohydrates of the food, or from sugar abnormally produced in the
bod) 7 . The condition of acidosis however is often brought on directly
as the result of putting the patient on a strict anti-diabetic diet, i. e. one
consisting chiefly or exclusively of fats and proteins, and may be produced
in a healthy man by simple starvation, when the body has only at its dis-
posal its stored-up fats and proteins. It occurs in a marked degree on
the administration of a diet consisting almost entirely of fats. Thus in
one experiment a healthy man took as his sole diet for five days a daily
ration of 250 grm. of butter, 200 grm. of oil, and a little wine. The result
was an intense acidosis, such as is only found in the severest cases of
diabetes, diacetic acid, oxybutyric acid, and acetone being found in the
urine in large quantities. On the last day of the experiment these acids
caused so much of the nitrogen in the urine to appear as ammonia that of
the 5-8 grm. total nitrogen excreted only 2-7 grm. were in the form of urea,
while as much as 2-1 grm. were present as ammonia.
If, during a period of starvation in man, a day is interpolated on which
100 grm. of protein are taken, the amount of acetone excreted falls below
that obtained on the other days when the individual is living chiefly at
the cost of his own fat. These facts indicate that the chief source of the
/5-oxybutyric acid and the diacetic acid is the fat of the food or of the
body. The condition of acidosis is more easily brought about by ingestion
of butyric acid than of the higher acids, such as palmitic or stearic, sug-
gesting that whatever fatty acid is given it is finally reduced to butyric
acid before its oxidation, and that in the condition of acidosis it is merely
the last stages of this oxidation which are at fault. We are thus justified
in concluding that the oxidative breakdown of fats occurs always by an
oxidation in the fi position.
We take, for instance, the 6-carbon stage :
CH 3 .CH 2 .CH 2 .CH 2 .CH 2 .COOH
the first change which probably occurs is the oxidation :
CH„.CH,.CH.,.CHOH.CH,.COOH
THE HISTORY OF FAT IN THE BODY 837
A further change is the complete oxidation of the last two groups and the
production of Butyric acid :
CH 3 .CH 2 .CH 2 .C'OOH
This then undergoes again oxidation hi the yS position, with the production
of /?-oxybutyric acid :
CH 3 .CHOH.CH 2 .COOH
and then again is converted to diacetic acid,
CH 3 .CO.CH 2 .COOH
In the normal individual this last stage undergoes complete oxidation,
both oxybutyric acid and diacetic acid given to a healthy person being
completely destroyed in the body. It is only under the abnormal conditions
which we have mentioned above that these last stages fail of complete
oxidation, and are excreted unchanged in the urine.
THE QUESTION OF THE FORMATION OF SUGAR FROM FAT
The ease with which the anirnal body performs the difficult chemical
operation of transforming carbohydrate into fat suggests that under
appropriate conditions it might effect the reverse change. Is there any
evidence that in the animal body sugar may be derived from fat ? Such
a conversion is of normal occurrence during the germination of fatty seeds,
starch sugar and cellulose being formed at the expense of the stored-up
fats of the seeds. If such seeds be allowed to germinate over mercury in
a confined volume of oxygen, they are found, like seeds containing chiefly
carbohydrate reserves, to absorb oxygen and to give off carbon dioxide.
Whereas however in the latter case the amount of carbon dioxide evolved
is almost equal to the oxygen absorbed, in the case of the fatty seeds much
less carbon dioxide is given out than would correspond to the volume of
oxygen absorbed, so that the total volume of gas above the seeds diminishes.
The same change in the relation of oxygen intake to carbon dioxide
output is found under certain conditions in animals. During hibernation,
as Pembrey has shown, the marmot has a very low respiratory quotient,
which may not be greater than 0-3 or 04. This means that the animai
takes in more oxygen than the carbon dioxide which it gives out, and this
intake of oxygen can be so marked as to cause an appreciable increase in
the weight of the animal, which imder such circumstances is literally living
on air. This retention of oxygen can only be explained by assuming' that
there is a conversion of substances containing a small amount of oxygen
into substances containing a larger amount of oxygen going on in the body,
such a conversion as that of fats into carbohydrates. Just as the high
respiratory quotient obtained from a marmot during the period of putting
on fat was shown to be associated with a conversion of carbohydrate into
fat, so does the abnormally low quotient obtained during hibernation
indicate the reverse change of fat into carbohydrate.
The same conversion has been alleged to take place in certain cases of
838 PHYSIOLOGY
diabetes. In many cases when the diabetic animal is living on a purely
protein diet, a uniform ratio lias boon found to exist between the glucose
or dextrose and the nitrogen excreted.
- equals generally 2-8.
In certain other cases se constant D : N ratio of 3-65 has been found. The
former represents a conversion of 45 per cent., the latter of 58 per cent.,
of protein into sugar. In a few cases however, even during complete
starvation, the ratio D : N has been found to be much greater than that
given above and to amount to as much as 10 or 12. These animals are
stated to be practically free from carbohydrates, so that the sugar excreted
in the urine can come only from the breakdown of proteins or fats. ,It is
impossible by any means whatever to break up a protein molecule so as to
get from it ten times as much dextrose as corresponds to the nitrogen, and
Pfliiger concludes that in cases where such a high D : N ratio exists the
dextrose must have been derived by a conversion of the fats of the body.
This conclusion is by no means generally accepted (cp. p. 852). If correct, it
would bear out the general statement made above, namely, that in the living
body practically all the chemical changes are reversible, and that the living
cell can so regulate the conditions of the reaction that the reversible reaction
becomes practically complete in either direction, the direction being deter-
mined by the needs of the body at the time.
Accepting this generalisation, the chemical mechanism by which fats
are converted into carbohydrates must be the reverse of that by which
carbohydrates are changed into fats. The 2-carbon group split off from
the large fatty molecules would be utilised for the building up of the sugar
molecule. We know that such a synthesis can take place from such simple
groups as formic, glycollic, or glyceric aldehyde. Though it is impossible
to deny to any cell of the body the power of effecting the conversion of
fats into carbohydrates, or carbohydrates into fats, the chief centre for
such conversions is probably the chemical factory of the body, namely,
the liver. It is significant that in the course of fatal diabetes, in which
the fat disappears entirely from the body, and there is wasting of prac-
tically all the tissues, the liver is the only organ which retains its weight
imchanged. During this disease there has been an enormous amount
of work done in the conversion of proteins and possibly of fats into carbo-
hydrates which could not be utilised by the body, and the large size of
the liver at death suggests that the work of transformation has been performed
by this organ.
SECTION IV
THE METABOLISM OF CARBOHYDRATES
All the carbohydrates which are taken in with the food are ultimately
transformed in the alimentary tract, or in its walls, into the three mono-
saccharides, glucose, fructose, and galactose. These three, together with
mannose, are the only sugars which are directly fermentable and directly
assimilable by higher animals. A consideration of their structural formulae
shows that they are fairly easily interconvertible, galactose presenting the
greatest divergence from the general type. This conversion actually takes
place in watery solution. If a solution of any one be left for some months,
it will be found to contain all four at the end.
Since these monosaccharides, for the greater part glucose, must enter
the blood in large quantities during the absorption of a heavy carbohydrate
meal, one would expect to find a greater proportion in the blood during
such a meal than during a pericd of starvation. The amount of reducing
sugar in the blood however is practically constant, and varies between
0-1 and 0-15 per cent.
Searching for the origin of this constant proportion of reducing sugar,
Claude Bernard found that the blood of the hepatic vein in a fasting animal
contained more sugar than the blood taken at the same time from the portal
vein. Although the reliability of this experimental result has been put in
doubt by more recent investigators, it was important in that it attracted
Bernard's attention to the liver. If the liver be taken from an animal which
has been dead for some time, and extracted with water, the extract is found
to contain a large quantity of reducing sugar (glucose). If however it be
removed immediately the animal is dead, its vessels washed out with ice-cold
saline fluid, and it be then cut up and thrown into boiling water, ground and
extracted, the extract, after separation of the coagulable proteins, contains
hardly a trace of sugar, and no more than is present in the blood. The
fluid is however opalescent ; and Bernard found that this opalescence was
due to the presence of a substance at that time new to science, belonging to
the class of polysaccharides. This substance he called glycogen, i. e. the
sugar-former.
After a carbohydrate meal, glycogen may be present in very large
amounts in the liver, up to 12 per cent, of the weight of the fresh liver.
Prom its solution in water it can be thrown down by the addition of alcohol
to 60 per cent. When collected and dried, it forms a snow-white powder,
839
840 PHYSIOLOGY
tasteless and odourless, with a formula identical with that of starch, viz.
C c H 10 5 . Like starch, it is hydrolysed by the action of acids and super-
heated water, or of amylolytic ferments, into dextrine, maltose, and finally
glucose. It gives with iodine a mahogany-red colour, which disappears on
boiling, but returns again on cooling.
It is not possible to extract the whole of the glycogen from a tissue by merely
boiling it with water. Kiilz introduced on this account the method of dissolving
the tissues in caustic alkali, then throwing down the protein with phosphotungstic
acid, and in the filtrate precipitating the glycogen with alcohol. This method has
been modified by Pfliiger as follows : 100 grm. of the tissue (fiver or muscle) are heated
with 100 c.c. caustic potash containing 00 to 70 per cent. KHO for twenty-four hours
in the water bath. The solution is then cooled, diluted with 200 c.c. of water, and
treated with 800 c.c. alcohol of 96 per cent. The precipitate of glycogen is filtered off
and washed several times with 66 per cent, alcohol. The precipitate of glycogen is
now washed with a little water into a small beaker, neutralised carefully with acetic
acid, and then introduced into a 100 c.c. flask. To the solution 5 c.c. of hydrochloric
acid of 1-19 sp. gr. are added, and the mixture is made up to 85 c.c. The flask is then
heated in the water bath for three hours. By this means the whole of the glycogen
is converted into glucose, which can be estimated by Fehling's method or by Allihn's
method. In practice it is more accurate to estimate the glycogen in the form of sugar
than to weigh it directly. If large quantities of glycogen are expected in the tissue,
the inversion of the glycogen must be carried out in a larger beaker, and only an aliquot
portion taken for titration.
The large amount of sugar found in the liver which has been left in the
body is due to the conversion of glycogen into glucose. This conversion has
been variously ascribed to the activity of the surviving liver-cells, or to the
action of an amylase ferment present in the liver-cells. That it is really a
ferment action is proved by the fact that the liver may be dehydrated with
alcohol, dried and powdered, and kept for months in this condition without
any alteration occurring in the glycogen. If however the coagulated liver
be mixed with water and allowed to remain at the temperature of the body
for some hours, the glycogen is found to disappear and give place to glucose.
FORMATION OF GLYCOGEN
Glycogen is most readily formed from the carbohydrates of the food.
In order to obtain a large amount from the liver, the animal is fed twelve to
twenty-four hours previously on a meal which is rich in carbohydrates.
Not all carbohydrates will give rise to the formation of glycogen. Only
those which we have mentioned as directly assimilable, i. e. which will give
rise in the alimentary tract to mannose, glucose, fructose, or galactose, will
cause an increased formation of glycogen. The conversion involves a direct
polymerisation of the glucose, produced either directly from the foods or by
a molecular rearrangement taking place in one of the other three of these
monosaccharides .
Glycogen can also be formed from the proteins of the food, or from the
products of their disintegration, the ammo-acids. By means which we
THE METABOLISM OF CARBOHYDRATES 841
shall consider shortly, it is possible to free the liver of animals entirely
from glycogen : if such animals be fed on a diet of washed fibrin or of pure
caseinogen, or even on the ultimate products of pancreatic digestion of
proteins (containing therefore only amino-acids), and be killed shortly after-
wards, the liver is found to contain glycogen. It does not seem to be possible
for the liver to manufacture glycogen out of fats. At any rate, that is the
interpretation which is generally placed on experiments on feeding with
fats. In these experiments it is found that if fats be administered to an
animal after the liver has been freed from glycogen, although the liver may
store up fats it does not store up any glycogen.
If an animal be starved, the glycogen gradually disappears from the
liver, although even at the end of ten or twelve days' complete deprivation
of food small traces of glycogen may still be found in this organ. If starva-
tion be combined with hard work; if, for instance, a dog be made to drag
about a milk-cart on the second day of the starvation period, its liver
becomes quite free from glycogen. The same disappearance of glycogen
may be produced by any means which evoke an increased muscular
activity, e. g. poisoning with strychnine. Of the various reserve materials
which are available, the carbohydrate is the first to be called upon to
meet the increased needs of the tissues during functional activity, such as
muscular work or increased heat production. Thus the glycogen rapidly
disappears from the liver of a rabbit which has been immersed in a
cold bath.
The glycogen of the liver represents a reserve material analogous to the
reserve carbohydrates stored up as starch in different parts of plants.
When the blood is loaded with carbohydrates, a considerable proportion is
laid down as the inert polysaccharide glycogen. As soon as the supply of
sugar to the blood is withdrawn, the tissues continue to use the sugar of the
blood, which is made up at the expense of the glycogen in the liver. In every
liver-cell therefore, a twofold process is always going on, namely, a building
up of glycogen by the activity of the liver-cells, and a breaking-down of
glycogen under the action of the ferment formed in the liver-cells. Which of
these two processes preponderates depends, in the normal animal, on the
percentage amount of sugar in the blood which is circulating through the
organ.
On account of the importance of glycogen as a reserve material it is
produced and stored up in almost all growing tissues, to be utilised in their
subsequent development. Thus it is foruid in large quantities in the placenta
during a certain period, in foetal muscles, and in various other situations. It
is found in yeast, in oysters, and in the muscles of the body generally. In
fcetal muscles it may amount to as much as 40 per cent, of the total dried
solids. The glycogen of the adult muscle is apparently utilised during
muscular work, and diminishes in amount with activity of the muscle. In
adult muscles it never reaches anything like the percentage which is found in
the liver. The average ameunts found by Schondorf in the different tissues
were as follows :
842
PHYSIOLOGY
Maximum ncr cent.
of fresh tissue.
.Minimum percent. 1
(if fresh tissue.
Liver .....
18-69
7 -.300
Muscle .
3-72
0-720
Heart .
1-32
0-104
Bone
1-90
0-197
Intestines
1-84
0-026
Skin .
1 -68
0-090
Blood .
0-0066
00016
THE UTILISATION OF SUGAR IN THE BODY
Arterial blood is always found to contain between 0-12 and 0-15 per
cent, of sugar in the form of glucose. The same amount is found whether
the blood be taken from an animal after a heavy carbohydrate meal or
from one in a condition of complete starvation. The constancy of the sugar
content of the blood suggests that this substance is a necessary constituent
of the circulating fluid, necessary, that is to say, for the nutrition of the
tissues. That it is being used up in all the processes of the body is shown
by the immediate alteration in the respiratory quotient which occurs
when the food is changed from a mixed diet to one consisting mainly of
carbohydrate. An important factor in the maintenance of a constant sugar
content in the blood is the reconversion of the stored-up glycogen of the
liver into sugar. The glycogen is not however the sole source of the sugar,
since in complete starvation the sugar content of the blood remains constant
even after the last traces of glycogen have disappeared from the liver. If the
liver be cut out of the body or removed from the circulation, during the
few hours that the animal survives there is a steady diminution hi the blood
sugar, pointing to the liver being the chief, if not the sole, source of the blood
sugar. In some animals, e.g. the carnivora, it would seem that the liver
can continue to supply sugar to the blood on a diet which includes only
proteins and fats, and we have already seen that in such animals glycogen
itself can be stored up at the expense of protein. It is doubtful whether a
perfectly normal existence is possible in man in the total absence of carbo-
hydrates from the food, though there is no doubt that in the northern nations,
e.g. the Eskimos, the amount of carbohydrate consumed is very small in
comparison with the fats and proteins. During muscular exercise the
increased output of energy is associated with a corresponding increase in the
absorption of oxygen and in the output of carbon dioxide, pointing to a
consumption of carbohydrate and fat in the contracting muscles. We might
therefore assume that sugar is being normally released by the liver into the
blood-stream so as to maintain the proportion of this substance in the blood
at a certain level, and that the sugar is as constantly being taken up and oxi-
dised in the muscles, where it serves as a source of energy. According to
Chauveau and Kaufmann the venous blood flowing from a contracting
muscle contains less sugar than the arterial blood flowing to the muscle.
THE METABOLISM OF CARBOHYDRATES 843
A similar consumption of glucose occurs in the isolated contracting
mammalian heart when fed with Ringer's fluid containing a small trace of
glucose. A heart, fed with blood and performing a normal amount of work,
may use about 4 mg. sugar per gramme of heart muscle per hour. That the
question of utilisation of sugar by the tissues is highly complex is shown by
a study of the conditions under which sugar may appear in the urine. We
learn thereby to appreciate to some extent the significance of carbohydrates
both as sources of energy and as foods for the tissues, though we are still a
long way from unravelling all the changes which the sugar must undergo
in the cell before it appears once again in the oxidised products, carbon
dioxide and water.
GLYCOSURIA
Normal urine always contains a small proportion of sugar, about 1 part
per 1000, i. e. about the same as the blood itself. For the detection of these
small traces of sugar in the urine special methods are necessary. The term
glycosuria is not employed unless sugar appears in quantities large enough
to give a reaction with Fehling's solution or with the phenylhydrazine test.
Such a condition may easily be brought about by the injection of sugar
subcutaneously or intravenously. It is then found that any trace of the di-
saccharides, cane sugar or lactose, introduced in the circulation, is excreted
in the urine. A rather larger quantity of maltose may be injected slowly
without appearing in the urine, since the blood serum contains a ferment,
maltase, which converts the maltose into glucose. Glucose, fructose, man-
nose, or galactose, if introduced slowly into the circulation, are stored up
as glycogen in the liver. If however the percentage of sugar in the blood
rises above 2 parts per 1000, the sugar (generally glucose) appears in the
urine. When this condition of hyperglycsemia (excess of sugar in the blood)
is set up, the concentration of the sugar in the urine no longer corresponds
to that in the blood. If the blood contains, e. g. 4 parts per 1000, the urine
may contain from 2 to 7 per cent, of sugar. Up to a certain point then,
blood-sugar is kept back by the kidneys as a necessary food material for the
tissues. Any excess above the normal apparently acts as a foreign substance
and is excreted by the kidneys in a concentration much greater than that
in which it exists in the blood serum.
(1) ALIMENTARY GLYCOSURIA. A state of hyperglycaemia may be
induced by the administration of abnormally large quantities of glucose
by the mouth. The amount has to exceed in a healthy individual
100 grm. in order that it shall appear in the urine. In certain individuals
the power of assimilating glucose may be deficient so that an alimentary
glycosuria may be caused by any over-indulgence in carbohydrate food.
In the healthy person it is hardly possible to produce glycosuria by the
administration of starchy foods, since the liver can store up the excess of
glucose as fast as it is produced from the starch by digestion and absorbed
into the blood stream.
(2) DIABETIC PUNCTURE. It was shown by Claude Bernard that
puncture of the floor of the fourth ventricle in rabbits is often followed
844 PHYSIOLOGY
immediately by an excessive secretion of urine and the appearance of sugar
in this fluid. The glycosuria may last from twenty-four to thirty hours.
If at the end of this time the animal be killed, the liver is found to be free
from glycogen . A sample of blood taken during the height of glycosuria may
contain from 3 to 4 parts of sugar per 1000. In order that the experiment
may succeed it is important that the animal be 'previously well fed. If the
puncture or ' piqfire ' be carried out on an animal that has been starved or
whose liver has been freed by any means from glycogen, no glycosuria
is produced. It is evident that the effect of the pvmcture has been to cause
a rapid conversion of the glycogen previously stored up in the liver into
glucose. The glucose so formed escapes into the blood, raising the sugar
content of this fluid above the normal, and the excess is immediately excreted
by the kidneys together with an increased amount of water. A similar
temporary hyperglycaemia and glycosuria may be brought about by fright,
struggling or the administration of anaesthetics; but the effect is absent,
if both splanchnic nerves have been previously divided above the supra-
renals. It has been shown (Elliott, Cannon) that all these conditions are
associated with an increased discharge of adrenaline from the medulla of
the suprarenals into the circulation. Since the injection of adrenaline itself
causes a condition of diabetes similar in all its limitations and aspects to
' puncture diabetes,' it is now generally believed that the two conditions are
identical, and that the diabetic puncture acts through the splanchnic nerves
on the suprarenals, setting free adrenaline, which passing to the liver causes
a rapid ' mobilisation ' of the stored-up glycogen, and a consequent hyper-
glycsemia and glycosuria, lasting as long as the glycogen store holds out.
(3) PHLORIDZIN DIABETES. Phloridzin is a glucoside extracted from
the root cortex of the apple-tree. It may be decomposed into a sugar
and phloretin. When phloridzin or phloretin is administered by the mouth
or subcutaneously, it gives rise to glycosuria, unaccompanied, at first at any
rate, by any other symptom. The urine may contain from 5 to 15 per cent,
of glucose. The glycosuria induced in this way differs from the forms
already described in the fact that it is not due to hyperglycsemia. Analysis
of the blood shows that the sugar is slightly diminished rather than increased.
The excretion of glucose seems to be due to a specific effect of the drug
upon the kidneys. If cannulas be placed in the two ureters so as to collect
the urine from each kidney separately, and a small dose of phloridzin be
then injected by a hypodermic syringe into the left renal artery, the urine
flowing from the left ureter will in two minutes be found to contain sugar,
while the urine from the right kidney will not contain any sugar for another
five- or ten minutes. The effect therefore is rapidly to drain off sugar from
the blood. In order to maintain the sugar content of the blood at its normal
height, the liver must manufacture fresh sugar to take the place of
that lost by the kidneys. In the first instance the liver will utilise its
stored-up glycogen for this purpose. If a dose of phloridzin be given to
each of two animals and one animal killed as soon as the excretion of sugar
is coming to_an end, the liver will be found free from glycogen. If now a
THE METABOLISM OF CARBOHYDRATES
845
second dose of pliloridzin be given to the other, which may be regarded as
free from glycogen, glycosuria is produced as before, and the excretion of
sugar can be continued indefinitely by repeated administration of the drug.
So long as sufficient food is given, including carbohydrates, the loss of sugar
does not entail any increase in the destruction of the tissues ; but if the drug
be administered to starving animals the waste of sugar has to be made good
at the expense of material other than carbohydrate. The source of the
sugar excreted under these circumstances is the protein of the tissues. The
nitrogen excreted in the urine rises in amount in proportion to the quantity
of sugar excreted, and there is a constant ratio between the amount of
nitrogen and the amount of sugar excreted in the urine. In different experi-
ments this ratio D : N varies from 2-8 : 1 to 3-6 : 1. If meat be administered
to such starving animals with glycosuria, the D : N ratio does not alter ; the
amount of nitrogen in the urine increases, but the sugar increases in the
same proportion. The sugar production is therefore proportional to the
protein metabolism and must be derived from protein. The source of the
sugar is the amino-acids of which the protein is composed. It has been
shown by Lusk, Embden, and Dakin that the following amino-acids yield
large amoimts of glucose when administered to a phloridzinised animal :
glycine, alanine, serine, cystine, aspartic acid, glutamic acid, ornithine,
proline and arginine. We must assume that these amino-acids produced
in digestion or by the autolysis of the tissues undergo deamination and that
the sugar is formed by a process of synthesis from the oxyacids thereby
produced. On the other hand leucine, tyrosine and phenylalanine give no
increase in the output of sugar. It is however just these amino-acids which
seem to follow the fine of fat metabolism, since they are converted into
aceto-acetic acid when perfused through a dog's hver; and the adminis-
tration of fats to phloridzinised dogs is also without effect on the sugar
excretion. The drain of sugar from the organism determined by the action
of phloridzin on the kidneys thus necessitates a continued breakdown of the
nitrogenous tissues of the body in the effort to maintain a normal supply of
sugar to the tissues, and unless excessive feeding be employed the animal
must waste. The great increase in the nitrogenous output resulting from the
condition of phloridzin diabetes is shown in the following table (Lusk) :
Goat
Uoa
D
N
D:N
n
63-55
65-30
65-84
64-60
N i D : N
Fasting
Fasting
Fasting and diabetic
Fasting and diabetic
Fasting and diabetic
Fasting and diabetic
20-33
26-08
23-39
19-01
3-72
3-71
4-90
8-83
8-06
6-84
4-15
2-95
2-90
2-78
4-04 , —
4-17 ; —
12-66 .vui; i
18-76 3-38
18-57 3-54
17-29 3-71
1 The high D:N ratio on the first day is evidently due to the conversion of
the glycogen still present in the body.
846 PHYSIOLOGY
The constant drain of sugai will in time involve a relative carbohydrate
starvation of the tissues, which will make good their energy requirements as
much as possible at the expense of protein and fat. The administration of
meat will diminish the fat metabolism to a certain extent, but since it does
not alter the D : N ratio, it would appear that the latter does not depend in
any way on the quantity of fat undergoing oxidation. This is shown in the
following respiration experiment (Mandel and Lusk) on a dog with phloridzin
glycosuria, in which the metabolism during starvation and after ingestion of
meat was determined :
jj . N 1 Calories from
protein
Calories from 1 Calories
fat total
Fasting . . . 3-69 80-2 274H 354-6
300 grm. meat . ! 3-55 161-9 261-7 123-6
The enormous waste of energy involved in such a constant loss of sugar
will be apparent if we consider that a D : N ration of 3-65 means that 52-5
per cent, of the energy in the protein taken as food or set free from the tissues
is lost to the organism in the form of glucose. According to Rubner 28-5 of
the energy of meat protein is not utilised in the body, but is liberated simply
as heat (specific dynamic action). If we accept this view and add this
28-5 per cent, lost as heat to the 52-5 per cent, lost as sugar, there would
remain a balance of only 19 per cent, actually available for the vital activities
of the tissues. It is not to be wondered at that the nitrogenous metabolism
may be increased three- to five-fold as a result of the artificial induction of
the diabetic condition.
The carbohydrate starvation has other deleterious effects, since we have
evidence that a certain amount of carbohydrate food is a necessary con-
dition for both fat and protein metabolism. The necessity of carbohydrate
for the assimilation of protein is brought out in an experiment by Cathcart.
It has long been known that carbohydrate administration has a sparing
effect on protein metabolism. If an animal or man be starved, the nitro-
genous output sinks to a certain level and there remains practically stationary.
If now pure carbohydrate food be administered sufficient to meet the energy
requirements of the animal or man (about 35 Calories per kilo), there is at
once a rapid drop in the output of nitrogen and therefore in the protein
waste of the tissues. Fat has a much slighter or no sparing effect on the
nitrogenous metabolism. Indeed in certain experiments by Cathcart the
administration of fat caused an actual rise in the nitrogenous output.
The importance of carbohydrates is borne out by the results of feeding animals
with proteins which have been digested with pancreatic juice until the biuret reaction
has disappeared. After Loewi had shown that it was possible to maintain nitrogenous
equilrbriuru in dogs witli such a digest, Lesser was unable to confirm his results.
But it has been pointed out that the essential difference between the two observers
«;is that Loewi gave an abundant supply of carbohydrates with the digest, while Lesser
omitted carbohydrates altogether and administered fats and protein digest alone.
THE METABOLISM OF CARBOHYDRATES 817
The evidence that the carbohydrates play a necessary part in the meta-
bolic history of fats has already been mentioned (v. p. 836). We have seen
that in the absence of carbohydrates the last stages in the oxidation of fats
make default, so that the partially oxidised fatty acids, oxybutyric acid and
aceto-acetic acid, accumulate in large quantities and are excreted as such or
as acetone in the urine. Not only does this involve a loss of energy to the
body, but these organic acids require other bases for their neutralisation.
Up to a certain point they will be excreted in the urine in combination with
the fixed alkalies. When these are no longer present in sufficient quantity,
the acids will be excreted in combination with ammonia, so that the ammonia
of the urine is largely increased. If the condition of carbohydrate starvation
be continued, this mechanism of neutralisation is insufficient and the pheno-
mena of acidosis dyspnoea and coma ensue, resulting in the death of the
animal.
Another effect of continued administration of phloridzin is fat infiltration
of the liver. This is merely a result of the carbohydrate starvation. A
similar condition of fat infiltration can be brought about by feeding with
pure protein plies fat. The liver seems to be able to act as a storehouse
either of fat or of carbohydrate, so that there is an inverse ratio between
the amount of glycogen and the amount of fat stored up in the liver at
any given time. It has been shown that the fat in the liver under these
circumstances is simply fat which has been transferred to this organ from
the ordinary fat depots, subcutaneous tissues, etc., of the body.
(4) PANCREATIC DIABETES. Von Mering and Minkowski found that
total excision of the pancreas gives rise to a severe and rapidly fatal diabetes,
which presents many similarities to the severer cases of diabetes in man.
Owing to the fact that the tissues of a diabetic are extremely prone to in-
fection, it is often difficult after total excision of the pancreas, when diabetes
has been set up, to procure healing of the wounds without suppuration.
The operation is therefore usually carried out in two stages. In the first
stage one small portion of the tail of the pancreas is transplanted under the
skin of the abdomen, while the rest of the gland is excised. Such animals
do not get diabetes and therefore recover quickly from the operation. When
the wounds are quite healed the transplanted portion is removed through a
simple skin incision. The second operation is followed in a few hours by the
appearance of a large amount of sugar, 5 to 10 per cent., in the urine. The
glycosuria persists, the animal rapidly wastes, and finally dies at the end
of two or three weeks from diabetic coma. From the nature of the operation
it is evident that the condition of diabetes observed under these circumstances
has nothing to do with the presence or absence of the pancreatic secretion
from the intestine, since this secretion is cut off at the first operation, and
diabetes does not make its appearance until the second small portion of the
gland is removed. Moreover ligature of the ducts of the pancreas or obstruc-
tion of the ducts by the injection of melted paraffin does not give rise to
diabetes. The excretion of sugar by the kidneys is due to an increase in the
BUgar content of the blood. The blood-sugar may amount to between 4 and
848 lMIYSIOLOGY
5 parts per 1000. This state of hyperglycemia and the excretion of sugar
in the urine persist even when the animal is completely starved oris fed on a
pure protein or protein plus fat diet. Moreover, as in phloridzin glycosuria,
we find a constant ratio between the sugar and the urinary nitrogen, the D : N
ratio being usually about 2-8. The administration of protein food to an
animal previously starved increases the output of nitrogen, but increases
at the same time the output of glucose. No similar increase in the glucose
excretion is observed as a result of the administration of fat. We must
conclude therefore that, in the absence of carbohydrate from the diet, the
excess of sugar in the blood as well as that escaping by the urine is derived
from the breakdown of the proteins of the tissues. On the other hand, the
power of the animal to assimilate or utilise carbohydrate is diminished and
sometimes entirely abolished, so that glucose administered to a starving
animal with pancreatic diabetes may appear quantitatively in the urine.
The amount absorbed by the alimentary canal is simply added to the amount
which would have been excreted if no food had been given. In most cases,
at any rate during the first week after total extirpation, there is apparently
still some power of carbohydrate assimilation, since administration of
glucose causes a transitory rise in the respiratory quotient (Moorhouse).
Glycogen disappears entirely from the liver; but the muscles, especially
the heart, may contain a normal or an increased amount of glycogen. There
is a rapid wasting of all the tissues of the body, including the fats and pro-
teins, and finally the animal is destroyed by the accumulation of the products
of imperfect oxidation of the fatty acids.
It is still very difficult to say definitely why removal of the pancreas
brings about this condition or what disturbance of metabolism is primarily
responsible for it. Two views have been put forward. According to one,
the primary disturbance is the diminished or absent power of utilisation
of sugar by the tissues; according to the second, an increased production
of sugar by the liver. There is no doubt that in the diabetic animal the
power of utilising carbohydrates is deficient.- This is shown by the low
respiratory quotient and by the fact that administration of glucose to
the animal causes an almost corresponding increase in the amount of
glucose excreted in the urine. But the loss of power of utilisation is not
absolute, at any rate in the first week of the disorder. Administration of
glucose causes a slight and temporary rise in the respiratory quotient,
and if 20 gins, of glucose be administered, it is often possible to recover
only about 15 to 18 grns. from the urine. Moreover the increased amount
of glycogen in the heart muscle of diabetic dogs points to a persistent power
of assimilation of sugar by this organ. The heart from a diabetic animal,
if fed with its own blood, can be shown to use up not only the sugar circu-
lating in the blood but also its store of glycogen, and this utilisation is
especially marked if the heart be made to work excessively by raising the
arterial resistance and administering adrenaline; but taken as a whole the
power of utilising glucose is very inferior to that possessed by normal
animals. One of the most striking features of the condition caused by total
THE METABOLISM OF CARBOHYDRATES 819
extirpation of the pancreas is the rapid diminution of the fat depots of the
body, attended by a marked condition of lipaemia and accumulation of fat
in the liver. The blood is so full of fat globules that it ha3 been compared
in appearance to strawberries and cream. One of the first effects of extir-
pation of the pancreas is therefore a rapid fat mobilisation, and the respiratory
quotient agrees with that obtained when the metabolic needs of the body
are being mainly satisfied at the expense of the fat. The sugar of the urine,
after the depletion of the glycogen store of the liver, is derived from the
protein, and the protein tissues of the body therefore diminish as rapidly
as the fat stores. On the theory of deficient utilisation, it is thought that
th.'-.' tissues suffer from carbohydrate starvation, even though they are
bathed in a medium containing an increased amount of sugar, and that
the liver hi response to some call from the tissues turns first its glycogen
and later on the proteins of the body into sugar to supply this lack — all
to no purpose however since the tissues are unable to avail themselves of
the sugar or ferment.
According to the second view, the primary disorder affects only the
liver. This organ is freed from some restraining influence on its power of
manufacturing sugar from glycogen and from protein, so that the blood is
flooded with sugar, which is therefore excreted in the urine. Any deficient
utilisation of the sugar would be regarded as secondary to a poisoning of
the tissues by this overloading of their nutrient fluids with sugar. It is
certain that the sugar production in diabetes is excessive, as is shown by
the rapid wasting of the protein tissues to give rise to the sugar; and that
this over-production takes place in the liver is proved by the fact that
extirpation of this organ in the diabetic animal causes a rapid disappear-
ance of the sugar from the blood.
According to the Vienna school (Rudinger, Falta, and others), a close
interaction exists between the thyroid, the suprarenals, the pancreas, and
the liver; the thyroid to a slight extent, the pancreas still more, inhibiting
the glycogenic tunctions of the liver, while the suprarenals through their
tion of adrenalin stimulate this function. Glycaemia and glycosuria
d by extirpation of the pancreas would therefore be ascribed to an
unchecked activity of the suprarenals. An important difference however
to exist between the two conditions. Adrenalin glycosuria comes
to an end when the glycogen store of the liver is exhausted, whereas pan-
creatic diabetes continues until the death of the animal, long after all traces
of glycogen have disappeared from the liver. We do not yet know how the
pancreas affects sugar production or utilisation in the normal animal. It
is generally assumed that it secretes into the blood stream a hormone which
may, according to the view of the nature of diabetes which we adopt, pass
to the tissues and enable them to utilise sugar, or pass to the liver and inhibit
the sugar production in this organ. A very small portion of the pancreas
is sufficient for this purpose, but we have been unable to imitate the action
of t he pancreas still in vascular connection with the body by injection or
administration of extracts cf this organ. Even connection of a healthy
54
850 PHYSIOLOGY
animal with a diabetic animal by means of its blood vessels, so as to allow
the healthy blood, presumably provided with the products of .secretion of
the pancreas, to circulate through the diabetic animal, does not abolish
the condition of hyperglyceemia in the latter, though connection of the
portal vein of the healthy animal with that of the diabetic animal has,
according to Hedon, had the effect of stopping the condition of glycosuria.
Further work is required on this point.
We thus see that the pancreas has a two-fold function, namely, the
secretion of a digestive juice into the intestine and the exercise by some
•I l- - * ■: k '«iu' ..- ■■• • :■:• • -• ■
•*ii#** : *s ml
V-
® §■
.-•'/.''
Fig. 367. (A) and (B) show an islet with the surrounding tissue in a resting gland (A)
and after exhaustion with .secretin (B). In (A) the secreting acini are charged with
zymogen granules. In (B) these have entirely disappeared. On the other hand no
change is noticeable in the cells of the islet. In the latter the granular cells are
the b cells, and the clear hyaline cells are the a cells, (m) showing what aro called
Minkowski granules. Tho granulation of this cell is regarded by Bensley as due to
postmortem changes.
means or other of an influence on general metabolism, the absence of which
is followed by the supervention of diabetes. Corresponding with this
two-fold function, two kinds of structures are present in the gland, the
secreting acini and the islets of Langerhans. These latter, though arising
in connection with the ducts, are solid masses of cells and have no com-
munication with the lumen of the ducts. According to Bensley and Lane
the islet cells may be divided into two varieties which have been given the
name of A and B cells, according as their granules are fixed respectively
by alcoholic or watery solutions. It has been shown both by Bensley and
by Homans that these cells undergo no alterations when the gland is excited
to secrete by the injection of secretin. On the other hand, if four-fifths
of the pancreas be removed, the remaining part may gradually become
inadequate to prevent diabetes, and Homans has shown that when under
these circumstances diabetes supervenes, the granules disappear from the
THE METABOLISM OF CARBOHYDRATES 851
B cells. Changes have also been found in the islets of Langerhans in fatal
cases of diabetes in man. It seems therefore probable that what we may
term, for lack of a better word, the antidiabetic functions of the pancreas,
are associated with and dependent on the integrity of the islets of Langerhans.
(5) DIABETES IN MAN. In its severer forms the diabetes of man
resembles very closely that produced in the dog by total extirpation of
the pancreas. The output of urine is largely increased and the frequency
of micturition is often the first symptom noticed. On examination the
urine, though light in colour, is of a high specific gravity, 1030 to 1035,
and may contain from 5 to 10 per cent, of sugar. The appetite is largely
increased, but in spite of the large amount of food taken the body wastes.
The excessive quantity of fluid lost by the body gives rise to a constant
thirst. The patient may die after some months or years in a condition
of diabetic coma. Warning of the onset of this condition is given by the
rise of ammonia in the urine and by the appearance of oxybutyric and
diacetic acids. The breath may smell of acetone, and this substance may
also be present in the urine. On the other hand, the diabetic state is
attended by diminished resistance of the tissues to infection. A pimple
nun- become a carbuncle ; a slight sore on the foot may give rise to a rapidly
spreading gangrene of the lower extremity; tubercular infection of the
lungs spreads rapidly to the whole organ so as to stimulate pneumonia.
The patient may thus die of some such intercurrent infection before the
onset of coma. In a few cases the pancreas is found to be atrophied or
diseased, but in the large majority no marked pathological change is to be
observed in this organ. Yet the condition is essentially similar to that
which occurs in pancreatic diabetes. The radical defect is the inability,
relative or complete, of the organism to assimilate carbohydrate. We
may find all grades between such cases and those in which there is still a
considerable power of assimilation. In order to determine the grade of the
disorder, it is usual to give a test diet with a certain proportion of carbo-
hydrate, e.g. 100 grro. of bread with meat, bacon, eggs, butter, green
vegetables, cheese, lettuce, coffee and wine. If the urine remains free
from sugar on this diet, the diabetes is mild in character. More bread
may then be added to the diet from time to time until sugar appears in
the urine and the limit of tolerance for carbohydrate has been reached.
In many cases the sugar will disappear from the urine on the administration
of, a diet consisting entirely of proteins and fats. When this has been
effected, carbohydrates may be added in small proportions to the diet until
the limit is found at which the assimilatory powers of the patient are reached.
It seems that administration of any carbohydrate in excess of this limit is
of disadvantage to the patient and hastens the progress of his disorder.
When the power of assimilating carbohydrates is entirely abolished, the
prognosis is almost absolutely fatal. This point may be determined in
two ways. In the first place, a patient with no power of carbohydrate
assimilation will continue to excrete sugar in the urine on a pure protein-
fat diet, and the D : N ratio will be 2-8 or higher. Information may also
/
852 PHYSIOLOGY
I btained from a study of his respiratory quotient. The production oi
dextrose from protein involves the absorption of oxygen. Oxygen will
therefore be taken in which will not reappear as carbon dioxide in the
expired air. In severe cases of diabetes bherefore, tin", respiratory quotient
will fall below that representing fat metabolism, i. e. below 0-7. In most
cases of diabetes, where there is still some power of assimilating carbo-
hydrate and of storing up glycogen, the respiratory quotient will be found
approximately normal. A very low respiratory quotient is a sign of the
severity of the disorder.
This study of the conditions of carbohydrate metabolism shows how all
three classes of foodstuffs co-operate in the maintenance of the chemical
processes which he at the root of the existence and the activities of living
organisms. We see how fallacious were the ideas that the proteins alum:
were necessary for life and that protoplasm was simply living protein.
Protoplasm, i. e. the material substrate of life, must be regarded as a complex
in which proteins, fats, carbohydrates, nucleins, salts, and water all play
a part and of which each is an essential constituent. In the higher animals
proteins are necessary to furnish the proteins of the tissues, and the food
must contain just those ammo-acids which are requisite for the building
up of the proteins characteristic of each separate tissue. Moreover certain
groups of the protein molecule appear to be destined to serve as mother-
substances of hormones and other chemical compounds which play a
dynamic rather than a static part in the phenomena of life, and supply con-
ditions of activity rather than material for the production of energy. The
carbohydrates not only act as sources of energy, but are necessary to the
building up of the proteins into the protoplasmic complex. Without
them moreover, this complex caimot properly utilise the fat contained in
itself or supphed in its food. On the other hand, the carbohydrates by
themselves are not available as food, but require some connecting link,
which may be protein or nitrogenous in character, to enable their associa-
tion with the active part of the protoplasm and their utilisation by oxidation.
At the same time there is a certain possibility of interconversion between
these different substances; sugar may be formed from proteins, fats from
carbohydrates. On the other hand, the formation of fats from proteins is
apparently impossible in the cells of the higher animals, and the evidence
for the formation of sugar from fat is limited to the study of the respiratory
quotient in hibernating animals. With the exception of a few cases quoted
by Pfluger and von Noorden, no support for such a conversion is obtained
from the conditions observed in the glycosuria caused by the administration
of phloridzin or by extirpation of the pancreas.
CHAPTER XII
THE BLOOD
In the unicellular animals and in the lowest metazoa, the cells are bathed
by the medium in which the organisms live, and are therefore exposed to
all the changes in the composition of this fluid which may be brought about
by cosmic events. With the evolution of a body cavity filled with fluid,
the tissue cells are set free from the necessity of adapting their metabolism
to wide ranges of chemical composition, being bathed by an internal medium
which is maintained practically constant in its characters for any given
type. With increasing differentiation the fluid of the ccelorn, which may
he called blood, becomes enclosed in branching systems of tubes, and its
circulation is provided for by the development of contractile chambers at
some point or points of the tubes. In all the higher animals, the blood,
the common medium and means of exchange for all parts of the body,
circulates through a closed system of tubes, a constant flow being kept up
by the action of the heart. It is separated from the tissue elements them-
selves by the walls of the blood vessels. The free interchange of material
between blood and tissues is facilitated by the tenuity of the vascular wall.
Tim- interstices of the tissues contain a fluid, the 'tissue fluid,' any excess
di' which is drained off by special channels known as lymphatics and carried
hack to the blood. Interchange between the blood and the tissue cells
can be effected partly by diffusion, partly by a direct exudation or filtration
of the fluid parts of the blood with certain of its constituents through the
capillary walls. Since the function of the blood is to act as the common
nutritive medium of all parts of the body, it has to convey food materials
In. in (he digestive organs and oxygen from the lungs to the tissues. From
these it receives in exchange their waste products, namely, carbon dioxide
and the results of nitrogenous metabolism, and carries them away to the
excretory organs, such as the lungs and kidneys, by which they are elimin-
ated. It is evident that the composition of the blood must vary from time
to time and place to place according to the condition of activity and the.
In i h.i ion of the organ which it is traversing. The organs of the body arc
adjusted to respond to very minute changes in the composition of the cir-
culating fluid, and add to or subtract from its constituents according as
these arc present in deficiency or excess. The changes are therefore kepi,
within infinitesimal limits; in most cases they are within the limits of
853
854 PHYSIOLOGY
errors of analysis, and we may therefore treat the blood as a fluid of approxi-
mately constant composition and qualities.
Blood obtained from a mammal is an opaque fluid varying in tint
according to the vessel from which it is derived, being scarlet when taken
from an arterj purplish in colour when taken from a vein, the difference
1„ in- determined by the degree of oxygenation of the blood. On shaking
venous blood with air, it takes up oxygen and acquires the scarlet colour
characteristic of arterial blood. If examined in a thin layer under the
microscope, its opacity is seen to be due to the fact that it is not homo-
geneous, but consists of a number of
corpuscles of different kinds sus-
pended in a light yellow transparent
fluid. In order to make out the
characters of these corpuscles the
blood should be diluted with some
fjjjSp (nethcemoglobin. This
substance, although not of normal occurrence in the body, is foimd in urine
and in blood whenever there is a sudden breaking down of red blood
corpuscles with the setting free of haemoglobin m the blood plasma. It may
be prepared by the addition of a ferricyanide, permanganate, or nitrite, or
other oxidising or reducing agents to the laked blood or to solutions of oxy-
haemoglobin. It is a chocolate-brown substance, crystallisable, and gives a
distinct absorption band in the red between Fraunhofer's lines C and D. It
is unaltered by exposure to a vacuum. On treatment with reducing agents
however, such as Stokes's fluid, the methsemoglobin is converted into
haemoglobin, from which by shaking with air oxyhaemoglobin can be
reformed. The fact that met haemoglobin cannot be reduced by exposure
to a vacuum indicates that it is a compound of oxygen with haemoglobin, in
which the oxygen is in a different state of combination. According to
Buckmaster methsemoglobin contains only half as much oxygen as oxy-
haemoglobin, so that the composition of the two bodies might be represented.
A
Hli (oxyhaemoglobin) and Hb = O (methsemoglobin).
\d
The change from oxyhaemoglobin to methsemoglobin is not effected however
by a simple shifting of the oxygen groups, but must be assumed to involve
two distinct events. The whole of the oxygen in loose combination with
haemoglobin is given off, and the oxygen in the methaemoglobin molecule is
derived from the oxidising agent added, so that ferricyanide of potash, for
instance, is converted into ferrocyanide. 1 Since the whole of the oxygen
in the oxyhaemoglobin is given off on the addition of potassium ferricyanide,
we may use this fact in order to determine the total amount of oxygen in
combination in the blood.
1 Whin the change is effected by reducing agents, we must assume that the oxygen
of the water or air is the source of that required for the oxidation of the reduced haemo-
globin to methsemoglobin.
868 PHYSIOLOGY
^DERIVATIVES OF HEMOGLOBIN. Hemoglobin is a compound of
an iron-containing coloured group (the prosthetic group) with a protein,
which probably varies somewhat in different animals. The prosthetic group
is identical in every case where it has been examined. A separation of the
prosthetic group from the protein moiety can be effected with extreme ease,
and occurs whenever the hsemoglobin is treated with weak acids, with
alkalies, or is heated above 70° C. The protein group is known as globin.
In order to separate globin, oxyhemoglobin crystals are dissolved in water and
treated with small quantities of very dilute hydrochloric acid. A precipitate of pig-
ment forms which, if the hsemoglobin used be free from inorganic salt, rapidly dissolves
in excess of the acid. Alcohol and ether are then added in such relative quantities
that the ether separates rapidly from the aqueous solution. The colouring matter
(hamiatin) dissolves in the ether, whilst the protein (globin) remains in solution
in the water. The solutions are separated by a
»* ""'i-^x.-r-t separating funnel and ammonia added carefully to
■ ' \ -Jjy % " vJr ' the aqueous solution. This throws down a pre-
"^~U « *% "r - v cipitate of the protein, which is soluble in acids
vfe f I ^_ "^ 'i ^ ^ 4 and alkalies and coagulable on heating ; the coagu-
, ^v \ * V" ^ 4 l um however is soluble in acids. It is precipitated
1 / V ^ W\-\'N by ammonia in the presence of ammonium chloride.
r^t K ' j ^ ^. _ _ n contains as much as 16-89 per cent, nitrogen,
y* s i 7 ant l yields a considerable amount of the basic
' ,, -£■ ^' ., "' 1 1 derivatives on hydrolysis. It is therefore classified
*>•'•? rh . ^^ *K'\- ^' with the histones.
^A. » _ + Hsemoglobin yields about 94 per cent, of
t >-\ globin and about 4-5 per cent, of the chromo-
Fm.373. Haemiu crystals. genie group, hsematin. In order to obtain
hcematin in a pure condition, it is usual to
start with the crystalline derivative of hsemoglobin known as hwmin.
When some dried blood is heated with a crystal of common salt and
placed in acetic acid on a slide, a residue is obtained in which a number
of reddish-brown needles are embedded known as Teichmann's crystals or
hsernin crystals (Fig. 373). The preparation of these crystals is often used
as a convenient test for the identification of blood.
In order to obtain them in large quantities the following method, devised by
Chalfejew, is employed. One volume of defibrinated blood is added to four volumes of
glacial acetic acid previously heated to 80° C. As soon as the temperature has fallen to
00° C. the liquid is again warmed, and then allowed to cool. Crystals are formed
which are allowed to stand for twelve hours and are then separated and washed by
decantation, first with distilled water and then with graduated strengths of alcohol.
In order to purify these crystals, the crude material is shaken for fifteen minutes with a
mixture of chloroform and pyridine. The solution is filtered and then thrown into
glacial acetic acid previously saturated with sodium chloride and heated to 105° C.
A few drops of concentrated hydrochloric acid are then added and the mixture allowed
to stand for twenty-four hours. The crystals which separate out are filtered off,
washed with dilute acetic acid, and then dried.
Hsernin crystals have been regarded as hydrochloride of hsematin.
Elementary analysis shows that they have the following formula (Will-
statter) : (C 33 H 3 OiN 4 Cl Fe. By dissolving hsernin in alkalies and throwing
THE RED BLOOD CORPUSCLES
869
the solution into an excess of acid, a precipitate is obtained which is haematin.
Haematin forms a powder of bluish-black colour, and metallic lustre. It is
insoluble in water, alcohol, or ether, but is slightly soluble in glacial acetic
acid and in absolute alcohol. It is easily soluble in concentrated sulphuric
acid, but undergoes decomposition, losing its atom of iron and being trans-
formed into hcematoporphyrin, which forms a deep purple solution. The
formula of haematin has not yet been ascertained with certainty. It is
J?ig. 374. Absorption spectra of haemoglobin and its derivatives.
1. Oxyhemoglobin. 2. Reduced haemoglobin. 3. Methaemoglobin.
4. Alkaline methaemoglobin. 5. Acid haematin in other. 6. Alkaline
haematin in rectified spirit. 7. Reduced haematin. 8. Acid haematopor-
phyrin. 9. Alkaline haematoporphyrin. • (From MacMunn.)
probably C33H32O4N.jFe.OH. Its compounds with acids and alkalies are
spoken of as acid and alkaline haematin, and each gives a characteristic
absorption spectrum (Fig. 374). The alkaline solutions exhibit one indis-
tinct absorption band between C and D, the acid solutions an absorption
band also between C and D but nearer to C, and resembling somewhat the
band presented by methaemoglobin. According to Hoppe-Seyler and
Gamgee, perfectly pure solutions of haematin in alkalies are quite unaffected
by reducing agents; in the presence of certain foreign matters however,
alkaline haematin, when treated with reducing agents, exhibits a spectrum
known as that of reduced alkaline haematin, which is identical with that of
870 PHYSIOLOGY
haemochromogen. The same change is further observed when alkaline
haematin, made by the action of alkalies on ordinary blood, is treated with
reducing agents such as ammonium sulphide. Since this substance, hsemo-
chromogen, is responsible for the respiratory functions of the haemoglobin,
i. e. the power of its molecule to form unstable compounds with oxygen, its
preparation merits fuller consideration.
Hcemochromogen is prepared by the action of caustic alkalies on
haemoglobin in the absence of oxygen. For this purpose a test-tube con-
taining a solution of sodium or potassium hydrate is placed in a bottle with
two necks containing a solution of haemoglobin, care being taken not to
spill any of the alkaline solution. Hydrogen is then passed through the
larger bottle until the haemoglobin is entirely reduced and all the air is
replaced by hydrogen. The bottle is then inverted so as to mix its contents
with the caustic alkali, when haemochromogen is formed and can be recog-
nised by its characteristic colour and spectrum. The haemochromogen in
solution has a cherry-red colour, and when sufficiently diluted shows two
well-marked absorption bands identical with those given by reduced alkaline
haematin (Fig. 374, 7). Of the two absorption bands which are situated
between D and E, that nearest to D has very sharply denned borders ; the
position of the two absorption bands may be given in terms of their wave-
lengths as follows : /. 567 to 547 and /. 532 to 518. The band nearest D is
given by haemochromogen solutions diluted until there is only one part
of the pigment in 25,000 parts of water, so that the formation of reduced
alkaline haematin is an even more delicate test for blood than the spectrum
of oxyhemoglobin itself. When CO-haemoglobin is treated in the same way
with alkali in the absence of oxygen, a body CO-hsernochrornogen is formed
which contains exactly the same volume of CO in combination as the original
CO-haemoglobin. This fact, combined with the possibility of reducing
ordinary alkaline haematin by the action of ammonium sulphide or Stokes's
fluid, indicates that the group of atoms which in haemoglobin is responsible
for taking up oxygen or carbon monoxide gas passes unchanged into the
haemochromogen molecule. Haemochromogen therefore represents an iron-
containing coloured radical which can combine with protein bodies to
form haemoglobin, and is responsible for the oxygen-combining powers of the
latter. We may assume therefore that oxyhemoglobin and CO-haemoglobin
contain oxyhaemochromogen and CO-haemochromogen respectively.
Hamatoporphyrin. If haemoglobin, haematin, or haemin be mixed with
concentrated sulphuric acid, it dissolves forming a purple-red solution.
On pouring this solution into a large quantity of water, haematoporphyrin
is thrown down in the form of a brown precipitate. In order to prepare
haematoporphyrin, pure crystallised haemin is added to a saturated solution
of hydrobromic acid in glacial acetic acid. The whole is allowed to stand
for three or four days and then thrown into distilled water. The resulting
mixture is filtered and the haematoporphyrin thrown dow r n by careful
neutralisation of the hydrobromic acid with caustic soda. Haemato-
porphyrin is easily soluble in alkalies and somewhat less readily so in acids,
THE RED BLOOD CORPUSCLES 871
forming alkaline and acid haematoporphyrin respectively. The formula of
haematoporphyrin has been given by Nencki and Sieber as C J6 H 18 N.,0 3 ,
and is according to them isomeric with the chief bile pigment, bilirubin.
According to Willstatter its formula is C 33 H 3g N 4 6 . An alcohohc solution
of kamiatoporphyrm acidulated with hydrochloric acid shows two absorption
bands : one, the fainter, between C and D ; and the other, broader and
more denned, midway between D and E. Solutions of alkaline haemato-
porphyrin show four absorption bands : a weak band between C and D ;
another between D and E ; a more strongly marked band nearer to E ; and
a fourth band, darkest of all, between b and F. It will be observed that,
in the formation of hamiatoporphyrin from haematin, the iron of the latter
has been split off by the action of the strong acid. Laidlaw has found
that the splitting off of iron occurs much more readily in the absence of
oxygen. If reduced hemoglobin be taken, or defibrinated blood which
has been allowed to stand until it is thoroughly reduced, it is sufficient to
add 15 per cent, hydrochloric acid in order not only to convert the greater
part of the haemoglobin to haematin but to split off the iron of the latter
and form haematoporphyrin. Haematoporphyrin occurs in minute quantities
in normal urine and in larger quantities in certain toxic conditions, especially
in poisoning by sul phonal, when the urine may have a bright purple colour.
Ir is important to remember that, although urine is acid from the presence
of acid sodium phosphate, urinary haematoporphyrin is always alkaline
haematoporphyrin and gives the spectrum of this body.
CHEMICAL RELATIONSHIPS OF HAEMATIN. Haematin, or haemochromogen,
is widely diffused through the animal kingdom, occurring in the form of haemoglobin
in a large number of the inveitebrata, as well as in all the vertebrata except perhaps
Amphioxus. Since the respiratory function of haemoglobin depends on the power of
its iron-containing radical to combine with a molecule of oxygen, forming an easily
dissociable compound, it becomes of interest to try whether by a study of its disin-
tegration products we can throw any light on its chemical relationships and on the con-
ditions of its formation in the living organism. When haematin is oxidised with sodium
bichromate and acetic- acid, two new acids are formed, called the haematinic acids.
One of these has the formula C g H 9 4 N, and the other C 8 H 8 5 . The first acid is con-
verted into the second by the action of alkalies. The relationship of the two haematinic
acids can be represented by the following formulae :
/CO / C0 \
C 5 H,( >0 C 5 H, NH
COOH COOH
If, on the other hand, haemin or hosmatoporphyrin be reduced by the action of hydriodic
acid dissolved in acetic acid with the addition of phosphonium iodide, and the product
be distilled with steam, the distillate contains a mixture of substituted pyrroles formerly
known as haemopyrroes. The mixture readily oxidises to a red substance on exposure
to the air. If ammonia be added to the coloured solution, the colour changes to yellow
which, on the addition of an ammoniacal solution of zinc chloride, changes to pink
with .1 green fluorescence. These reactions are also given by urobilin, one of the
urinary pigments ami the chief pigment of the faeces, as well as by hydrobilirubin, a
substance obtained by the action of tin and sulphuric acid on an alcoholic solution of
haematin.
872
PHYSIOLOGY
The hsemopyrroles, according to Willstatter, are three in number and have the
following formula :
CH 3
Cryptopyrrolc
( 'JF;
2"5
CH 3
NH
CH S jC 2 H 5
CH 3 ; xCH 3
NH
Isohaimopyrrolo
CHj C 2 H 5
CH
NH
The same substances can be obtained from the chlorophyll of plants. On treatment
with acid, chlorophyll loses magnesium and is converted into phacophytin. From
this three COOH groups can be split off, leaving a substance, setioporphyrin.
It is interesting that hsematoporphyrin also can be readily converted into setio-
porphyrin. On treatment with pyridine and alcoholic potash, it is converted into
hasmoporphyrin and this heated with soda lime gives setioporph3Tin (C 31 H 36 N 4 ).
Thus the same group forms the basis both of the substance which is responsible in the
plant for the assimilation of carbon from carbon dioxide, and of the pigment which
in the animal is the carrier of oxygen between the tissues and the surrounding medium.
According to Willstatter, setioporphyrin and hsematoporphyrin are both built up of
four substituted pyrrol rings.
Thus hsemato porphyrin has the following structural formula :
C.CH=CH.OH
COOH.GVH.C
/
CH,.C=^C.CH.
C=C.C 2 H 4 .COOH
CH,.C=C.CH,
and the same worker suggests the following formula for hsemin :
CH 3 C
C.CH,
C.CH,
THE SYNTHESIS OF THE BLOOD PIGMENTS. Chemists have not
yet succeeded in the artificial formation of ha?matoporphyrin. Given
hsernatoporphyrin however, evidence has been brought forward both by
Menzies and Laidlaw of the possibility of forming artificially both hsematin
and haemoglobin, or some substance indistinguishable from the latter.
THE RED BLOOD CORPUSCLES 873
Reduced haemoglobin is a compound of haeniochromogen and a protein,
globin. The splitting off of the prosthetic chromatogenic group — haemo-
chromogen — can be effected either by acid or alkali. When the latter is
employed, we obtain a red solution which is fairly stable and can be con-
verted by shaking up with air into ordinary alkaline hsematin. With acids
the decomposition is easily carried further. Even with 2 per cent, hydro-
chloric acid a certain amount of haematoporphyrin is formed, and if the
strength of the acid be increased to 15 per cent, the whole of the iron is
split off and the haemochromogen is converted entirely into haematoporphyrin.
If oxyhemoglobin be treated in the same way, it yields acid or alkaline
haematin directly, so that hsematin must be regarded as an oxyhaemo-
chromogen. The distinction drawn by Hoppe-Seyler between hsemo-
chromogen and reduced alkaline hsematin had its chief ground in the fact
that pure haematin is not reduced to hsemochromogen by the action of
such reducing agents as ammonium sulphide. The conversion can how-
ever be easily effected by using a strong reducing agent, such as hydrazine
hydrate. Whether the haematin contains the whole of the oxygen of the
oxyhsemoglobin is doubtful. According to Ham and Balean, when
oxyhaemoglobin is converted by means of acids into acid haematin, exactly
half the oxygen of the oxyhsemoglobin is given off, so that haematin
would contain only one-half of the oxygen of the oxyhaemoglobin. There
is a marked difference between the stability of haematin and haemochromogen.
Li the oxidised form of hsematin the iron is firmly bound and can be split
off only by using strong sulphuric acid, concentrated hydrochloric acid
being insufficient for the purpose.
It has been shown by Laidlaw that the change in the reverse direction,
i. e. the combination of iron with haematoporphyrin to form haemochromogen,
may be effected with equal ease. One grrn. haematoporphyrin prepared
by Nencki's method is dissolved in dilute ammonia and warmed in a flask
on the water-bath. Some Stokes's fluid, prepared from about 2 grm.
ferrous sulphate, and a few drops of a 50 per cent, hydrazine hydrate
solution are added. At the end of one or two hours the solution is seen
to be of a bright red colour when examined in thin layers, and on dilution
shows the typical absorption spectrum of haemochromogen, which changes
to that of alkaline hsematin on shaking with air. Strong potash is added,
and the ammonia is boiled off in an evaporating dish with free exposure
to the air. The hydrazine is decomposed, and a solution of hsematin
remains which can be precipitated by acidification with hydrochloric acid.
The pigment obtained in this way agrees in every respect with that prepared
from oxyhaemoglobin. Analysis of the product gave 9*58 per cent, of iron,
which agrees with Nencki's formula for hsematin, C 32 H3 N 4 O 3 Fe.
A pigment called turacin, occurring in the wing feathers of certain birds, was shown
by Church to contain copper and to yield, on treatment with strong sulphuric acid,
a substance indistinguishable from haematoporphyrin. Laidlaw has succeeded in
syn the rising this pigment by treating ordinary haematoporphyrin obtained from blood
with ammoniacal copper solution, showing that it is a compound corresponding to
hseniarin, in which the place of iron is taken by copper.
874 PHYSIOLOGY
It was stated some years ago by Menzies that a solution of impure
haemochromogen , prepared by the action of ammonium sulphide on alkaline
hsematin obtained in the ordinary way from blood, on standing for some
days was reconverted into reduced haemoglobin. Hani and Jialean have
confirmed this observation, and have shown in addition that haemo-
chromogen. prepared by the action of ammonium sulphide on an alkaline
solution of pure haemin, though perfectly stable by itself, was rapidly
reconverted into haemoglobin if a solution of globin were added to the
mixture. The same change took place if egg-white were used instead of
globin. The haemoglobin thus formed was changed into oxyhemoglobin
on shaking with air. Although in these experiments the oxyhaemoglobin
was not separated in the crystalline form, its colour and spectral characters
are so very distinctive that we are justified in concluding, not only that it
is possible to effect a recombination of the haemochromogen and globin,
but also that other proteins can take the place of globin in the haemoglobin
molecule.
THE LIFE-HISTORY OF THE RED BLOOD CORPUSCLES
The growth of the embryo as well as of the young animal must be
attended with a continual increase in the number of red blood corpuscles
present in the body. In the developing embryo the first formation of red
corpuscles occurs in the vascular area. In the chick, about the twentieth
hour of incubation, the area opaca, which surrounds the blastoderm and
will later become the area vasculosa, presents on examination imder the
low power a network of anastomising strands more opaque than the rest
of the area. On section these strands are seen to be made up of cellular
masses, the ordinary mesenchyma, with branched cells and amoeboid
corpuscles lying between. The cells in these cords are continually multi-
plying by indirect division. Those on the outer side of the cord become
the endothelium of dilated blood vessels, while those in the interior acquire
a yellowish colour from the laying down of haemoglobin in their cytoplasm.
The cords become canalised and, as soon as a connection is established
with the vascular system of the embryo, the newly formed blood corpuscles
move slowly on into the general circulation. The red corpuscles in the
bird are true erythrocytes, i. e. are nucleated cells. The leucocytes seem
to arise by the immigration of wandering cells from the surrounding
mesenchyma. Other places in the foetus where a similar growth of corpuscles
proceeds throughout foetal life are the liver and the spleen, and later on
the bone marrow.
In the mammal the nucleated erythrocytes, though forming the majority
of the red corpuscles in early foetal life, become fewer and fewer in number
as gestation advances, so that at birth practically the whole of the cor-
puscles are of the non-nucleated type. These however can be shown to
be derived from nucleated red corpuscles by a process either of extrusion
or of degeneration and solution of the nucleus (Fig. 375). The formation
of red corpuscles does not cease with the end of foetal life or even with the
THE RED BLOOD CORPUSCLES
875
attainment of full stature by the animal. We have definite proof that a
continual formation of red corpuscles can proceed and is proceeding
throughout the whole of adult life. In an adult the total volume of blood
and the total number of corpuscles remain approximately constant. By
bleeding an animal we can diminish the total aniotuit of corpuscles. The
first effect of such a bleeding is that the fluid parts of the blood are made
up, so that the volume of the blood is restored to normal and the blood
Fig. 375. Part of a blood vessel from the yolk sac of the rabbit embryo, showing
the changes which occur in the formation of erythrocytes. (From Schaper
after Maximo w.)
a, megaloblasts ; b, normoblasts changing into erythroblasts ; c, erythroblasts,
in which the nuclei are disappearing; d, an erythrocyte fully formed, but not yet disc -
shaped: en, phagocytic endothelial cells; /, lymphocytes; k, a divided lymphocyte;
n. erythroblasts, shrunken with atrophic nucleus.
therefore becomes relatively poor in corpuscles. In a few weeks however,
the corpuscular content of the blood is found to be once more normal,
showing that the loss of corpuscles has been followed by a compensatory
regeneration. The fact that the pigments constantly leaving the body
with the urine and faeces, namely, urochrome and urobilin or stercobilin,
are derived by means of the liver from haemoglobin, shows that a constant
destruction of red corpuscles must be proceeding. Since the number of
corpuscles remains vuialtered, this loss of haemoglobin must be made
good by a continual regeneration of fresh haemoglobin and new red corpuscles.
The seat of the formation of red corpuscles in the higher vertebrates is the
870
PHYSIOLOGY
bone marrow. Here we have a structure protected from pressure where
the capillaries and veins are dilated and thin-walled, and allow a slow passage
of blood and the entry of newly formed corpuscles through the imperfect
walls into the blood stream (Fig. 376). That the marrow is involved
in the process is shown by the fact that it is the only tissue of the
body which undergoes an alteration in appearance when blood formation
is stimulated by such means as repeated bleeding or destruction of cor-
puscles by the injection of toxic agents. Under such conditions the red
marrow, which in adult mammals is present only in the epiphyses, is found
to have increased in extent and in many cases to occupy the greater part
■fi _ »d
Fig. 376. Section of red marrow of mammal. (Bohm and Davidoff.)
a, e, erythroblasts; 6, recticulum; c, myeloplax; d, g, marro%v cells;
/, a marrow cell dividing ; h, a space which was occupied by fat.
of the shaft of the bone, having taken the place of the yellow marrow. It
is in the red marrow therefore that we must seek the precursors of the red
blood corpuscles. In the bird the erythroblasts, i. e. the precursors of the
nucleated red blood corpuscles, form a sort of inner lining to the dilated
capillaries of the marrow (Fig. 377). Here we can see all grades between
the colourless nucleated corpuscle which lies nearest the periphery and
the adult red oval corpuscle containing haemoglobin, lying next the
lumen and ready to be carried away in the blood stream. If blood forma-
tion has been stimulated by repeated bleeding, this blood-forming tissue is
found to occupy the greater part of the lumen of the marrow capillaries.
If however blood formation has been reduced to its lowest extent by a
process of chronic starvation, the erythroblasts form a single layer of cells
just inside the dilated capillaries, and intermediate stages between the ery-
throblasts and the fully developed erythrocytes are almost entirely wanting.
In the frog this process of blood-corpuscle formation occurs only at one
period of the year, namely, in the early summer, and it is only at this time
that the bones are found to contain red marrow. In mammals the process
THE RED BLOOD CORPUSCLES
877
is very similar. Li the red marrow are a number of nucleated cells con-
taining haemoglobin, which are thought by Lowit to be themselves derived
from colourless nucleated cells. In the confused medley of colourless cells
which are found in the bone marrow and are precursors of all the varied
corpuscles found in the blood, it is difficult to be certain of the identity
of the colourless erythroblasts and to distinguish them from the smaller
colourless cells engaged in bone formation or in the production of leuco-
cytes. The haemoglobin-containing cells are often to be seen in process
of division, and the nucleated daughter-cells appear to undergo a process
of nucleolysis, the nucleus being extruded or dissolved. When blood forma-
tion is quickened as the result of previous destruction or loss, some of these
Fig. 377. Section of red marrow of pigeon. (Denys.)
Ic, eosinophile leucocytes ; eg, fat cells ; e, nucleus of endothelial cell of
blood vessel; ca, blood capillary; cr, erythroblasts lying within vascular
endothelium ; glr, fully formed red corpuscles.
immature nucleated blood discs may make their way into the circulation
and be found in the blood, where they are spoken of as normoblasts.
How long a corpuscle continues to exist in the circulating blood is not
known. The experiments, made to determine the length of time during
which foreign corpuscles such as those of birds can be recognised after
injection into the circulation of a mammal, are evidently beside the mark,
since these foreign cells will be destroyed by the serum and rapidly taken
up by the phagocytes of the body. Sooner or later however, every cor-
puscle undergoes disintegration, a process which is generally ushered in
by the ingestion of the corpuscle by some phagocyte cells. Thus in the
haemolyniph glands and in the spleen, we find large cells which have englobed
red corpuscles and in which we can recognise pigment granules derived
from their destruction. The chief place of disintegration of the haemoglobin
is certainly the liver, i. c. the organ where the haematin is converted into bile
pigment. Injection of haemoglobin into the circulation causes increased
secretion of bile pigment. A section of normal liver immersed in potassium
878 PHYSIOLOGY
ferrocyanide and then in acid alcohol shows the presence of iron by the
assumption of a blue colour. The amount of iron which can be dernorj
strated in the liver in this way is enormously increased by any condition
which augments the rate of blood destruction. In the pathological condition
known as pernicious anaemia, as well as after poisoning by the injection of
pyrogallic acid or tohrylene diamine, both of which agents cause a great
destruction of red blood corpuscles, the liver on treatment in this way
assumes a deep blue colour. In some cases crystals of haemoglobin have
been seen within the nucleus of the liver cell. In the destruction of the
corpuscles the haemoglobin is dissociated first into its protein and chromo-
genic moieties; the haemochromogen then loses its iron and is converted
into bile pigment. Tire iron remains in the liver and is probably retained
in the body and utilised for the formation of the fresh haemoglobin necessary
for the newly forming red blood corpuscles in the bone marrow.
SECTION III
THE BLOOD PLATELETS
The very existence of these, the third class of formed elements of the
blood, is still a matter of dispute. If a drop of osmic acid be placed on the
finger, which is then pricked through
the drop so that the shed blood may
mix with the fixing fluid directly it
leaves the vessels, a drop of the mixture
when examined under high powers is
seen to present a number of granular
bodies from one-third to one-half the
diameter of a red blood corpuscle. Their
number has been variously stated from
180,000 to 800,000 per cubic millimetre,
so that they rank second in point of
, i i ■ i Fio. 378. Blood platelets, highly mag -
number among the morphological con- nified, showing the amoeboid forms
StituentS of the blood. Their shape which they assume when examined
* under suitable conditions, and also
varies considerably, home are bi-convex exhibiting the chromatic particle
structures ; others are flatter with numerous *hjmoglobin.
QUANTITY AND COMPOSITION OF THE BLOOD IN MAN 899
The relative saturation of the blood in carbon monoxide is determined by the colorimetric
method. A number of narrow test-tubes of exactly equal diameter and each holding
about 6 c.c. are taken, and 2 c.c. of water saturated with air measured off into each.
Two cubic millimetres of the blood of the subject are measured off in the ordinary way
by means of a ha?moglobinometer pipette into each of the six tubes, the solutions being
well mixed. Four cubic millimetres of this blood are thoroughly saturated with coal
gas and placed in another shorter tube, which is filled full and tightly corked. In this
tube the haemoglobin is completely saturated with carbon monoxide. After the subject
has breathed the carbon monoxide, a sample of his blood is taken and diluted as before.
The solution in this tube is, of course, pinker than those in the other tubes. A standard
solution of carmine is now added from a narrow burette to one of the tubes of normal
blood solution until its tint is the same as that of the blood taken after the inhalation.
Addition of the carmine is then continued until the tint is equal to that of the blood
solution which is entirely saturated with carbon monoxide. Supposing that 0-45 c.c.
of carmine was required to produce equality of tint with that of the blood taken during
the experiment and 2-5 c.c. to produce equality of tint with that of the saturated blood,
then as 2'5 c.c. of carmine in 45 c.c. of liquid were required to produce saturation tint,
and only 0-45 c.c. of carmine in 2-45 c.c. of liquid to produce the tint of the blood under
examination, the percentage saturation of the latter could be calculated by the following
sum :
100:*
2-5 j45
f5 2^45
.-. x = 331
Although this method requires careful execution in order to avoid
fallacies, it is possible to attain results, as has been shown by Douglas,
closely agreeing with Welcker's method. The error is probably not greater
than 10 per cent., which is negligible in comparison with the large changes
in total blood volume which have been found to occur in certain cases of
disease. The total record of two such observations by Haldane and Lorrain
Smith may be here quoted :
Body weight
in
kilogrammes.
72-9
89-0
Normal Individual
Volume of dry CO. Percentage
absorbed in c.c. saturation of
at 0° C Hb with CO.
116 . 18-9
116
Oxygen capacity Total amount
per 100 c.c. of of blood
blood in c.c. in grammes.
18-7 . 3455
18-2
2970
22-7
Grammes of blood
per 100 gnu. of
body weight.
4-75
3 : 34
Dry oxygen
capacity of
blood in c.c.
014
511
C.c. of oxygen
per 100 grm. of
body weight.
0-84
0-57
In applying this method in cases of disease it is important not to give too
large a dose of carbonic oxide gas. In a normal individual 30 per cent,
of the haemoglobin may be combined with carbon monoxide before any
oxygen hunger is felt, and it is possible to saturate half the haemoglobin
with this gas, though with considerable discomfort to the individual. In
cases such as heart disease, where the patient is at the very margin of his
resources, even 30 per cent, diminution of the oxygen capacity of the blood
may have serious results, and the carbon monoxide inspired must be there-
fore kept at the lowest limit at which it is possible to carry out a reliable
determination of the relative carbonic oxide saturation of the blood sample.
900 PHYSIOLOGY
A simpler method of determining the total blood volume has been worked out by
Keith, Rowntree and Geraghty. The method consists in injecting a non-toxic, non-
diffusible dye substance into the blood stream and estimating its dilution. The dye
used is ' vital red,' a chemical compound belonging to the triphenyl-methane series.
In performing the test 6 to 8 c.c. of blood are removed from an elbow vein. From
10 to 18 c.c. of a 1-5 per cent, solution of the dye in distilled water is then slowly injected
by the same needle. Five minutes later a second specimen of blood is withdrawn into
a third syringe. The blood samples are prevented from clotting by the addition of
potassium oxalate. A part of this is drawn into a hasmatocrit tube and centrifuged
for 'twenty minutes at a high speed in order to determine the relative volume of cor-
puscles and plasma. The rest of both samjiles of blood are centrifuged in order to
obtain the plasma. Samples of plasma before and after are then compared in the
following mixture :
[ 1 part of the diluted dye solution.
Standard- 1 part of the plasma before dye injection.
[2 parts 0-8 per cent. NaCl solution.
Test
1 part of plasma after dye injection.
3 parts 0-8 per cent. NaCl solution.
The two solutions are compared in a colorimeter and the test solution read off as a
percentage of the standard. The following formula will give us the plasma volume :
If R be the percentage reading of test solution.
- X c.c. dye injected X 100 = c.c. plasma.
R
The blood volume is calculated from the hematocrit reading.
100 X c.c. plasma
Total blood volume = — -. — - — ; — =-. — r-
percentage plasma in blood.
The total blood volume probably varies appreciably with alterations
in the condition of the animal, and may be found different on two suc-
ceeding days. It is certainly influenced by the height of the blood pressure
as well as by the oxygen tension in the air breathed, and therefore alters
with the altitude. Some of these variations we shall have to consider more
fully in a later section. Any lowering of blood pressure causes an absorp-
tion of fluid from the tissues into the blood, so that the latter becomes more
dilute. The blood content during the last stages of bleeding may contain
little more than 50 or 60 per cent, of the haemoglobin which was present
in the first samples of blood, pointing to a corresponding dilution of the
blood during these few minutes by means of tissue lymph. By this means,
i. e. the absorption of fluid from tissues, the volume of circulating blood
after a limited haemorrhage is rapidly brought up to normal, so that there
is a circulation of a fluid impoverished in corpuscles. The latter are made
up in the course of a few weeks as a result of increased activity in the
bone-marrow.
Relative Amount of Plasma and Corpuscles. The relative amount of corpuscles
in a given sample of blood is most easily determined by Blix's method. The
blood is mixed with a definite amount of 2-5 per cent, potassium bichromate, and
the mixture is put into small graduated capillary tubes, which are then placed in
a centrifuge revolving about 10,000 times per minute. The corpuscles rapidly
accumulate in an almost solid mass at the bottom of the tube, and their volume
QUANTITY AND COMPOSITION OF THE BLOOD IN MAN 901
can be directly read off. It is often possible by working quickly to receive blood into
such graduated capillary tubes and to centrifuge it rapidly before it has had time
to coagulate. The corpuscles are hurried down to the bottom of the tube within
two or three minutes and their volume can be in this way directly determined.
An indirect method for the same purpose was devised by Hoppe-Seyler. The total
proteins of defibrinated blood are determined and compared with the total proteins
of the washed corpuscles and of the serum. Thus in one experiment 100 gmi. of
defibrinated pig's blood contained 18-90 grm. protein plus haemoglobin. The blood
corpuscles of 100 grm. of the same blood contained 15-07 grm. proteins plus haemo-
globin; therefore the serum of the same 100 grm. of blood contained 18-90 — 15-07 =
3-83 grm. proteins. One hundred grammes of serum contained 6-77 grm. protein. From
these figures the amount of serum in the 100 grm. of defibrinated blood may be
computed as follows :
— . 100 = 56-6 per cent, serum.
6-77 ^
100 — 56-6 =• 43-4 per cent, blood corpuscles.
The average volume of corpuscles in human blood can be taken as 50 per
cent, of the total amount, different estimations having given figures varying
from 48 to 54 per cent. In the horse the volume of corpuscles is 53 per
cent., in the dog 36 per cent.
• The Enumeration of the Corpuscles. In order to enumerate the red
corpuscles, the blood is diluted with a known amount of an isotonic
fluid and the number is counted in a measured volume of the mixture.
The average number of red corpuscles is about 5,000,000 per cubic milli-
metre in adult men and rather fewer, about 4,500,000, in adult women.
The enumeration of corpuscles is subject to considerable errors, probably
not less than 10 per cent. Moreover different conditions of the cir-
culation may cause variations in the relative distribution of plasma and
corpuscles respectively in different parts of the circulation, so that the
blood-count of a specimen from the capillaries of the finger or lobe of the
ear may vary considerably from a similar count of the corpuscles in blood
obtained directly from a minute vein or artery. More important therefore
is the determination of the haemoglobin. For this purpose a measured
quantity of the blood, 2 to 5 c.mm., is obtained in a capillary pipette and
mixed with a given volume of water. The red fluid thus obtained is com-
pared with a standard. This latter in von Fleischl's instrument is a prism
of coloured glass. In Oliver's instrument the standard consists of a series
of tinted glasses, one of which represents the colour of a measured quantity
of normal blood diluted with water and placed in a flat glass cell of a certain
size, while the others represent percentages of hsemoglobin below and above
the normal. The most accurate method is that due to Hoppe-Seyler and
Haldane, namely, the conversion of the blood sample into CO-hsemoglobin
and its comparison with a standard specimen of CO-haeinoglobin, which is
stable in solution and can therefore be kept in a sealed glass vessel for any
length of time.
The Gxygen Capacity of the Blood. Instead of determining the haemo-
globin we may measure directly the oxygen capacity of the blood, since
902
PHYSIOLOGY
the oxygen-binding power of this fluid is entirely dependent on the
amount of haemoglobin it contains. For this purpose we may make use
of the fact discovered by Haldane, that the combined oxygen in oxy-
haemoglobin is liberated rapidly and completely on addition of a solution
of potassium ferricyanide to laked blood, and may thus be easily measured
with the help of an apparatus similar to that used for determining urea in
urine by the hypobromite method.
The following description of the method is given by Haldane :
' Twenty cubic centimetres of the oxalated or defibrinated blood, thoroughly
saturated with air by swinging it round in a large flask, are measured out from a pipette
into the bottle a, which has a capacity of about 120 c.c. As it is important to avoid
^
Fig. 381. Haklane's method for determining the oxygen capacity of tho blood.
blowing expired air into the bottle, the last drops of blood are expelled from the pipette
by closing the top and warming the bulb with the hand.' Thirty cubic centimetres
are then added of a solution prepared by diluting ordinary strong ammonia solution
(sp. gr. 0-SS) with distilled water to ^^j. The ammonia prevents carbonic acid from
coming off, while the distilled water lakes the corpuscles. The blood and ammonia
solution are thoroughly mixed by shaking, and at the end of this operation the solution
should appear perfectly transparent when tilted up against the sides of the bottle. 1
About 4 c.c. of a saturated solution of potassium ferricyanide are then poured into the
small tube B (the length of which should slightly exceed the width of the bottle) and
placed upright in A. The rubber stopper, which is provided, as shown, with a bent
glass tube connected with the burette by stout rubber tubing of about 1 mm. bore, is
1 If the solution were not transparent this would indicate that the taking was
incomplete, and more ammonia solution would need to be added.
QUANTITY AND COMPOSITION OF THE BLOOD IN MAN 903
then firmly put in, and the bottle placed in the vessel of water c, the temperature of
which should be as nearly as possible that of the room and of the blood and water in
the bottle. If the stopper is not heavy enough to sink the bottle, the latter should be
weighted. By opening to the outside the three-way tap (or T-tube and clip) on the
burette, and raising the levelling tube which is held by a spring clamp, the water in
the burette is brought to a level close to the top. The tap is then closed to the outside,
and the reading of the burette (which is graduated to •05 c.e., and may be read to -01 c.c.)
taken after careful levelling.
The water-gauge (which has a bore of about 1 mm.) attached to the temperature
and pressure-control tube is now accurately adjusted to a definite mark. This is
easily accomplished by sliding the rubber tube backwards or forwards on the piece
of glass tubing D. The control tube is an ordinary test-tube containing some mercury
to sink it, and connected with the gauge by stout rubber tubing of about 1 mm.
bore.
As soon as the reading of the burette is constant, which it will probably be within
two or three minutes, the bottle is tilted so as to upset b, and is shaken as long as gas is
evolved. During this operation b should be repeatedly emptied, as otherwise the
oxygen dissolved in its liquid might not be completely given off. When the evolution
of oxygen has ceased the bottle is replaced in the water. If, as is probable, the pressure-
gauge indicates an alteration in the temperature of the water, cold water from the tap,
or warmed water, is added till the original temperature has been re-established and the
reading of the burette noted as soon as it is constant. The bottle is again shaken, etc.,
until a constant result is obtained, for which about fifteen minutes from the beginning
of the operations are required. The temperature of the water in the jacket of the
burette, and the reading of the barometer, are now taken, and the gas evolved is reduced
to its dry volume at 0° and 7C0 mm. To calculate the oxygen evolved from 100 c.c. of
blood, allowance must be made for the fact that a 20 c.c. pipette does not deliver 20 c.c.
of blood, but only about 19-6 c.c. The actual amount of shortage for a given pipette
can easily be determined by weighing the pipette after water, and again after blood,
has been delivered from it. A further slight correction is necessary on account of the
fact that the air in the bottle at the end of the operation is richer in oxygen than at the
beginning, so that, as oxygen is about twice as soluble as nitrogen, slightly more gas will
be in solution. With a bottle of 120 c.c. capacity and 20 per cent, of oxygen in the blood,
the air in the bottle at the end will evidently contain about 27 per cent, of oxygen, so
that, assuming that the coefficients of absorption of oxygen and nitrogen in the 54 c.c.
of liquid within the bottle are nearly the same as in water, the correction will amount
at 15° C. to -06 c.c. in the reading of the burette, or + 0-30 per cent, in the result.
The Specific Gravity of the Blood. The specific gravity of the blood
may be determined by directly weighing a sample, or more conveniently
by collecting blood in a capillary tube and discharging drops of it into
a series of vessels containing glycerin and water mixed in varying pro-
portions. When it is found that the drop of blood as it leaves the
capillary vessel neither rises nor falls in the glycerin and water mixture,
we know that the specific gravity of the blood is identical with that of
the mixture. A graduated series of these mixtures is kept in bottles
and their specific gravity is generally determined before the experiment.
Hammerschlag's method consists in placing a drop of blood in a mixture
of chloroform and benzene and then adding chloroform or benzene, as
the case may be, until the drop neither rises nor falls. The specific
gravity of the mixture is then taken. The specific gravity varies in man
between 1057 and 1066, and in woman from 1051 to 1061. It is increased
by loss of water, as after profuse perspiration, or by passive congestion
904 PHYSIOLOGY
of the part- from which the sample is taken. It is also increased as a
result of any operation upon a serous cavity in consequence of exuda-
tion of plasma in the inflamed or irritated part. It is diminished as the
result of bleeding. The specific gravity of serum is 1028 to 1032, of cor-
puscles about 1090. It is interesting to note that the specific gravity of
the blood is highest in the foetus at full term, when it amounts to 1066,
contrasting with that of the mother at the same time, the specific gravity
of whose blood is only 1050. The specific gravity rapidly falls to the
latter figure after birth.
THE REACTION OF THE BLOOD
The blood has long been described as alkaline owing to the fact that it
turns neutral litmus paper blue. This fact can be demonstrated by allowing
a drop to flow on a piece of glazed litmus paper and then wiping away the
blood with a piece of linen moistened with distilled water or neutral saline
solution. The alkalinity of the blood was determined by mixing a small
definite quantity with sulphate of soda solution containing a definite amount
of tartaric acid. The acid was then titrated against a decinormal solution
of sodium hydrate until a drop of the mixture gave a blue stain and was
placed on blue litmus paper. It must be noted however that this method
gave, not the alkalinity, but a measure of the alkaline reserve — i. e. of the
total amount of soda in combination with weak acids which can be replaced
by the tartaric acid. This alkaline reserve consists almost exclusively of
sodium bicarbonate, and the method indicated above is a means of estimating
the total amount of this salt in the blood.
In van Slyke's method the alkaline reserve of the plasma is determined by finding
out how much C0 2 is evolved from a given volume of the oxalated plasma (1 e.c), when
this is treated with 5 per cent, sulphuric acid so as to convert all the bicarbonate into
sulphate. Since the amount of carbonic acid taken up depends on the partial pressure
of the C0 2 in the atmosphere to which the plasma is exposed, the plasma is first shaken
up with alveolar air provided by the experimenter himself, which always contains about
5-5 per cent, of CO^
Normal human blood plasma treated in this way yields between 0'6 and - 7 c.c. of
C0 2 per cubic centimetre.
The reaction of the fluid, strictly speaking, depends on the relative pro-
portions of the H and OH ions present. Pure distilled water owes its
neutrality to the fact that it contains equal amounts of H and OH ions.
If the H ions increase and the OH ions diminish, the reaction becomes acid.
The relative concentration of H and OH ions in a fluid can be measured
electrically. In this method the potential difference is measured between
the fluid and a platinum electrode immersed in it, which is kept saturated
with hydrogen. In determining the reaction of the blood by this means,
care must be taken to make the estimation at the body temperature, and
also to keep a tension of 5 per cent, of an atmosphere of C0 2 in the gaseous
mixture in contact with the blood or blood plasma. If blood is raised from
QUANTITY AND COMPOSITION OF THE BLOOD IN MAN 905
15° to 38° C, the alkalinity increases fourfold; moreover, since the reaction
depends upon the relation of the free carbonic acid to the bases which are
present in the fluid, any escape of C0 2 from the blood will diminish the
hydrogen ions present and increase the alkalinity. An easier method than
the electrical is to employ indicators which vary in their sensitiveness to
changes of reaction. By previous experiment it has been determined what
concentration of hydrogen ions is sufficient to cause a change of colour in the
different indicators. In the following Table, taken from a paper by Boaf,
are given the colours of a number of different indicators and the degree
of acidity — i. e. the hydrogen ion concentration which just suffices to change
their colours.
Indicator
Acid colour
Transitional
colour
Alkaline colour
Hydrogen ion concen-
tration at which colour
change begins
Dimethylamidc
azobenzol
" | Red
Orange
Yellow
IX 10- 3
Congo red
Blue [
Purple and
brown
| Red
IX 10- 4
Vesuvin brown
Brown
—
Yellow
1 x io- 4
Gallein .
Colourless
Pink
Red
IX lo- 4
Na alizarine
sulphonate
1 Yellow
Orange
Red
lx io- 4
Lacmoid .
Red
Purple
Blue
ix io- 4 -ix io- 8
Rosolic acid
Yellow
Orange
Red
lx io- 5
Litmus .
Red
Purple
Blue
ix io- s - lx 10 - 8
Neutral red
Red
Orange
Yellow
IX IO- 8
Alizarine
Yellow
Orange
Red
lx IO- 8
Phenolphthaleii
l Colourless
Pink
Red
IX IO- 9
It should be remembered that in distilled water of the highest state of purity the
concentration of H and OH ions respectively is about 1 X 10 _ 7 .
By these methods the hydrogen ion concentration of the blood at 38°
is found to be 04 x 10 ~ 7 so that it is just on the alkaline side of neutrality.
It might be thought that with such a feeble alkalinity the merest trace of
acid added to the blood would suffice to make it acid. It is found however
that a relatively large proportion of an acid must be added to the blood in
order to produce an appreciable change in its reaction. This is due to the
fact that the sodium bicarbonate acts as a ' buffer ' — i. e. a substance which
can take up acid or alkali with a minimal change of reaction. Thus, if some
acid be added to the plasma, it combines with the sodium and the equivalent
amount of C0 2 escapes, so that if the concentration of the latter gas be
retained constant in the atmosphere to which the plasma is exposed, the
reaction remains almost the same as before. In the same way, if some alkali
be added to blood in contact with an atmosphere containing 5 per cent.
C0 2 , it combines with the C0 2 to form sodium bicarbonate, and the reaction
is again practically unaltered. This property of the blood of retaining a
906 PHYSIOLOGY
constant reaction, even though fixed acids are added to it, is of immense
importance in the economy of the body. All cellular functions are acutely
sensitive to changes in reaction, and, as we shall see later, the activity of
the respiratory centre is primarily dependent on the livdrogen ion con-
centration of the blood with which it is bathed. This hydrogen ion con-,
centration depends in the normal animal on the partial pressure of the C0 2
in the medium with which the blood is in contact, so that the slightest rise
in the C0 2 tension in the alveolar air of the lungs causes at once a corre-
sponding increase in the H ion concentration of the blood, to which the
centre responds by increased activity. On the other hand, considerable
quantities of lactic acid, for instance, can be produced by the muscles and
poured into the blood without affecting more than a transitory alteration
in the activity of the respiratory centre.
The alkaline reserve of the blood is significant, since any diminution
indicates in all probability the production of fixed acids in the tissues, and
a progressive reduction will precede the point at which the ' buffer ' action
of the sodium bicarbonate is lost, and the blood then responds to any addition
of acid hy an appreciable change in reaction. It is only when the alkaline
reserve has been reduced to a minimum that a true condition of ' acidosis,'
with its rapidly fatal effects, can come into being.
THE OSMOTIC PRESSURE OF THE BLOOD
Since the blood serves as a circulating medium, by means of which
the composition of the tissues juices forming the i mm ediate environment
of all the cells of the body is maintained constant, its osmotic pressure
must be of considerable importance in regulating the normal exchanges
of the cells with their surrounding fluid. The osmotic pressure of the
blood depends on its molecular concentration and can be determined by
any of the methods mentioned earlier (p. 125). Of these the most con-
venient is the determination of the freezing-point. The depression of
freezing-point, A, of mammalian blood is about 0-56 and varies between
0-54 and 0-60. The depression of the freezing-point observed in blood
is equal to that of a 0-9 per cent, sodium chloride solution, which is there-
fore taken as isotonic with the blood. . Since the corpuscles are in osmotic
equilibrium with the plasma, their osmotic pressure must be equal to that
of the plasma, and laking the blood does not alter its freezing-point or its
osmotic pressure. The blood of the frog has a lower osmotic pressure,
the normal saline fluid for the frog's tissues being equivalent to 0-65 per
cent, sodium chloride solution.
THE ELECTRICAL CONDUCTIVITY OF THE BLOOD
In a solution it is only the dissociated ions which have the power of
carrying electric discharges. The conductivity of a solution of pure urea
or pure glucose would not differ appreciably from that of distilled water,
QUANTITY AND COMPOSITION OF THE BLOOD IN MAN 907
since neither of these substances is ionised in solution. The conductivity
of blood serum is therefore determined almost entirely by its content in
salts. Since this is approximately constant, the conductivity of serum
varies within very narrow limits. The conductivity of blood varies how-
ever within wide limits, since the outer limiting layer of the corpuscles
is impermeable to many of the ions of the salts of the serum. The corpuscles
present a resistance to the passage of the charged ions and therefore of the
electric current through them, so that the larger the number of corpuscles
contained in a given specimen of blood the lower will be the conductivity
of the latter. Stewart has made use of this fact as a basis for a method of
determining the relative volume of corpuscles and plasma.
The relative amount of serum can be given by the formula :
p = M 6) (174 -X (6))
where p is the number of c.c. of serum in 100 o.c. of blood ; A. (6), X (s), the conductivity
respectively of the blood and serum (both measured at or reduced to 5" C. and expressed
in reciprocal Ohms X 10 8 ). A reciprocal Ohm is the conductivity of a mercury column
1063 metres long and 1 square millimetre in section.
THE GENERAL COMPOSITION OF THE BLOOD
The general composition of the blood has been determined by Karl
Schmidt hi man, and by Abderhalden in the horse and bullock. The
results are given in the Tables on pages 908 and 909.
The important points to be drawn from these analyses may be sum-
marised as follows. Human blood contains from rather over one-third to
one-half of its weight of corpuscles. It contains from 20 per cent, to 25 per
cent, solids. Blood plasma is resolved by clotting into serum and fibrin.
The fibrin forms only 0-2 to 0-4 per cent, of the total weight of blood. The
serum contains in 100 parts 8 to 9 parts of solids, of which 7 to 8 parts
consist of proteins, while the salts make up about 1 part. The chief salt
present in the serum is sodium chloride, which constitutes 60 per cent,
of the ash. Next to this comes sodium carbonate, about 30 per cent.,
and besides these two we find traces of potassium, sodium, and calcium
chlorides and phosphates. Traces of fats, cholesterin, lecithin, dextrose,
urea, and other nitrogenous extractives are constantly found in the serum.
The fats are much increased after a meal rich in them and may give the
serum a milky appearance. The red corpuscles contain from 30 to 40 per
cent, total solids. Of the solid constituents haemoglobin forms nine-tenths ;
the other tenth corresponds to the stroma consisting of stroma protein
(nucleo-protein), lecithin, cholesterin, and salts. There is a striking con-
t rast between the salts of the corpuscles and those in the serum, the former
consisting chiefly of potassium phosphate, the latter of sodium chloride
which in some animals is entirely wanting in the corpuscles.
908
PHYSIOLOGY
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QUANTITY AND COMPOSITION OF THE BLOOD IN MAN 909
Blood of a Man Twenty-five Years of aoe
One thousand Grammes of Blood contain
513-02 Blood corpuscles.
349-69
water ....
Substances not vaporising
at
ottrvv
120° . . . .
163-33
7-70 (including 0-512 iron)
Hxmatin
' Blood-casein,' etc. .
151-89
Inorganic constituents
3-74 (excluding iron)
Chlorine
0-898\
Chloride of potassium
, 1-887
Sulphuric acid
0-031
Sulphate of potassium
. 0-068
Phosphoric- acid
0-695
Phosphate of potassium
. 1-202
Potassium
1-586
Phosphate of sodium .
. 0-325
Sodium ....
0-241
Soda
. 0-175
Phosphate of lime .
0-048
Phosphate of lime
. 0048
Phosphate of magnesium .
0-031
Phosphate of magnesium
. 0-031
Oxygen ....
0-206/
Total
. 3-736
486-98 Interstitial Fluid (Plasma).
Water " .
439-02
Substances not vaporising
at
120° ....
47-96 - .
3-93
Fibrin ....
' Albumen,' etc.
39-89
Inorganic constituents
4-14
Chlorine
l-722\
Sulphate of potassium
. 0-137
Sulphuric acid
0-063
Chloride of potassium
. 0-175
Phosphoric acid
0-071
Chloride of sodium
. 2-701
Potassium
0-153
Phosphate of sodium .
. 0-132
Sodium ....
1-661
Soda
. 0-746
Phosphate of lime .
0145
Phosphate of lime
. 0-145
Phosphate of magnesium .
0-106
Phosphate of magnesium
. 0-106
Oxygen ....
0-221
Total
. 4-142
Specific gra
vit
y = 1-0599
THE PROTEINS OF THE PLASMA
The plasma is generally described as containing a number of different
proteins belonging to the class of coagulable proteins. No albumoses or
peptones are present. Since the plasma in clotting gives rise to fibrin
and serum, we may divide its protein constituents into those which are
the precursors of fibrin and those which are still contained in the serum.
The Precursors of Fibrin. Most of these have been dealt with in
discussing the causation of coagulation. It remains for us here only to
mention some of the chemical features of fibrinogen and its product
fibrin. Fibrinogen is best separated by Hanunarsten's method, namely,
half -saturation with sodium chloride, or by the use of ammonium sulphate.
910 FHYSIOLOGY
Fibrinogen is precipitated between 13 and 28 per cent, saturation with
ammonium sulphate, whereas no other globulins are precipitated until
the saturation amounts to 29 per cent, of ammonium sulphate. Fibrinogen
obtained in either of these ways can be purified by re-solution and re-
precipitation, but loses its solubility in the process, so that every time it
is precipitated some of the substance becomes insoluble. The insoluble
fibrinogen resembles fibrin in many characters, but does not swell in the
presence of dilute acids as fibrin does. Fibrinogen is soluble in dilute
alkali, from which it may be precipitated by careful neutralisation. Fib-
rinogen in salt solution coagulates at 56° C. A small amount however
remains in solution and is not coagulated until 65° C. is reached. Fibrinogen
can be therefore described as a globulin occurring in the plasma and con-
verted on coagulation into fibrin. The other precursors of fibrin, namely,
those involved in the production of thrombin and called thrombokinase
and thrombogen, seem to be phosphorus-containing proteins, perhaps
belonging to the class of nucleo-proteins. Their chief characteristics have
already been dealt with.
FIBRIN. Fibrin is easily obtained by whipping blood as it flows from
the vessels with a bundle of wires or twigs, and then washing the stringy
threads so obtained under a stream of water. As prepared in this way
it always contains fragments of leucocytes, blood platelets, and stromata,
which have become entangled in its meshes. In order to prepare fibrin
in a pure state, it is necessary to get it by the action of fibrin ferment on
a pure solution of fibrinogen. Fibrin is a white stringy substance insoluble
in water and in dilute salt solutions. It slowly dissolves in 5 per cent,
solutions of sodium chloride, sodium sulphate, potassium nitrate, etc.,
but is converted in this process into soluble globulins. It is probable
that its solution is effected by the agency of minute traces of proteolytic
ferment present in the blood and adherent to the fibrin as it is precipitated.
This probability is strengthened by the fact that a certain amount of
album'oses is always foiuid in the fluid along with the soluble globulins.
In dilute acid, such as 0-2 per cent, hydrochloric acid, fibrin swells into a
clear jelly which very slowly undergoes solution with the formation of acid
albumen and proteoses.
THE PROTEINS OF THE SERUM. The serum proteins are generally
grouped in two classes, namely, the serum albumens and the serum globulins.
All the proteins are completely precipitated by saturation with ammonium
sulphate. By half-saturation with this salt only the globulins are pre-
cipitated and can be separated from the serum albumens by filtration.
The proportion of globulin to albumen as determined in this way is known
as the ' protein quotient.' It varies in different animals, but in the same
individual it is almost constant in the blood, serum, lymph, and serous
transudations, though the total amounts of protein in these may be very
different.
SERUM ALBUMEN. Serum albumen remains in the serum after half-
saturation with ammonium sulphate. It can be precipitated from this by
QUANTITY AND COMPOSITION OF THE BLOOD IN MAN 911
complete saturation with ammonium, sulphate or sodio-magnesium sulphate,
or in the crystalline form by slight acidification, as in Hopkins' method
described on p. 73. Serum albumen is soluble in distilled water. Its
solutions therefore can be dialysed indefinitely without any precipitation
taking place.
THE GLOBULINS. The globulins of serum, known as paraglobulin 01
serum globulin, are obtained by half -saturation with ammonium sulphate.
Their solutions in salt coagulate at about 75° C. Since globulin is insoluble
in distilled water, it is precipitated on dialysing serum against distilled
water. The precipitate obtained in this way is not however so great in
extent as that obtained on half -saturation, and on this account the globulin
fraction of the serum proteins has been divided into two fractions, namely,
cuglolmlin. precipitable by dialysis, and pseudo-globulin, not precipitable by
dialysis, but thrown down on half-saturation with ammonium sulphate.
A thorough study of serum globulin by Hardy has shown that this body forms
adsorption combinations with acids, alkalies, or neutral salts. With acids and alkalies
the globulin forms ' salts " which ionise in solution so that in an electric field the entire
mass of protein moves. These salts cannot be precipitated by dialysis. In them the
globulin acts much more strongly as an acid than as a base, so that a weak acid, such as
acetic acid, has a much smaller dissolving power over globulin than has the equivalent
amount of hydrochloric acid, and boracic acid has a very slight power indeed. The
weak basic character of globulin causes its salt in weak acids to undergo hydrolysis
with separation of globulin, so that in order to reach the same grade of solution with
a weak acid as with a strong acid a great excess of the acid is necessary. Owing to the
much stronger acid character- of globulin it is found that weak ammonia dissolves it
almost as well as strong alkalies. With neutral salts globulins form molecular com-
pounds which are soluble, but are readily decomposed by water with liberation of the
insoluble globulin. They are therefore stable only in the presence of a comparatively
large excess of salt. The globulins differ from the albumens of the serum in containing
constantly organic phos]morus as an integral part of their molecule. In all its solutions
globulin is present in large molecular aggregates, so that it is impossible to filter a globulin
solution through a porous clay cell.
THE CONDITION OF THE PROTEINS IN THE BLOOD SERUM
Although it is easy by such simple means as the addition or removal
of neutral salts to separate one or more different forms of protein from
serum, we have strong evidence that these proteins do not exist side by
side in the serum, but are combined to form what we may term serum
protein, which acts as a whole and differs in its qualities from many of
those of its constituent globulins or albumens. When a current is passed
through blood serum no movement of protein takes place (Hardy). Alkali
globulin therefore cannot be present. Salt globulin might be assumed
to be present since it does not ionise in solution, but sertun is not preci-
pitated by simple addition of acid, which would readily precipitate salt
globulin in alkaline solution. Moreover serum can be readily filtered
through a porous cell, and this method is adopted for obtaining it free
from contamination by micro-organisms. Globulin in any of its solutions
will not pass through a, porous cell. If globulin he present as such in the
912 PHYSIOLOGY
serum, it is therefore not ionised, but the agent which dissolves it must be
something more than alkali or salt, since either alone or together they will
not produce a solution which will pass through a porous cell. Serum has
still the power of taking up globulin and will dissolve almost its own volume
of precipitated globulin, though in oxalate serum there is not a trace of
alkali globulin nor of any ionised protein. We are justified therefore in
concluding that serum protein may be regarded as a complex unit. By
simple means, such as dialysis, dilution, or addition of salt, this unit can
be broken up with the separation of the various proteins which we have
designated as serum albumen and serum globulin, etc. The question
naturally suggests itself whether in plasma we have not a similar com-
bination of all its varied colloidal constituents to form one labile mass of
fluid protoplasm.
CHAPTER XIII
THE PHYSIOLOGY OF THE CIRCULATION
SECTION I
GENERAL FEATURES OF THE CIRCULATION
In order that the nutrition of the tissues may be properly carried out, and
that they may receive a continual supply of nourishment from the ali-
mentary canal, and of oxygen from the lungs, and be able to free themselves
of their waste products, the blood which flows through them must be
continually renewed. For this purpose every part of the body is supplied
with tubes — blood vessels — of various sizes and structures.
In the tissues the blood is passing continuously through a thick mesh-
work of capillaries, hair-like vessels with walls consisting of a single layer
of delicate endothelial cells, which permit of a free interchange of material
by diffusion between the blood within and the tissue fluid outside the
vessel. The movement of the blood is maintained by a hollow muscular
organ, the heart, placed in the chest, the blood being brought from the
heart to the tissues by thick-walled tubes, the arteries, and being carried
back from the tissues to the heart by a system of thin-walled vessels, the
veins.
In all the vertebrates the vascular system is closed, i. e. communicates at no point
with the tissue spaces or ccelomic cavity. It is found in its simplest form in fishes
(Fig. 382, a), where the heart consists of one auricle and one ventricle. The blood is
'1 from the great veins into the auricle. The walls both of auricle and ventricle
contract rhythmically. By the contraction of the auricle the blood is forced into the
ventricle, and this, when it contracts, sends the blood on into t lie bulbus arteriosus.
From the bulbus the blood passes through the branchial arteries into the gills, where
it takes up oxygen from the surrounding water, and then flows on into the aorta, by
Which it is distributed to the various organs of the body. From the capillaries of these
organs the blood is i ollected by the veins and is carried once more back to the auricle.
She fish heart is thus entirely on the venous side of the vascular system.
In amphibia, such as the frog, the heart consists of two auricles and one ventricle.
The right auricle receives venous blood from the body by means "I the venae cavse and
forces it by its contraction into the ventricle. From the ventricle the blood passes
into the aorta, whence it is carried partly by the pulmonary artery to the lungs, partly
by arteries to the different organs of the body. The blood, which has passed through
the lungs and been arterialised, flows through the pulmonary veins to the left auricle,
whence it passes into the ventricle and mixes with the venous blood which is arriving
from the right auricle. The pulmonary circulation is thus merely a branch of the
general 01 systemic circulation. The bulbus aortae in the frog is divided into two parts
58 913
914
PHYSIOLOGY
by means of a spiral valve, by which a partial separation of the blood coming from the
right and left auricles is effected, and the venous blood from the right auricle directed
especially into the pulmonary artery.
In birds and mammals the heart has become entirely divided into two halves, right
and left, which have no communication with one another except by way of the blood
vessels and capillaries. The right auricle receives the venous blood from all parts of
the body and sends it on to the right ventricle, whence it is forced into the lungs along
the pulmonary artery. In the lungs it takes up oxygen and becomes arterial and is
returned by the pulmonary veins to the left auricle and so to the left ventricle. The
rhythmic contractions of the left ventricle then force the blood into the aorta, whence
by the branching arteries it is carried to all parts of the body.
A B C
Fia. 382. Diagram of circulatory system in A, fish; B, amphibian (frog); C, mammal.
v, ventricle; a, auricle; K, gill capillaries; A, aorta; c, systemic capillaries;
L, lung capillaries; r, I, right and left auricles; rV, IV, right and left ventricles.
The whole vascular system is distensible and elastic, so that its capacity
will increase with the pressure of the blood contained in it. Since the
driving force is furnished by the heart, the pressure which causes the flow
of blood through the system must decline as we pass from the arterial to the
venous side. The chief function of the large arteries is to serve as elastic
conduits, whereas the small arteries or arterioles leading from the arteries
to the capillaries have in addition the function of regulating the amount of
blood flowing through the capillary area of the organs which they supply.
The veins have the function of conducting blood at a low pressure from
capillaries to heart and of storing up any excess of blood which is not
immediately taken up by the heart.
Corresponding to this difference in function we find variations in the structure of the
blood vessels according to their situation in the circuit. The vessels which carry the
blood from the heart to the tissues, the arteries, are thick-walled, and contain an
abundance of muscular and elastic elements in their walls. The typical medium-sized
GENERAL FEATURES OF THE CIRCULATION
915
artery is described as consisting of three coats (Fig. 383) : an Mima lined by a continuous
layer of flattened endothelial cells, which rest on a well-marked lamina of yellow elastic
tissue; a media composed of unstr.'ated muscular fibres arranged longitudinally and
circularly; and an external coat or adventitia of fibrous tissue, with a number of longi-
tudinal elastic fibres. Near the heart, in the great vessels such as the aorta and its
Fig. 3?o. Transverse section of part of the wall of the posterior
tibial artery ( X 75).
a, endothelial and sub-endothelial layers of intima; 6, lamina of elastic tissue;
. c, media consisting of muscle fibres ; d, adventitia. (Schafer.)
larger branches, there is a preponderance of elastic tissue as compared to the muscular ;
and we find in the media alternate layers of muscle fibres and fenestrated elastic mem-
branes. In the smallest arteries on the other hand, the arterioles, the elastic element
entirely disappears, so that the wall consists of muscle fibres, chiefly circular, fined by
the endothelium. In the latter vessels a contraction of their walls may result in an
entire obliteration of the lumen, so shutting off altogether the supply of blood to the
capillaries beyond. In the veins the same three coats can be distinguished as in the
typical artery, but the wall of the vessel is much thinner in proportion to the lumen.
In the vein moreover there is a preponderance of the fibrous tissue elements, the mus-
cular and elastic tissue being but little marked. On this account the vein collapses
unless it is distended by some internal pressure.
Capacity in c.c.
_____
7
-
'
— :
/
120 130 140 150 160
nun. Hg.
Fio. 3S4. Curves of distensibility of an artery (thick line) and of a vein (thin line). The
figures at the left side of the diagram represent the capacity of a section of the vessel
when distended under a certain pressure, expressed by the figures on the base line in
mm. Hg. (Constructed from figures given by Roy.)
The histological difference between veins and arteries is of considerable
importance for the understanding of the distribution of pressures in the
vascular system, since the distensibility and reaction to pressure of these
vessels are conditioned by their structure. In Fig. 384 is represented the
916 PHYSIOLOGY
distensibility, i.e. the increase in capacity of an artery and a vein under
gradually increasing internal pressure. It will be seen that an artery, which
has a certain capacity at zero pressure, gradually distends with increasing
pressure. The increase in capacity is small at first, and becomes most
rapid between 90 and 100 mm. Hg. After this point every increment of
pressure brings about a gradually diminishing increment of capacity. Thus
a change of internal pressure causes the greatest change in capacity when
the pressure in the artery corresponds, as we shall see, to the average arterial
pressure in the normal animal. In the vein, on the other hand, the capacity,
which is nothing at zero pressure, becomes considerable on raising the
pressure to 1 mm. Hg. A further rise of pressure to 10 mm. Hg. causes a
considerable increase in volume, but from this point the increments of volume
with rising pressure rapidly diminish. Whereas the artery is most distensible
at about 100 mm. Hg., the vein has its limits of optimum distensibility
between and 10 mm. Hg.
As the arteries branch, although each branch is smaller than the parent
vessel, the total area of the two branches into which the vessel divides is
greater. Thus there is a continual increase in the cross area of the bed
of the blood stream as we pass from the heart towards the periphery.
This increase is especially marked at the junction between the capillaries
and the arterioles on one side and the venules on the other, so that the
total area of the bed iu the region of the capillaries can be taken as about
800 times that of the area of the aorta where the blood leaves the heart.
On cutting through an artery, blood escapes from the central end, i. e.
that nearest the heart, with great force and in a series of jerks, each of
which corresponds to a contraction of the ventricles. This manner of
escape shows that in the arteries the blood is at a high pressure, and that
the flow from the heart to the periphery is a pulsatory one. The same
lesson may be learnt by connecting a long tube with the central end of a
divided artery. This experiment, which' was first performed by the Rev.
Stephen Hales, may be described in his own words :
" In December I caused a mare to be tied down alive on her back ; she was fourteen
hands high, and about fourteen years of age, had a Fistula on her Withers, was neither
very lean, nor yet lusty : Having laid open the left crural Artery about three inches
from her belly, I inserted into it a brass Pipe, whose bore was one sixth of an inch in
diameter; and to that, by means of another brass Pipe which was fitly adapted to it,
I fixed a glass Tube, of nearly the same diameter, which was nine feet in length : Then
untying the Ligature on the Artery, the blood rose in the Tube eight feet three inches
perpendicular above the level of the left Ventricle of the heart : But it did not attain
to its full height at once; it rushed up about half way in an instant, and afterwards
gradually at each Pulse twelve, eight, six, four, two, and sometimes one inch : When
it was at its full height, it would rise and fall at and after each Pulse two, three, or four
inches ; and sometimes it would fall twelve or fourteen inches, and have there for a
time the same. Vibrations up and down at and after each Pulse, as it had, when it was
at its full height; to which it would rise again, after forty or fifty Pulses."
The method adopted by Hales of measuring the lateral pressure of
blood in the vessels offers very considerable drawbacks. The manipula-
GENERAL FEATURES OF THE CIRCULATION
917
tion of such long tubes is awkward, and the blood which escapes into the
tubes very soon clots and renders further observation impossible. It is
therefore customary when we desire to gain an idea of the average pressure
in any blood vessel, especially in an artery, to use a mercurial manometer
for this purpose.
This instrument, which was first applied to physiological purposes by Ludwig, con-
sists of. a U-tube with two vertical limbs about eighteen inches in height, which is half-
filled with clean mercury. On the surface of the mercury of one limb is a float of
vulcanite from which a stiff fine rod of straw, glass, or steel rises, bearing on its upper
end the writing-point. This point may be adjusted so as to write on the blackened
glazed surface of a moving sheet of paper (Fig. 385). (The arrangement for imparting
a continuous movement to a sheet of
glazed paper is known as a kymograph.)
Instead of smoking the paper, a pen may
Ijc fitted to the end of a rod and its
excursions recorded in ink on a moving
band of white paper. The other limb
of the manometer is connected by a
flexible inextensible tube with a small
tube or cannula which is tied into the
central end of an artery, a clip being
previously placed on the artery so as
to prevent the escape of blood during
the insertion of the cannula. To the
manometer is connected a three-way
tap by means of which the manometer
can be placed in communication with
the artery alone, or with the artery and
a pressure bottle. By means of the
latter the whole system is filled with
magnesium sulphate solution (25 per
cent.) or a half -saturated solution of
sodium sulphate, at a pressure of 150
mm. Hg. The pressure bottle is then
cut off so that the manometer remains
in connection only with the cannula, the
mercury in one linib being 150 milli-
metres above that in the other. The
clip is then taken off the artery. The
pressure in the cannula being greater than that in the artery, a small amount of the
fluid used to fill the tubes rims into the circulation. The mercury in the manometer
drops to a height of 100 to 120 mm. Hg. and stays about that level, rising and falling
slightly with each heart beat (Fig. 387). The blood which enters the cannula at each
heart beat does not clot for a considerable time owing to its admixture with the saline
fluid used for filling the cannula and connecting tubes.
Fia. 385. Arrangement of an apparatus for
taking blood-pressure tracing.
a, artery (carotid); c, cannula; d, threo
way cock; m, mercurial manometer; 6, drum
covered with smoked paper; r, tube to pressure
bottle.
If a vein be ligatured, it swells up on the distal side of the ligature.
In the vein be cut across, blood escapes chiefly from the peripheral end,
and instead of spurting out to a considerable distance with each heart
beat it flows steadily, but with very little force, so that light pressure by
a bandage is sufficient to restrain the hemorrhage. If a mercurial mano-
meter be connected with the vein, the pressure in its interior is found to
amount to onlv a few mm . Hg.
918
PHYSIOLOGY
By taking the pressure at different parts of the circulation, we obtain
a distribution which is represented roughly in the accompanying diagram
(Fig. 386). The blood pressure, which is about 100 to 120 mm. Hg. in
the large arteries near the heart, falls only slowly in these arteries, so that
Fig. 38G. Scheme of blood pressure in — A, the arteries; c, capillaries; and v, veins.
oo, line of no pressure; lv, left ventricle; ka, right auricle; bp, height of
blood pressure.
ii\ the radial artery it is not very much below that in the aorta. Between
the medium-sized arteries and capillaries there is a very extensive fall of
pressure as the blood passes through the arterioles, so that in the capillaries
the pressure on an average may be taken as 20 to 40 mm. Hg; from the
capillaries to the veins the blood pressure falls steadily imtil in the big
veins near the heart it may be negative.
SECTION II
THE BLOOD PRESSURE AT DIFFERENT PARTS
OF THE VASCULAR CIRCUIT
THE ARTERIAL BLOOD PRESSURE. The arterial blood pressure as
recorded by a" mercurial manometer exhibits a series of pulsations corre-
sponding to each heart beat (Fig. 387). These pulsations are due to the
fact that the" artery becomes fuller each time the ventricle forces more
blood into it during its systole. Between the
beats of the heart, i. e. during diastole, the aortic
valves are closed, and blood escapes from the
arteries into the capillaries and veins, so that
the blood pressure falls. The mercurial mano-
meter does not register these rapid changes of
pressure, in the artery with any accuracy. The
inertia of the mercury is such that it takes some
time to be set into movement by the rise of I
pressure in the artery, and before it has attained I
its full height the pressure in the artery has Fig. 387. Blood-pressure
i ii- r n -vir-j.1. -j j. -u j tracing taken with mer-
already begun to fall. With a very wide-tubed curia i manometer (from
manometer the oscillations may be almost irn- carotid of rabbit),
perceptible owing to the mass of mercury that A ' • b "5i£j M of no
has to be moved at each heart beat. Such a
manometer gives a true record of what is known as the ' mean arterial
pressure.' In order to determine the true course of the pressure in the
heart, it is necessary to diminish to the utmost possible extent the inertia
of the moving parts of the recording instrument, and to employ some
manometer such as that of Hurthle or of Frank, in which the pressure is
measured by recording the stretching of an elastic membrane. Such
instruments will be described later in dealing with the changes of pressure
in the ventricle during contraction.
In the living animal the variation in the arterial pressure at each heart
beat is much greater than would be anticipated from an inspection of the
tracing given by the mercurial manometer. The highest pressure which
occurs while blood is passing from the heart into the aorta is called the
systolic arterial pressure ; the pressure at the end of diastole, just before
the heart begins to force a fresh quantity of blood into the aorta, is the
diastolic pressure ; and the range between these two extremes is known
919
920 PHYSIOLOGY
as the pulse pressure. Thus in the dog, with a mean pressure of about
120 mm. Hg. in the aorta, the systolic pressure may be as much as 160,
while the diastolic pressure is only Kid mm. In this case the pulse pressure
would be (io mm. Hg. In man the systolic pressure, as measured in the
brachial artery, is under normal conditions about 110 mm., while the
diastolic pressure is only 65 to 75 mm., so that the pulse pressure is about
15 nun. Hg. As we pass outwards towards the periphery the pulse pressure
becomes less and less marked, until finally in the capillaries and veins
there is no pulse wave perceptible.
THE DETERMINATION OF THE BLOOD PRESSURE IN MAN
It is important for clinical purposes to be able to determine even approximately the
blood pressure in the different parts of the vascular system in man, and various methods
have been devised for this purpose. The determination of the systolic blood pressure
in the arteries is easily carried out by the use of Riva Rocci's sphygmomanometer.
This apparatus (Fig. 388) consists of a leather or canvas band about 10 cm. wide, which
b^ a * m
Fig. 388. Riva Rocci's sphygmomanometer. Flo. 389.
(C. J. Martin's pattern. Hawksley.)
can be buckled closely round the upper arm. Inside this band is a rubber bag of the
same shape, which communicates by a rubber tube with a mercurial manometer and by
a three-way tap with a pressure bulb or bicycle pump, or with the external air. The
band is buckled round the arm and the fingers of the observer are placed on the radial
pulse. The bag is then distended with air so that it exercises a pressure on the arm,
the pressure being indicated on the mercurial manometer. Air is forced in until the
radial pulse disappears. By means of the three-way tap the air is then let slowly out
of the bag until the radial pulse is just perceptible. The height of the mercurial mano-
meter at this moment is equal to the systolic pressure in the main arterial trunk from
which the brachial artery takes origin. The principle of this method will be made
clear by reference to the diagram (Fig. 389). If we imagine A as a segment of the brachial
artery passing through the tissues which are surrounded by the rubber bag, we see that
so long as the pressure in the interior of the artery is greater than that exerted by the
tissues on the exterior, the artery will be patent and the pulse can pass through. If
however the pressure in the tissues becomes greater than the maximum pressure
inside the artery at any time of the heart beat, the segment of artery will collapse (as
in b), thus stopping the transmission of blood and of the pulse wave. If we exclude the
elasticity of the tissues themselves, we may take the pressure in the bag as representing
the pressure in the tissue fluids surrounding the artery, so that the pulse-obliterating
pressure in the bag will correspond to the maximum or systolic pressure in the artery.
By a slight modification of the apparatus it is possible to determine also the diastolic
pressure. For this purpose the rubber bag is connected also with a manometer of small
inertia, giving a true representation of the actual changes of pressure. It is evident
BLOOD PRESSURE AT PARTS OF VASCULAR CIRCUIT 921
that, when the pressure in the bag and in the tissues surrounding the artery exactly
corresponds to the diastolic pressure, the artery will be completely collapsed when the
pressure arrives at its lowest point and will then dilate almost to the utmost with the
systolic rise of pressure. If we are taking a record of the pressure changes in the bag
in this way, the pulse waves as recorded by the manometer will slowly increase in size
as the pressure in the bag is gradually raised. At one point the waves rapidly increase
and reach a maximum, marking the pressure at which the artery is just completely
collapsed at the lowest point of each pulse wave (the diastolic pressure). As the pressure
is still further raised, the excursions of the manometer tend to diminish in size, first
Fig. 390. Erlanger's apparatus for recording systolic and diastolic
blood pressures.
I ln\\ ly and then rapidly, and the point of rapid diminution corresponds to the systolic
pressure. Above this point the manometer still shows small oscillations, due to the
impact of the unoccluded stump of the artery on the upper bolder of the india-rubber
bag.
Many different methods have been introduced for the purpose of recording the
pressure oscillations in the ba<_'. In Erlanger's apparatus the lubber bag is put into
connection with a thick-walled rubber ball rs contained in a glass chamber. The
chamber (Fig. 390) communicates with a sensitive tambour and also, by means of a
capillary opening provided with a stop-cock, with the cxteinal air. By this means the
slow expansion of the ball PS is not recorded by the tambour, which moves only with
the sudden oscillations of pressure due to each heart beat. With this instrument it
is ea6y to read on the accompanying mercurial manometer the point at which the
922
PHYSIOLOGY
oscillations of pressure in the bag suddenly become maximal, and so to determine
approximately the diastolic pressure in the artery.
VENOUS PRESSURE. To determine the venous pressure in man we may use
some modification of von Recklinghausen's method. A circular, disc-shaped, incom-
plete rubber bag (Fig. 391) is made by cementing
together at the circumference two rubber discs,
each of which has a hole in the centre. This is
placed over a peripheral vein and a glass plate
laid on the top (Fig. 392). A tube leads from
the interior of the annular rubber bag to a water
manometer and to a bicycle pump or bellows for
the injection of air. On blowing air into the bag
the pressure in its interior rapidly increases. If the
skin and glass plate have been previously smeared
with glycerin, the air does not escape but distends
the bag, pressing it against the skin on the one
hand and the glass plate on the other. Through
the hole in the rubber bag it is easy to see the
pressure at which the vein collapses — that is to say,
the point at which the pressure in the bag is equal
to the pressure within the vein. By a similar method, using a smaller bag, we may
determine the pressure which is just sufficient to obliterate the capillaries in any given
area of the skin, so causing a blanching of the skin lying under the bag.
EJ
Fig. 391.
The following Table may serve to give an idea of the average height
of the mean blood pressure (not systolic) at different parts of the vascular
system in man, in the horizontal position. The pressures are all subject
to considerable variations according to the activity of the individual and
the physiological activity of the various parts and organs of the body :
Large arteries (e. g. carotid)
Medium arteries (e. g. radial)
Capillaries
Small veins of arm .
Portal vein .
Inferior vena cava
Large veins of neck
. 90 mm. mercury (65-1 10).
85 mm. „
about 15 to 40 mm. mercury.
9 mm. mercury.
10 mm. „
3 mm. „
from to -8 mm. mercury. -
The cause of these peculiarities in the circulation in different parts of the vascular
system will be rendered clearer by a study of a flow of fluid through a tube of uniform
bore (Fig. 393). If the tube AG be connected with the reservoir e, fluid will flow from
A to G under the influence of the pressure difference between the fluid in the reservoir
and that at o. The pressure on the fluid at each part of the tube can be measured by
attaching at a series of points — e. g. at b, c, d, e, r — vertical tubes in which the fluid
will rise to a height corresponding to the lateral pressure existing at these several
BLOOD PRESSURE AT PARTS OF VASCULAR CIRCUIT 923
points. When fluid is flowing from A to a, it will be found that the heights of the fluid
in the tubes show a continuous descent, so that the line joining the tops of the fluid
in the various tubes is a straight one. The movement of the fluid from b to c can be
regarded as due to the difference of the pressure between B and c, i. e. P 2 -IV It will
be noticed in the diagram that the straight line joining the tops of the fluid does not
strike the surface of the fluid in R, but falls a little below it. Of the total pressure in R,
H, the large portion h' is employed in overcoming the resistance of the tube AG, while a
small portion h represents the force necessary to give to the fluid as it leaves the reservoir
at a a certain velocity. If the flow of fluid be diminished by partially clamping the
end at G, the rate of fall of the pressures will be diminished. The same effect will be
produced either by raising the level of G or by lowering the level of the reservoir and so
the pressure at a.
The difference of pressure between any two points, i. e. between d and e, may be
led as that pressure which is necessary to maintain a certain velocity of the fluid
against the resistance offered by the friction of the fluid in contact with the walls of
the tube. This friction, and therefore the resistance to the flow, can be altered by
6!iminishing the diameter of the tube, when a larger difference of pressure will be
necessary in order to maintain the same velocity of flow. This can be shown by in-
troducing a resistance between d and e by partially clamping the tube at this point
(Fig. 394). The continuity of the fall of pressures in the vertical tube is at once abolished.
Between A and d there is a continuous fall, which is succeeded by a steep fall between
D and E, and this again by a gradual fall between E and G. In any system of tubes
therefore through which fluid is flowing, the fall of pressure between any two points
924 PHYSIOLOGY
will be proportional to the velocity of the flow between these two points. The velocity,
on the other hand, will vary directly as the difference of pressures, and inversely as the
resistance between the two points. These relations may be expressed by the formula
it.
In the vascular system, while the circulation is maintained, the largest
difference of pressure exists between the arteries on the one side and the
small veins on the other, a great fall occurring between the arteries and
the capillaries themselves. This distribution of pressure points to the
chief resistance in the vascular system as being situated in the arterioles.
The resistance presented by these vessels is due to the fact that they are
maintained in a state of tonic contraction by the agency of the central
nervous system. The total bed of the stream in the region of the arterioles,
while greater than that of the arteries, is considerably less than that of
the rich meshwork of capillaries, while the difference between the diameters
of arterioles and capillaries is not very great. On this account the velocity
of the blood in the arterioles is very much greater than that obtaining in
the capillaries, and since friction and therefore the resistance varies as the
square of the velocity, the resistance to the flow of blood through the
arterioles must be much greater than that presented by the capillaries.
The large part taken by the arterioles in determining the difference of
pressure between the arteries and veins is shown by the fact that this
difference can be diminished to one-half by any means which causes a
dilatation of the arterioles, as, for example, destruction of the vasomotor
centre.
THE CONVERSION OF AN INTERMITTENT INTO A
CONSTANT FLOW
■ Not only is the blood pressure in the veins much lower than in the
arteries, but the flow of blood has been converted on its passage through the
peripheral resistance from a pulsatory into a continuous flow. This change
is connected with the distensible elastic nature of the arterial walls.
Since this is a purely mechanical question it will be more easily under-
stood by a simple illustration. The heart may be regarded as a pump,
forcing a certain amount of blood (in man about 60 c.c.) into the circulation
at each stroke. If a pump be connected with a rigid tube, every time
that a certain amount is forced into the beginning of the tube an exactly
equal quantity will be forced out at the other end. Increasing -the peri-
pheral resistance by partial closure of the end of the tube will not affect
the intermittent character of the flow, but will merely serve to diminish
the quantity thrown in, as well as the quantity which escapes at the other
end of the tube, supposing that the work done by the pump is equal in
both cases. If instead of a' rigid tube we employ an elastic tube and the
end be left open so that no resistance is offered to the outflow of the fluid,
the effect will be the same as when we used the rigid tube ; the outflow will
correspond exactly to the inflow and will be just as intermittent. But
BLOOD PRESSURE AT PARTS OF VASCULAR CIRCUIT 925
now, if the end of the elastic tube be clamped so as to increase the resist-
ance to the outflow, there will be a marked difference from the residts
obtained when the rigid tube was partially obstructed. Each stroke of
the pump forces a certain amount of fluid iuto the tube. Owing to the
peripheral resistance this cannot all escape at once, and so part of the
force of the pump is spent in distending the walls of the tube, and part
of the fluid that was forced in remains in the tube. The distended elastic
tube tends to empty itself and forces out the fluid which over-distends
it before the next stroke of the pump occurs. So now the outflow may be
divided into two parts, one part which is forced out by the immediate
effect of the stroke of the pump, and another part which is forced out by
the elastic reaction of the tube between the strokes. If the strokes be
rapidly repeated before the tube has time to empty itself thoroughly, it
will get more and more distended. Greater distension means stronger
elastic reaction, and therefore stronger outflow of the fluid between the
beats. This distension goes on increasing till the fluid forced out between
the strokes by the elastic reaction of the wall of the tube is exactly equal to
that entering at each stroke, and the flow thus becomes continuous.
The same thing occurs in the living body. A man's heart at each beat
oi contraction forces about 60 c.c. of blood into the already distended
aorta. The first effect of this is to distend the aorta still further. The
elastic reaction of the walls drives on another portion of blood, which
distends the next segment of the arterial wall, and so the wave of distension
is transmitted with gradually decreasing force along the arteries. This
wave of distension is what we feel on the radial, artery,- or any exposed
artery, as the pulse. After each heart beat the arteries tend to return
to their original size, and drive the blood on through the arterioles (the
peripheral resistance) into the capillaries and so into the veins. By the time
the blood has reached the veins. ;ill trace of the heart beat has disappeared
and the pressure has fallen to a few millimetres of mercury.
INFLUENCE OF THE CAPACITY OF THE VASCULAR SYSTEM
ON THE CIRCULATION
So far we have only considered the influence of changes of pressure
and resistance in a system of tubes with a head of pressure at one end and
a free outflow at the other. In the body however the vascular system
is a closed circuit of elastic tubes presenting varying resistances to the
flow of blood, and of varying distensibility at different parts of their course.
In this e]i. seil system is inserted a pump, the heart, with the function of
driving the blood through the system. Since all the blood vessels are
elastic and distensible, the capacity of the system is not fixed, but must
vary with the internal pressure to which the vessels are subjected. More-
over the position of the different parts of the circulation must have an
influence on the capacity of the system, since the dependent vessels will
be distended, not only by the average pressure of the fluid throughout the
926
PHYSIOLOGY
system, but also by the hydrostatic pressure due to the weight of the column
of fluid pressing on them. The elasticity of the tubes is also a varying
factor and can be considerably altered by the contraction of the muscular
coats of the vessels, or by pressure on the vessels exerted by the surrounding
muscular and elastic structures.
Fig. 395. Artificial schema to demonstrate the main features of the circulation.
The heart is an enema syringe with valves at v and v. The artery is a thick-walled
rubber tube. On the venous side is placed a length of wido thin-walled tubing,
to represent the large thin-walled distensible veins. The arterioles and capillaries
(peripheral resistance) are represented by wide glass tubes packed with sponges.
By opening the clamp on the tube D (' splanchnic area arterioles ') the peripheral
resistance can be removed, and a free passage of fluid allowed from arterial to
venous side.
It will simphfy the discussion of "the main factors of the circulation
in a closed system if, for the present, we neglect the variable factors and
see what would take place in such a system of elastic tubes all situated
on one horizontal plane. Such a system is represented in the diagram
(Fig. 396), and a working model of it in Fig. 395.
The heart h is interpolated at one part of the
circuit, while the free outflow of the fluid from B
to d is impeded by the presence of a peripheral
resistance at c. Such a system would have a
definite capacity at zero internal pressure, but
a very much greater amount of fluid might be
forced into it imder a positive pressure. We will
assume that the pressure throughout the system
is equal to 10 mm. Hg., i. e. the elastic tubes are
all slightly distended. If the heart h now begins
to contract, it will pump fluid from e into A.
The pressure in e will fall from 10 mm. to mm., while that in a will rise
to a corresponding extent, the resistance at c preventing the free escape
of fluid from b to d and so causing the heart to pile up the fluid which it
has taken from e into a.
If the texture of the tubes were uniform throughout the system, it is
BLOOD PRESSURE AT PARTS OF VASCULAR CIRCUIT 927
evident that the rise of pressure in a would approximate very nearly to
the fall of pressure in e. In the vascular system the veins are however
much more easily distended than the arteries. In Fig. 384 (p. 915) is
shown the dist eligibility of corresponding sections of arteries and veins
under gradually increasing internal pressures. An artery has a certain
capacity even at zero pressure. As the pressure in its interior is increased,
the artery is distended, and its capacity rises first slowly and then more
rapidly, the increment in capacity being greatest between 90 and 110 mm.
Hg. The vein, on the other hand, is collapsed when there is no distending
force in its interior, so that at zero pressure its capacity is nothing. The
slightest rise of pressure, even of 1 mm. Hg. causes a considerable increase
in its capacity, and the capacity rises rapidly with increasing pressure up to
about 20 mm. Hg. "Whereas the artery is most distensible at 100 mm. Hg.,
the vein is at its optimum distensibility at about 10 mm. Hg. If therefore
the tubes at e are made of thin-walled rubber tubing, they will be consider-
ably distended under a pressure of 10 mm. Hg., which has practically no
influence on the thicker-walled arterial tube a.
A small amount of fluid taken from e would cause very little fall of
pressure on this side. A considerable force will be necessary to send this
fluid into the more resistant arterial tube,- so that on pumping a given
amount of fluid from e to a, the pressure in e may fall 5 mm., while the
pressure in a has to be raised from 50 to 100 mm. Hg. in order to distend
the arteries to such an extent that they will accommodate the fluid taken
from e.
In such a system, when the heart is at rest, the pressure all over the
sj'stem will be * uniform, and in the example we have chosen the mean
systematic pressure was 10 mm. Hg. When the heart contracts, it takes
up fluid from the venous side and piles it up on the arterial side until the
pressure on the arterial side is sufficient to cause exactly the same amount
of fluid to flow through the peripheral resistance into the veins as is taken
by the heart from the veins at each beat. This rise of pressure in the
arteries may be many times greater than the fall of pressure in the veins.
If more fluid is injected into the system when the heart is at rest, the whole
system will be more distended and the mean systemic pressure will rise.
When the heart contracts, it will raise the pressure on the arterial side and
lower that on the venous side as before, but it is evident that, according
to the force of the heart heat, the arterial pressure may be less than, equal
to, or greater than the pressure attained before the introduction of fluid.
Since however the mean systemic pressure is raised, the increased amount
of fluid must be accommodated somewhere, so that if the arterial pressure
is as great as before, the venous pressure must be greater. In the same
way the withdrawal of a certain amount of fluid may lower the mean
systemic pressure, say from 10 to 5 mm. Hg. It is still possible for
the pump to maintain an arterial pressure equal to that produced when the
mean systemic pressure was 10 mm. Hg., but to produce this effect the
relative distribution of blood must be altered and the veins must be more
928 PHYSIOLOGT
empty than fchej were previously. The maintenance of a constant arterial
pressure with varying amount of fluid in the system can therefore be accom-
plished either by alterations in the work of the heart or by alterations in
the peripheral resistance, and therefore in the ease with which the blood is
allowed to escape from the arterial to the venous side.
Alterations of the capacity of the system will have the inverse effect
to alterations of its contents. Thus diminution in the volume of veins,
such as might be caused in the living body by the contraction of their
walls and which may be imitated in our model by pressure on the veins
from without, will drive the fluid into other parts of the system and there-
fore raise the mean systemic pressure. This rise of pressure may be con-
fined to the arteries by increased action of the heart, or it may be confined
to the veins by diminished action of the heart or decreased constriction of
the arterioles forming the peripheral resistance.
Similar change in capacity may be brought about if we bring in the
effects of hydrostatic pressure. If in the model illustrated (Fig. 395) we
allow the thin-walled vein to hang over the edge of the table, the pressure
of the column of fluid within it causes it to dilate and therefore to accom-
modate more fluid, and this increased capacity might be so great that the
pressure in the section of the ■ vein nea~r the heart might sink to nothing
and the heart receive no blood when it started to contract. The whole
arterial system might in this way be allowed to drain under the influence
of gravity into the distensible dependent segment of the venous tube.
All the conditions in our artificial schema have their exact analogue in
the living body. The determination of the mean systemic pressure in
the living body is difficult to carry out with accuracy. If, for instance,
we stop the heart, which we can do by stimulation of the vagus nerve, the
arteries will gradually empty themselves through the peripheral resistance
into the veins, and this process will tend to go on until the pressures are
identical throughout the system. Before this equilibrium is arrived at
however, reaction takes place on the part of the animal, tending to restore
the failing circulation. Thus the vessels contract strongly, so diminishing
the capacity. Movements take place, causing pressure on the veins of the
abdomen and the suction of the blood into the big veins of the thorax.
Moreover the vessels in an animal are not all on one plane and, if the animal
is in a vertical position, the hydrostatic pressure of the column of blood
between the heart and the dependent parts of the body may distend the
veins to such an extent that the whole of the blood is taken up in these
veins and none returned to the heart. The fact that, after stoppage of the
heart, the pressure is positive at all parts of the vascular system in the
animal with open thorax shows that there is actually a mean systemic
pressure, i. e. under normal circumstances, when the animal is in a hori-
zontal position, all parts of the system are slightly . distended. Direct
measurement shows that this mean systemic pressure is about 10 mm. Hg.
The smallness of this figure shows moreover that, under the influence of
gravity alone, the pressure will be easily, reduced to nothing at all in the
BLOOD PRESSURE AT PARTS OF VASCULAR CIRCUIT 929
upper parts of the body. In a man in the vertical position, in the absence
of the nervous reactive mechanism which we shall consider later on, the
whole of the blood would accumulate in the abdomen and lower parts of
t iic body, and the circulation would come to a standstill. On the other
hand, the pressure may be altered in any part of the vascular system in
any of the following ways :
(1) Alteration of capacity of the total system either by contraction of
walls of the vessels or by pressure on them from without.
(2) Alteration of the total volume of the circulating fluid.
Either of these two factors would affect, in the first place, the mean
systemic pressure. The distribution of pressure, i. e. the relative pressure
in the arteries and veins, will be determined by
(•$) Alteration in the output of the heart.
(1) Alteration in the peripheral resistance and therefore in the ease with
which the blood can escape from arterial to venous side.
In any change either in arterial or venous pressure at least two of these
factors are involved. Every constriction of arterioles causes not onlv an
in, ri ase in the peripheral resistance but also a diminished capacity of the
whole system, so that the arterial pressure is raised at the same time as
i he mean systemic pressure. Nearly always such a change will involve
immediate consequence some corresponding alteration in the heart
beat, so that at least three factors will co-operate in the production of the
rise or fall of blood pressure. We shall have occasion to deal with many
examples of these complex conditions when we are discussing the reactions
of the vascular system as a whole.
THE DEPENDENCE OF ARTERIAL PRESSURE ON OUTPUT
OF HEART
The importance of the heart beat in determining arterial pressure is
connected with its output in a given time. The arterial pressure is due
to the fact that the heart is taking up fluid from the venous side and pumping
it into the arterial side. The pressure on the latter side must rise so lonf
as the rate at which the fluid is put into the arterial system by the heart
ater than that by which it escapes through the peripheral resistance.
Arterial pressure therefore is a resultant of the two effects :
(a) The amount of blood entering the arterial system from the heart;
(b) The amount of blood leaving the arterial system through the peri-
pheral resistance.
It is evident that the pressure will be altered by altering either of tin-
two factors —peripheral resistance or output of the heart. The cardiac
output will depend on the amount of blood .contained in the heart at the
lie-inning of each contraction, on the strength with which the heart beats,
and on the number of contractions of the heart in any given period
of time. The filling of the heart at the begmning of each beat is
in its turn dependent on the amount of blood which is available to fill the
59
930 PHYSIOLOGY
cavities and therefore on the pressure in the great veins. Increased fre-
quency of heart beat need not therefore necessarily increase the, total
output of the heart into the arterial system. If the heart is beating with
optimum rate and force, it will keep the venous system, at any rate that
part nearest the heart, practically empty, and it is not possible for it to
obtain more blood to put into the arterial side, however frequently it may
beat. There will be an optimum frequency of the heart beat which will
depend on the state of filling of the great veins. Tire fuller these are the
more rapidly the heart may beat and increase the total output. On the
other hand, in a normal animal with the heart beating at its optimum rate
and with effective contraction of its muscular walls, while slowing the
heart rate will dimmish the total output and therefore the arterial pressure
increase in the frequency of the beat cannot raise the arterial pressure to
any appreciable extent, though the heart may tend to wear itself out by
beating at a greater rate than the optimum.
SECTION III
THE VELOCITY OF THE BLOOD AT DIFFERENT
PARTS OF THE VASCULAR SYSTEM
When fluid is flowing through a tube of uniform diameter, the amount
passing be1 ween any two points is practically in proportion to the difference
of pressure between these two points, and varies inversely as the resistance
fe be overcome. If the tube is of unequal bore, as represented in Kg 397
sine, the amount of fluid passing a during a given interval of time must be
equal lo the amount passing t-where the bed of the stream is wide-— the
veloc.t.N „l ( be flow must be smaller at b than at a. The same dependency
ol velocity on the total bed must
fcppiy in any closed system of ( [
tubes. Thus in a closed circuit , — *. ______
(Fig. 396) with a steady flow from ° I
the arterial to the venous side, h
the amount of fluid leaving the Fw. 397.
heart and passing a during a minute must be exactly equal to the total
amount of fluid passing from arteries to veins through the peripheral
pfesistance b.
The total area at c i.s probably one thousand times that of the aorta at a
and we should expect therefore a proportionate slowing of the blood stream'
matter of fact, while the velocity of the blood in the aorta of alarge
al may be taken as about half a metre per second, the velocity of the
b] l m thc capillaries is about half a millimetre per second. Moreover
Snnce ,he total cross-section of the big veins near the heart under a normal
distending pressure is about twice that of the first part of the aorta the
velocity of the blood in the great veins is only about half of that found in
rta. In such a closed circuit increased output of the heart will increase
the average velocity round the system, and the same effect may be produced
by diminution of the peripheral resistance.
In the living body a great dilatation of the arterioles, causing a fall of
the peripheral resistance, generally increases the total capacity of the system
The arterial relaxation therefore not only gives rise to an easier outflow
B»m arteries to veins but also causes a diminished dilatation of the ,
and therefore decreased filling of the heart during diastole The heart
output is therefore also lessened, so that a final result of a dilatation of the
Arterioles may be a diminished instead of an increased velocity throughout
the system. °
931
932 PHYSIOLOGY
The foregoing discussion of the factors, which determine the average
velocity across a given cross-section of the whole vascular system, musl
not be applied directly to the changes in the velocity following on local
all nations in the resistance presented by some particular vascular area.
In this case the local changes are insufficient to affect the general arterial
blood pressure, and the effect of diminution of peripheral resistance is to
furnish a short cut for a small portion of the total output of the heart from
the arterial to the venous side. Thus dilatation of the vessels of the sub-
maxillar gland, while not altering the general blood pressure as registered
in the carotid artery, causes the blood flow through the gland to be increased
six to eight times; and the peripheral resistance in the gland may be so far
diminished that the blood passes through the capillaries into the veins
without losing the pulsatile force imparted to it by each heart beat. The
pressures therefore in arterioles, capillaries, and veins are all increased by
this local vaso-dilatation. On the other hand, constriction of the arterioles
of any given part will diminish the velocity of the blood through this part
and also the pressure in its capillaries.
The larger the area affected by the change in the peripheral resistan. e,
the more difficult it is to predict a priori what will be the result on the
velocity of the blood and on the circulation as a whole, or in the parts
specially affected. Thus section of one splanchnic nerve in the dog causes
an increased flow of urine from the kidney on the same side, the paralysis of
the vessels in this organ causing an increased flow of blood through it and
an increased pressure in its capillaries. Section of the corresponding nerve
of the rabbit may cause a diminution rather than an increase in the amount
of urine secreted, owing to the fact that the total area supplied by the
splanchnic nerve is much greater relatively hi the rabbit than in the dog.
Thus section of this nerve may cause such a wide-
spread dilatation that the blood pressure falls; and
although the vessels in the kidney are relaxed, the
arterial pressure is not sufficient to drive through
these relaxed vessels as much blood as was previously
/ \ / \ driven through the normally contracted arterioles.
METHODS OF MEASURING THE VELOCITY
OF THE BLOOD
The velocity in an artery is measured by- placing some
apparatus in the path of the blood without intercepting its
flow; such an apparatus may be used to give the quick
v %qr IV < nm of variations in the velocity which occur in the course of each
LudwS ' fiSkr.' heart beat, or the average flow of blood through the cross-
section of the artery in a given space of time. For the latter
purpose Ludwig's Stromuhr, or current clock (Fig. 398), has been most used. This
instrument consists of two bulbs of equal size, a and 6, communicating with one
another above; their lower ends arc clamped in the disc c, which is pierced by two
openings serving to connect the lower orifices of the bulbs with the tubes t, I, cemented
into the lower disc ab.
An artery such as the carotid, being clamped at its central end and divided, a is
VELOCITY OF BLOOD AT PAETS OF VASCULAR SYSTEM 933
inserted into its central end. and 5 into its peripheral eut end. The tube a is .filled witii
' V sal solution or defibrinated blood. On damping the artery, blood flow*
,; :l,nd oSves the contained oil over into 6 the contents o I being n.anw nle for d
into the peripheral end of the artery. When blood has completely filled the bulb «. the
t mills are Versed, and the blood now entering the artery displace, ^dm.
and forces the blood which had entered a on into the peripheral end of the artery.
I '„, Lacity of the bulbs and the number of times it has been necessary to
SSita the couL, say. of one minute, we know also the amount of blood wluch
has passed across the section of the artery under experiment
I , order to determine from this volume the velocity of the blood across the section,
i e thro ughtiie artery, the total volume passing in the minute must be divided by the
.:,,;, s Son. Tins ,,11 give the velocity per minute. Many modifications of tins
Fig. 399. Diagram showing the
ruction of Ghauveau's
hEemadromograph.
Fig. 400. Diagram to show principle of
construction of Cybulski's photoha:mata-
chometcr.
apparatus have been devised, but none give any information of the rapid changes
occurring in the velocity of the blood during a single pulse wave. For this purpose we
must have recourse to some instrument such as Chauveau's hsemadromograph or
Cybulski's photohamatachometer. The Ticemadromograph (Fig. 399) consists of a
pendulum which is hung in a tube, through which flu- blood is allowed to flow placed
in the course of the artery. The deviation of I his pendulum from the vertical will be
in proportion to the velocity of the current, and if its upper end be connected, as in the
diagram with a tambour, the variations in velocity can be recorded on a blackened
surface by means of a lever. The photohcematacfumeter is based on an interesting
application of Pitot's tubes. If a current of blood be directed along the tube ab pos-
sessing two vertical side tubes c and d (Fig. 4). the pressure at c will be greater than
■that at d, since at c the momentum of the moving mass of blood is added to the
lateral pressure of the fluid. A tube of this shape is connected with an artery, such
as the- carotid, and the tubes h and V are attached at the points c and d. These two
031
PHYSIOLOGY
tubes are united at their upper extremities. In this ease so long as the blood flows
from a to b, the fluid in h will rise higher t hail in /<'. and the difference in height of the
fluid in the two tubes will be proportional to the velocity of the blood. A graphic record
of this difference of pressure is obtained by allowing a narrow beam of light to throw an
image of the menisci of the two columns of fluid through a slit on to a moving photo-
graphic plate. Such a record is given in Fig. 401. The width of the black space at any
point is proportional to the velocity of the blood at the moment at which this part of
Fig. 401. Record of blood velocity in the carotid artery of the rabbit. (C'ybulski.)
the record was being taken. Of course this instrument has to be calibrated if we wish to
determine the velocity of the blood in absolute measure. In Fig. 401 the velocity at the
points 1 and 1', corresponding to the cardiac systole, was 248 mm. per second. At 2 and
%', corresponding to the dicrotic elevation, the velocity was also 248 mm. At 3 and 3',
towards the end of diastole the velocity sank to 127 mm.
The velocity of the blood in the capillaries can be measured by direct observation
of the capillaries under the microscope, and noting the time it takes for a blood corpuscle
to move from one edge of the field to the other.
THE VELOCITY IN DIFFERENT PARTS OF THE
VASCULAR SYSTEM
During systole the velocity of the blood in any part of the arterial system
must lie greater than during diastole; thus in the carotid of the horse the
following figures were found :
During systole
During diastole
Velocity per second
520 mm.
150 mm.
The following figures of the average velocity have been obtained from
experiments on dogs (Tigerstedt.) :
Body
weight
Artery
Volume
per second
Linear
velocity per
second
Diameter
of artery
B.P.
Remarks
kg.
14-6
141
('rural.
Crural.
Carotid.
c.c.
0-63
1-69
1-95
nun.
128
275
241
2-5
2.8
3-3
mm. !!•,'.
77
88
93
Nerves un-
injured.
Nerves cut
Nerves un-
injured
SECTION IV
THE MECHANISM OF THE HEART PUMP
In the mammal the two sides of the heart are in communication only by
means of the blood vessels of the systemic and pulmonary area. Each
side ((insists of an auricle into which the veins open, and a ventricle which
receives the blood from the auricle and discharges it into the arterial trunk — ■
either aorta or pulmonary artery. Since the auricles have to act merely
as a receptacle for -part of the blood which enters during the relaxation or
diastole of the heart, their cavities are smaller than those of the ventricles,
and their -vails are thin, corresponding to the small amount of work thrown
on them in propelling blood into the relaxed ventricle. The ventricles have
the oitice of carrying on the main work of the circulation and of forcing
blood through the peripheral resistance. Their walls are much thicker
than those of the auricles. The right ventricle has a wall which is only about
one-fourth the thickness of the left ventricle, in conformity with the much
heavier work to be done by the hitter. On cutting a section through the
two ventricles in a contracted condition, the thin wall of the right ventricle
is seen to lie in the form of a crescent round the circular left ventricle. The
capacity of both ventricles is approximately equal, and amounts in man
to about 1 10 c.c. for each ventricle when the heart is completely relaxed.
The auricles are separated from the ventricles by a fibrotendinous ring.
From this ring tab origin most of the muscular fibres of the heart walls.
The muscular fibres of the auricles run in both circular and longitudinal
directions, the circular fibres being continued round both auricles, and
special rings of circular fibres surrounding the openings of the great veins.
From the fibrotendinous ring between the auricle and the left ventricle and
Erom the sides of the aorta, the muscular fibres forming the superficial layer
of the ventricular wall pass obliquely downwards to the left towards the
apex of the ventricle. Here they loop round into the interior of the ventricle
and pass up near its inner surface to end either in the papillary muscles or
in the auriculo-ventricular ring of fibrous tissue. Between these two layers
we find a third median layer of muscular fibres which is in the form of a
muscular cone. The fibres of this layer form complete loops round the left
ventricle. The middle layer is connected by many strands of muscular
Bbres with both inner and outer layers.
Mall divides the muscular fibres of the mammalian heart into four groups, two super-
ficial and two deep, as follows :
(1) The superficial bulbo-spiral fibres. These arise from the conns arteriosus, the
left side of the aorta and the left side of the auriculo-ventricular ring, and take an
935
93fi
rTTYSIOLOCJY
oblique course to the apex, where fchey make a Bpiral turn (the- vortex) and reach the
interior of the left ventricle, ending for the tnosl pari in the intraventricular septum
and the papillary muscles.
(2) The superficial sino-spiral fibres rise on the dorsal side of the heart from the right
auriculo-ventricular ring and run obliquely on the anterior surface of the right vent ricle
to the apex, where they also turn inwards, forming the anterior hom of the ' vortex,'
and end chiefly in the papillary muscles of the right ventricle.
(3) The deep bulbo-spiral fibres form a complete cylinder around the left ventricle,
and are attached chiefly to the dorsal side of the aorta.
Fig. 402. View of the heart from behind, to show the course of the chief
strands of muscle fibres. (Maix.)
The black lines represent- the bulbo-spiral fibres, the grey fines the sino-
spiral fibres.
(-1) The deep sino-spiral fibres arc attached to the dorsal aspect of the left auriculo-
ventricular ring, whence they enter the right ventricle and turn upwards towards tin-
base. The uppermost of these Sbres form circular rings round the conu.i arteriosus at
the base of the pulmonary artery.
The fact that the muscular fibres are continuous over both auricles and
over both ventricles respectively ensures the practically simultaneous con-
traction of each of these parts of the heart. Although on coarse dissection
there seems to be absolute division between the muscular tissue of auricles
and ventricles, it has been shown by Kent, His, and others that there is
continuity of muscular tissue between the two parts of the heart by a special
band of muscular fibres, ' the bundle of His,' which rises in the wall of the
right auricle and passes beneath the foramen ovale and across the auriculo-
THE MECHANTSM OF THE HEART PUMP
937
ventricular junction into the inter- ventricular septum. The exact course
of these fibres and their significance will be considered later.
The normal direction of the blood flow through the heart is determined
mainly by the valves which guard the auriculo-ventricular orifices and the
openings of the aorta and pulmonary artery. The auriculo-ventricular
valves are tubular membranes attached round the entire circumference of
the auriculo-ventricular ring. They are composed of fibrous and elastic
Fig. 403.
Left auricle and ventricle, with outer side cut away to show chief points
in anatomy i>f heart. (Testtjt.)
1, aorta; 2, pulmonary artery; 3, ant. coronary vessels; 5, 5', pulmonary veins;
6, Id! auricle; 7. auricular appendage; 10, cavity of left ventricle; 11, 12, mitral
valves; 13, 14. papillary muscles; 1(1, arrow pointing to aortic orifice.
tissue, covered on each side with endocardium, and project downwards into
tin' cavities of the ventricles. On each side the membrane is divided by
deep incisions into large Haps, three in number mi the right side (the tricuspid
valves) and two in number on the left side (the mitral valves). The sail-like
margins of these valves are connected by thin tendinous cords to the papil-
lary muscles, which are nipple-shaped projections of the muscular walls of
the ventricles. By this means the edges of the valves are kept close togel her
and prevented from eversion under the strong pressure exerted by the con-
tracting ventricle. By the downward pull of the papillary muscles on the
valves during the contraction of the ventricles, closure is rendered more
938 PHYSIOLOGY
complete, the inner surface of the valves being apposed over a considerable
area. The action of the valves is aided by the contraction of the fibres
surrounding the base of the heart, so that the auriculo-ventricular orifice
is much smaller during systole than during diastole.
From a purely mechanical standpoint the valves guarding the arterial
orifices are much more perfect than those just described, which depend for
their efficiency on the proper contraction of the ventricular wall and of the
musculi papiUares. Each orifice is provided with three valves, each of
which is semilunar in shape and attached by its convex borders to the
arterial wall, and presents in the middle of its free border a small fibro-
cartilaginous nodule, the corpus Arantii, from which fine elastic fibres pass
to all parts of the valve. The extreme margin of the valve, the lunula,
on each side of the corpus Arantii is very thin, beinu formed of little more
than the endocardium. Whenever the pressure in the arteries is greater
than that in the ventricles, these valves are closed, and the thin margins
come in contact with similar portions of the adjacent valves, so .preventing
the reflux of a single drop of blood. The borders of the valves under these
circumstances come together in the form of a star composed of three hnes
at angles of 120°, the three corpora Arantii being pressed together at the
centre of the star.
No valves are found at the orifices of the great veins into the auricles,
a reflux of blood in this situation during contraction of the heart being
limited by the contraction of the. muscular rings round the veins, which
always accompanies the auricular contraction.
The heart and the roots of the great vessels he almost free in a special
cavity, the wall of which is formed by a tough fibrous membrane, the
pericardium. This is attached below to the central tendon of the diaphragm,
and above to the arterial trunks. It is fined by a layer of endothelium
continuous with a similar layer covering the surface of the heart. The
two surfaces are kept continually moist by the pericardial fluid, so that
the heart can move freely within the pericardium without friction. One of
the chief functions of the pericardium appears to be to check an excessive
dilatation of the heart during conditions attended by a great rise of venous
pressure.
THE SEQUENCE OF EVENTS IN THE CARDIAC CYCLE
On opening the chest of an anaesthetised animal, while artificial respira-
tion is maintained, the heart is seen contracting rhythmically within the
pericardium. On incising this sac its restraining power on the dilatation
of the heart is shown by the fact that during diastole the wall of the heart
bulges through the opening, and the increased diastolic filling, consequent
on the removal of this restraining influence, is at once apparent, if in any
way the frequency of the contractions of the heart be diminished so as to
prolong the diastolic period.
Each beat of the heart begins l>v a simultaneous contraction of both
THE MECHANISM OF THE HEART PUMP 939
auricles, associated with a retraction of the auricular appendages, which
become pale and bloodless. After a pause of not more than a tenth of a
second, the contraction of the auricles is followed by that of the ventricles,
and blood is thrown out into the large arteries. The contraction of the
auricles lasts about a tenth of a second, that of the ventricles about three-
tenths of a second. The period of relaxation or diastole lasts about four-
tenths of a second. During this cycle of changes the following events are
taking place within the heart :
In the diastolic period the aortic valves are closed and the arterial
system is open only towards the capillaries. In consequence of the high
pressure established within the arteries by the previous heart beats, the
blood flows steadily through the arterioles, capillaries, and veins into the
rigHt heart, and similarly the pressure in the pulmonary artery causes a
partial emptying of this vessel with its branches through the pulmonary
capillaries into the left heart. The flow into the heart is assisted by the
elastic retraction of the lungs, which causes a negative pressure in the
structures between them and the chest wall, s<> that the blood is sucked from
the other parts of the body towards the thorax. During diastole there is
a continuous flow of blood from veins into auricles and from auricles into
ventricles and, as the walls of both these cavities are relaxed, there is no
impediment to the inflow of the blood until the dilating heart begins to
stretch the pericardium.
Under normal circumstances the diastole comes to an end before the
restraining influence of the pericardium can be effective. The contraction
of tlie auricles diives their contents into the ventricles and so still farther
increases their distension, no resistance being offered by the widely dilated
auriculo-ventricular orifices or by the flaccid wall of the ventricles. As the
Mood rushes from auricle into ventricle through the funnel-shaped opening
of the membranous tube formed by the valves, eddies are set up in the
ventricle tending to close the valves, so that they are held, as the resultant
oi the two opposing currents, in a condition midway between closure and
opening. The onset of the ventricular contraction is extremely rapid.
There is a quick rise ,,f pressure in the ventricle, which presses together
the flaps of the mitral or tricuspid valves, while the bases of these valves
.tie approximated by the contraction of the circular fibres at the base of
the ventricles. As the heart shortens in systole the papillary muscles also
shorten, so thai the valves are prevented from eversion into the auricles,
while the blood is pressed, so to speak, between the cone of the ventricular
wall and the cone formed by the tubular valves.
The outflow of blood from the ventricles does not however commence
immediately. Whereas at the beginning of systole the pressure in the,
ventricle cavity is quite small (only 2 or 3 mm. Hg.), there is a pressure in
the aorta of 50 to 80 mm. Hg. Before the semilunar valves separating the
lumen of the aorta from the ventricular cavity can be opened, the pressure
in the left ventricle must rise to a point which is greater than that in the
aorta, and similarly on the right side of the heart. As soon as this happens
940 PHYSIOLOGY
the valves open and the outflow of blood commences, and continues so
long as the pressure in the ventricles is higher than thai in the great arteries.
Directly however the ventricular pressure falls below the arterial pressure,
the valves must close and the output of blood come to an end.
In order to obtain an accurate idea of the exact duration of each of these
events in the cardiac cycle, it is necessary to study the changes occurring
in the pressure within the auricles and ventricles during the various phases
of the heart beat.
THE ENDOCARDIAC PRESSURE
A manometer which shall register accurately the changes in the pressure
within the heart must he capable of responding to very rapid changes. Thus
in the left ventricle at the beginning of the systole, there may be a rise of
130 mm. Hg. in •<)(> sec, i. c. 2170 mm. Hg. per sec. In a heart beating
rapidly and forcibly under the action of adrenalin, the rise may be still more
Fig. 404. Diagram of Marey's cardiac 'sound,' consisting of a Ion?: tube ah,
terminating at one end in the ampulla /«, which is covered with an elastic
mbrane. The side-piece r serves to indicate the position of the,anipulla
alter it has been introduced into the vessels.
rapid, e.g. 150 mm. Hg. in -025 sec. A mercurial manometer with its great
inertia would be quite unequal to registering such rapid changes of pressure.
a7id would moreover tend to enter into oscillations which would quite deform
the curve. We require an instrument with very small weight of moving
parts, so as to possess small inertia and be capable of registering a rapid rise
of pressure without entering into oscillations of its own.
Several methods have been adopted for this purpose. In one (< Ihauveau and Marey)
a cardiac 'sound ' (Fig. 404) is passed down the jugular vein into the right auricle or
ventricle, or down the carotid artery into the left ventricle. The cardiac sound is a
Fig. 405. Marey 's tambour.
a, axis of lever: h. metal tray covered with rubber membrane, and communi-
cating by tube / with free end of cardiac sound.
stiff tube having an elastic bulb or ampulla at the end which is to be inserted into the
heart. The bulb is supported by a. steel frame, so that it is not completely compressible
by external pressure. The free end of the tube is connected with a writing tambour
(Fig. 405), a small round metal tray covered with a delicate clastic membrane. To
THE MECHANISM OF THE HEART PUMP 94]
the top of the membrane a lever is attached by which any change of pressure on the
ampulla may be recorded on a moving smoked surface. The large size of these sounds
makes it difficult bo use them on any animal smaller than the ass or horse. In smaller
animals, such as the dog, the question has been investigated by the use of a manometer
such as that of Hiirthle. In this instrument (Fig. 406) the changes of pressure are
Fig. 406. Diagram to show construction of Hiirthle's membrane manometer.
recorded by the oscillations of a thick rubber membrane which covers a very small
tambour. The tambour is filled with magnesium sulphate solution, which is also used
to till the tube connecting with the heart. This tube can be inserted in the same way
as Maivv's cardiac sound.
Even Hiirthle's instrument is inadequate to give a correct representation of the very
rapid changes of pressure occurring in the contracting ventricle. A study of the theory
of recording instruments by Otto Frank has enabled him to lay down certain funda-
mental requirements of such a recording instrument. In order that an instrument
may reproduce correctly rapid changes of pressure, the mass moved must be as small as
possible in order to reduce the momentum, and therefore the tendency to overthrow of
the instrument, to the greatest possible extent. Moreover the movement of fluid into
and out of the instrument, which accompanies each change of pressure, must occur with
the smallest possible friction. This is accomplished, as in Hurtlile's instrument, by
using a very small tambour, covered with a strong, tightly stretched membrane connected,
by as short and wide a tube as is feasible, with the heart or blood vessel where it is
desired to register changes of pressure. A lever is entirely got rid of, the minute oscilla-
tions of the membrane being recorded by means of a beam of light which impinges on
EF
Fig. 407. Diagram of Piper's manometer.
a mirror attached to the rubber membrane and reflected on to a moving photographic
surface. In Fig. 407 is represented the construction of Piper's manometer, built on
the principles laid down by Frank.
It cimsists of a tube armed with a stiletto, A, which tits it accurately. At c is a tap
which, when opened, will permit the passage of the stiletto, and can close the tube
entirely when the stilette is withdrawn. About 2 cms. above the lower extremity of the
tube is a small drum-like enlargement, closed on one side by a thick membrane, E.
On the edge of this membrane is fixed by means of shellac a minute mirror, F, 1 mm. in
diameter. With the stilette protruding, the manometer is thrust directly into the
cavity of the heart, and tixed in position by a purse-string suture through the super-
ficial part of the heart muscle, tied tightly round the end of the manometer. The stilet te
is then withdrawn and the tap turned off, but alterations in pressure in the cavity of the
heart cause minute oscillations of the membrane, which can be recorded and magnified to
any desired extent by means of a beam of light reflected from the mirror on to a moving
y attaching one nostril to a delicate tambour by means of a tube,
while the other nostril and the mouth are kept closed. If a carotid pulse tracing be
taken at the same time, it will lie found that there is a fall of the lever attached to the
nasal cavity, synchronous with the rise of the pressure in the arteries and due to the
expulsion of blood from the heart.
954 PHYSIOLOGY
The normal filling of the heart during diastole can be prevented by
anything which hinders its expansion, such as the presence of fluid in the.
pericardial cavity. The same effect may be produced experimentally. If oil
be allowed to flow into the pericardium, when the pressure of the oil rises
to about 60 mm., the pressure of the vena cava rises to a height just above
that obtaining in the pericardial cavity. On increasing the pressure, a
point is finally reached at which no more blood can be driven from the veins
to the heart, so that the arterial blood pressure falls to zero and death ensues.
In order to maintain the arterial pressure it is necessary that the amount
of blood, driven into the arterial system by the contraction of the left ventricle,
should be exactly equal to that leaving the arteries to pass into the capillaries
during the period which elapses between each systole.
Over-filling of the heart is prevented to a certain extent by the resistance
of its walls. The danger of over-filling is therefore most marked in the
right ventricle. An important part is played moreover by the pericardium
in this regard. Even when beating normally, the heart during diastole
tends to protrude through a slit made in the pericardium, and Barnard
has shown that the right auriculo-ventricular valve ceases to be entirely
efficient when the pericardium has been freely opened, the closure of this
valve being dependent on the support afforded to the heart by the
pericardium.
SYSTOLIC OUTPUT OF THE HEART
The amount of blood which passes through the whole body and is avail-
able for the metabolic exchanges of all the tissues depends on the amount
of blood which leaves the heart each minute. The. height of the arterial
pressure also depends on the relation between the amount of blood leaving
the arterial system by the capillaries and that entering from the heart.
The determination of the output of the left ventricle is therefore one of
the most important problems in physiology. The output of the right ventricle
must be equal to that from the left ventricle, otherwise the blood would
accumulate on one or other side of the heart and bring the circulation to
a standstill. It is therefore immaterial on which side of the heart the
output be determined.
The methods which have been devised for determining the cardiac
output fall into two classes. In the first class it is sought to determine
the total volume of blood leaving the right or left ventricle in the course
of a given time, say one minute. If this amount be divided by the number
of heart beats in the same time, the output of each ventricle per beat is
at once obtained. A second method consists in the determination of the
volume changes in the ventricles at each beat of the heart. During diastole
the ventricles are receiving blood and increase in volume, during systole
they expel blood and therefore diminish in volume. The change in volume
at each beat nives therefore the combined output of right and left ventricles
and must be divided by half in order to give the output of either ventricle
separately.
THE MECHANISM OF THE HEART PUMP 955
METHODS OF DETERMINING OUTPUT. In a method devised by the author
it is possible to determine the output of the left ventricle under all manner of conditions
and to vary at will the arterial resistance, the venous pressure, the filling of the heart,
or the temperature of the blood supply to the heart. The arrangement of the apparatus
is shown in Fig. 415. Artificial respiration being maintained, the chest is opened under
an anaesthetic. The arteries coming from the arch of the aorta — in the cat, the innomi-
nate and the left subclavian — are then ligatured, thus cutting off the whole blood supply
to the brain, so that the anaesthetic can be discontinued. Cannula? are placed in the inno-
minate artery and the superior vena cava. The cannulae are filled beforehand with a solu-
tion of hirudin in normal salt solution so as to prevent clotting of the blood during
the experiment. The descending aorta is closed by a ligature. The only path left for
lie:. 416. Arrangement of apparatus for working on the isolated mammalian
beait. ('Heart-lung preparation.*) The different parts are not drawn to
scale, and the lungs are not shown. (Starling.)
the blood is by the ascending aorta and the cannula CA in the innominate artery.
The arterial cannula communicates by a T-tube with a mercurial manometer M' to
record the mean arterial pressure, and passes to another T-tube, v, one limb of which
projects into a teat-tube B. The air in this test-tube will be compressed with a rise
of pressure and will serve as a driving force for the blood through the resistance. It
thus takes the part of the resilient arterial wall. The other limb of the T-tube passes
to the resistance R. This consists of a thin -walled rubber tube (e. g. a rubber finger-
stall) which passes through a wide glass tube provided with (wo lateral tubulures w, v.
One of these is connected with a mercurial manometer M' and the other with an air
reservoir into which air can be pumped. When air is injected into the outer tube, the tube
E collapses, and will remain collapsed until the pressure of the blood within it is equal
or superior to the pressure in the air surrounding it. It is thus possible to vary at VI ill
the resistance to the outflow of the blood from the arterial side. From the peripheral
end of R the blood passes a1 a Lovi pressure through a spiral immersed in warm water
into a large glass reservoir. From the reservoir a wide india-rubber tube leads to a
cannula, which is placed in the superior vena cava SVG, all the branches of which
956 PHYSIOLOGY
have beon tied. This cannula ia provided with a thermometer to show tho temper-
ature of the blood supplied to the heart. A tube placed in the inferior vena cava and
connected with a water manometer shows the pressure in the right auricle. On the record-
ing surface we thus have a record of the arterial pressure, and of the pressure within the
right auricle. The output of the whole system can be measured at any time by opening
the tube X, clamping F, and allowing the blood to flow for a given number of seconds
into a graduated cylinder.
This method, although of considerable importance in giving information as to the
conditions which determine the output of the left ventricle and the maximum capacity
of the heart as a pump, tells us nothing as to the output of the left ventricle under
normal conditions in the intact animal. For this purpose some indirect means must
be adopted which can be used on the intact animal and if possible on man himself,
so that the output can be measured under different conditions of rest and activity.
Moreover the output as measured on the other side of the artificial arterial resistance
represents the ventricular output minus the blood flow through the coronary arteries.
It is possible however to insert a cannula into the coronary sinus, and so to measure
the blood flow through the heart muscle. The coronary circulation must be added
to the flow through the arterial resistance in order to arrive at the correct total output
of the left ventricle. The two chief methods for the determination of the ventricular
out put in the intact animal are those of Zuntz and of Krogh.
ZUNTZ'S METHOD. This is based on a comparison of the differences in gases
contained in the arterial and venous blood and the actual amount of oxygen taken
from the air in the lungs. Thus in one ease he found that in a horse weighing 3(50
kilos. 2733 c.c. of oxygen were taken up in the lungs per minute, while the arterial
blood contained 10-33 per cent, more oxygen than the venous blood. Since therefore
every 100 c.c. of blood that passed through the lungs had taken up 10-33 c.c. of oxygen,
and 2733 c.c. had been taken up in the course of a minute, it is evident that
100 X 2733
10-33
20,457 c.c.
of blood must have passed through the lungs in the time. This therefore was the output
of blood by the right ventricle in a minute and was equivalent to -00122 of the body
weight per second.
In a similar experiment on a dog the output per second of the right ventricle was
found to be -00157 of the body weight. In order to get the output at each beat it will
be necessary to divide the output per minute by the number of heart beats in the same
time. From the results of determinations made in this way Zuntz concluded that the
output of the right ventricle in man at each beat varies between 50 and 100 c.c. and
may be taken on an average at 60 c.c.
KROGH 'S METHOD. In Krogh's method an endeavour is made to determine
the volume of blood flowing through the lungs in a given time by finding out how
much nitrous oxide is taken up from a mixture of nitrous oxide and air, with which
tin 1 lungs are filled. Nitrous oxide is chosen because it can be breathed in considerable
proportions without injury, and is itself very soluble in water or in the blood. The
estimation is carried out in the following way. A small recording spirometer is filled
with about 4J litres of a gas mixture containing 10 to 25 per cent. N 2 and 20 to 25
per cent, oxygen. The subject, seated in a chair or on a bicycle ergometer, expires to
the greatest possible extent, and then takes a deep inspiration from the spirometer.
He holds his breath for five to fifteen seconds, breathes out sharply into the spirometer,
expiring at least one litre. At the end of this sharp expiration, a sample of his alveolar
air is taken by connecting the tube from his face-piece with an evacuated glass bulb,
as in Haldane's method of determining alveolar air. The breath is now held for a
period varying between six and twenty-five seconds. He then makes a final sharp
ample expiration into the spirometer, a sample of his alveolar air being taken at the
end of this expiration. The excursions of the spirometer indicate exactly what volume
of air he has breathed in and breathed out at each part of the experiment. These are
THE MECHANISM OF THE HEART PUMP 957
recorded on a travelling surface, so that the duration of the experiment is represented
by the horizontal distance between the lines showing the moments of sampling (Fig.
416).
By comparison of the composition of ordinary alveolar air with the alveolar air ob-
tained after the first sharp expiration, the amount of residual alveolar air is determined,
so that the total volume of gas contained in the lungs at each part of the experiment
is also known. During the time when the breath is being held, nitrous oxide is being
taken up in solution by the blood as it passes through the lungs, its solubility being such
that 1 c.c. of blood, if exposed to an atmosphere of pure nitrous oxide, will take up
0-43 c.c. of this gas. From the data obtained in this way, the amount of blood passing
t hrough t he lungs during the period between the two expirations can be calculated. The
following record of one experiment may serve as an example. The volume of air in
the lungs at the beginning of the experiment was 3-25 litres and contained 12 per cent,
nit runs oxide, so that the total quantity of nitrous oxide in the air of the lungs was
3250 c.c. X 1 1 ,,"fy = 390 c.c. At the end of the period the total volume of air in the
lungs was three litres, containing only 10 per cent, nitrous oxide, so that the lungs
28/ sec
I 5 sec
Fig. 416. (Kiioan.)
now contained only 300 c.c. nitrous oxide, 90 c.c. nitrous oxide having been taken up
by the blood. This 90 c.c. was taken up from an air in which the mean pressure of
this gas was -- =11 per cent. During the period of observation, from a gas
containing ;it atmospheric pressure 11 per cent, of nitrous oxide, each c.c. of blood
will take up — = 0-047 c.c. In order to take up 90 c.c. therefore. 1-9 litres of
100
blood must have passed through the lungs during the time of the observation. The
erperimenl lasted twenty-eight seconds. The amount of blood passing through the
lungs per minute was therefore 4-2 litres. This figure represents the output from the
right ventricle during one minute, and if the pulse rate is 70 per minute, the output
ner heat will be - ' — = 60 c.c. per beat. The figure, arrived at in this way for the
1 70
a \ erage out put of each ventricle in man during rest, thus agrees with the figure obtained
by Zuntz. The output of both ventricles is of course the same.
According to Krogh, the ventricular output per minute in man may vary from 2-8
litres to 21 litres of blood per minute. The latter is an extreme figure and was obtained
in a powerful athlete doing hard work. In the case of Krogh himself, the maximum
output was about 12 litres per minute. It is interesting to note that the same perform-
ance may be obtained from a dog's heart in the heart-lung preparation, allowing for
the difference in size between the hearts of the dog and man respectively.
CARDIOMETRIC METHOD. Of the various methods which have been devised for
recording plethysmographically the changes in the volume of the heart at each beat (as
tirst carried out by Roy), the simplest is that devised by Henderson. The chest and
pericardium being opened, a glass cardiometer, of the shape shown in Fig. 417, is slipped
over the heart. This cardiometer consists of a glass sphere with a wide opening. To
the margin of the opening is tied a rubber diaphragm with a hole in it, which accurately
fits the heart as it lies in the auriculo-ventricular groove. The tube of the cardiometer is
958 PHYSIOLOGY
connected with some form of pisl icorder or a tambour with a slack membrane.
The disadvantage of this method is that the graphic record of rapid and am pic changes
in volume is one of the mosl difficult problems in experimental physiology, the inerl ia
and friction of the moving piston tending to deform the shape of the curve obtained.
Straub has therefore used a soap bubble as the volume measurer, photographing its
edge and using the record as an index to the change in volume. It is possible how-
ever to obtain a piston recorder moving sufficiently freely to give a fairly correct
reproduction of the volume changes of the heart, provided that these do not occur with
too great rapidity. It has been suggested by Piper to convert the volume changes
into small pressure changes, and to record these latter by one of the methods described
above.
The factors which determine the output of the left ventricle are bust
■studied in the heart-lung preparation. In this it can be shown that, pro-
vided the venous inflow remains constant, the output is also constant and
is unaffected by considerable alterations of arterial resistance and of the
Fro. 417. Henderson's glass cardiometer.
rate of the heart. Thus with a moderate venous inflow the output remains
constant whether we maintain the average arterial pressure at 60 mm. Hg.
or at 160 mm. Hg. It is also unaffected by altering the rate of the heart
from 80 beats per minute up to 160, or even 200, beats per minute. On
the other hand, the output is at oiice altered by alterations in the venous
inflow and, as already stated, can be altered in a heart weighing 50 gms.
from a few c.c. up to 3000 c.c. per minute. The only essential in this
preparation is that the output from the left ventricle shall be sufficient
to maintain a circulation through the coronary vessels and so keep the
active muscle properly supplied with blood.
With increasing inflow of blood into the heart the large veins, auricles,
and ventricles naturally become more filled during diastole, and during
systole of the ventricles, when the auriculo-ventricular valves are closed,
the blood rushing in from the venous system must accumulate in the big
veins and auricles to a still greater extent. The venous pressure therefore
rises with increased venous inflow. In so far as venous pressure is an
index of venous inflow, we may say that the output of the heart increases
with the venous pressure so long as the heart is functionally capable of
dealing with the blood it receives during diastole. But although the
ventricular output is practically independent of the frequency of the heart
beat and a constant venous inflow, the venous pressure tends to fall as
THE MECHANISM OF THE HEART PUMP 959
the heart beat Increases in rate. The optimum venous pressure is that
which fills the ventricle during its diastole to the maximum extent to
which it is able to respond. As the rate of the heart increases, the inflow
of blood can also be increased without causing over-distension of the
ventricles. The increase of heart rate therefore is an important factor
hi enabling this organ to deal with the maximum amount of blood. Although
increase of rate does not alter the output with constant venous inflow, it
does increase the maximum amount of inflowing blood which the heart is
able to expel.
We thus see that alterations in the vigour of the circulation depend in
the first instance on the venous circulation. The greater volume of the
blood that is brought up to the heart by the accessory factors of the cir-
culation, the greater will be the output of this organ. The changes in rate
and force of the heart which accompany its increased activity and increased
output, e.g. during exercise, represent merely the means by which this
organ is able to deal in the most advantageous manner with the increased
inflow.
THE WORK OF THE HEART
The energy of the ventricular contraction is expended in two ways :
first, in forcing a certain amount of blood into the already distended aorta
against the resistance presented by the arterial blood pressure, which
itself is directly conditioned by the resistance in arterioles and capillaries ;
and secondly, in imparting a certain velocity to the mass of blood so thrown
out. Thus the energy of the muscular contraction is converted partly
into potential energy in the form of increased distension of the arterial wall
and partly into the kinetic energy represented by the momentum of the
moving column of blood. The work done at each beat may be calculated
from the formula :
wV 2
W = QR + —
2g
where \\ stands for work, to for the weight, and Q for the quantity (volume
in c.c.) of blood expelled at each contraction; R is the average arterial
resistance or pressure during the outflow of blood from the heart, and V is
the velocity of the blood at the root of theaorta. In this equation QR is
vJV 2 .
the work done in overcoming the resistance, 1 and — is the energy expended
in imparting a certain velocity to the blood.
If we take Ho c.c. as the average output of each ventricle. Km mm. Hg.
as the average pressure at the beginning of the aorta, and 500 mm. per
1 This expression, QR, is only approximately correct. Supposing the pressure in
the aorta at the beginning of systole is 50 mm. Hg. and at the end of systole 150 mm.,
the work could not be deduced accurately from the average pressure, but would need a
simple application of the integral calculus for its determination. The expression
employed above deviates from the real value by at most 10 per cent., and is thereforo
sufficiently accurate for our purpose.
960 PHYSIOLOGY
second as the velocity imparted bo the blood thrown into the aorta, we can
calculate the work done by the human heart at each beat.
QR = 60 X 0-100 m. X 13-6 = 81-6 grammetres,
or roughly 80 grammetres. On the other hand, the expression
»
wW- 60 X (0-5) 2 n _ .
— = — - = 0-7 grammetres.
2<7 2 • 9-8
It. is evident that this latter factor is negligible, and that for all practical
purposes we may regard the work of the heart as proportional to the output
multiplied by the average arterial blood pressure. Taking tin' average
pressure in the pulmonary artery at 20 mm. Hg., the work of the right
ventricle at each beat would amount to about 16 grammetres, a total for
the two ventricles of about 100 grammetres per beat, which is equivalent
to about 10,000 kilogrammetres in tw r enty-four hours for a man at rest.
During muscular work this figure would be largely increased. Not only
does QR become much larger, but the velocity factor is no longer negligible,
since the work done in imparting velocity to the blood increases as the
cube of the output per minute. If we take, as an example, a maximum
effort on the part of an athlete, we may assume an output per beat of 180 c.c.
and a pulse rate of 180 per minute (an output per minute of 32-4 litres)
and an average arterial pressure of 120 mm. Hg.
Then
QR = 180 X -120 X 13-6 = 294 grammetres.
To determine the velocity of output, we assume that 180 c.c. of blood
are thrown out into the aorta during § of J second, the time of outflow
being about § of each cardiac cycle This gives a velocity of 2-3 metres
per second, assuming a cross section of 625 mm. 2 at the root of the aorta.
Therefore
wV°- 180 x (2-3) 2 . ,
= * = 5 grammetres.
2;/ 2 x 9-8
The total work of both sides of the heart will be :
294 -\- 5 -\- 59 + 5 = 363 grammetres per beat, or 65 kilogrammetres per
Left side. Eight side. minute.
This rati' of work could probably not be maintained for more than a few
minutes.
This work is done by a contraction of the muscle fibres surrounding the cavities
of the ventricles. It is important to remember that the strain or tension, winch is
thrown on these "fibres and which resists their contraction, will be determined not only
by the blood pressure which has to be overcome, but also by the size of the ventricle
cavities. Since the pressure in a fluid acts in all directions, the tension caused by any
given pressure on the walls of a hollow vessel will increase with the diameter of the
vessel. Thus if we take a sphere with a radius of 10 cm. filled with fluid at a pressure
of 10 cm. Hg., there will be a pressure on each square centimetre of the inner surface
of the sphere of 136 grm. The total distending force, i. e. the pressure on the whole of
the inner wall of the sphere, will be equal to this pressure multiplied by the area,
THE MECHANISM OF THE HEART PUMP 961
i. e. to 136 X 47rr 2 = 136 X 47r X 100. If by a contraction of the walls the radius
be reduced to 5 cm., the total pressure on the internal surface will be reduced to
136 X 4r X 25, i. e. will be one quarter of the previous amount. Moreover in the
case of the heart, with increasing distension the wall becomes thinner and the number
of muscle fibres in a given area fewer, so that the larger the heart the more strongly
will each fibre have to contract in order to produce a. given tension in the contained,
lluid. At the beginning of systole the distended heart must therefore contract
more strongly than at the end of the systole, in order to raise the blood it contains to
a pressure sufficient to overoome that in the aorta.
It is evident that an unrestricted diastolic filling of the heart is not of
unqualified advantage to this organ. If during diastole the heart be too
forcibly distended, as may easily occur after opening the pericardium, or
in cases of enfeeblement of the heart's action by chloroform poisoning or
otherwise, the muscle fibres of the heart may be quite unable to contract
against the distending force represented by a pressure in the heart equal
to that in the aorta. Under such conditions we may have sudden heart
failure, which can be relieved only by diminishing the diastolic distension,
as, e. g. by letting blood from the veins opening into the heart.
61
SECTION V
' THE FLOW OF BLOOD THROUGH THE ARTERIES
THE PULSE. Owing to the elasticity and distensibility of the arterial wall,
the rhythmic rise of pressure corresponding to each heart beat causes an
expansion,* which can be felt by the finger placed on any exposed artery,
such as the radial, and is spoken of as the pulse. Just as the blood pressure
diminishes from heart to periphery, so the amplitude of the pulse decreases
as we go farther away from the heart.
If the arterial system were perfectly rigid, the increased pressure due
to the forcing of the blood into the arterial system at each ventricular
systole would occur practically simultaneously at every point. The arteries
are however elastic and distensible, so that the first effect of the flow of
blood into the aorta is to distend the section of the aorta nearest to the
heart. The elastic reaction of this forces a portion of the blood into the
nearest section, so that the increased pressure is transmitted from segment
to segment of the arteries in the form of a wave at the velocity of about
seven metres per second.
It is important not to confuse the velocity of the pulse wave with that
of the blood flow; the latter is never greater than 0-5 metre per second,
and is very much less than this in the smaller arteries. Perhaps the differ-
ence between the two quantities may be marie clearer by illustration :
If the hindmost of a row of billiard balls be struck sharply with a cue, the
foremost ball flies off and the others stop still; in this case the energy
imparted to the first ball by the stroke has been transmitted from ball to
ball, just as the effect of the ventricular contraction is transmitted from
section to section of the arterial bloodstream. If the balls are struck s<>
that the cue continues pressing on the hindmost after the stroke is delivered,
the front ball flies off, while the others move slowly along in the direction
of the stroke. Li the arteries this continuous pressure is furnished by
the elastic reaction of the arterial wall, and we see how the impact of the
blood may travel quickly as a wave of increased pressure, while the blood
itself is moving slowly along, impelled by the reaction of the arterial wall.
If we imagine a rigid tube ab (Fig. 418) provided with a piston at the
end a, and filled with an incompressible fluid, an inward movement of
the piston at A will cause a simultaneous outflow of fluid at the end B. If
the end B is closed, the piston at A cannot be moved at all. Pressure applied
to the piston will raise the pressure simultaneously at all points in the
tube ab. The increased pressure applied at A is therefore transmitted
with practically no loss of time to all parts of the tube ab This immediate
spread of the wave of pressure apphes only 7 to an incompressible fluid
within a rigid tube. If the fluid were compressible, if it consisted, e. g. of
962
THE FLOW OF BLOOD THROUGH THE ARTERIES 963
air, a sudden movement inwards of the piston at A would not be felt imme-
diately at B. The propagation of the wave of pressure from a to B would
take a finite period of time, its velocity being identical with that of the
velocity of propagation of a wave of sound in air, i. e. 1100 feet per second.
A
=1
s
The same retarding effect will be produced if we have an incompressible
fluid within a tube whose wall is distensible and elastic. If we imagine
(Fig. il'J) an elastic tube bc filled and distended with water and connected
at b to a rigid tube, which is provided with a piston, the first effect of a
rapid movement of fluid driven in by the piston will be a rise of pressure
at the point immediately in front of the piston, viz. at a. The wall being
distensible, and pressure being propagated along the fluid in every direction,
the rise of pressure at a -will be spent partly on the particles of fluid in
front of it . viz. at b, but also on the walls of the tube, so that this is stretched
and the cross-section of the tube enlarged. The distended segment at a
will then exert a pressure on the contained fluid, driving this backwards
and forwards. The fluid on its side towards the piston will tend to come
to a stop, while that towards the distal end of the tube will be accelerated.
The distended wall therefore returns to its original diameter, and the next
segment at 6 is stretched in its turn, so that a wave of increased pressure
is propagated along the tube in the direction of the arrow.
The velocity with which this wave is propagated depends on the density of the
fluid, i. e. its inertia, and on the resistance of the walls of the tube to distension, since
this will determine the rapidity of its recovery. The velocity of propagation of the
of increased pressure, or the wave of expansion of the artery, is expressed by the
following formula :
fgea
v = *V T>d
where v is the velocity per second,
sq. mm. in area, is placed on the last joint of the finger.
Fig. 42S. Apparatus of Attached to this glass plate is a small scale pan on which
von Kxies for measuring weights are placed until the pressure is just sufficient to
capillary blood pressure. blanch the underlying skin. In using this method the
calculation of the capillary pressure is made as follows :
Supposing that the size of the glass plate is 4 sq. mm. and 1 grm. in the scale pan is
just sufficient to cause a change of colour in the skin, then
a weight of 1 grm. = 1 c.c. H,0 = 1000 c.mm. H 2
is present on an area of 4 sq. mm. The height of the column of water supported by
1 sq. mm. is therefore = 250 mm. H,0. The errors of this method are consider-
able, since the pressure thus determined is not the total capillary pressure, but this
minus the pressure in the tissue spaces on the outer side of the capillary wall. The
result will therefore vary not only with capillary pressure but also with the tension of
the skin and the amount of fluid in the tissue spaces.
The pressure in the capillaries as found by this method necessarily varies with the
THE FLOW OF BLOOD THROUGH THE ARTERIES 975
position of the part under investigation, i. e. with the hydrostatic pressure of the column
of blood between it and the heart. The following figures were found by von Kries :
Finger : Mm. H 2
Distance of finger
below head
328
329
513
73S
B
mm.
205 mm.
490 mm.
840 mm.
20 mm. Hg.
of Babbits : 33 nun. Hg.
Frog's Web (Roy) : 100-150 mm.
H.O.
Capillary venous pressure of brain (Hill) :
(1) Animal in horizontal position : 10 mm. Hg.
(2) ,, ,, feet-down position : zero or less.
(3) During strychnine convulsions : 50 mm. Hg.
Owing to the fact that a varying and unknown resistance — that of
the arterioles— lies between the capillaries and the arteries, the pressure in
the capillaries must stand in much closer relationship to that in the veins
than to that in the arteries. One cannot therefore argue that a fall of
arterial pressure necessarily involves a fall of capillary pressure in all parts
of the body. We can only judge of changes in the capillary pressure by
taking simultaneously the pressures in both the afferent and efferent
:1s. If these both rise or fall together -we may be certain thai the
capillary pressure also rises or falls. Where the arterial and venous
pressures move in opposite directions, it is difficult to say what alterations,
if any, will be produced in the capillary pressure.
The resistance to the flow of blood through the capillaries is determined
by the internal friction, i.e. the viscosity of the blood; this varies in
different animals between three and five times that of water. It has been
calculated that the fall of pressure undergone by the blood in passing
through any given capillary area is only about 20 to 60 nun. of blood, and
at the most is never more than 150 mm. blood, ('. e. about 10 nun. Hg. This
bears out the conclusion to which we have already come, viz. that the
chief seat of the resistance in the vascular system is in the arterioles, and
it is in this region that the chief fall of pressure occurs.
No part of the circulation however shows greater variations than the
capillary system. We must think of this as a vast irrigation system of
canals -the greater part of which are closed under normal circumstances.
and open only when t he chemical changes in the tissue require a large increase
in the supply of blood. In muscle the capacity of this irrigation system ma]
be increased 750 times during activity. A similar opening up of capillary
channels may be observed in the skin and connective tissues as a result of
irritation or injury. It seems probable that such changes will affect arterial
pressure by their influence on the total capacity of the vascular system (if of
wide enough occurrence) rather than by alterations thereby produced in
the peripheral resistance
SECTION VI
THE FLOW OF BLOOD IN THE VEINS
In the veins there is a constant decrement of pressure as we pass from the
periphery towards the heart. This decrement of pressure is the conse-
quence of the pumping action of the heart, so that the flow through the
veins must be ascribed to the same force as that which determines the
flow through the arteries, viz. the heart beat. Owing to the fact that no
appreciable resistance lies between the veins and the heart, the difference
of pressure necessary to maintain a constant flow through these vessels
is very small. Thus in the horizontal position the pressure in the femoral
veins may be from 5 to 10 mm. Hg., and in the inferior vena cava from
1 to 5 mm. The pressure in the great veins near the heart is generally
negative owing to the aspiration of the thorax, and this negative pressure
is naturally increased during inspiration. Opening the thorax therefore
causes a rise of pressure in all the large veins. In the latter the pressure
depends chiefly on the heart activity, being lowered by vigorous action
of the heart pump and raised when this fails irr any way. In the peri-
pheral veins the pressure is more dependent on the flow. through the corre-
sponding arteries. If an artery of a lirnb be ligatured, the pressure in the
small veins of the lirub sinks until it is reduced to the pressure in the nearest
large trunk in which a flow of blood continues.
Each cardiac cycle causes variations in the pressure in the great veins
next the heart in two ways :
(1) By the transmission along the veins of the alterations in the intra-
auricular pressure.
(2) By the diminution in the volume of the heart in consequence of the
expulsion of its blood along the arteries with each heart beat.
On this account the jugular veins show pulsations with each heart beat
which are somewhat complex in character and resemble closely those
occurring in the auricle (vide p. 946.) In Fig. 429 a tracing from the
wall of the jugular vein is given. It will be seen that each heart beat
gives rise to three variations in pressure within the veins. These three
undulations are evidently exactly analogous to those given in Fig. 410
as occurring in the auricular tracing. We should therefore regard a as the
auricular contraction, c as the elevation due to the closure of the auricilo-
ventricular valves, v as the elevation due to the accumulation of blood
in the auricles during the ventricular systole. The curve c is often spoken
976
THE FLOW OF BLOOD IN THE VEINS 977
of ae the carotid elevation, and has been ascribed by Mackenzie to direct
propagation to the jugular vein from the underlying carotid artery. He
has come to this conclusion because he has not found it in tracings of the
liver pulse hi cases of incompetent tricuspid valves. There is no doubt
however that the elevation cau be seen on tracings from the inferior vena
cava. The explanation of its absence from liver tracings is probably to
be ascribed to the fact that the great mass of the liver substance is unable
to transmit the very rapid oscillation of pressure due to the closure of
the auriculo-ventricular valves. These venous pulsations are much more
marked in cases of heart disease, where there is partial failure of the heart
pump and overfilling of the venous system, often combined with incom-
petence of the auriculo-ventricular valves.
Besides the favourable influences exercised on the circulation through
the veins by the aspiration of the thorax, a considerable part is played in
the venous circulation by the contraction of the muscles of the body as
well as by the passive movements of different parts. The adjuvant effect
Jug. V.
Rod. art.
Fio. 429. Venous pulse tracing from jugular vein compared with the
arterial pulse tracing from the radial artery.
of passive or active movement on the circulation through the veins is ren-
dered possible by the existence in these vessels of valves, which are semilunar
folds of the intima projecting into their lumen, and so arranged that they
allow the passage of blood only towards the heart. Two such valves are
as a rule situated opposite to each other. Every movement of a limb,
active or passive, causes an external pressure on the veins and therefore
empties them towards the heart. Thus in walking, each time the thigh is
moved backwards the femoral vein becomes empty and collapses, and fills
again as soon as the leg is brought forward to its former position or is flexed
in front of the body. When muscular movements become general, as in
walking or running, the active compression of the veins thus brought about
plays an important part- in hurrying the blood into the right heart, so that the
output of this organ is increased and the arterial blood pressure is raised.
Since the blood in the vessels is subject to the influence of gravity, we
should expect to find that the pressure in the veins of the foot was equal
to the pressure hi the veins, say, of the hand at the level of the heart plus
the pressure equivalent to the column of blood between these veins and
the heart, i.e. about a metre of blood. On measuring the pressure by
von Recklinghausen's or by Hill's method in these veins, this is not found
62
978 PHYSIOLOGY
to be the case. The pressure indeed in the veins of the Eoot is but little
higher than that in the veins of the hand. Von Recklinghausen found
that, after subtracting the distance between the l and the heart, the
pressure in the veins was negative by as much as 40 cm. In the same
way. as Hill has shown, the pressure in the capillaries of the foot is about
the same as in the capillaries of the hand. When a man assumes the
upright position, the arteries of the leg and foot contract until, under the
combined influence of the heart's contraction and gravity, the blood
supply to the capillaries is sufficient only to keep the pressure in these
vessels at a certain moderate height. The return of the blood from the
dependent parts cannot be ascribed to the heart beat a1 all. but is due to
the extrinsic mechanism of circulation through the veins, i.e. the contrac
tions of the muscles of the limb which press all the deep and superficial
veins, and in virtue of the valves force the blood contained therein by
Poupart's ligament into the abdomen. The fact that circulation through
the legs is dependent on the contractions of their muscles explains why
it is so difficult to stand still for any length of lime without moving, and
emphasises the need of moderate exercise for the maintenance of a normal
circulation.
SECTION VII
THE PULMONARY CIRCULATION
In the Lungs there is an extensive system of wide capillaries presenting
very little resistance to the flow of blood. The arterioles are wide and have
only a slight amount of muscular fibre in their walls, so that a slight pressure
suffices to drive the blood from the right to the left heart. The determina-
tion of the normal average pressure in the pulmonary artery presents con-
siderable difficulties, but it probably does not exceed 15 to 20 mm. Hg.,
i. e. about one-sixth of the mean aortic pressure.
The capillaries of the lungs may vary passively in size according to the
condition under which they may be placed. Thus, whereas at the height of
inspiration the blood contained in the lungs is about one-twelfth of the
whole blood in the body, this amount is diminished during expiration to
between one-fifteenth and one-eighteenth, and by forcible artificial inflation
of the lungs may be lessened to one-sixtieth. These changes exercise a
considerable effect on the systemic blood pressure and are largely responsible
for the respiratory variations observed therein. On the other hand, the
distensibility of the lung capillaries may play an important part in enabling
the lungs to act, so to speak, as a reservoir for the left side of the heart.
If, in consequence of raised arterial pressure or other factor, there is a
temporary excess of output on the right side that cannot be dealt with at
once by the left heart, the excess is taken up for a time in the lung
capillaries.
Ya so-motor fibres to the lung vessels have been described as running in
the anterior roots of the third, fourth, and fifth dorsal nerves. Their action
is however of little importance, and their very existence is questioned
by some observers. The fact, that injection of adrenaline causes some vaso-
constriction in the lungs, points to the presence of a vaso-motor sympathetic
supply to those organs.
If we examine a tracing of the arterial blood pressure, we notice that it
presents certain periodic oscillations which accompany the movements of
respiration. With each inspiration the blood pressure rises; with each
expiration it falls. The synchronism of the rise and fall with the respiratory
movements is not exact, since the rise continues for a short time after the
beginning of expiration before it begins to fall, and the fall continues right
into the beginning of the next inspiration, so that the highest point of
the curve occurs at the beginning of expiration and the lowest point at the
beginning of inspiration. During the fall which accompanies expiration the
heart beats may become less frequent. This change of rate is marked in
the dog, but is by no means constant in man. On dividing both vagi,
979
980 PHYSIOLOGY
this difference in the pulse rate during inspiration and expiration disappears,
but the main features of the blood pressure curve remain the same; so thai we
must look for some mechanical explanation of the respiratory undulations.
We have already seen thai under normal conditions the lungs arc in a
state of over-distension, and that in consequence of this condition they arc
c stantly tending to collapse, and are therefore exerting a pull on the chesl
wall. As soon as we admit air into the pleural cavity by perioral ing the chest
wall, the kings collapse. The force with which the lungs tend to collapse
amounts to 6 mm. Hg. at the end of a quiet expiration, so we say that in the
pleura] cavity there is normally a negative pressure of G mm. Hg. As the
chest expands in inspiration it drags the lungs still more open. As these
become more distended, their pull on the chest wall becomes greater, and
hence the negative pressure iir the pleura may be increased during forcible
inspiration to 30 mm. Hg. It must be remembered that the heart and great
veins and arteries are in the thorax separated from the pleural cavity only
by a thin yielding membrane, so that they are practically exposed to any
pressure, positive or negative, which may exist, in the pleural cavity. Hence
even at the end of inspiration the heart and large vessels are subjected to a
negative pressure of 6 mm. Hg. Outside the thorax all the vessels are
exposed to a positive pressure, conditioned in the neck by the elasticity
of the tissues and in the abdomen by the contractions of the diaphragm
and abdominal muscles.
Blood, like any other fluid, will always flow from a point of higher to
a point of lower pressure. There must thus be a constant aspiration of blood
from peripheral parts into the thorax. This aspiratory force will not
influence arteries and veins alike. The arteries, having thick, comparatively
nou-distensible walls, will be very little affected by the negative pressure
obtaining in the thoracic cavity, whereas the thin-walled distensible veins
will be largely influenced by the same factor. The total result then of the
negative pressure in the pleural cavities is to increase the flow of blood from
the veins into the heart without affecting to any appreciable degree the
outflow of blood from the heart into the arteries. The more pronounced the
negative pressure in the thorax, the greater will be the amount of blood
sucked into the heart from the veins. During inspiration therefore the
heart will be better supplied with blood than during expiration, and this
factor in itself will tend to raise the arterial blood pressure. The inspiratory
descent of the diaphragm wall moreover tend to increase the inflow into the
heart by raising the positive pressure in the abdomen, so that blood is pressed
out of the abdominal veins and sucked into the heart and the thoracic veins.
Another factor which must play some part is the influence of the respiratory move-
ments on the circulation through the lungs. In trying to understand this influence, it
must be remembered that the pulmonary capillaries lie in a certain amount of elastic
and connective tissue and are separated, on the one side by the alveolar epithelium
from air at the ordinary atmospheric pressure, and on the other by the pleural endothe-
lium from the pleural cavity, where the pressure varies from 6 to 30 mm. Hg. below
the atmospheric pressure. We may therefore consider the pulmonary capillaries as
lying between, and attached to, two concentric elastic bags, Under normal conditions,
THE PULMONARY CIRCULATION 981
since these bags are always tending to collapse, the inner one must be pulling away from
the outer one. and the outer one from the chest wall. Hence there must be a negative
pressure in the tissues between these two bags — a negative pressure which in the expira-
tory condition will be something between and - 6 mm. Hg., and in the inspiratory
condition between and - 30 mm. Hg. H we regard the average pressure within
the pulmonary capillaries as constant, these capillaries must be more dilated in the
inspiratory than in the expiratory condition. This dilatation of the pulmonary capil-
laries will have two effects. Their capacity will be increased and the resistance they
present to the flow of blood will be diminished.
Let us now consider what effect these changes will have on the general arterial
blood pressure. We will assume that during expiration the pulmonary vessels have
a capacity of 25 c.c. and that the beat of the right heart is forcing through them 10 c.c.
of blood per second. So long as the chest remains in the expiratory condition 10 c.c.
of blood will be flowing into the left heart and into the aorta, so that the systemic blood
pressure will remain constant. Now let us suppose that an inspiratory enlarge-
ment of the thorax takes place, the negative pressure in the pleura is increased, the two
walls of the lungs are pulled farther away from one another, and there is a general enlarge-
ment of the pulmonary capillaries. We will assume that this enlargement increases the
capacity of the pulmonary capillaries from 25 to 30 c.c. Owing to this increased capacity,
the first 5 c.c. of blood which flows into the lungs after the beginning of inspiration will
not flow out through the pulmonary vein, but will simply serve to bring the capillaries
into the same state of distension as before. Hence at tlie beginning of inspiration the
flow through the pulmonary vein will be diminished; there will be less blood discharged
into the left heart, and therefore a fall in systemic pressure. As soon however as the
increased capacity of the pulmonary vessels is made up, the dilating effect of the inspira-
tory movement of these vessels wiil aid the flow through the lungs, in consequence of
the diminution of resistance, so that the same force of the right heart which drove 10 c.c.
of blood per second through the former resistance during expiration will now drive
more, say 12 c.c. of blood. There is thus more blood entering the left heart, and there-
fore a rise of systemic pressure during the last three-quarters of the inspiratory move-
ment. Expiration will have exactly the reverse effect. At the beginning of expiration
there is a diminution of capacity in the pulmonary vessels from 30 to 25 c.c. Hence
daring (lie first second of expiration the outflow of blood from the pulmonary vein into
the left heart will be 17 c.c. (12 c.c. + 5 c.c). After this, the increased resistance in
the pulmonary capillaries in consequence of their constriction will come into play, and
the flow of blood through them will fall once more from 12 c.c. to 10 c.c. Hence at the
beginning of expiration the inflow of blood from the pulmonary vein into the left heart
is greater than at any period. The arterial pressure will therefore rise to its greatest.
height at the beginning of expiration, and will fall during the last three-quarters of
expiration, but will attain its minimum only at the beginning of the next inspiration.
Li this way the effect of tin 1 respiratory movements on the systemic
blood pressure could be entirely explained by the influence they exert on
the lung vessels or lesser circulation. On the other hand, Lewis regards the
pericardial pressure, i. e. the direct influence of the thoracic movements on the
heart, as playing a much more important part than changes in the pulmonary
circulation in the production of the respiratory undulations in the M >od
pressure. Ee shows moreover that in man the effect of respiration on
J blood pressure may vary according to the type of respiratory
movement, a deep intercostal inspiration (not prolonged) causing a pure
fall, while a deep diaphragmatic inspiration gives a pure rise of blood
pressure. In expiration the reverse effects hold. He concludes that in
man it is not possible to make any general statement as to the nature of
the blood pressure response to a particular respiratory act.
SECTION VIII
THE CAUSATION OF THE HEART BEAT
If the heart be cut out of the body of a cold-blooded animal, such as the
frog or tortoise, it will continue to beat with the normal sequence of its
different chambers for hours, or even days, provided that it be kept cool and
moist. In the case of a warm-blooded animal, the heart is similarly capable
of continuing its rhythmic contractions for some little time after excision.
The period of survival of the heart is less in warm-blooded than in cold-
blooded animals. The fact that in both cases the heart will continue to beat
after removal from all its connections with the central nervous system, and
when blood is no longer flowing through it, shows that the causation of the
heart beat is to be sought in the walls of the heart itself.
The heart wall consists of a muscular tissue resembling in many respects
voluntary muscle ; like this, it presents longitudinal and transverse striations ;
like this, it is capable of contracting in response to direct stimulation.
Normally voluntary muscle contracts only in response to impulses from the
central nervous system. When Remak described the existence of collections
of ganglion cells in the sinus venosus, it was natural that physiologists should
ascribe to these collections of nerve cells the same automatic rhythmic
functions that had been found by Flourens and others to be associated with
the grey matter of the medulla oblongata in connection with the maintenance
of the respiratory movements.
ANATOMY OF THE FROG'S HEART
The hearts of the frog and of the tortoise have figured so largely in the researches on
the causation of the heart beat that it may be profitable to mention briefly the main
points of their anatomy.
The frog's heart consists of the sinus venosus, which receives the anterior and
posterior venae cava?, two auricles, one ventricle, and the bulbus arteriosus, which opens
into the two aorta?. The venous blood from the body flows into the sinus venosus by
the three venae cavae, and thenoe into the right auricle, while the left auricle receives
the blood from the lungs. The ventricle thus receives mixed arterial and venous
blood, the arterial blood being directed by the spiral valve of the bulbus aortas so
as to flow chiefly towards the head.
The muscular fibres of the heart are less highly developed than those of the mamma-
lian heart. They are spindle-shaped, and only dimly cross-striated. The cross-striation
becomes more distinctly marked as we proceed from sinus to ventricle, the sinus muscle
fibre representing the most primitive condition. There is complete muscular con-
tinuity between all the cavities of the heart. The circular ring of muscle at the junction
of sinus with auricles and of auricles with ventricles presents only slight traces of cross-
striation (Gaskell).
The heart is well supplied with nerve fibres and ganglion cells. The two vagi enter
982
THE CAUSATION OF THE HEART BEAT
983
the sinus venosus and branch just under the pericardium. Here they become con-
nected with a collection of nerve cells, known as Remak's ganglion. From the sinus
the two vagi, now called septal nerves, pass down in the interauricular septum, one in
front and the other behind. Near the auriculo-ventricular groove they enter two collec-
tions of ganglion cells, called Bidder's ganglia. From these ganglia non-medullated
fibres are distributed to surrounding parts of the auricle and to the whole of the ventricle.
In the upper third of the ventricle occur scattered ganglion cells attached to the nerve
These are quite absent in the lower half or two-thirds.
In the tortoise (Fig. 431) the two auricles are bound together by a flat band of
t issue, which serves also to connect the sinus with the ventricle. The septum between
Fro. 430. Diagram of frog's heart. (After
Cyon.)
v. ventricle: E.A, L.A, right and left auricles
(atrium); s.V, sinus venosus; P. v. pulmonary
veins; L.v.c.s and R.v.c.s. left and right su-
perior vena cava; v.c.i, vena cava inferior;
tt.a, truneus arteriosus.
Fio. 431, Tortoise's heart (after
Gaskell) as it appears when sus-
pended for registering the auricu-
lar and ventricular contractions.
N, nerve-trunk with fibres con-
necting Remak's and Bidder's
ganglia ; cob. V, coronary vein.
the auricles arises from the central line of this junction wall. The two vagus nerves
nlo a large accumulation of ganglion cells in the sinus, and thence along the basal
wa 11 to the auriculo-ventricular groove, lying just under the pericardium. In the groove
i hey pass into a collection of ganglion cells, whence fibres are given off to both auricles
and ventricle. As they leave the sinus, a branch is always given off by the right nerve
■ nipany the coronary vein, which conveys blood from the ventricular wall to the
Thus the nerves of the tortoise's heart are altogether more accessible than those
of (lie frog's heart. In other points the tortoise's heart is similar to the frog's heart,
i < msiderably larger.
THE AUTOMATIC CONTRACTION OF THE FROG'S HEART
The frog's heart in the body, or when removed from the body intact,
beats regularly, the contraction starting in the sinus, then travelling to
auricles, ventricle, and bulbus. If however the heart be removed by
cutting it across the sino-auricular junction, or if the auricles be functionally
separated from the sinus by a ligature round this junction (Stannius' liga-
ture), the auricles and ventricle stop in an uncontracted condition (diastole),
while the sinus goes on boating regularly. After the lapse of a period varying
from five minutes to half an hour, the detached part of the heart begins to
beat, at first slowly and then more rapidly, but never attaining the rate of the
sinus. The auricles beat first, and then the ventricle. If now the ventricle
be cut away by ait incision in the auriculo-ventricular groove from the auricles,
the latter go on beating; while the former, after a few beats due to the
excitation of the incision, stops beating, and only after a considerable time
may begin again to contract very slowly.
On the other hand, a ventricle-apex preparation (that is to say, the lower
984 PHYSIOLOGY
two-thirds of the ventricle separated functionally from the rest of tln v heart),
never beats again under normal circumstances. To single stimuli it responds
with a single beat, not with a series of beats as the whole heart does. If the
lower third of the ventricle be separated functionally in the living frog by
crushing the ring of tissue between it and the upper third, it never gives a
spontaneous beat again, although it is under the most normal conditions pos-
sible in the circumstances. There is thus a descending scale of automatic
power in the different parts of the frog's heart — from the sinus, where it
• is highest, to the lower parts of the ventricle, where it is apparently absent.
From this fact it has been thought that the automaticity of the
frog's heart is dependent on the ganglia present in it. The contraction was
supposed to be started by impulses proceeding from the sinus ganglion.
If this were cut off, Bidder's ganglia or the scattered cells in the upper
third of the ventricle could, it was thought, take up its task of originating
impulses. The muscle cells under this hypothesis act as the servants of the
ganglion cells", just as the voluntary muscles wait on the commands of the
cells in the spinal cord and brain.
The view that the ganglion cell sends out rhythmic impulses had how-
ever to be discarded when it was discovered that the muscle forming the
lower third of the ventricle either of the frog or the tortoise, though free from
ganglion cells, could be excited by various means to rhythmic contractions.
Thus it could be set into rhythmic action when supplied with salt solution
under pressure through a perfusion cannula, or when excited by the passage
of a constant current or of weak induction shocks. The fact that the heart
muscle responded to continuous stimulation by a rhythmic discharge sug-
gested that the function of the ganglion cells was to furnish a constant
stimulation to the muscle cells and so maintain these hi rhythmic activity.
The theory of the ganglionic origin of the cardiac rhythm was seriously
affected by a series of researches carried out by Gaskell and by Engelmann.
The arguments against the ' neurogenic ' hypothesis may be summarised
as follows :
(a) The cardiac muscle, free from any ganglion cells whatsoever, can be
excited by various means to rhythmic contraction. When, in the living frog,
the apex of the ventricle is crushed off from the base so as to leave only
material continuity between the two parts, the circulation of the blood is
maintained by the contraction of all the parts of the heart except the apex,
which never resumes its activity. If however the intraventricular pressure
be raised by clamping the aorta, the apex begins to beat at its own rhythm,
which is independent of the rhythm of the rest of the heart. Moreover a.
strip free from ganglion cells can be cut from the apex of the tortoise's
ventricle (Fig. 432) which, on keeping in a moist chamber and moistening
occasionally with normal salt solution, enters into rhythmic contractions.
(b) In the frog it is possible to excise the interauricular septum with
its ganglia, and a considerable portion of the ganglia in the sinus venosus and
at the base of the ventricles, without interfering in any way with the cardiac
rhythm. This experiment is still easier to carry out in the tortoise's heart
THE CAUSATION OF THE HEART BEAT
985
where the nerves and ganglia run in the basal portion of the auricles. This
can be excised, leaving the two auricular appendages in connection with the
sinus venosus and with the ventricles.
(c) The heart in the developing chick can be seen beating at a time when
it is quite free from nerve cells, which only extend into it at a later date.
(d) Remak's ganglia are situated at the point where the two vagus nerves
enter the heart, and under the microscope can be seen to be connected with
the fibres of these nerves. We have now, from the discovery of Langley and
Dickinson, a means of judging of the action of ganglion cells in the drug
nicotine, which first stimulates and then paralyses nerve cells themselves,
or the synapses between the cells
and the nerve fibres in connection
with them. Direct application
of nicotine to the heart, after a
primary period of slowing, leaves
the heart beat practically iui--4
altered, the normal sequence of
beat in the various cavities being
unaffected. After the application
of the drug however, stimulation
of the trunk of the vagus is with-
out effect, though slowing or stop-
page of the heart may still be
produced by excitation of the
post-ganglionic nerve fibres of
the vagus, which arise from the
cells of Remak's ganglia. These
iglia must therefore be re-
garded not as a motor centre for
the heart, but merely as a distri-
buting centre for the inhibitory
fibres of the vagus. Since tetani-
sation of the heart with weak currents also causes local inhibition, it would
seem that the finer nerve fibres ramifying throughout 1 he muscular substance,
are, to a large extent at all events, inhibitory in their function. This is
confirmed by the fact that atropine, which paralyses the inhibitory fibres
of the vagus, also abolishes the direct inhibitory effect of tetanisation on the
heart muscle. Gaskell and Engelmann therefore came to the conclusion
that the source of the cardiac rhythm was to be found, not in the ganglia
scattered about its cavities, but in the muscular cells themselves.
The normal sequence of events— i. e. the subordination of the ventricle to
auricles and auricles to sinus so that the beal always follows in the order,
sinus, auricles, ventricle, bulbus— can be ascribed to the difference be
the natural rhythms of these different cavities. It is possible to record the
contractions of each of these parts of the heart separately, after having divided
them either functionally by crushing the intervening tissue or by actual
Fig. 432. Tortoise's heart from dorsal surface.
(Gaskell.)
S, simis; J, sino-auricular junction; A, auri-
cles; C, coronary vein; V, ventricle (The
dotted line shows how a strip may be cut from
the ventricle apex.)
98G
PHYSIOLOGY
section. Under such conditions it, is found that there is a descending scale
of rhythm from sinus to bulbus, the contractions of the sinus being most
frequent, those of the ventricle and bulbus the least frequent. Thus it is
impossible for the ventricle to beat at its own rhythm, since before it is ready
to beat again after performing one beat, it receives an impulse from the
auricles causing an excited beat. That the normal sequence of contractions
is dependent simply on the natural rhythm of the sinus is shown by the fact
that, by exciting the ventricle by means of induction shocks repeated at a
rhythm slightly quicker than that of the sinus.it is possible to excite a reversed
rhythm, the order of the beat being now ventricle, auricles, sinus venosus.
The dependence of the ven-
tricular rhythm on the beat of the
sinus may be shown by a simple
experiment. The ventricle is con-
nected with a lever suspended by
a spring so as to record its con-
tractions on a dram. A platinum
loop connected with a galvanic
battery is put round the heart,
K either round the sinus or round
the ventricle (Fig. 433). When
a current is allowed to pass
through the inner loop, the
corresponding part of the heart
is warmed. When ' the ventricle
alone is warmed, the beats be-
come larger, but the rhythm is
Fig. 433. unaltered. On lowering the loop
so as to warm the sinus, the
rhythm of the whole heart is quickened, but the size of the ventricular
beats is unaffected. The different rhythmic power of these parts of the
heart, is apparently connected with the histological characters of the
muscle fibres at each part. The lowly differentiated sinus cell has well-
marked rhythmic power and a quick rhythm of beat, but is not able to
exert such force in its contraction. The more highly differentiated
ventricle cell has only a slight rhythmic power, but beats forcibly and
is a good servant of the sinus.
THE PROPAGATION OF THE WAVE OF CONTRACTION
The normal contraction started in the sinus venosus is propagated to the
auricles, thence to the ventricle, and thence to the bulbus aortae. Between
the contractions of each of these cavities there is a slight pause, whereas
the contraction spreads so rapidly over each cavity that all parts, say of the
auricles or ventricle, appear to contract simultaneously. It is obvious that
the excitatory wave might be propagated through the heart from one
THE CAUSATION OF THE HEART BEAT
987
muscle cell to another, or by means of nerve fibres which would excite the
muscular tissue of each cavity to contract.
The distinct pause which intervenes between the contractions of auricles
and ventricle was long regarded as evidence for the nervous character of the
contraction, and as showing the operation of a nerve centre in the co-
ordination of the contractions of different cavities. A contraction wave
may however be started at any part of the heart and may travel from this
to all other parts. Thus, although the normal direction of the contractions
is from sinus to ventricle, it is possible, by stimulating the apex of the
ventricle, to excite contractions in the reverse order, viz. from ventricle to
sinus. Such a fact is at variance with all our present knowledge of excitation
1
Fig. 434. Heart of tortoise ■p-ith auricle slit up so as to cause a partial
block. (Gaskell.)
of motor nerves. Excitation of the nerve going to the sartorius, or of any part
of the nerve, may excite contractions of all the fibres of which the muscle
is composed. On the other hand, excitation of a part of the muscle which
is free from nerve fibres causes a contraction which is limited to the muscle
fibres directly excited and does not extend to the nerves. If motor nerves
arose from the hypothetical motor ganghon of the heart and passed to the
ventricular muscle, one would not expect that contraction of the ventricular
muscle could excite these nerves and so cause the propagation of a wave of
contraction in the reverse direction.
That the propagation cannot be due to any nerve trunks running from
sinus to ventricle is shown by various experiments of Engebnann and
Gaskell. Thus, if the auricle is slit up by a series of interdigitating cuts, 1 he
contraction wave starting from the sinus travels along the auricular muscle
iiound the end of each section and finally, on arrival at the ventricle,
causes a contraction of this cavity. In the heart of the tortoise the nerve
trunks run, not in the interauricular septum, but in a band of tissue joining
the sinus to the ventricle; this hand can be exercised with all its contained
988' PHYSIOLOGY
nerves without interfering in any way with the normal sequence of contrac-
tions. Moreover the pause observed between the contractions of auricles
and ventricles has been shown by Gaskell to be due to the retardation of the
excitatory wave which occurs in its propagation through the muscular
tissue in the auriculo-ventricular junction. A similar retardation of the
wave can be produced at any point either in auricles or ventricle by diminish-
ing the conducting muscular tissue to a sufficiently small extent. Thus,
if the auricle of the tortoise be divided as in the diagram (Fig. 434), it will
be noticed that the sinus first contracts, then the auricular half As: a
distinct pause then occurs while the contractile process is passing over the
' bridge,' and finally Av contracts, followed by the
ventricle. The apparent pause between the contrac-
tion of the auricles and ventricle is due therefore to
a partial ' block ' at the auriculo-ventricular junc-
tion. If the block be increased in the experiment
just quoted, as, for instance, by allowing the bridge
of tissue to dry or by making it still narrower, it may
be found that only one out of every two contractions
passes across the bridge (Fig. 435), and the slightest
Fig. 435. Contraction increase in the resistance to the propagation of the
or auricles and ventn- .
cle of tortoise hoart. wave may lead to the block becoming complete. On
The aimculo-ventricu- mo istening the bridge again every contraction may
lar groove has been ° ° D J J
clamped so as to pro- be seen to pass.
fSo^g V *X e b v°ej B Y the methylene-blue method it is possible to
second contraction to demonstrate a close network of non-medullated fibres
pass. (Gaskell.) surrounding all the muscle cells of the heart. It is
obvious that the experiment just quoted would not
exclude the possibility of propagation occurring through such a nerve
network. The properties of the network would have to differ from those
of any of the nerve tissues with which we are acquainted ; whereas we know
that under certain circumstances impulses may be transmitted from fibre to
fibre, even in striated muscle, and such a mode of propagation is the most
obvious explanation of the phenomena observed in the heart.
If the auricles be soaked for some time in distilled water, they enter into
a condition of what is known as water-rigor (Wasserstarre). In this con-
dition they are incapable of contracting, but can still propagate the wave from
sinus to ventricle. This experiment has been regarded as a demonstration
of the part taken by nerve fibres in the propagation of the wave, but such
an explanation is not necessary, since a similar condition of water-rigor in a
voluntary muscle fibre has been shown to allow the passage of an excitatory
wave through the affected part to the normal portion of the muscle, which
then responds by a contraction.
A series of interesting researches by Carlson on the mechanism of the heart beat in
tin- king-crab Limulus' h&B been thought to throw light on the vexed question of the
automatism of the vertebrate heart.
In Limulus the heart forms a segmented tube of ordinary striated muscular fibres.
In large specimens the tube may be from 10 to 15 cm. long and 2 to 2i cm. broad.
THE CAUSATION OF THE HEART BEAT
08'J
Like the lie-arts of most other invertebrates and of all vertebrates, it has a local system
of ganglion cells, but so situated that they can be cut away entirely from the muscular
portions of the organ. The arrangement of the cardiac nervous system in Limulus is
shown in Fig. 436.
The ganglion cells are collected chiefly in a dorsal nerve ganglion cord which runs
almost the whole length of the heart. Prom this cord non-mcdullated nerve fibres pass
directly into the substance of the heart, and also send branches to two lateral nerve
trunks, by which fibres are distributed to all parts of the heart.
The heart normally contracts about forty times per minute. Each contraction
affects all parts practically simultaneously, though in the dying heart the posterior
portions apparently contract slightly before the anterior, and may continue to contract
after the anterior end has come to a standstill.
os mnc In la'
l-'io. 430. Heart of Limulus from dorsal surface. (Carlson.)
mnc, median nerve cord; In, lateral nerve trunks.
Division of the muscular tissue leaving the nerve strands intact does not alter in
any way the synchronism of contraction of the two ends of the heart. Division of the
nervous cord into two parts, the section being carried between the posterior third and
anterior two-thirds, causes complete lack of co-ordination between the two ends; both
ends of the heart continue to contract, but at different rhythms. Extirpation of the"'
nerve cord abolishes spontaneous contractions. If the anterior half of the dorsal
ganglionic cord be excised, all parts of the heart will continue to contract in unison.
If now the lateral nerve trunks be divided, the anterior half of the heart ceases to con-
tract, showing that it was being excited by impulses arising in the posterior part of the
Fig. 437. ' Nerve-muscle preparation ' of heart of Limulus consisting of the muscle
of the two anterior segments, with the two lateral norves. (Caklson.)
ganglionic cord. It is possible therefore to make a nerve-muscle preparation of the
anterior part of the heart, consisting of the muscle of the first two segments with a
longer stretch of the lateral nerves (Fig. 437). Stimulation of the lateral nerves with
a single shock causes a single beat of the anterior segments ; tetanising shocks cause
a continued contraction of the muscle preparation.
There seems to be no doubt that in this animal the beat of the heart is originated
and co-ordinated by the action of the local ganglionic centres. Moreover Carlson has
Shown that the inhibitory nerve to the heart acts, not by direct influence on the muscle-
fibres, but by an inhibition of the automatic activity of the ganglionic cells, thus con-
tinuing for this special case the general view of inhibition long ago put forward by
Morat, hut not now generally accepted.
The heart muscle does not show a refractory period, but on din nutation with
repeated shocks there may bo a summation of contractions, which maj fuse to a com-
plete tetanus. The question naturally arises how far the heart of Limulus is to be
990 PHYSIOLOGY
regarded as a special ca le, or how far we may transfer results gained from experience
on this heart to those of other hearts in which a perfect separation between ganglion
cells and muscle fibres is ao1 so easily attainable. Carlson has sought to show the
applicability of his results to the explanation of the cardiac mechanism in vertebrate
by a series of observations on other invertebrates' hearts, where the muscular ami
nervous tissues are not so ea ib di ociable. Such hearts present phenomena verj
analogous to those of the frog's heart. According to him the phenomenon of the
refractory period, the ' all or none ' law of contraction, and the absence of tetanus in
the heart of the frog is due, not to the peculiar functions of the muscle fibres, hut to
the fact that in all our experiments we are affecting muscular and nervous tissues
simultaneously.
In the absence of more perfect knowledge of the properties of the nerve nets which
surround involuntary and cardiac muscle fibres, a decision of the point is not yet possible.
The muscle and nerve fibres of Limulus show however important differences from the
cardiac muscle of the frog in their reaction to chemical stimuli. Acceptation of the
neurogenic theory would necessitate the predication of a type of nervous tissue endowed
with properties for which we have no analogy in any of the nerve tissues which have
been the subject of exact investigation, whereas the myogenic theory ascribes only to
t he muscle cells of the heart properties which are the common attribute of all protoplasm
or arc displayed in a less marked degree by the ordinary skeletal muscle fibres. It
would, at any rate, be premature to transfer unreservedly all the results obtained on'
the heart of the Limulus, the muscle fibres of which have the structure and behaviour'
of skeletal muscle fibres; to the explanation of the phenomena exhibited by the hearts
of vertebrates.
THE HEART BEAT AS A WAVE OF CONTRACTION
If the beat of the frog's ventricle, or a strip of mammalian ventricle, be
recorded, the curve obtained resembles closely the twitch of a voluntary-
muscle produced in response to a single excitation. Whereas however a
single contraction with the subsequent relaxation of voluntary muscle lasts
only about one-tenth of a second, the contraction of the mammalian ventri-
cular muscle lasts three-tenths of a second, of the frog's ventricle about
half a second, and of the tortoise ventricle about two seconds. 1 In the heart,
as in a voluntary muscle fibre, the contractile process originates at the
stimulated point and travels thence to all other points.
The progress of the excitatory wave is well seen if a record be taken of the
electrical changes resulting in the frog's heart from a single stimulation. If
the two ends of a strip of ventricular muscle be connected with the two
terminals of a capillary electrometer, stimulation at one end causes a diphasic
variation, showing that the excitatory process starts at the stimulated end
and travels to the other end of the heart. Thus if the acid of the electro-
meter be connected with the base of the ventricle and the mercury of the
capillary be connected with the apex, stimulation at the base causes a wave
passing from base to apex. Directly after the stimulation therefore the base
becomes negative and the column of mercury moves towards the acid;
a moment later the contraction extends to the apex. All parts of the
heart are now in a similar condition of excitation : there is no difference of
potential between the two terminals, and the mercury comes back quickly
1 The duration of the contraction depends on the temperature. The figures given j
are for the mammalian heart at 37° C. and for the amphibian heart at about 15° C.
THE CAUSATION OF THE HEART BEAT
991
to the base line. Relaxation, like contraction, starts first at the base
and proceeds thence to the apex. There is thus a small period during
which the apex is still contracted while the base is relaxed and the apex
is therefore negative to the base. This terminal negativity of the apex
is shown on the capillary electrometer by the excursion of the column
of mercury away from the point of the capillary (cp. Fig. 87, p. 231).
Analogous effects are obtained on leading off the spontaneously
beating heart in the frog or tortoise (Fig. 438). The conditions are
however rather more complex, and the most usual variation, as Gotch
has shown, is triphasic. In its most primitive form the vertebrate heart
is composed of a simple tube, in which a contraction starts at the venous
end and is propagated in a wave-like maimer along the tube to the
■
■ -
■ i i
t (1
"5
^
Auricle'
HVcntriclt
mm
Fig. 43S. Electrometer record of variation of spontaneously beating tortoise
heart. (Gotch.)
arterial end. In the higher vertebrates the heart at its first appear-
mie tubular form, but the simple tube very rapidly
becomes modified, partly by twisting on itself, partly by the outgrowth
of the dorsal or the ventral wall of the tube to form the cavities of the
auricle and ventricle. Gotch suggests that the excitatory process follows
the course of the original tube, and that the typical form of the curve
is due to the base becoming excited twice, first at the part in con-
tinuity with the auricle, and secondly when the wave sweeps up to
the bulbus aorta;. But it is possible that in the cold-blooded as in
the mammalian heart, there may be a special conducting tissue which
leads the excitatory process to many different parts of the ventricle
almost simultaneously.
There is no doubt that the ventricular systole is comparable with a
simple muscular twitch and cannot be regarded as the summation of several
contractions. Since the excitatory process extends in the form of a wave
992 PHYSIOLOGY
not only to all parts of the same cavity but to all parts of the heart, it is
evident that the musculature of the heart is to be compared, not with skeletal
muscle composed of many fibres, but to a single muscle fibre in which all
parts are in functional continuity.
THE BEAT OF THE MAMMALIAN HEART
The mammalian heart, like the heart of cold-blooded animals, will beat
for some time after it has been cut out of the body, and a perfectly rhythmic
acl ivity may be maintained for hours by feeding the heart from the coronary
arteries either with defibrinated blood or with oxygenated Ringer's solution,
with or without the addition of glucose.
Ganglion cells are found in the mammalian heart around the openings of the great
veins, along the border of the interauricular septum, in the groove between auricles
and ventricles, and in the basal parts of the ventricles.
The ventricles of mammals are endowed with a greater rhythmic power
than the corresponding cavities in the frog and tortoise. It is possible to
sever or crush all the nervous and muscular connections between auricles and
ventricles without destroying their mechanical connection by means of fibrous
tissue. Such a procedure does not, even for a moment, stop the contractions
of the ventricles, which go on beating at a rhythm which is independent of and
slower than that of the auricles. Porter has shown that a mere fragment
of the ventricular wall, perfectly free from ganglion cells, may maintain
rhythmic contractions for some hours if fed by an artificial circulation through
a branch of the coronary artery. We may therefore conclude that in the
mammalian as in the amphibian heart, the cause of the rhythm is to be
sought in the properties of the muscle fibres themselves, and that every part
of the heart muscle possesses the power of rhythmic activity, the normal
sequence of the beats being determined by the greater frequency of the
natural rhythm of the venous end of the heart.
In the mammalian as in the amphibian heart, the excitatory condition
started at one point in the muscle spreads through the muscle in all directions,
and the process of conduction of excitation seems to be independent of nerve
fibres. The excitatory process may be conducted not only in the ordinary
direction from auricles to ventricles, but also from ventricles to auricles.
If the ventricles be excited at a rhythm of higher frequency than the natural
beat which is starting at the venous end of the heart, we may obtain a
reversed rhythm in which the order of the beats is ventricles — auricles.
It is difficult to conceive of an arrangement of neurons which would propa-
gate impulses impartially from auricles to ventricles or from ventricles to
auricles. Such a condition would seem to be in contradiction to the law
of forward direction which obtains throughout the nervous system. On the
other hand the phenomena are easily explained on the assumption that the
whole of the musculature of the heart acts in many respects as a single
muscle fibre, along which an excitatory process may be propagated in any
direction. But in the adult mammalian heart, on superficial dissection,
THE CAUSATION OF THE HEART BEAT
993
the muscle fibres both, of auricles and ventricles are seen to arise from a fibro-
cartilaginous ring surrounding the auriculo-ventricular junction, leaving
apparently no muscular continuity between the two cavities. On this
account it was thought for many years that the propagation of the contrac-
tion from auricles to ventricles must
occur by means of nerve fibres, and
it was only with the discovery by
His of a distinct band of modified
muscle fibres, passing from the auri-
cles to the ventricles, the ' auriculo-
ventricular bundle,' that an anato-
mical basis was furnished for the
physiological behaviour of the heart.
The heart is developed from a mus-
cular tube in which at the beginning
we must assume muscular continuity
throughout. The primitive vertebrate
heart is formed by a, modification of
this muscular tube. In this heart, as
Keith has shown, we may distinguish
five chambers, namely, the sinus
venosus, the auricular canal, the
auricle, the ventricle and the bulbus
(Fig. 439). The musculature of these
chambers is continuous throughout.
In the adult heart, e.g. of man, the
anatomical relations of the different
cavities have become considerably
modified in the course of develop-
ment. The sinus venosus, i. e. the
part where in the lower vertebrates the contraction wave takes its
origin, is now represented merely by the termination of the superior
vena cava and of the coronary sinus in the right auricle. These two
veins are derived from the right and left ducts of Cuvier in the embryo.
The sinus venosus is also represented by a small amount of tissue under-
lying the taenia terminalis of the right auricle, as well as by the remains
of the Eustachian and venous valves. The auricular canal gives rise
to the auricular septum and to the auricular ring surrounding the auricu-
lar-ventricular orifice, and in some hearts it is prolonged into the ventricle
as the intraventricular or invaginated part of the auricular canal. In the
adult heart two accumulations of more primitive tissue are found in the
region corresponding to the sinus venosus of the embryo, and these are known
as the sino-auricular node and the auriculo-ventricular node. The sino-
auricular node (Fig. 440) lies in the groove between the superior vena cava
and the right auricle. The auricular-ventricular node lies at the base of
the auricular septum on the right side, below and to the right of the opening
63
Fig. 439. A generalised type of
vertebrate heart. (Keith.)
o, sinus venosus ; b, auricular canal ;
c, auricle; d, ventricle; e, bulbus cordis;
/, aorta; 1-1, sino-auricular junction and
venous valves ; 2-2, canalo-auricular junc-
tion; 3—3, annular part of auricle; 4-4,
invaginated part of auricle; 5, bulbo-
ventricular junction.
994
PHYSIOLOGY
of the coronary sinus. From this point a bundle of muscular fibres (the
bundle of His or the auriculo-ventricular or A.V. bundle) runs along the top
of the interventricular septum just below its membranous part and then
divides into the right and left septal divisions, which pass down in each ven-
tricle on the interventricular septum into the papillary muscle arising IV
the septum. Each half of the bundle gives off several branches which break
up more and more, finally forming a reticulated sheet of tissue over the
greater part of the interior of the ventricles just below the endocardium.
The fibres composing this tissue are more primitive in character than the
rest of the cardiac musculature and have long been distinguished as the
Superior I'ena Cava .
Srnoaurici/farnodCi
Sulcus lirminalis
Auriculo - Vent.
'Biirnllv
Left Branch
Foramen Ovale.
Auriculo - Vent
~Li 0(l a
ComnarySim/s
Tricuspid Valve
Aorta
RtAppendix
I'k;. 440. Diagrammatic representation of course of A.V. bundle.
' fibres of Purkinje.' In them the fibrillation is confined to the periphery of
the muscle cell. They are distinguished by a high glycogen content. They
may be regarded as a part of the muscular wall of the heart specially -differen-
tiated for the rapid conduction of the excitatory process to all parts of the
ventricles (Figs. 441 and 442).
Numerous nerve fibres and ganglion cells are found to accompany the muscle fibres
of the auriculo-ventricular bundle. We have however no reasons for regarding the
nervous structures as concerned in the. propagation of the excitatory wave.
The auriculo-ventricular bundle forms the only continuous muscular
tissue between the auricles and ventricles, and destruction of it causes com-
plete abolition of the normal sequence of beat between auricles and ventricles.
By leading off different parts of the heart to the string galvanometer, it is
possible to determine the time relations of the excitatory process. It is
then found that the mass of Purkinje tissue, known as the sino-auricular
THE CAUSATION OF THE HEART BEAT
995
node, is the starting-point of the excitatory process concerned in each heart
beat. It is therefore spoken of as the ' pace-maker ' of the heart. At each
beat a contraction starts at the sino-auricular node, spreads a short way up
the great veins, and alone; the auricular muscle in all directions. When it
Fig. 441. Left ventricle, laid open to display the interventricular septum, on
which the course of the left division of the auriculo-vontricular bundle and
its ramifications are shown in black. (After Tawara.)
Fig. 442. Fibres of Purkinje, from the subendocardial network. (Tawaka.)
arrives at the auriculo-ventricular node, the impulse is carried on to the
ventricles along the auriculo-ventricular bundle, spreading along the branches
of this bundle to almost all parts of the ventricular muscle. Although
normally the sino-auricular node initiates each heart beat, this node can be
put out of action by injury or cooling without stopping the rhythmic
sequence of the heart beat, the office of pace-maker being now taken up by
996 PHYSIOLOGY
the auriculo-ventricular node. A specialisation of function accompanies
the differentiation in structure which we find in the auriculo-ventricular
bundle and its branches. Lewis has shown that the conduction of the
excitatory process along the auriculo-ventricular bundle of the Purkinje
tissue occurs about ten times as fast as the conduction through the ordinary
muscular tissue of the heart, the rates being about 5000 mm. and 500 mm.
per second respectively. Although all parts of the ventricles receive the
impulse to contraction almost simultaneously, the contraction wave, as
judged by the electrical changes, is found to commence slightly earlier at two
points, namely, on the anterior surface near the apex to the right of the
groove separating right and left ventricles, and at the extreme apex of the
heart where the endocardiac tissue comes very close to the surface. On
the other hand, the conus arteriosus is the last part of the heart to begin
contracting.
The limitation of the muscular continuity to a single narrow bundle, which is
endowed with greatly increased conducting powers and ends in a network of tissue
endowed with similar powers, is evidently designed (to use an old-fashioned but
convenient word) to ensure that all parts of the ventricles contract practically
simultaneously. If this were not the case, the sudden contraction of the muscle fibres
near the base of the ventricles would simply bulge out the still uncontracted portion
near the apex, and there would be a risk of injury or even rupture of the uncontracted
part of the ventricle under the stress of the pressure produced by the contracting part.
On the other hand, if all parts of the heart were endowed with a similar rapid power of
conduction, any part slightly more excitable or irritated than the rest, might serve as
a centre for emitting excitatory waves, wliich would interfere with those transmitted
from the auricles ; and the tendency to heart delirium would be enormously increased.
THE HUMAN ELECTROCARDIOGRAM
The passage of the excitatory wave over the different heart cavities is
associated with corresponding electrical changes resulting in differences of
potential. If we lead off any two parts of the heart's surface to a string
galvanometer or capillary electrometer, we obtain movements which are
caused, partly by changes occurring in the muscle just underlying the
electrode, partly by changes occurring at a distance and transmitted by the
intervening muscle acting simply as a moist conductor. These two kinds of
effect may be alluded to as direct and indirect. If we lead off, not from the
heart itself, but from neighbouring tissues in contact with the heart, we
shall still obtain the indirect effect of the electrical changes at each heart
beat, and these can be obtained, as Waller has shown, when the intact
animal is led off to the electrometer or galvanometer by his hmbs. In an
animal such as the dog the two fore hmbs may form one lead and the two
hind hmbs the other. In man, where the heart hes asymmetrically, it is
usual to lead off the right arm and left arm, the right arm and left leg, or the
left arm and left leg, the hand or foot being immersed in salt water con-
nected to the galvanometer by a zinc electrode contained in a porous pot full
of saturated zinc sulphate solution. By this means an electrocardiogram
is obtained similar to that shown in Fig. 443.
THE CAUSATION OF THE HEART BEAT
997
In view of the mechanism of the propagation of the excitatory wave
in the ventricle, we should not expect the cardiogram obtained in this
indirect fashion to be easy of interpretation, at any rate so far as regards
the course of the wave through the ventricular muscle. Such an electro-
Fiq. 44o. Electa
jlf frc
the two hands
,gram of man. obtained by leading
to a string galvanometer.
c is the carotid pulse tracing. The different parts of the curve are designated
by the letters P, Q, R, s, T, first applied to them by Einthoven.
cardiogram however is of considerable use clinically, especially for the
determination of the relation between the auricular and the ventricular con-
tractions. The different points in a typical tracing, such as that contained
in the figure, are designated by the letters p,. Q, R, s, t, which were first
applied to them by Einthoven and are retained because they do not involve
any theoretical interpretation of the curves. Of these p is certainly due to
Rod. art.
Fiq. 444. Simultaneous tracings of the jugular venous pulse and the radial arterial
pulse, from a case in which the A.V. bundle was destroyed by disease. The
contractions of the auricles are marked by the a waves on the venous pulse.
They are more rapid than and quite independent of the ventricular contractions.
(Mackenzie.)
the auricular contraction and Q marks the beginning of the ventricular
contraction. The A.V. interval is given by the distance between p and Q,
the total duration of the excitatory condition in the ventricle by the distance
between q and T.
The fibres of the auriculo-ventricular bundle may be destroyed by disease- In
such eases we get a series of phenomena known under the name of Stokes-Adams
disease, the main characteristic of which is the slow contractions of the ventricle, accom-
panied by a rapid venous pulse at a rhythm entirely independent of the ventricular
pulse. The automatic activities of auricle and ventricle are in fact dissociated (Fig. 444)
998 PHYSIOLOGY
At certain intervals or at certain stages of the disease, the fibres of the bundle may
present only a partial block, so that the ventricle responds once to every second con-
traction of the auricle. The existence of this disease is shown at once on the electro-
cardiogram by the dissociation of the normal relation between the auricular and
ventricular variations. It may be also shown by a study of the venous pulse (Fig- 444).
THE PHYSIOLOGICAL PROPERTIES OF THE CARDIAC MUSCLE
THE RESPONSE OF HEART MUSCLE TO DIRECT EXCITATION
When a skeletal muscle is directly stimulated with induction shocks of
varying strength, within narrow limits the height of the contraction is
proportional to the strength of the stimulus. If the frog's ventricle, rendered
motionless by a Stannius ligature, be stimulated with a single induction
shock, if it responds at all it will respond with a maximal contraction, no
change in the extent of the contraction being obtainable, however the stimu-
lus may be increased. There is thus no proportionality in the heart between
strength of stimulus and height of contraction. The heart, if it contracts
at all, always contracts to its utmost, the height of the contraction being
dependent, not on the strength of stimulus, but on other conditions affecting
the muscle at the time of its response.
Although much stress has been laid on this supposed difference between
heart muscle and voluntary muscle, a renewed investigation of the response
of the latter to graded stimuli by Gotch and by Keith Lucas tends to show
that the distinction is not so fundamental. According to these observers the
fact, that the response to a minimal stimulus in skeletal muscle is smaller than
the response to a maximal stimulus, is simply owing to the fact that in the
former case only a small proportion of the muscle fibres is active, so that
increasing the strength of the stimulus merely increases the number of fibres
thrown into contraction. According to this view therefore a maximal con-
traction of skeletal muscle would be one involving all the fibres. In the
heart muscle all the muscle fibres are functionally continuous, so that a stimu-
lus, if it excites at all, must excite all the fibres, and every contraction must
be analogous to the maximal contraction of a skeletal muscle. The existence
of the ' all or none ' law in any contractile tissue would be therefore
dependent on the existence of functional continuity between all the con-
tractile elements of the tissue.
Li the retractor penis of the dog it is possible to get graded contractions
with graded strength of stimuli, and in this case it is easy to observe that
with increasing strength of stimulus a greater extent of the muscle is thrown
into the contractile state. Closely connected with this maimer of response
is the fact that in heart muscle, under normal circumstances, it is not possible
to get summation of contractions by putting in a stimulus, however strong,
before the muscle has returned to rest. If however the propagation of the
first contraction throughout the heart muscle be retarded or prevented by a
partial death of the tissue, or by stimulus of the vagus nerve, it is possible,
as Frank has shown, to obtain an apparent summation of two stimuli, i. e.
a curve in which the second contraction is superposed on and rises higher
THE CAUSATION OF THE HEART BEAT 999
than the first. Such a result, on the explanation given above, would be due
to a phenomenon of ' block,' limiti ng the propagation of the first contractile
wave and yielding more to the second. This however is not the explana-
tion given by the original observer.
SUMMATION OF STIMULI
If an isolated frog's ventricle, which is not beating, be stimulated with
inadequate shocks, it may be found, on repeating these shocks at short
intervals of time, that they become adequate and cause a contraction of the
ventricle. A stimulus therefore, which is subminimal,
may nevertheless cause some change in the heart
muscle, so that the latter responds more readily to
subsequent stimuli.
A similar improving effect of previous stimulation Fig. 445. Group of pul-
. r x . sations showing stair-
on the condition of the heart muscle may be observed case ' character.
on the contractions themselves. Thus in a Stannius
preparation, if the ventricle be excited with single induction shocks, once
in every ten seconds, the first four or five contractions form an ascending
series, each contraction being rather higher than the preceding one. This
is often spoken of as the 'staircase phenomenon' (Fig. 445).
THE REFRACTORY PERIOD
At each contraction of the heart muscle there is a sudden decomposition
of contractile materia! which, so far at least as concerns the incidence of an
external stimulus, is maximal, i. e. complete. Directly this has occurred, a
process of assimilation or re-formation of contractile material begins. This
lasts throughout the diastolic period, and the store of contractile material is at
its maximum just before the next contraction. A mechanical analogy is
furnished by a bucket into which a stream of water is constantly flowing,
and which tips up automatically and empties out its contents as soon as the
water reaches a certain height. It is evident that the power of the heart
muscle to contract in response to a stimulus (its ' irritability ') must be at a
minimum immediately after the automatic discharge or decomposition has
taken place, and will continually increase from this point as the store of con-
tractile material grows, until it arrives at such a height that the explosive
discharge occurs spontaneously. Hence in each cardiac cycle there is a
period, known as the refractory period, in which stimuli applied to the hearl
have no effect. This will be followed by a period in which a stimulus is
followed by an extra contraction, but with a prolonged latent period. Just
before the next spontaneous contraction the irritability is at its height, and
the heart muscle responds with a contraction to a minimal stimulus. These
facts are well shown in Fig. 446.
When a tracing is being taken from part of the heart, e.g. the ventricle,
which is beating rhythmically in consequence of a stimulus comnuuricated
to it from some other part such as the sinus venosus, an extra contraction is
followed by a ' compensatory pause,' and in certain cases the first contraction
1000
PHYSIOLOGY
after the pause is considerably augmented. This is due to the fact that
one of the impulses travelling from the sinus arrives at the ventricle during
the refractory period ensuing on the application of the artificial stimulus;
hence it produces no effect and the ventricle has to wait for the arrival of the
next succeeding excitatory wave from the sinus before it gives its next beat.
Fig. 446. Tracings of spontaneous contractions of frog's ventricle, to show refractory
period. In each series the surface of the ventricle was stimulated by an induction
shock at E, as indicated by the tracing of the signal. In 1, 2 and 3, this stimulus
had absolutely no effect, since it fell during the refractory period. In 4, 5, 6, 7
the effect of the shock was to interpolate an extra contraction in the series, the
latent period (shaded part) gradually diminishing from 4 to 7 (diastolic rise of
irritability). In 8 the irritability of the preparation was already considerable,
and the latent period inappreciable. The ' compensatory pause ' after the
extra beat is also well shown in 4, 5, 6, 7, 8. (Makey.)
Hence the compensatory pause does not occur when we are testing the effects
of artificial stimuli on the sinus venosus.
On account of the refractory period which ensues on the commencement
of the contractile process on heart muscle, it is impossible to throw the
muscle into a tetanus, since all the stimuli which fall during systole are
entirely ineffective. By using very strong stimuli it is possible to intercalate
extra contractions before the heart has returned to the base line, i. e. before
diastole is complete. So that in this way one may obtain almost a continuous
contraction (presenting however waves on its summit), which differs from
the tetanus of skeletal muscle in the fact that its height is no greater than
the height of a single contraction.
THE CAUSATION OF THE HEART BEAT 1001
Only when the functional continuity of the heart muscle is impaired by
the ' block ' effect of vagal stimulation or by the administration of muscarine
is it possible to obtain phenomena even superficially analogous to the sum-
mation of contractions in skeletal muscle. 1
FACTORS MODIFYING THE ACTIVITY OF CARDIAC MUSCLE
INFLUENCE OF TENSION AND DISTENSION
When we examine the behaviour of a heart isolated from the central
nervous system and from the rest of the body, as for instance in the heart-
lung preparation (vide p. 955), we find that it has a marvellous power of
adaptation, i. e. of regulating its activity according to the mechanical demands
which are made upon it. Thus while we may maintain the venous inflow
constant so that the heart is sending out a litre of blood per minute, it makes
no difference to the output of the heart whether the average arterial pressure,
and therefore the resistance to the outflow of blood, be maintained at 80 or
160 mm. Hg., although in the latter case the heart must do exactly twice as
much work in order to maintain the outflow at the same level. Again
if we maintain the arterial pressure constant and alter the venous
inflow, we find that within very wide limits the heart is able to expel
against the arterial resistance the whole of the blood which flows into it from
the veins. In this way we can alter the output of a small heart of 50 gms.
from 300 to 3000 c.c. per niinute. As we should expect, this variation in
the work done by the heart is associated with corresponding variations
in the chemical changes which occur at each heart beat. Evans has shown
that the respiratory exchanges of the heart increase pari passu with the
work it has to do. Thus in an isolated dog's heart, weighing 70 grms., with
a constant inflow and output of 35 litres per hour, raising the arterial pressure
from 80 mm. Hg. to 140 mm. Hg. increased the oxygen consumption from
228 to 404 c.c. per hour. In another experiment with a heart of 59 grms.,
in which the arterial pressure was maintained constant at 80 mm. Hg.,
increasing the output from 9-3 to 92 litres per hour raised the oxygen con-
sumption from 155 to 649 c.c. per hour. In these experiments the maximum
/ work done in calories \
efficiency of the heart — — ; , , .. : ; — — varied between 20 and
Vtotal metabolism in calories/
30 per cent., and was of the same order as that found for voluntary muscle.
Careful investigation of the volume and pressure changes of the heart
under varying conditions of arterial resistance and venous filling enables
us to throw some light on the mechanism of this power of adaptation.
Let us take first the changes in volume as recorded by the cardiometer.
A heart is contracting 100 times per minute and forcing out at each beat
10 c.c. of blood into the aorta against an average pressure of 80 mm. Hg.,
with systolic and diastolic pressures respectively of 100 and 60 nun. Hg. In
order that the left ventricle may force 10 c.c. of blood against this resistance,
1 According to Mines the effect of vagus excitation in enabling the production of
summation is due to the shortening of the refractory period which results from vagal
stimulation.
1002
PHYSIOLOGY
the pressure in its interior must rise at each heart beat above the maximum
systolic pressure in the aorta, e.g. to 110 mm. Hg. The aortic valves will
open as soon as the pressure rises above 60 mm. Hg. The arterial resistance
is now increased so as to bring the average pressure up to 120 mm. Hg. The
heart now may raise the pressure in its interior to 120 mm. Hg. This will
be higher than the diastolic pressure
in the aorta and a certain amount
of blood will escape, but the outflow
of blood will cease as soon as the
pressure in the aorta is equal to
that in the ventricle. Diastole will
then occur, the ventricle will relax
before it has emptied out 10 c.c. of
blood. Let us assume it has forced
out 3 c.c. of blood — it will then
contain an excess of 7 c.c. of blood
at the end of diastole. Meanwhile
the venous inflow is proceeding at
the same rate as before, so that at
the end of diastole it has 7 c.c. more
blood than it had at the end of
the previous beat, i. e. its diastolic
volume will be increased and the
heart will be dilated. At the in-
creased beat we find that the con-
traction of the ventricle is much
more forcible. The maximum pres-
sure now rises to 130 mm. Hg. and
8 c.c. of blood are sent out into
the aorta. At the end of this beat
the heart will be still fuller than
before, containing an excess of
9 c.c. of blood. The third beat
is still more forcible, the intra-
ventricular pressure rising to a
maximum of 140 mm. Hg., and
10 c.c. of blood are expelled. After this the heart goes on beating regularly,
expelling 10 c.c. of blood at each beat, i. e. the same amount as it receives
from the veins, and the arterial pressure is maintained constant at an average
of 120 mm. Hg. But the heart remains more dilated than it was previously,
since it contains an excess of 9 c.c. of blood. If now the arterial resistance
be suddenly reduced to its previous amount, the first beat after the change
may send out 17 c.c. of blood, the second beat 12 c.c. of blood and the third
beat 10 c.c. as before. We see therefore that the energy set free at each
contraction of the heart is increased by increasing the volume of the heart ;
but increased volume of the heart means increased length of the muscular
Fig. 447. Effect of increased arterial pres-
sure on the volume changes of the heart,
with a steady inflow of 154 c.c. blood per
10 seconds.
C. =cardiorueter curve. B.P. =artorial blood
pressure. V.P. =pressure in the inferior
vena cava. The hues 100 and 80 show the
height of the blood pressure in mm. Hg.
THE CAUSATION OF THE HEART BEAT
1003
fibres composing its wall, so we arrive at a statement similar to that made
previously for voluntary muscles, namely, that the energy of contraction is
a function of the length of the muscle fibres, i. e. to the extent of active surface
involved. This reaction of the heart to increasing distension has long been
known but was ascribed to the excitatory influence of tension on the muscle
fibres. It is evident that in a resting heart increasing distension of its
cavities will tend to stretch its muscle fibres and therefore to exert a
Fia. 448. Effect of alterations in venous supply on volume of heart. Heart, 67 gms.
Arterial
Venous
Output of heart
pressure
pressure
in 10 sees.
124
=
95
= 80
130
=
145
= 140
124
=
55
= 33
A .
B .
C .
• The curved lino at tho side represents the value of the cardiomutor excursions
in capacity of ventricles in c.c.
tension on them. By an accurate record of the pressure changes within
the contracting ventricle imder varying conditions, it is possible to exclude
the tension on the fibres as the determining factor. In a heart bea
regularly the inflow of blood is proceeding during diastole, during the relaxa
tion of the ventricles, i. e. the muscles are giving before the inflowing > >1< »< >< 1
The latter is therefore able to distend the heart without exercising more than
a minimum pressure on its walls, and it is found that the pressure in the ven-
tricles may be approximately zero at the end of diastole whether the heart
is contracting against a resistance of 80 mm. Hg. or a resistance of 120 mm.
Hg., or whether it is receiving 5 c.c. or 10 c.c. during the peril id of diastole.
1004 PHYSIOLOGY
With a larger outflow or a bigger resistance the energy of contraction is
increased, although the tension on the heart wall at the beginning of the
contraction is not altered. The only condition then, which always changes
pari passu with the energy of contraction, is the distension of the heart
cavities, i.e. the length of its muscle fibres; and we are therefore justified
in regarding this last factor as the one which determines the energy of the
response of the muscle to excitation. Naturally if the distension increased
beyond a certain extent, it would be associated with increased tension on the
muscle fibres. But the changes of initial tension and excitatory response
are not proportional. It is evident that the capacity of the heart for adapting
itself to changes in mechanical demands made upon it will be limited by the
inability of the heart to dilate further, as is probably the case in the intact
animal, where its dilatation is limited by the pericardium or by the mechani-
cal disadvantage at which the further dilated heart acts. The more the
heart attains a globular form, the greater the mechanical disadvantage of
the muscle fibres in raising the pressure in the interior of the ventricles (vide
p. 960), so that by continually increasing the demands on the heart, we shall
finally arrive at a stage at which this organ is unable to deal with the blood
applied to it and rapidly fails to expel any of its contents.
The physiological condition of the heart is measured by the maximum
pressure which it is able to produce in its cavities when it contracts, starting
from a certain initial size or length of fibres. As the heart becomes fatigued
this pressure falls, so that the heart must dilate in order that each contraction
shall produce the same maximum pressure as before. Fatigue of the heart is
shown therefore, not by failure to do its work, but by the fact that it can
do its work only when it is undergoing considerable dilatation. Dilatation
is therefore a measure of fatigue. What is often spoken of as the tonus
of the heart is really synonymous with physiological condition. A heart
in good condition has a high tonus. It empties itself almost completely
at each beat, even when receiving a considerable quantity of blood during
diastole. A heart with a low tonus is in the condition of a fatigued heart.
It is widely dilated and when it has finished contracting still contains a large
amount of residual blood.
This property of the cardiac muscle is responsible for the power of
' compensation ' possessed by a diseased heart. We may take as an example
the destruction of one aortic valve, a lesion which can be produced experi-
mentally in a dog. In this case, immediately after the lesion is established,
no additional resistance is offered to the expulsion of the blood, and the ven-
tricle will send the normal amount into the aorta. During the succeeding
diastole the blood at a high pressure in the aorta will leak back into the
ventricle through the damaged valve. The arterial pressure therefore falls
rapidly, and the ventricle receives blood from two sides, i. e. by regurgitation
through the aortic valves, and in the normal way from the auricles and veins.
At the end of diastole the ventricle is therefore overfilled. Increased
stretching of its fibres however has the effect of exciting an increased con-
traction, and the heart at its next systole throws out not only the normal
THE CAUSATION OF THE HEART BEAT 1005
quantity of blood but also that which it has received back from the aorta.
The arterial system thus receives at each beat the normal quantity of blood
plus the amount which leaks back into the ventricle after each systole ;
so that the amount of blood remaining in the aorta and available for passage
on to the capillaries is the same as in the normal animal. On this account,
after a lesion of the aortic valves has been established, the average of the
arterial pressure remains the same as before, although the oscillations of
pressure with each heart beat are increased in extent. The augmented
output by the ventricles naturally involves increased work on the part of their
muscular walls, which react in the same way as skeletal muscle does to
increased work, i. e. by hypertrophy. The final effect therefore is a heart
bigger than normal, with hypertrophied and thickened .walls, but capable
of maintaining an adequate circulation throughout all parts of the body;
in other words, in the healthy animal complete compensation has taken
place.
4
Fig. 449. Tracing of contractions of a frog's heart (by Ringer), showing effect
of adding a trace of GaCl 2 to the NaCl solution used previously for perfusion.
The arrow marks the point at which the addition was made.
INFLUENCE OF TEMPERATURE ON THE HEART RATE
The frequency of the heart varies directly with the temperature. The
higher the temperature the greater the frequency. At 40° C. the contraction
of the mammalian heart may be four times as frequent as at 25° C.
INFLUENCE OF THE CHEMICAL COMPOSITION OF THE
SURROUNDING MEDIUM ON THE HEART MUSCLE
The tissues of the heart, like all other cells of the body, require for the
normal display of their functions a definite osmotic environment, i. e. a
certain molecular concentration of the fluid with which they are bathed.
This is equivalent to a 0-65 per cent, sodium chloride solution for the frog's
heart, and to a 0-9 per cent, solution for the mammalian heart. As Ringer
first showed, the nature of the neutral salt employed for making up the
normal solution is all-important to the heart muscle. Thus a strip of
muscle from the apex of the tortoise's ventricle as a rule does not beat
spontaneously. If it be immersed in a 0-7 per cent, solution of sodium
chloride, it begins to beat rhythmically after a short latent period. The
contractions soon reach a maximum and then gradually die away. Sodium
chloride therefore acts as a stimulus to contraction, but is unable tq
maintain the beats for any considerable length of time. The strip of
muscle ceases contracting in a condition of relaxation. On now adding
1006 PHYSIOLOGY
to the solution a trace of calcium chloride or calcium sulphate, the con-
tractions begin again (Fig. 449). The relaxations after each contraction
then become more and more incomplete, until finally the heart stops in a
tonically contracted condition. If now a trace of potassium chloride or
phosphate be added, the contractions recommence and may last for many
hours, although the solution contains nothing which can furnish energy
to the contracting muscle. It has been suggested that the rhythmic con-
tractions of the heart muscle may be the result of the constant chemical
stimulus of the inorganic salts present in the blood plasma, sodium acting
as a stimulus to contraction, while the calcium salts are necessary for the
maintenance of the systolic tone, and the potassium salts for the occurrence
of relaxation.
The exact significance of these different salts for the functions of cardiac
and other forms of muscular tissue, though they have been the subject of
many detailed investigations, must be still regarded as an open question.
Fig. 450. A frog's heart, poisoned by excess of calcium salts, recovers its spontaneous
rhythm on adding a trace of KC1 to the perfusion fluid. (Ringer).
The fluids, containing the three salts mentioned above in slightly varying
proportions, are commonly used to maintain the beat in an excised heart
either of a cold- or of a warm-blooded animal. In the case of the latter it
is necessary to keep the fluid saturated with oxygen. According to Locke
the addition of glucose to the solutions enables the beats to go on for a
longer period of time, and will in fact renew the rhythm of a heart which
has ceased beating while being fed with pure saline solution.
The following represent the fluids most frequently used :
Ringer's Fluid
(for frog's heart) •
1 per cent, sodium bicarbonate . . . .1 c.c.
1 ,, calcium chloride . • • .1 c.c.
1 „ potassium chloride .... 0-75 c.c.
0-6 „ sodium chloride . . .to 100 c.c.
Locke's Fluid
(for mammalian heart)
0-015 per cent, sodium bicarbonate,
0-024
0-042
0-92
,, calcium chloride,
„ potassium chloride,
,, sodium chloride,
0-1
„ glucose,
in distilled water.
The influence of the chemical composition of the medium on the contraction of the
heart may be investigated in the following ways :
THE CAUSATION OF THE HEART BEAT
1007
One of the simplest methods is that devised by Goteh, represented in the diagram
(Fig. 451). The apparatus consists of a small glass jar with inlet and outlet tubes.
A disc of cork is fixed on to a brass rod so that it can be let down into the fluid. On
the upper end of the brass rod is poised a light lever with a paper point. To fix the
heart in the apparatus, the top of the ventricle is transfixed by a fine hook to which is
attached a thread connected with the lever. The heart is fastened to the cork by a pin
through the bulbus aorta?. The glass jar is filled with the fluid whose action it is
desired to investigate. It is usual to start with Ringer's fluid in order to obtain a
normal beat, and then to try in turn the various constituents of this fluid.
"NT
Fig. 451. Gotch's frog heart apparatus.
Fit;. 452. Brodie's perfusion
apparatus for the mamma-
lian heart.
Another method of investigating the action of the heart of cold-blooded animals is
by perfusing the heart cavities with the fluid under investigation. Two forms of
perfusion are made use of. In the method first introduced by Williams a double
cannula is tied into the ventricle, the rest of the heart being cut away. The tubes
leading to and away from the perfusion cannula are armed with valves so as to allow
the fluid to pass only in one direction. The contractions of the ventricle may be
recorded either by connecting the outgoing tube with a manometer, which may bo a
mercurial or a membrane manometer, or by connecting some form of recording apparatus
with the vessel in which the heart is contained, so as to register changes in the volume
of the ventricle. A large number of different forms of apparatus have been devised
for these purposes.
In another method the fluid is allowed to flow through the whole heart pa sing in
by the sinus and out by the aorta. Here again the activity of the heart may be registered
either by recording the pulsations in the arterial column of fluid or by connecting a
tambour or piston recorder with the vessel in which the heart is contained.
1008 PHYSIOLOGY
The heart of warm-blooded animals can also be investigated by a somewhat similar
method. It was shown by Porter that the mammalian heart could be kept alive by
transfusing oxygenated blood serum through the coronary vessels, and Locke found
that the same results could be obtained by using oxygenated Ringer's solution, modified
so as to have the same tonicity as mammalian blood. Brodie's apparatus for this
purpose consists of a chamber a to contain the heart, and of a tube B, through
which the perfusion fluid is carried to the heart (Fig. 452). Both are enclosed in a
large outer jacket c, through which is kept flowing a stream of water at body tempera-
ture. The chamber a is bell-shaped and is fitted into the jacketing tube c by a ground-
glass joint d. Its upper orifice is closed by a piece of rubber tubing of such size that
the perfusion tube b slips through it easily. By means of the glass handle v, fused into
the tube about half-way down, B can be drawn up or lowered into any desired position.
To its lower end the heart cannula is attached by a ground joint. Its upper end is
fitted by a second ground joint with a small bulb w, which has two tubes, E and S, fitted
into it. These latter are connected by rubber tubing with aspirators containing the
solutions to be perfused. The lower half of the tube B is nearly filled up with a thermo-
meter L, the bulb of which projects into the heart cannula T. The upper half is almost
filled with a piece of glass tubing sealed at both ends, so that the perfusion fluid passes
in a thin layer down the tube and thus offers a large surface for heating purposes. Also
by filling the interior of the tube in this way its capacity is reduced to a very small
amount. The large outer tube O is kept supplied with warm water, entering through the
tube o and overflowing through a side-tube at the top into a wide T-piece n. By raising
or lowering this T-piece the level of the water in the jacket is adjusted. The water-
supply comes from a cold-water tap, but on its passage to g passes through a metal
spiral heated by a Bunsen burner. By varying the rate of flow and the position of the
burner, the temperature of the water can be regulated with considerable accuracy.
The upper end of the supply-tube G is provided with a thermometer so that the tempera-
ture of the inflowing water can be seen and regulated. In using the apparatus the
heart cannula is removed, and the tube b is then passed through e and pushed down
until its lower end issues just below the level of the chamber A. The circulation of the
warmed water through the jacket is thenstarted and adjusted to the proper temperature.
One of the rubber tubes, s,is next attached to the reservoir containing the main perfusion
fluid, and the tube b filled with fluid and left to warm while the heart is being prepared.
The heart having been excised and washed well in saline so as to remove as much
blood as possible, the cannula is tied into the aorta. The cannula is now held under
the perfusion tube, filled with the warm saline, and at once attached in its proper
position and the perfusion started. A bent pin, to which a long thread is tied, is hooked
into the apex of the heart, and the perfusion tube pulled up until the heart lies quite
within the warm chamber. When thus drawn up the bulb w lies just below the surface
of the water in the outer jacket. The tube is held firmly in position by a clamp which
fixes one arm of the handle J\ The heart cannula is provided with a side opening v,
on to which a long piece of fine rubber tubing is passed. This renders possible the
removal of any gas bubbles that may collect in the cannula, or the washing out of the
cannula with a stream of fluid if necessary. The beats of the heart are recorded by
means of a simple lever attached by the thread previously fixed to the heart.
THE SIGNIFICANCE OF THE REACTION OF THE BLOOD FOR THE
HEART BEAT. It was long ago shown by Gaskell that the reaction of the
perfusing fluid has a marked influence on the frog's heart. When weak
acids are transfused through this heart, there is a gradual diminution of
tonus, the beats become smaller and finally disappear. A similar relaxation
may be obtained as the result of the action of carbon dioxide. Weak
alkalies on the other hand produce a gradual decrease of tonus, so that the
heart is finally arrested in a contracted condition. There will thus be
some reaction, intermediate between the weak acid and the weak alkaline
THE CAUSATION OF THE HEART BEAT 1009
fluids, which will represent the optimum reaction for the beat of the frog's
heart. Mines has shown that this optimum reaction differs for the different
cavities of the heart, and also for the hearts from various animals, a
shifting of the reaction of the transfusing fluid to the acid side always
bringing about a diminished contraction and tonus, while the opposite
effects are produced by an increase in the alkaline reaction. In the
mammal under normal conditions, the chief factor affecting the reaction of
the blood is the tension of carbonic acid in this fluid ; and an increase in the
carbonic acid of the blood, when sufficiently pronounced, always brings
about dilatation of the heart. The resistance of the hearts of different
animals is however not of the same strength. Thus, a dog's heart is much
I
rapi'ii'ii'lll I
Fig. 453. Volume curve or ventricles (cat) (lower curve). The upper curve is the
arterial pressure, maintained by an adjustable resistance at 130 mm. Hg.
Between the arrows the air used for artificial respiration was replaced by a
mixture containing 20 per cent. CO, and 25 per cent, oxygen. Note the
dilatation with impaired contraction, followed by increased amplitude of
contraction.
more susceptible to the presence of a small excess of carbonic acid in the
blood than is the cat's heart (cp. Fig. 453). There is probably an optimum
tension of carbon dioxide in the blood, varying between 5 and 6 per cent,
of an atmosphere, at which the physiological condition of the ventricular
muscle is at an optimum, but the tension may be reduced considerably
below this without causing any marked change in the action of the heart.
V uidell Henderson found that vigorous artificial ventilation of the lungs brought
about a condition in which the heart's contraction was very forcible and the heart's
cavities almost empty. He ascribed this condition to the hypertonicity of the heart
muscle produced by washing the carbonic acid out of the blood. These results were
however probably due to the mechanical influence of the respiratory movements
on the venous filling of the heart; and there seems no reason to believe that the
condition of ' acapnia ' (deficiency of carbon dioxide in the blood) had anything to
do with the results observed. The improving effects of administration of carbon
dioxide, described in the first edition of this work, have not been confirmed b\
recent and accurate experiments.
THE NUTRITION OF THE HEART
Li the frog's heart the muscle fibres are supplied directly by the blood
within the cavities, the spongy ventricular wall permitting the access of
64
1010 PHYSIOLOGY
blood between the fibres. In the mammalian heart the muscular tissue is
nourished through the coronary arteries, which break up into a mesh-work
of capillaries around all the fibres.
The flow of blood through the coronary circulation may be measured, either in
the whole animal or in the heart-lung preparation, by introducing a cannula through the
wall of the right auricle into the coronary sinus and collecting the blood from the latter
outside the body. Another method is to feed a heart from the aorta through the
coronary arteries with blood and collect the total outflow from the cut pulmonary artery.
By a comparison of these two methods, it is found in the dog that the blood flow through
the coronary sinus forms about three-fifths of the total blood passing through the
coronary arteries. It is therefore possible to measure the flow through the coronary
sinus in the heart-lung preparation under varying conditions of pressure and output.
The figures so obtained multiplied by f: will represent approximately the total flow
through the coronary circulation.
Blood enters the coronary arteries from the aorta both during systole
and diastole, though it is probable that the systole of the ventricles exercises
a direct effect in increasing the resistance to the flow of blood through the
heart, and squeezes out the contained blood into the coronary veins. This
may be one reason why the flow of blood through the coronary system is
greater in a beating heart than in a heart which is quiescent. The most
important factor in determining the flow through the coronary vessels is the
arterial pressure. The marked effect of this factor is shown in the following
Table :
Heart weight, 107 gms. Total output per minute, 1400 c.c.
Arterial Coronary circulation
pressure per minute
60 50
100 90
128 124
166 208
190 500
We see from this Table that the heart muscle is supplied with blood
in proportion to its needs, since its work and its respiratory exchanges
increase continuously with the rise of arterial resistance. Indeed in this
particular experiment, under the severe test of contracting against an average
pressure of 190 mm. Hg., over one-third of the whole blood leaving the heart
was passing through its muscular walls, one gramme of muscular tissue being
irrigated with 5 c.c. of blood per minute. Another important factor in
determining the coronary flow is the effect of the metabolites produced
by the contracting heart muscle itself. This is well shown when the heart
is asphyxiated. Thus in one experiment while the arterial pressure was main-
tained constant, the total coronary flow was 56 c.c. per minute. Artificial
respiration was then discontinued, and during the succeeding minutes the
coronary circulation was 61, 72, 150, 180. The circulation then failed. Car-
bonic acid produces also an increase in the flow through the coronary arteries,
but it is impossible with the highest attainable percentages of carbon
dioxide in the blood to effect such an increase in the coronary flow as is
observed during asphyxia. The dilatation of the coronary vessels, which
THE CAUSATION OF THE HEART BEAT 1011
occurs in the latter condition, must therefore be ascribed to non -gaseous
metabolites produced by the contracting muscle. Thus the heart contains
in itself a mechanism for increasing the flow of blood through its tissues,
whenever this becomes inadequate and the muscle is suffering for lack of
oxygen. Mechanical and physiological factors thus co-operate in providing
the most important muscle in the body with oxygen sufficient for its needs.
If a coronary artery be ligatured, the heart very 'often beats for one or
two minutes with unimpaired force, then a beat is dropped occasionally,
and very shortly afterwards the heart stops altogether and the blood
pressure falls to zero. On inspection of the heart immediately after the
blood pressure has fallen, its muscular wall is seen to be in a state of fibrillar
contractions, or ' delirium cordis.' All the strands of muscle fibres are
contracting more or less rhythmically, but the rhythms of no two parts
coincide, so that the heart dilates and is incapable of carrying on the circula-
tion It is probably in this way that sudden deaths occur in cases where
the coronary arteries are diseased or calcified. In such cases a man may
drop down dead, having previously shown no symptoms of heart mischief.
Delirium cordis may be explained as the result of block, produced by
interference with the nutrition of a large part of the cardiac wall. The con-
tractile wave arriving at this part, in some directions will not spread at all,
in others will spread at a lower rate, so that different parts of the heart
receive the impulse to contract at different times and a state of inco-
ordination results. The same condition can be produced by freezing the
apex of the ventricle, so causing a block, or by stimulating the surface of the
ventricle at a rate which is greater than can be taken up by the ventricle as
a whole, as, e.g., by tetanising currents. Such a condition in the higher
animals, as the dog and man, is practically irrecoverable, although in the
rabbit, and very rarely in the dog, it is sometimes possible to bring the heart
back to a state of rhythmic contraction by kneading it rhythmically.
According to Mines delirium cordis is susceptible of a simpler explanation. This
condition is easily brought on in the mammalian heart by stimulation of its surface with
strong faradic currents. The effects on the heart muscle of increased frequency of con-
traction are to decrease the rate of propagation and to decrease the length of the wave
of excitation. Ordinarily in the naturally beating heart the wave of excitation is so long
and spreads so rapidly, that it excites the whole of the ventricle at a considerable
interval before it has ceased ill any one part. When however the muscle is stimulated
more frequently, the wave becomes slow and short, so that more than one wave can
exist at one time in a single chamber. The main factor then, in the production of
delirium cordis after obstruction of the coronary artery, would probably be a diminished
rate of conduction through the affected part.
SECTION IX
THE NERVOUS REGULATION OF THE HEART
In order that the activity of the heart may be adapted to the needs of the
body as a whole, its automatic mechanism must be subject to the centra!
nervous system, which must be able to affect the heart in either of two ways,
viz. by increasing or diminishing its activity. This subjection to the
integrative action of the central nervous system is also necessary for the
sake of the organ itself; otherwise the peripheral adaptation of the heart
muscle to change in arterial resistance might result in its exhaustion and
permanent damage.
The regulation is effected through the intermediation of afferent and
efferent nerve fibres connecting the heart with the central nervous system.
The importance of these nerves is shown by the behaviour of animals in
which they have been extirpated. Thus a dog, in whom all the nerves of the
heart had been divided, survived the operation for eight months, the pulse
reading during the time not having appreciably altered and the animal being
in a fair condition of health. Although he regained his normal weight after
the operation, he was found incapable of carrying' out even a moderate
amount of work, such as that represented by running, since the mechanism
for increasing the action of the heart in response to the needs of the muscles
had been lost.
THE EFFERENT CARDIAC NERVES
The heart in vertebrates is supplied with nerve fibres from two sources :
from the medulla oblongata along the vagus nerve, and from the upper
dorsal region of the spinal cord through the mediation of the sympathetic
system.
The fibres, which run through the sympathetic system, take a somewhat
different course in the animals on which the regulation of the heart's activity
has been chiefly studied, viz. the frog and the mammal. In the frog
(Fig. 454) the sympathetic fibres leave the spinal cord by the anterior root
of the third spinal nerve ; they then pass through the ramus communicans
to the corresponding sympathetic ganglion, whence they run up through
the second ganglion and the annulus of Vieussens to the first ganglion;
they then pass into the cervical sympathetic strand to the ganglion trunci
vagi ; here they join the vagus and pass down with the true vagus fibres
to the heart.
In the dog (Fig. 455) the sympathetic fibres leave the spinal cord
by the anterior roots of the second and third dorsal nerves, run in the
THE NERVOUS REGULATION OF THE HEART 1013
white rami communicantes to the stellate ganglion, and thence by the
Hamulus of Vieussens to the inferior cervical ganglion. Cardiac branches
convey the sympathetic fibres to the heart and are given off from the
stellate ganglion, the inferior cervical ganglion, and from the trunk of
the vagus.
By the nicotine method it is possible to trace out the cell connections of
these fibres. As they leave the cord they are medullated nerve fibres, similar to the
.^Juq. Gancjl. Vagus
Vago-symparhft
Vert. I.
Aorta
FIG. 4f>4. Sympathetic chain of frog (right side) to show connection with vagus
nerve. The sympathetic ganglia with their branches are black. Of the
peripheral branches only the splanchnic nerve is represented. (Modified
from E(
other fibres making up the visceral outflow throughout the dorsal region; the white
Sbrea pass along the ramus communicans to the stellate ganglion, where they end.
forming synapses with the cells of the ganglion. Here fresh relays of fibres, winch
are non-medullated, start and carry the impulses to the heart along the various cardiac
nerves just mentioned. In the heart these fibres are distributed to the muscle fibres
without the intervention of any other ganglion cells. On the other hand the fibres,
which leave the sragus to pass to the heart, make connection with the cells of Bemak's
ganglion, and probably with all the other intrinsic cardiac ganglia described above,
whence mm medullated fibres carry their impulses to the heart muscle.
ACTION OF THE VAGUS
The action (if the vagus fibres on the heart is almost identical in frog and
mammal. If in the dog the peripheral end of the cut vagus he stimulated,
11)1 1
PHYSIOLOGY
while the arterial blood pressure is being recorded by means of a mercurial
manometer, the pulse is seen to become slower, or with a stronger stimulus
to cease altogether, and the blood pressure falls towards zero. On discon-
tinuing the stimulus, the heart begins to beat again and the pressure rises
after a few beats to normal (Fig. 456).
If the stimulation of the vagus be prolonged, the blood pressure, on dis-
X r.Sp. \c.
Fig. 455. Diagram of cardiac inhibitory and accelerator fibres in
the dog. (From Fostek.)
r.Vg, roots of the vagus ; r.Sp.Ac, roots of the spinal accessory ; G.J, ganglion
jugulare; G.h.V, ganglion trunci vagi; Vg, trunk of vagus nerve; C.Sy, cervical
sympathetic; G.C, inferior cervical ganglion; A.V, annulus of Vieussens; A.sb, sub-
clavian artery ; n.c, cardiac nerves ; G.St, ganglion stellatum ; D2, D3, D4, D5,
second, third, fourth, and fifth dorsal spinal roots; G.Th, ganglia of the thoracic
chain.
continuance of the stimulus, may rise above normal owing to the asphyxia
of the vaso-motor centres produced by the prolonged cessation of the
circulation. Even during the application of the stimulus the heart often
begins to beat again with a slow rhythm. In this case we speak of an
' escape ' of the heart from the vagus influence. This escape is generally
confined to the ventricles, and the heart beats are found on opening the chest
to be purely ventricular, the auricles and great veins remaining in a state of
THE NERVOUS REGULATION OF THE HEART 1015
diastole. Vagus escape is favoured by distension of the heart cavities, and
is often synchronous with the respiratory efforts, which supervene after a
certain duration of inhibition as a result of the asphyxia of the respiratory
centre.
When the arterial system is dilated, so that the mean systemic pressure,
and consequently the venous pressure during cardiac inhibition, are low, or
when the asphyxial gasps of the animal are prevented by anaesthesia or by a
section of the spinal cord, the heart may fail to recover from the inhibition
produced even by a transitory stimulation of the vagus. In such cases it is
necessary to knead the heart in order to reatore its rhythmic action.
To study the influence of the vagus on the auricles and ventricles
respectively, it is necessary to work with the chest opened and to record
separately the contractions of the different segments of the heart . It is then
Fig. 456. Blood pressure tracing from carotid of dog (taken with Hiirthle's
manometer), showing effect of excitation of vagus (between the arrows).
o, abscissa line of no pressure.
found that the vagus may affect the heart in one of several ways. Its most
marked action is on that part of the heart where it enters, viz. the venous
end. It may affect that part of the auricle corresponding to the primitive
sinus venosus, where the rhythm of the whole heart is determined. In this
case the sole effect of the vagus on the auricles and ventricles will consist in
an alteration of rhythm. They may cease to beat altogether or they may
give beats of normal strength but at a slower rhythm than before. Often
indeed under these conditions the beats of the ventricles may be increased
in size, since the strength and extent of their contractions are determined,
not by the strength of the stimulus arriving from the auricles, but by
the length of their fibres, and this will be greater with any prolongation
of the diastolic period, and consequent increased diastolic filling of the
ventricle.
If the vagus acts on the auricles without affecting the sinus part of the
auricles (sino-auricular node), the rhythm will be unaltered, but the response
of the auricles to the impulses received by them will be diminished, and the
amplitude of the excursions of the lever attached to them will therefore be
considerably reduced. Indeed the auricular contractions may be reduced
to such an extent that they cause no movement of the lever. It is only
by observing their surface that one may perceive a, slight contraction of
L016 PHYSIOLOGY
their fibres. Under such circumstances the rhythm of the ventricles will be
unchanged.
Generally the vagus absolutely stops the action of all parts of the auricles ;
in such cases the ventricles also cease beating. Very often after a short
pause the ventricles commence to beat at a slow rhythm, and it is then seen
that they are contracting independently of the auricles and sinus. That
the ventricle is really inaugurating the beat is shown by the fact that occa-
sionally one may observe a reversed beat, i. e. a contraction of the auricle
following instead of preceding each ventricular contraction. Whether the
vagus has a direct action on the mammalian ventricle is still doubtful; its
effect is at any rate very slight as compared with that on the venous end
of the heart. The fact that stimulation of the vagus causes as a rule
temporary cessation of the ventricular beat, while functional separation of
the ventricles from the auricles causes no such temporary stoppage, would
seem to indicate that this nerve has a direct, though slight, action on the
ventricles.
Finally the vagus may affect the tissue which conducts the excitatory
process from one cavity to another. Under vagus stimulation the auricles
may- beat at a greater rhythm than the ventricles, a block having been
produced in the tissue passing from auricles to ventricles, viz. the auriculo-
ventricular bundle.
Engelmann has described these effects of vagus excitation as negatively chronotropic
(diminution of rhythm), negatively inotropic (diminished strength of contraction),
and negatively dromotropic (diminished conductivity), and has distinguished a fourth
action, viz. one on the irritability of the muscle to direct stimuli, which he calls nega-
tively batltmotropic. He. ascribes these four actions to four different sets of nerve fibres,
but it is evident that they are due not so much to a difference in the nature of the
impulse as to a difference in the place of incidence of the impulse.
Thus, if the, vagus fibres which are distributed to the remains of the sinus are
specially active, we shall get alterations of rhythm affecting the whole heart. If those
which supply the A. V. bundle are excited, the most pronounced effect will be on the
propagation of the excitatory process from auricles to ventricles.
Practically the same description will apply to the action of the vagus
on the frog's heart. Since it is easy in this animal to register the contrac-
tions of the empty heart, it is possible to show that the vagus has a direct
inhibitory action on the ventricles, diminishing the strength of its contrac-
tion in response to the stimuli transmitted to it from the venous end. This
action of the vagus on the ventricle is not however universal, and in the
tortoise it is impossible to show any such action. In both these animals
the auricles show the same effects as in the mammal, viz. an influence
limited to the rhythm when only the sinus is affected, or a diminution of the
strength of contraction w r hen the sinus is unaffected and the chief action of
the vagus is on the auricular muscle.
Ever since the discovery in 1845 by the brothers E. H. and E. F. Weber
of the action of the vagus on the heart, much work has been expended with
a view to determining the intimate nature of the inhibitory process. In
the former neurogenic theory it was supposed that the vagus altered the
THE NERVOUS REGULATION OF THE HEART 1017
activity, perhaps by a process of ' interference,' of the ganglion cells respon-
sible for the origination of the rhythm. Many facts however point to the
inhibitory impulses as being continued to the heart muscle itself. Thus
tetanisation of any portion of the frog's ventricle, especially if it be filled
with blood, causes an evident relaxation of the part between the electrodes.
Application of nicotine to the heart prevents stimulation of the trunk of the
vagus from having any influence on the heart, presumably from paralysis
of the cells of Remak's ganglion, which he at the termination of the vagus
fibres, or of the synapses between the vagus fibres and the ganglion cells.
It is still possible to inhibit the heart by direct stimulation either of the
fibres leaving this ganglion in the sino-auricular junction, or of the nerve
trunks which run in the inter-auricular septum. We must conclude therefore
that the inhibition of the heart muscle is peripheral and depends on the
direct action of the nerve fibres on the muscle cells themselves. These nerve
fibres are paralysed by atropine, after administration of which no inhibitory-
effects can be produced by stimulation of nerve or muscle or any part of the
heart. On the other hand, muscarine apparently stimulates the inhibitory
nerve-endings, and when applied to the isolated auricle or ventricle causes
weakening of the beat and finally complete inhibition, an effect which can
be removed by its antagonist atropine.
Two views have been held as to the essential, nature of the inhibitory
process. According to that put forward by Claude Bernard, the natural
tendency of any tissue during rest is towards anabolism. Activity involves
disintegration or breaking down of the living material, and this disintegra-
tion must be succeeded by a process of building up or anabolism, which
restores the tissue to its previous functional condition. On this view the
state of inhibition would merely prolong the period of rest intervening
between two periods of activity, so allowing a greater time for restitution to
take place, with a corresponding improvement in the functional capacity of
the tissue. According to Hering and Gaskell a state of anabolism can be
induced in a tissue comparable to the state of sudden disintegration which
is associated with activity. Excitation of the vagus nerve does not merely
allow the normal process of building up, which goes on during rest, to take
place, but actually hastens this process, just as the excitation of a motor
nerve to a skeletal muscle induces an active breakdown of the contractile
tissue, or the excitation of the augmentor nerve to the heart induces an
increased rate of beat and therefore increased functional activity.
If stimulation of an inhibitory nerve induces the opposite chemical
change to that occurring during activity, one would expect to find that,
just as an active part of a tissue is negative to an inactive part, so a part of
the tissue which is under the influence of an inhibitory stimulus should be
electro-posi/uc to any part which is not being so stimulated. According to
GaskeD this condition is realised in the heart of the tortoise. The auricles
are brought to a standstill by separating them from the sinus venosus. The
apex of one auricle is then injured by heat, and the injured point and
uninjured base are led off to a galvanometer. The usual demarcation current,
1018 PHYSIOLOOxY
dependent on the difference of potential between the injured and uninjured
portion, is thus observed. If the vagus be now stimulated, the auricles
remain at rest but the demarcation current is increased, i. e. a positive
variation is produced — an electrical condition opposed in sign to that which
would take place when the auricles contract. Doubt still exists however as
to the exact interpretation to be put on this experiment-
It was mentioned above that potassium salts promote relaxation of the ventricle,
so acting as antagonists to calcium salts. If potassium salts be present in a sufficient
concentration in the circulating fluid, the heart is brought to a standstill in a condition
of diastole, as if the vagus mechanism were in action. On removal of the excess of K
ions, the heart at once starts beating again. Howell has shown that during stimula-
tion of the vagus the amount of potassium in a diffusible form in the heart muscle is
increased. He has therefore suggested that the action of the vagus in stopping the
heart is due to the liberation of potassium salts. Potassium normally exists in a
large percentage in the heart muscle, but in a combined form; and Howell assumes
that stimulation of the vagus effects a dissociation of this combined potassium, so that
the liberated ions arc able to exert their inhibitory influence on the heart.
THE TONIC ACTION OF THE VAGUS
If both vagi of a mammal be divided, the heart as a rule beats more
frequently, showing that under normal circumstances tonic impulses are
constantly descending the vagi and holding the heart's action in check.
The extent of the quickening, which is produced by section of the vagi, varies
in different animals and is apparently associated with the conditions of life
of the animal and its powers of carrying out prolonged muscular exertions.
Thus in the dog or horse the pulse, which is normally slow, may be doubled
in frequency by section of the vagi. In the rabbit, which has a frequent
pulse and is able to run only for a short distance, division of both vagi
causes very little alteration in the pulse rate. It is stated that the tonic
action of the vagi is much greater in the hare than in the rabbit.
This tonic action may be increased by various conditions of the blood,
e.g. the presence of drugs such as morphia.
ACTION OF THE SYMPATHETIC CARDIAC NERVES
Stimulation of the sympathetic cardiac nerves at any part of their course
has an effect on the heart the exact reverse of that produced by stimulating
the vagi. In most cases the pulse frequency is increased in consequence
of the action of these nerves on that part of the heart from which the rhythm
starts. The frequency, which is attained by maximal stimulation of the
accelerator nerves, is independent of the previous rate of the heart beat. The
increase in rate involves a shortening of the time of the. cardiac cycle, which
chiefly affects the diastolic period. The size of the auricular and ventricular
contractions may be increased at the same time as their rate. In fact,
like the vagus nerves, the sympathetic fibres of the heart can influence
rhythm, strength of contraction, or conduction from auricle to ventricle,
according to the part of the heart muscle which is affected.
THE NERVOUS REGULATION OF THE HEART
1019
The augmentor effect on the strength of the ventricular beats is often
very marked. The sympathetic fibres are much less easily tired than the
vagus fibres, and have a longer latent period. Whereas the latent period
of the vagus in the mammal is considerably less than one second, that of
the accelerator nerves may amount to ten or even twenty seconds (Fig. 457).
mmtrmfmmnmi^^
Fig. 457. Tracings of ventricular (upper curve) and auricular
contractions (lower curve).
From x to y the accelerator nerves stimulated. Lowest line — seconds.
Flo. 458. Tracing to show effect of stimulation of the vago-sympathetic nerve on the
frog's heart. The rhythm is unaltered, but the beats of auricle and ventricle
are much decreased in size. On ceasing the stimulation the beats become augmented.
(( I \SKEIX.)
Fig. 459. A tracing similar to Fig. 458. In this case however, the stimulation caused
complete stoppage (inhibition) of both auricular and ventricular beats. (Gaskell.)
Hence if the vago-sympathetic of the frog be stimulated, the first effect is
inhibition due to vagus action. The vagus nerve-endings then become
fatigued, and the influence of the accelerator fibres makes itself apparent;
the heart commences to beat, and the beats become more rapid and forcible
than before (Figs. 458, 459).
Like the vagus, the sympathetic nerve fibres appear to exercise a tonic
influence on the heart so that, after extirpation of the stellate ganglion on
each side, the pulse frequently becomes permanently slowed.
1020
PHYSIOLOGY
THE ACTION OF ADRENALINE ON THE HEART
The medullary part of the suprarenal glands forms and secretes into the
blood stream a substance, adrenaline, which has a marked action both on the
heart and blood vessels and plays therefore an important part in the regula-
tion of the circulation. Whether this secretion is a constant one has not yet
been fully ascertained, but there is no question that under certain specified
conditions there may be a marked influx of this substance into the blood
stream. The action of adrenaline on any part of the body is practically
identical with that of excitation of the sympathetic nerve supply to the same
part. Its isolated action on the heart is best studied on the perfused heart or
-
150
100
a
50
Fig. 400.
Intraventricular pressure tracings (left ventricle) from dog's heart (heart-lung
preparation). (To be read from right to left.) The scale shows pressure
in mm. Hg.
a. Under influence of adrenaline.
b. Under simultaneous influence of adrenaline and C0 2 (15 per cent.) (Patterson).
in the heart-lung preparation. On adding j 1 ,, mgm. of this substance to the
500 c.c. of blood circulating through the heart-lung preparation, a maximum
effect is at once produced and this lasts for 15 to 20 minutes. The action is,
like that of the sympathetic nerve, accelerator and augmentor. Through
its influence on the sinus or the sino-auricular node, the rhythm of the heart
is markedly increased, in the dog to about 240 per minute. At the same time
the energy of each contraction is augmented. This is especially shown in a
heart which is beginning to fail and is therefore undergoing a certain degree
of dilatation. Directly the adrenaline reaches the heart, the contractions
become extremely energetic so that the heart rapidly diminishes in volume,
the venous pressure falls, and the blood flowing into it at each diastole is
thrown out with violence into the aorta. The more powerful beat enables
the output of the heart at each beat to be maintained or even increased, in
spite of the shorter duration of the systole. With each beat the maximum
pressure in the ventricle therefore rises to a marked extent (see Fig. 460).
THE NERVOUS REGULATION OF THE HEART 1021
The strain oil the ventricular wall of this sudden contraction, which is
necessary to empty the heart during the period of systole, is often so great
that small haemorrhages are produced throughout the substance of the
muscle. The stimulation effect of adrenaline is shown moreover by the
considerable rise in the respiratory exchanges of the heart under the influence
of this substance, the oxygen intake being increased two or three times above
that which obtained before the administration of the adrenaline. The action
of adrenaliue therefore is in general to enable the heart to cope with a bigger
strain, either in the shape of arterial resistance or increased venous inflow,
than it could do without the stimulus of this substance.
The wonderful adaptation of the heart to its functions is illustrated
moreover by the fact that adrenaline, which increases the metabolism of
the heart to such an extent, exercises at the same time a dilator effect on
the coronary vessels, so that apart from the high arterial pressure and the
metabolites produced by the contracting heart muscle, the vessels are
dilated by the action of the same hormone which evokes the need for an
increased flow of blood through the working muscle.
There is thus a marked antagonism in the influence of the two common
hormones on the heart, both of them being produced during general muscular
activity. Carbonic acid in excess causes dilatation of the heart, diminished
functional activity, slowing of rhythm. Adrenaline causes increased func-
tional activity, diminution of cardiac volume, and increased rhythm. The
action of adrenaline is so pronounced that it is possible to administer 20 or
30 per cent, carbonic acid to a heart-lung preparation without altering
its output, if adrenaline be administered at the same time. The heart is
slowed by the carbonic acid, but the beat is maintained and contraction is
effective in emptying the heart of its content.
THE HEART REFLEXES
The part of the nervous system chiefly concerned in the central co-
ordination of the various afferent impulses which act on the heart is the
medulla oblongata. It is in this situation that we find the nerve cells giving
origin to the efferent fibres of the vagus nerves, and also the collection of
grey matter in which the afferent fibres of the vagus terminate. Direct
stimulation of the vagus ceutre may cause slowing and stoppage of the
' heart. The tonic influence of the vagi can be abolished by destruction of this
centre. In this region we also find the vaso-motor centre, so that the
activity of one can affect that of the other. This cardiac centre may be
played upon by impulses arriving at it through various afferent nerves or
from the higher parts of the brain and uivimj; rise to the changes of the pulse
rate associated with the emotional conditions, or it may be directly affected
by the composition of the blood circulating through its capillaries.
The nerve cells, which give off the accelerator or augmentor fibres, are
situated in the interrnedio-lateral tract of the spinal cord, near the point of
origin of these fibres. We might therefore speak of an augmentor centre in
1022
PHYSIOLOGY
this region; but it seems probable that the activity of these cells is sub-
ordinate to impulses arriving at them from the common meeting-place
of visceral impulses, viz. the medulla.
The most important of the afferent nerves, which affect refiexly the
action of the heart, are the nerves coming from the heart itself and the aorta.
In the mammalian ventricle, nerve fibres can be seen running over the
surface of the ventricle which are entirely afferent, stimulation of their
peripheral ends causing no effect on the heart beat. Stimulation of their
central ends may cause one of four conditions :
(a) Slowing of the heart.
(b) Kise of blood pressure from constriction of the splanchnic area.
(c) Fall of blood pressure by dilatation of the arterioles of the body.
Sup-, lar. n. .
Depressor
I
sec.
Vagus-
Sup-, lar. n.-j
y
-S
ymp.
-Vagus
y-- Sup-. Cerv. Gang.
--Depressor
-Cerv. symp. n.
— Vago. symp.
RABBIT
DOG
Fig. 461. Diagrams of the connections of the depressor nerve in the rabhit and dog,
according to Cyon. It will bo noticed that in the latter animal the depressor nerve
runs in the vagus trunk, together with the sympathetic nerve, for the greater part
of its course.
(d) Reflex movements. The heart does not seem to be provided with the
nerves of ordinary or tactile sensibility. There is no doubt however that
under abnormal circumstances impulses arising in the heart can give rise to
sensations of pain, which are referred not so much to the heart as to the
surface of the body over the left side of the chest and left arm, in the region
of the distribution of the cutaneous branches of the second and third dorsal
roots.
An important afferent nerve coming from the heart, or rather from the
beginning of the aorta, is the depressor nerve. In the rabbit this rises by
two roots, one from the trunk and the other from the superior laryngeal
branch of the vagus, and runs parallel with the vagus to the cardiac plexus
(Fig. 461). It is purely afferent, stimulation of its peripheral end causing no
effect. On stimulating its central end, fall of blood pressure (Fig. 462) and
reflex slowing of the heart are produced, the latter effect being abolished by
section of both vagi. It has been shown by Bayliss that the depressor effect
THE NERVOUS REGULATION OF THE HEART 1023
is due to universal dilatation of the blood vessels of the body, the greater
part however being played by the splanchnic area. This nerve is probably
brought into action whenever the pressure in the aorta is so high as to con-
stitute a serious check to the expulsive action of the heart. It is stated that
under these conditions a current of action may be detected in the trunk of
the depressor nerve and that, if both depressor nerves be cut when the aortic
pressure is high, the blood pressure rises still higher. It presents a means by
which the heart can be relieved of a load too great for its powers, and there-
fore dangerous to its future welfare. In many animals the depressor fibres
are bound up with the trunk of the vagus and cannot be excited separately.
Via. 462. Blood -pressure curve from rabbit, showing effect of excitation of central
end of depressor nerve (mercurial manometer). (Bayliss.)
Stimulation of the central end of the vagus generally causes reflex slowing
of the heart through the cardiac centre and the other vagus. Inflation of
the lungs causes acceleration of the heart — whether due to diminution of
the tonic action of the vagi, or to reflex excitation of the accelerator nerves,
is not known. Most sensory nerves of the body when stimulated give either
a slowing or a quickening of the heart. Stimulation of the fifth nerve, as
in the nasal mucous membrane, always causes reflex inhibition.
There are two very important reflex mechanisms associated with the
heart itself. II the arterial pressure be raised, either by stimulation of the
splanchnic nerves or by obstruction of the aorta, the heart is slowed. In
this slowing, which is effected through the vagus, two factors are concerned.
In the first place any rise of arterial pressure within the skull raises the intra-
cranial pressure and excites the vagus centre directly. In the second place
impulses starting in the root of the aorta and in the left ventricle travel to
the central nervous system chiefly by way of the depressor fibres and cause
a reflex slowiug of the heart. According to ' Marey's law ' the pulse rate
1024 PHYSIOLOGY
varies inversely as the blood pleasure. This relation, though general, is not
universal. Thus the rise in blood pressure and the increased filling of the
heart associated with muscular exercise are attended by an increased pulse
rate. In the quickening of the heart, which accompanies bodily exercise,
another reflex mechanism comes into play, to which attention has been
called by Bain bridge. Any distension of the right auricle evokes a reflex
quickening of the pulse rate, chiefly by diminishing the vagus tone but
also probably to a less extent by reflex stimulation of the reflex accelerator
nerves. It thus seems that the heart is connected with the heart centre
in the medulla, governing its rate of beat, by two sets of afferent nerves,
which are stimulated by a rise of pressure within the cavities to which they
are distributed. Stimulation of the one set coming from the arterial end —
e. g. the left ventricle, causes a reflex slowing of the heart. Stimulation of
the other set, which are distributed to the venous end of the heart, evokes
increased frequency of the heart beat. Both these sets of impulses are of
great importance in correlating the activity of the heart and the amplitude
of the circulation with the metabolic needs of the body as a whole.
THE PULSE RATE IN MAN
The normal pulse rate in man is about 72 per minute. It is largely
influenced by bodily movements. It varies considerably with age. The
following Table represents the average pulse rate in man at different ages :
Age in years Pulse rate per minute
. . • 136
5 . . 88
10-15 . . 78
1.5-60 . . 68-72
It must be remembered that marked differences in the pulse rate may be
found in different individuals without having any pathological significance.
Thus pulse rates of 30 per minute and 120 per minute have been observed in
men who were otherwise perfectly healthy. The pulse rate is raised by
warmth and diminished by cold apphed to the surface of the skin. It is
also increased somewhat by the taking of food. The act of swallowing causes
a reflex quickening of the rate by inhibition of the tonic vagus action.
SECTION X
THE NERVOUS CONTROL OF THE BLOOD VESSELS
During muscular activity the metabolism of the body as a whole, judged
by its gaseous interchanges, may be increased six or eight fold. This
increase is due almost exclusively to the additional metabolic changes
consequent on muscular activity. The muscles therefore during activity
require a greater supply of blood in order to obtain from it the oxygen
necessary for their contraction, and to get rid of the carbon dioxide, which
is the end-result of their activity. In the same way every organ of the
body requires an increased blood supply during activity. Blood must be
diverted from the inactive to the active tissues. All parts of the body must
co-operate in subordination to the activity of that tissue whose function
for the time being is of the greatest importance to the organism. This
subordination of the part to the whole, i. e. of every part to the organ whose
activity is specially evoked by the needs of the whole organism, is chiefly
effected through the central nervous system, though local and chemical
mechanisms also play some part in the process.
Our knowledge of the nervous control of the blood vessels dates from the
discovery by Claude Bernard that nerve fibres run in the cervical sympa-
thetic to the blood vessels of the head and neck, and maintain them in a
state of tonic constriction. Bernard showed that if in the rabbit the cervical
sympathetic on one side be divided, the vessels in the corresponding ear
dilate. Vessels come into prominence which were previously invisible, and
on account of the greater flow of blood thus produced, the ear on the side
of the section becomes warmer than the normal ear. If the head end of the
divided sympathetic nerve be stimulated, all the vessels of the ear contract,
and the ear becomes colder than that of the other side. The fact, that the
dilatation of the vessels is produced by section of the cervical sympathetic
and lasts for a considerable time after any irritant effect of the section
must have passed off, shows that the ear vessels are continually under the
influence of tonic constrictor impulses proceeding to them along the nerve
fibres of the cervical sympathetic.
It can be easily shown that these impulses take their origin in the central
nervous system. The paralysis of the ear vessels, though lessening the resist-
ance to the flow of blood there, affects too small a vascular area to have
any marked influence on the total resistance of the circulation and therefore
on the arterial blood pressure. If the spinal cord be divided on a level
with the origin of the first dorsal nerve, the blood pressure sinks considerably.
65 1025
1026 PHYSIOLOGY
In the dog it may fall from 120 mm. Hg. to 40 or 50 mm. Hg. The heart
after the section beats more rapidly than before, so that the fall of pressure
must be ascribed to a change affecting the blood vessels and lowering the
resistance to the flow of blood. Since a maximal effect on the blood pressure
is produced by section of the cord at this level, one may conclude that the
tonic constrictor impulses to all the vessels of the body pass through this
segment of the cord before leaving it to be distributed to the arterial walls.
The source of these impulses may be made out by studying the effect of
sections through different levels of the nervous system. Division of the
cord at about the first or second lumbar nerve causes no effect on the blood
pressure. On making a section at the sixth dorsal root a considerable fall
of pressure is produced, almost but not quite as great as that observed after
section at the first dorsal segment ; stimulation of the lower end of the cut
cord causes almost universal vascular constriction and a large rise of blood
pressure. On the other hand, the fall of pressure is maximal when the
section is carried through the first dorsal segment or through any part of the
cervical cord. Section of the crura cerebri, or of the brain stem at the upper
border of the fourth ventricle, leaves the blood pressure unaffected. Destruc-
tion of a small region of the medulla situated on each side of the middle line
in the neighbourhood of the facial nucleus, i. e. in the forward prolongation
of the lateral columns after they have given off their fibres to the decussating
pyramids, causes an immediate and maximal lowering of the blood
pressure.
We must therefore conclude that all the vessels in the body. are kept
in a state of tonic contraction by impulses arising in this portion of the
medulla oblongata, travelling down the cord as far as the dorsal region, and
then passing out of the cord by the dorsal and upper lumbar nerves. This
conclusion is confirmed by the fact that, whereas stimulation of the anterior
roots of the cervical and lower lumbar and sacral nerves has no influence on
the blood pressure, a rise of arterial pressure can be obtained by stimulating
any of the anterior roots from the first or second dorsal to the second or
third lumbar. The same effect is produced by stimulation of the white
rami communicantes from these roots to the sympathetic system, or by
excitation of the sympathetic system itself.
The portion of the medulla concerned with the sending out of the tonic
vaso-constrictor impulses is spoken of as the vaso-motor centre. In this
region it is exposed to and played upon by afferent impulses from all portions
of the body, from the higher centres of the brain and the cortex cerebri, and
especially by afferent impulses travelling by the vagi from the viscera of
the chest and abdomen. Whether in the absence of all afferent stimuli the
centre would be active is doubtful; all we know is that the sum of the
stimuli arriving at the centre produces a state of average continued activity,
which is responsible for the maintenance of arterial tone and for the regulation
of the arterial blood pressure.
The centre may also be affected directly by changes in its blood supply,
or in the composition of the blood flowing through it. Thus anything which
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1027
interferes with tire gaseous exchanges of the centre, whether obstruction to
respiration, absence of oxygen in the air breathed, or a failure of the blood
supply as by ligature of the cerebral arteries, calls forth an increased state
of activity of the centre. This can be best studied by observing the changes
in the blood pressure produced in a curarised animal by the cessation of
artificial respiration.
These changes depend partly on the stimulation of the vaso-motor and
vagus centres by the venous blood, and partly on the affection of the heart
itself. We will first consider them with both vagi cut, in order to shut
out the action of the vagus centre. The blood pressure is registered by
means of a mercurial manometer in connection with the carotid artery.
On leaving off the artificial respiration, the blood pressure may remain
at the same height for some seconds, the only change noticed being the
absence of the respiratory oscillations. Sooner or later the blood pressure
suddenly rises rapidly (Fig. 463, a), and in another ten seconds may
reach a height twice as great as it was previously. The heart beats a little
more forcibly in consequence of the increased cardiac tension, but its fre-
quency is almost unaltered. The blood pressure remains at this height
for about a minute and then gradually falls, the heart beats becoming
smaller and smaller until the pressure has sunk to a point very little above
the abscissa line (level of no pressure). This fall in pressure is due to the
fii Hi, re of the heart. The heart, badly supplied with oxygen, cannot overcome
the high resistance presented by the contracted arterioles; it gets overfilled,
and gradually loses the power of expelling any of its contents. If, when the
blood pressure has sunk to its lowest point, the heart be rapidly cut out of the
bodj it will begin to beat fairly forcibly, being relieved of the excessive
internal tension. The vessels however remain constricted until the death
of the animal. This is shown by two facts. If, while the pressure is sinking,
artificial respiration be recommenced, the heart supplied with oxygen at once
begins to beat more forcibly, and the blood pressure may rise to an e in
er height than immediately after the commencement of the asphyxia.
Agahij if the volume of the kidney be recorded by means of the oncometer,
the rise of general blood pressure produced by asphyxia is seen to be accom-
panied by a .marked shrinking of the kidney, and this shrinking endures until
the animal dies, showing that the fall of blood pressure following the rise
is due, not to a giving way of the arterial resistance, but to failure of the
heart.
Similar results are obtained when the vessels to the brain are ligatured,
or when the animal has to respire an indifferent gas free from oxygen, such
as nitrogen (Fig. 463, b) or hydrogen. In the imcurarised animal the rise
of blood pressure is associated with increased respiratory movements and
finally with convulsive spasms which may involve practically every muscle
of the body.
We have spoken above of the phenomena of asphyxia as being due to
the circulation of venous blood. There are however two factors which may
be concerned and which may influence the medullary cent res and the heart.
I (US
PHYSIOLOGY
When the renewal of the lung ventilation is stopped by ligature of the
trachea or by cessation of the respiratory movements, the increasing venosity
of the blood involves a diminished percentage of oxygen and an increased
percentage of carbon dioxide; and when asphyxia is excited by cessation
of the circulation through the medullary centres, these centres may suffer
at the same time from lack of oxygen and from the accumulation of carbon
dioxide. The question arises whether one or both of these factors are con-
cerned. It is easy to investigate the action of each separately. A pure
oxygen lack may be brought about by allowing an animal to breathe some
inert gas, such as nitrogen or hydrogen, or in the curarised animal one of thesa
gases may be administered by the pump used for artificial respiration. The
effects of accumulation of carbon dioxide in the blood and tissues may be
A
200 *
wmmmmtt \
r
A
/
-150 on
ml
r
t
1 1
Resp. off
MM I
-100
M M J
Fig. 463. Blood-pressure changes in a cat. A, after cessation of respiratory move-
ments. B, as a result of artificial respiration with nitrogen. (Mathison.)
produced by the administration of gaseous mixtures containing excess of
oxygen, i. e. 30 to 40 per cent., with varying percentages of carbon dioxide.
In the first case, the tension of the carbon dioxide in the blood will be kept
below normal; in the second case, the tension of oxygen in the blood will
be kept above normal. In order to obtain results uncomplicated by the
influence of anaesthetics, the experiments may be carried out in animals
which have been deprived of consciousness by destruction of the brain above
the superior corpora quadrigemina. At different times physiologists have
been inclined to ascribe the excitatory phenomenon of asphyxia either to
absence of oxygen or to excess of carbon dioxide. Mathison has shown that
both conditions may concur in the production of the rise of blood pressure
in asphyxia. In Figs. 463 and 464 the rise of arterial pressure produced by
a short period of asphyxia is compared with that produced by oxygen lack,
by a surplus of carbon dioxide, and by the injection of lactic acid into the
circulation. There are certain minor details in these curves which are of
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1029
interest. When the oxygen of the lungs is rapidly washed out with a neutral
gas, the asphyxial rise conies on about half a minute later than it would
with pure asphyxia. In the latter case it seems that the first rise is due
to the accumulation of carbon dioxide. The rise however under nitrogen,
when it occurs, is extremely abrupt, and the subsequent fall of blood pressure,
i. e. the heart failure, is earlier in onset and more rapid than with ordinary
asphyxia. When excess of carbon dioxide is administered, i. e. 5 to 10
per cent., a marked rise of pressure occurs which, like that produced by
oxygen lack, is almost entirely conditioned by stimulation of the vaso-motor
centres and resulting constriction of the peripheral arterioles. If a loop of
intestine be placed in a plethysmograph, it will be seen that the rise of
A
220-
/A.
-/
i
hoo-
on
I'l 1 1 1
C0 2 12- 4 per cent
2 30 per cent
i i } n n n i
-220
V
Lactic
2c.c.M
15
i i i I I
Fig. 404. Asphyxial blood-pressure changes in cuiarised cat. A, inhalation of
C0 8 . B, injection of lactic acid. (Mathison.)
pressure coincides with a shrinkage in volume of the intestine, pointing to
a vascular constriction (Fig. 465). The rise of blood pressure due to the
vascular constriction may be maintained for a considerable period, e. g. ten
to fifteen minutes, and we do not get the rapid fall of pressure due to failure
of the heart that is observed in an ordinary asphyxia tracing. If partial
oxygen lack or abnormally increased tension of carbon dioxide be continued
for some time, a state of narcosis or paralysis finally ensues which affects
not. only the higher centres but also those of the medulla, so that death may
result without convulsions or excessive rise of blood pressure.
Is there any common factor in the two conditions of oxygen lack and
carbon dioxide excess, which may account for the similarity in their effects ?
It has been shown that, whenever there is a deficiency of oxygen, the metabo-
lism of the tissues undergoes alteration, so that as a result of activity, e. g. in
muscles, lactic acid is formed instead of carbon dioxide. Lactic acid can
1030
IMIYSloUXiY
Jnf. Vol.
i off
*^«*,V'"*%/ VV -100
B.P.
C0 2 7%
therefore be detected in the blood whenever violent exercise is taken sufficient
to produce dyspnoea, or when the access of oxygen is diminished by poisoning
with carbon monoxide, or by reducing the tension of this gas in the air
breathed. Oxygen lack can bo regarded therefore as synonymous with the
production of lactic acid. Lactic acid
introduced into the blood stream, as
is shown in the curve in Fig. 464, B,
is equally efficacious with oxygen lack
or with carbon dioxide excess in the
production of a rise of blood pressure
indistinguishable from the asphyxia!
rise. It seems therefore that the
common factor in asphyxia is the
increased acidity or H' ion concen-
tration of the blood. We shall have
occasion to return to this question in
dealing with the regulation of the
respiratory movements.
If in the dog, and to a less extent
in other animals, the vagi be left
intact, the blood pressure tracing
during asphyxia has quite another
appearance. At the point of the
tracing, corresponding to the rapid
rise in the previous experiment, there
is in this case only a slight rise of
pressure, but the heart begins to beat
very slowly. At each beat it neces-
sarily sends out a greater volume of
blood than when it is beating more
frequently, and hence the oscillations on the blood pressure curve caused by
the heart beats become very large. This slow beat is due to the action of the
vagus centre, and is at once abolished by section of the two vagi. The sparing
of the heart by means of this vagus action enables it to last longer, and
the final fatal fall of blood pressure due to heart failure comes on rather
later than when the vagi are divided. In the increased vagus action, which
occurs during asphyxia, two factors are probably involved. The cardio-
inhibitory centre in the medulla probably partakes of the general excita-
tion of the medullary centres due in the first place to carbon dioxide excess,
in the second to oxygen lack. More important is the direct action of the
rise of blood pressure on the medullary centre. The rise of arterial pressure
causes increased mtracranial tension, and any increase of the latter excites
the vagus centre and produces slowing of the pulse. The vagus slowing
is therefore absent in asphyxia if the arterial blood be allowed to escape
through a mercury valve so as to prevent any rise of pressure in the brain
cavity.
on
Fio. 465. Tracing of arterial blood
pressure and of intestinal volume,
to show the influence of a moder-
ate increase in the C0 2 tension of
' the blood. (Mathison.)
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1031
During the period of increased pressure, waves are often observed on the
blood-pressure curve. These are of two kinds. In completely curarised animals
we may observe oscillations of blood pressure, corresponding with the respira-
tory rhythm before the administration of curare, or if the vagi are cut, presenting a
rhythm similar to that usual in animals with divided vagi. They are certainly due to
irradiation of impulses from the excited respiratory centre to the vaso-motor centre in
the medulla. In fact if the curarisation is not complete, a slight twitch of the diaphragm,
insufficient by itself to have any mechanical influence on the circulation, may be observed
to accompany each rise on the blood-pressure curve. Besides these curves others are
occasionally seen which must arise in a slow rhythmic variation of the constrictor
impulses sent out from the vaso-motor centre. These waves are known as the Traube
curves and are not to be confused with the waves on an ordinary pressure curve due to
respiration, being much slower in their rhythm than the latter. They are observed not
Fig. 406. Blood-pressure tracings showing Traube curves
only dining asphyxia, but may occur in blood-pressure tracings from normal dogs, and
are frequent in dogs poisoned with morphia. Fig. 466 represents tracings obtained from
under I In' influence of morphia and curare. The upper curve, taken while artificial
ation was being carried en, shows the three forms of curves — the oscillations due
to the heart beat next in size those due to the respiratory movements, which in their
t in ii arc superposed on the slow prolonged curves. The lower curve is taken immediately
alter cessation of the artificial respiration and shows only the heart beats and the
Traube curves. The presence of these waves may generally be ascribed to a state of
abnormal excitation of the vaso-motor centre. This excitation may arise in various
ways. A very frequent cause is the one just described, viz. increased venosity of the
blood supplied to the centre. Well-marked Traube curves are often observed in cases
of hemorrhage. In spite of the loss of blood, the vaso-motor centres maintain a normal
arterial blood pressure by means of vascular constriction. As the bleeding continues.
this means becomes inadequate, and at this point the ' efforts ' of the centres take on a
rhythmic character, giving well-marked Traube curves, just as the arm of a man holding
up a weight begins to shake before he is obliged to give way through fatigue. If the
bleeding still continues, the pressure sinks steadily and the curves disappear. The
ourves may also be often observed during operations involving exposure of the cord,
and may possibly be ascribed in this case to abnormal irritations ascend im; the posterior
columns.
The vaso-motor centre may also be directly affected by drugs such a.s digitalis or
Btrophanthus, both of which cause a rise in general blood pressure from stimulation
of the centre.
1032
PHYSIOLOGY
SPINAL CENTRES
The great fall of blood pressure observed after section of the cord in the
lower cervical region is not permanent. After one or two hours the pressure
begins to rise, and if the animal be kept alive may attain a height only a
little inferior to that found in normal animals.
If the spinal cord of such an animal be destroyed, the blood pressure
sinks practically to zero and the circulation comes to an end, because the
animal lias been, so to speak, bled to death into its own dilated blood vessels.
In addition to the chief vaso-motor centre in the medulla there is a series
of subsidiary centres in the spinal cord, centres which we may probably
locate in the portions of grey matter situated in the lateral horns of the
cord and giving origin to the fibres which go to make up the white rami
iosecs
Fig. 407. Blood-pressure tracing taken by a mercurial manometer from carotid
artery of a dog, three hours after section of the cord, just below the medulla
oblongata. At o the artificial respiration was discontinued. A general spasm
of the skeletal muscles occurred between x and x. The muscles then relaxed,
and were flaccid during the rest of the rise of blood pressure.
communicantes. By means of these spinal centres a certain degree of
adaptation is possible between the blood supply of the various parts of the
trunk. The important co-ordination between the state of the blood vessels
and the condition of the central pump, the heart, is however wanting,
since the blood vessels are now cut off from the cardiac centres and from
the part of the central nervous system which receives the afferent impulses
carried by the vagi.
The spinal centres, like the chief vaso-motor centre, are susceptible to
changes in the composition of the blood supplied to them. If an animal be
kept alive by means of artificial respiration for a little time after division
of the cord just below the medulla, the blood pressure slowly rises as the
spinal centres begin to take on their automatic f mictions. If artificial
respiration be now discontinued the asphyxia excites the centres of the cord.
The motor discharge to the skeletal muscles reveals itself in a single prolonged
spasm, since the respiratory centre is unable to take any part in directing the
motor discharges. Simultaneously with the spasm of the skeletal muscles
general constriction of the blood vessels occurs which outlasts the muscular
spasms and causes a considerable rise of blood pressure (Fig. 467).
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1033
In this rise of pressure the main factor is lack of oxygen, and precisely
similar curves are obtained whether the asphyxia be produced by cessation
of artificial respiration or by administration of nitrogen. The same effect
may be produced by a very large excess of carbon dioxide, or by the injection
of acids into the circulation. There is a striking difference between the
sensibility of the spinal centres to these substances as compared with the
medullary centres. Thus the medullary vaso-motor centre is readily
i'xi ited by ventilation with 5 per cent, carbon dioxide, whereas a rise of
blood pressure is obtained from the spinal animal only when mixtures con-
taining 25 per cent, and upwards of carbon dioxide are employed. The
excitation of the medullary centre comes on about thirty seconds after the
administration of nitrogen has commenced, in contrast to that of the spinal
centres which does not occur until two minutes or more have elapsed. In
the intact animal a maximal stimulation of the vaso-motor centre is pro-
duced in the cat by the injection of 2 c.c. N/20 lactic acid, whereas 5 c.c.
of X 2 acid are required to excite spinal cord centres. Here therefore, as in
the medulla, the common factor is probably increased H ion concentration,
the excitation threshold for the medullary centres being only about one-
fifth that of the spinal centres.
The local spinal centres are connected with the medullary vaso-motor
centre on each side by tracts of nerve fibres which descend in the lateral
columns of the cord.
THE PERIPHERAL TONE OF THE BLOOD VESSELS
Division of the sciatic nerve causes an immediate dilatation of the
vessels of the lower limbs in consequence of their severance from the tonic
activity of the vaso-motor centres. This dilatation passes off in a day or
two and the vessels acquire a tone, i. e. remain in a state of average constric-
t ion which can be increased or diminished by local conditions. This recovery
of tone has been ascribed by many physiologists to the existence of a third
set of nerve centres in the walls of the arteries. In the absence of any
direct histological evidence of the existence of such centres, it seems more
rational to ascribe the tonus to the automatic activity of the muscular fibres
themselves.
THE COURSE AND DISTRIBUTION OF THE VASO-MOTOR NERVES
Since the blood vessels, like the heart, are the seat of an automatic
activity, complete nervous control of these tubes can be secured only by the
provision of two sets of nerves : one set — augmentor or motor — which will
increase the state of constriction of the vessels; another set — inhibitor or
dilator — which will diminish the tone of the arteriole muscle and cause
vascular dilatation. Our knowledge of the existence of this second class
of nerve fibres to the vessels we owe also to Claude Bernard, who observed
that stimulation of the chorda tympani nerve not only evoked secretion
from the submaxillary gland but also increased the blood flow through its
vessels five or six fold. Subsequent researches have revealed the fact that
1031
PHYSIOLOGY
nearly all the vessels of the body receive vaso-constrictor fibres, and that
many receive also vaso-dilator fibres. In order to determine the course
and distribution of the vascular nerves, it is necessary to have means at our
disposal for investigating the condition of the blood flow through different
parts and organs of the body.
Let us see what effects will
ensue on the local circulation
by constriction or dilatation
of the arterioles with which
it is supplied. If the arte-
rioles a in the organ b
dilate (Fig. 468), the first
effect is a diminution of the
resistance to the flow of
blood into the capillaries
beyond. Supposing that the
arterial pressure in the trunk
c remains constant, a local
diminution of resistance in
A will at once determine an increased flow of blood through the arterioles,
and the fall of pressure from A to the capillaries will be less than when
the arteriole was constricted. If the organ is distensible and elastic, the
increased pressure in the arterioles and capillaries will cause dilatation of
these vessels, and a consequent dilatation of the whole organ. The same
effect on intraeapillary pressure, and therefore on the volume of the part,
may be caused by obstruction to the flow of blood from the veins.
Provided that there is no obstruction to the flow of blood through the vein, and
that the general blood pressure in c remains constant, dilatation of an
organ may be taken as an expression of vaso-dilatation in the arteries
with which it is supplied. The diminution of the resistance in A may also
increase the velocity of the flow through the part, since the amount of blood
flowing in a given period of time through any vessel varies directly as the
difference of pressure, and inversely as the resistance in the vessel.
We can therefore use the following criteria for the occurrence of a vaso-
dilatation in the arterial supply to any part or organ :
(1) If the surface of the part is translucent, the increased filling of the
blood vessels will cause redness or blushing.
(2) The increased size of the vessels will cause an increase in the volume
of the organ concerned.
(3) An increased velocity of blood flow will, if the part be normally
below the temperature obtaining in the central organs of the body, raise its
temperature, and vaso-dilatation can thus be detected by the application of
the hand or of a thermometer.
(4) Any of the methods mentioned in a previous chapter may be used
to determine the velocity in the arteries going to the part, and an increased
velocity may be interpreted as due to vaso-dilatation.
(5) The increased flow through the part may be detected by cutting
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1035
the main efferent vein and measuring the total volume of blood which flows
from it- in a given time.
Of these methods the two most used are those based on determination
either of the volume of the part, or of the venous outflow from the part.
A fallacy may however arise, unless means be taken to ensure that the
general arterial pressure remain constant during the experiment. A rise
of geseral blood pressure will cause an expansion of the vessels and of the
part supplied, and also increased velocity of blood flow through the part.
In all cases therefore where it is desired to investigate the conditions of the
local circulation, it is necessary to combine a determination of the general
blood pressure with some means of estimating changes in the local conditions.
We may take as an instance an experiment on the blood supply to the
kidney.
to oncometer
Fio. 469, Diagram of oncometer.
Fig. 470. Diagram of oncograph.
For this purpose we may use a kidney plethysmograph or oncometer. The structure
of Roy's oncometer is shown in Fig. 469. The oncometer is a metal capsule, the two
halves of which an- hinged together and come in contact at the whole of their circum-
ference except at h, where a small depression is left in each half for the passage of the
kidney vessels and ureter. A piece of peritoneal membrane is attached to the rim of
each half of the oncometer, the space between this and the brass capsule being filled
with warm oil. The kidney rests in the oncometer on tliis bed of warm oil, from which
it is separated by a membrane. A tube leads from the cavity between the brass capsule
and membrane to a registering apparatus, or oncograph (Fig. 470), which is a piston
recorder containing oil. Any swelling of the kidney will drive oil out of the oncometer
into the cylinder of the oncograph and so raise the piston, the excursions of which are
recorded by a lever writing on a blackened surface.
Schafer's plethysmograph (Fig. 471). which can be adapted to almost any organ of
the body, is made, of vulcanite 1 previously moulded to the. size of the organ whose
volume is the object of investigation. In one side of the box a depression is left sufficient
to accommodate easily the vessels, nerves, or ureter going to the organ. The oncometer
i red «illi a jlass lid which is made air-tight by means of vaseline, the space
between the lid and the vessels being also packed with cotton- wool and vaseline. A
ulass tube is fixed into i corner of the plethysmograph and leads to a piston recorder
"i tambour. Every variation in the volume of the organ causes a movement of air into
or out of the oncometer and thus gives rise to a corresponding movement of the recording
lever.
1 A very good material for this purpose is 'Stent's composition,' used by dentists
for taking a mould of the jaw in fitting artificial teeth.
1036
PHYSIOLOGY
The kidney being placed in some such apparatus, a cannula is inserted
in the carotid artery and connected with a mercurial manometer, so that
two tracings are obtained at the same time on the moving blackened surface.
Fig. 471. Diagram of Schafer's air plethysmograph.
In the Figure given (Fig. 472), the upper curve represents the carotid blood
pressure, while the lower is the tracing of the oncograph lever. At the
beginning of the experiment the lower dorsal nerve roots had been dissected
out and prepared for stimulation. The peripheral end of the anterior root
Blood pressure
Kidney volume
Fig. 472. Simultaneous tracings of- carotid blood pressure and volume of kidney.
Between X and X the peripheral end of the divided tenth dorsal nerve was
stimulated. Time-marking = seconds. (Bradford.)
of the tenth dorsal nerve was excited by means of an interrupted current
at the point marked with a cross on the tracing. This stimulation was
followed by a rise of blood pressure together with a diminution in the kidney
volume. The increased blood pressure would by itself tend to force more
blood into the kidney and so increase its volume. The fact that the kidney
volume diminished shows that there must have been active contraction of
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1037
the arterioles of the kidney, emptying this organ of blood and so causing it
to decrease in size. This contraction of the vessels would tend to cause a
rise in general blood pressure and must have taken some part at any rate
in the rise actually observed. If the oncometer in this experiment had
been used alone, it would have been impossible to determine whether the
shrinkage of the kidney might not be due to a lowering of general blood
pressure, in consequence of vaso-dilatation occurring elsewhere, or in con-
sequence of the failure of the heart's activity. On the other hand, without
the oncometer it would have been possible to determine only that there
was increased peripheral resistance somewhere or other in the body.
Instead of taking the volume of the kidney, we might have determined the blood
flow through its vessels either directly by means of a cannula in the renal vein, or by
the indirect method of Brodie. This method depends on the fact that under normal
conditions the amount of blood leaving an organ is equal to that entering it during any
short space of time. If the efferent vein be clamped for five or ten seconds, the blood
entering the organ during this time cannot escape, and therefore accumulates in the
organ and increases its volume. If the organ be in a plethysmograph, the increase of
volume during this period may be measured and is exactly equal to the volume of blood
passing through the artery into the organ during the five or ten seconds of the closure.
The vein must not be obstructed too long, otherwise the increasing distension of the
organ will appreciably increase the resistance to the entry of blood, and so diminish the
velocity of the blood in the artery.
The direct determination of the venous outflow is not well a'dapted to large organs
on account of the very rapid loss of blood which occurs through the open vein. The
method is however of great value in dealing with the circulation through small organs
such as the submaxillary glands. In such a case it is usual to hinder or prevent the
clotting of the blood by the preliminary injection of leech extract, and then, after
placing a cannula in the efferent veins of the organ, to allow blood from the cannula
to drop on to a mica disc attached to a Marey tambour. This tambour is connected
by a tube with a registering tambour, every drop on the -disc giving rise to a small
elevation of the lever of the second tambour.
COURSE OF THE VASO-CONSTRICTOR FIBRES
In investigating the course of the vaso-constrictor fibres we have to
detennine :
(1) The origin of the fibres from the central nervous system;
(2) The course of the fibres on their way to their peripheral distribution
in the blood vessels;
(3) Their connections with nerve cells.
The two first details can be found by stimulating various nerves and
nerve roots in different parts of their course and observing the effects pro-
duced on the local and general circulation. The importance of the third
heading is due to the fact that the vascular nerves, like the visceral nerves
generally, do not have their last cell station in the spinal cord. The fibres
carrying vaso-constrictor impulses, on- leaving the cord, do not pass direct
to the blood vessels, but come to an end in a collection of ganglion cells,
which may belong to the main chain of the sympathetic, or be situated more
peripherally and belong to the group of collateral or peripheral ganglia.
1038 PHYSIOLOGY
These fibres, as they leave the central nervous system, are small medullated
nerves. They end in the ganglion by arborising round ganglion cells,
whence a fresh relay of fibres starts and carries the impulses on to the
muscle fibres of the blood vessels. The post-ganghonic fibres differ from
the pre-ganglionic fibres in being non-medullated.
The discovery of the ganglia, with which any given set of nerve fibres
is connected, is rendered easy by the fact that in many animals the sympa,-
thetic ganglion cells are paralysed by nicotine (Langley). The nicotine
may be painted on the ganglion or may be injected into the blood stream.
The first effect of the drug is. a powerful stimulation of the ganglion cells,
so that, if the drug be injected, there is an enormous rise of blood pressure
owing to the universal vaso-constriction that is produced. The stimulation
gives place to a condition of paralysis; the blood pressure falls below
normal, owing to the cutting off of the peripheral vascular nerves from the
vaso-motor centre. Stimulation of the pre-ganglionic fibres is now without
effect, although the normal results follow stimulation of the post-ganghonic
non-medullated fibres.
By these methods it has been determined that all the vaso-constrictor
nerves of the body leave the spinal cord by the anterior roots of the spinal
nerves from the first dorsal to the third or fourth lumbar inclusive. From
the roots they pass by the white rami communicantes to the ganglia of the
sympathetic chain lying along the front of the vertebral column. Here
they take different courses according to their destination.
The fibres to the head and neck leave by the first four thoracic nerves,
pass into the sympathetic chain through the ganglion stellatum and ansa
Vieussenii to the inferior cervical ganglion, and up the cervical sympathetic
trunk to the superior cervical ganglion. Here they end, and the impulses
are carried by a fresh relay of fibres, which start from cells in this ganglion
and travel as non-medullated fibres on the walls of the carotid artery and
its branches.
The constrictors to the fore limb in the dog leave the cord by the white
rami of the fourth to the tenth thoracic nerves. The fibres run up the
sympathetic chain to the stellate ganglion, where they all end in synapses
round the cells of this ganglion. The impulses are carried on by non-
medullated fibres along the grey rami of the sympathetic to the cervical
nerves which make up the brachial plexus, and run down in the branches of
this plexus to be distributed to the vessels of the fore limb.
The constrictor impulses to the hind limb in the dog arise from the
nerve roots between the eleventh dorsal and third lumbar roots. All
the fibres end in connection with cells in the sixth and seventh lumbar
and first and second sacral gangha of the sympathetic chain, whence
the impulses are carried by grey rami to the nerves making up the sacral
plexus.
The most important vaso-motor nerve of the body is the sjjlanchnic
nerve. This nerve receives most of the fibres forming "the white rami from
the lower seven dorsal and upper two or three lumbar roots, the latter fibres
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1039
often taking a separate course as the lesser splanchnics. The fibres can be
seen to pass through the sympathetic chain of the thorax without inter-
ruption, and for the most part have their cell station in the large ganglia,
especially the semilunar ganglia, of the solar plexus, whence a thick mesh-
work of non-medullated fibres is distributed along all the vessels of the
abdominal viscera. The area of the vessels innervated by this nerve is so
large that section of this nerve on each side causes a considerable fall in the
general blood pressure. This fall is more marked in animals such as the
rabbit and other herbivora, in which the alimentary canal is proportionately
very much developed and has a correspondingly large blood supply.
VASO-DILATOR NERVES
(Since the arteries are in a constant condition of moderate contraction,
a dilatation might be brought about by a relaxation of this tone by an
inhibition of the normal constrictor impulses proceeding to the vessels from
the vaso-motor centre. We find however in many parts of the body
evidence of the existence of a nerve supply to blood vessels antagonistic
in its function to the vaso-constrictors. Thus, if the chorda tympani nerve
going to the submaxillary gland be cut, no change is evident in the blood
vessels of the gland. But if its peripheral end be stimulated, there is instantly
free secretion of saliva from the gland, and all the blood vessels are largely
dilated. In consequence of this dilatation the blood rushes through the
capillaries so quickly that it has no time to lose much of its oxygen; the
blood flowing from the vein is therefore bright arterial in colour, and is
increased to six or eight times the previous amount. If atropine be injected
into the animal, the action of the chorda tympani on the blood vessels is
unaffected, although the secretion on stimulation is abolished. The chorda
tympani is therefore said to contain vaso-dilator fibres for the vessels of the
submaxillary gland. Other examples of vaso-dilator (or dilatator) nerves
are the small 'petrosal nerve to the parotid gland, the lingual nerve to the
blood vessels of the tongue, and the nervi erigentes or pelvic visceral nerves
to those of the penis.
The course of these typical dilator nerves differs widely from that of the
constrictors. Whereas the latter leave the central nervous system over a
limited area of the cord, the vaso-dilators take their origin together with
any of the cerebro-spinal nerves. Thus the chorda tympani fibres, and
probably those contained in the petrosal nerve, arise from the nervus inter-
medius between the seventh and eighth cranial nerves. The nervi erigentes
leave the lower end of the cord by the anterior roots of the second and third
sacral nerves. All of them, like the vaso-constrictors and probably all
visceral nerve fibres, are interrupted by ganglion cells before reaching to
their destination. These cells however he, not in the lateral chain of the
sympathetic, with which the nerves have no connection at all, but peri-
pherally, and are generally embedded in the organs to which the nerves are
distributed. Thus the chorda tympani fibres to the submaxillary glands are
1010
PHYSIOLOGY
interrupted by cells embedded in the gland itself. The nervi erigentes pass
to ganglion cells in the hypogastric plexus lying on the neck of the bladder.
Whether any large numbers of the fibres making up the sympathetic
system of nerves are vaso-dilator in function is still uncertain. In the dog
dilatation f>f the vessels of the soft palate and gums can be produced by
stimulation of the cervical sympathetic of the same side, or of the stellate
ganglion or its rami communicant es. The effect has not yet been observed
in any other animals. It is probable that the splanchnic nerves convey vaso-
dilator fibres to the vessels of the abdomen, since stimulation of these nerves
may cause a fall of blood pressure, provided that the constrictor fibres, which
predominate, have been paralysed by the previous administration of large
doses of ereotoxin, derived from ergot.
K
/
Nerve freshly divided.
Constriction.
Nerve four days degenerated.
Dilatation.
Fig. 473. Plethysmographic tracing of hind limbs, shewing effect of stimulating
the sciatic nerve on the volume of the limb. A, immediately after section of the
nerve; B, four days after section. The nerve was stimulated betweeen the two
vertical lines. Curves to be read from right In left. (Bowditch and Warren.)
The presence of vaso-dilator fibres in the nerves going to the limbs has
been the subject of much debate. Since these nerves contaiu also con-
strictor fibres, the effect of the constriction overpowers any effects due to
simultaneous stimulation of possible dilator fibres. Moreover the dilators
apparently do not conduct any tonic influences to the blood vessels, so that
the only effect of section of a mixed nerve is that due to the removal of the
tonic constrictor influences, and the vessels in the area of distribution of
the nerves are dilated.
Various methods have been employed to show the presence of dilator
fibres in such a mixed nerve trunk. Of these the chief two are those depend-
ing on the unequal time taken for the two sets of fibres to degenerate and
on the varying excitability of the two sets of fibres to different kinds of
stimulation. Thus, if the sciatic nerve be cut, a primary dilatation of the
vessels of the leg and foot is produced which however passes off after two
or three days. If now the peripheral end of the divided nerve be stimulated,
dilatation of the vessels is brought about (Fig. 473). Apparently the con-
strictor fibres degenerate before the dilator fibres so that, at a certain period
after the nerve section, only the latter respond to stimulation. On the
other hand, it is often possible in the freshly cut nerve to obtain dilatation
by stimulating its peripheral end with induction shocks repeated at slow
intervals — one to four per second. The effects of different rates of stimula-
tion on the limb nerves of the cat are shown in Fig. Hi.
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1041
When we endeavour to trace these limb dilator fibres back to the cord,
we find no trace of their passage through the sympathetic system. It was
shown by Strieker and Morat that dilatation of the vessels of the hind limb
can be produced by stimulating the posterior roots of the nerves going to the
limb, i. e. far below the point of origin from the cord of the constrictor fibres
to the same part of the body. Since it has been definitely shown by embryo-
logists and histologists that in higher mammals all the fibres making up the
posterior roots have their origin in the cells of the posterior root ganglion,
this observation was widely discredited, until it was confirmed by Bayliss
Flo. 474. Effect on the volume of the hind limbs of the eat of stimulating the sciatic
nerve with induction shocks at different rates. It will be noticed that with one
shock per second there is hardly any constriction, but considerable dilatation,
whereas with <>4 shocks per second the only effect produced is vaso-eonstriction.
Curves to be read from right to left. (Bowditcii and Waiiren.)
for all manner of stimuli. Stimulation of the posterior roots, either before
in after they have passed through the ganglia, causes dilatation of the vessels
in the area of the supply qf the roots, whatever be the nature of the stimulus
employed, whether electrical, chemical, or mechanical (Fig. 175). This effect
is not destroyed by previous section of the posterior roots on the proximal
Bide of the ganglia, showing that the fibres by means of which the dilatation
is produced have the same origin and course as the ordinary sensory nerves
to the limbs. Since the vaso-dilator impulses pass along these nerves in a
direction opposite to that taken by the normal sensory impulses, Bayliss
lias designated them as antidromic impulses. So far this phenomenon of
a nerve fibre functioning (not merely conducting) in both directions is
almost without analogy in our knowledge of the other nerve functions of
(ifj
1042
PHYSIOLOGY
the body. There is do doubt however that similar antidromic impulses are
involved in the production of the so-called trophic changes, such as localised
Fig. 475. Effect of excitation of peripheral end of the seventh lumbar posterior
root in the dog. (Bayliss.)
Uppermost curve, volume of left hind limb; next below, arterial blood
pressure; the third line marks the period of stimulation; bottom line, time-
marking in seconds.
erythema or the formation of vesicles (as in herpes zoster), which may occur
in the course of distribution of a sensory nerve, and is always found to be
associated with changes, inflammatory or otherwise, in the corresponding
sup. nerve p/ex.
Fig. 476. Diagram to illustrate the production of vasodilatation in the area
of distribution of a sensory nerve.
prg, posterior root ganglion; sens.nf, sensory nerve fibre, branching to supply
dilator fibres to the skin arteries, and sensory fibres to the skin.
posterior root ganglion. Moreover evidence has been brought forward that
these fibres may take part in ordinary vascular reflexes of the body, that
in fact they are normally traversed by impulses in either direction.
Some observations by Hans Meyer and Bruce tend to indicate that in
the antidromic vaso-dilatation, as well as in the reddening and inflammatory
changes ensuing on local excitation, we are dealing with axon reflexes, perhaps
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1043
the only remains of the local reflexes of a primitive peripheral subcutaneous
nervous system. If croton oil or mustard oil be applied to the skin or to the
conjunctiva, redness, swelling, and all the signs of a local inflammation are
produced. The course of events is not altered by destruction of the central
nervous system or by section of the sensory nerve roots (posterior spinal
root or trigeminus) on the central side of the ganglion. If however they
be divided peripherally of the ganglion, and time be allowed for complete
degeneration of the nerve fibres to their peripheral terminations, the applica-
tion of croton or mustard oil, even to the delicate conjunctiva, is without
effect. The same results may be produced if the peripheral terminations of
the nerves be paralysed by the subcutaneous injection of local anaesthetics.
We must assume that the axons of the peripheral sensory nerves branch,
some branches going to the surface, others to the muscle cells of the cutaneous
arterioles, as indicated in the"diagram (Fig. 476).
^wjtmi^
^»*^ lM *^ta» Mta ,
FlG. 477. Blood-pressure curve from carotid of dog. Between the arrows the
central end of a sensory nervt was stimulated. (Hurtkle's manometer.)
Gaskell has drawn an analogy between the nerves distributed to the
blood vessels and those going to the heart, which is indeed only a specialised
part of the general blood tubes of the body. These nerves, according to
their action on the metabolic activity of the. tissues supplied, are divided by
Gaskell into anabolic and catabolic nerves. The anabolic nerves, as indicated
bv their name, cause a building up or regeneration of the contractile tissue.
They therefore act as inhibitory nerves. This class would include the vagus
and the vasodilator fibres. The catabolic nerves cause an increased activity
of the contractile tissue, and active contraction is associated with and
derives its energy from disintegration or catabolism of the muscular
substance. An ordinary motor nerve to a muscle is therefore a catabolic
nerve. This class would include the accelerator nerves to the heart, and
the vaso-constrictors. The course of these two sets of nerves bears out this
comparison, the path taken by the accelerator nerves being identical at
first with that of the vaso-constrictor fibres to the head and neck.
VASO-MOTOR REFLEXES
The vasomotor centre with its efferent tracts is constantly played upon
by impulses arriving at it from the vascular system, including both heart
and blood vessels, from the viscera, from the muscles, and from the surface
of the body. The reflex effects produced by stimulation of the various
1014
PHYSIOLOGY
afferent nerves may be classified, according as they affect the general blood
pressure or the circulation through restricted areas of the body, as general
and local.
The afferent impulses affecting the general blood pressure are distin-
guished as pressor and depressor, and these names are sometimes applied
to the nerves which carry the impulses. A pressor reflex is one which
induces a rise of general blood pressure by constriction of the blood vessels,
especially in the splanchnic area (Fig. 477). Effects of this kind are pro-
duced by stimulation of nearly
all the sensory nerves of the
B p skin. Practically all impulses,
which if consciousness were
present would be attended with
pain, cause also a rise of general
blood pressure. A rise of pres-
sure may be produced by the
stimulation of such nerves as the
Spleen fifth, the central end of the
splanchnic nerves, or of the
nerves distributed to the surface
of the body. This rise occurs
in all animals under morphia
and curare. In the rabbit, when
anaesthesia is induced by means
of chloral or chloroform, stimu-
lation of sensory nerves may
cause a fall of blood pressure.
The chief example of a depressor nerve we have already studied in
dealing with the reflexes from the heart. The fall of pressure produced by
stimulation of this nerve is effected chiefly by dilatation of the splanchnic
area (Fig. 478), though, as Bayliss has shown, practically all the vessels of
the body partake in the relaxation. The lowering of blood pressure produced
by stimulation of this nerve differs from that obtained on stimulating the
sensory nerves of the rabbit under chloral, in that its effect lasts as long as
the stimulation is continued, whereas in the latter case the effect shows signs
of fatigue and disappears before the excitation is shut off.
So far as the general blood pressure is concerned, the most important
impulses arriving at the centre are those from the vascular system, especially
from the heart itself, and those from the higher parts of the brain. Whatever
the condition of the heart, the brain always demands a normal arterial
pressure, since on this depends the supply of a proper quantum of blood to
the master tissues of the body. A failing heart therefore evokes indirectly
constriction of the blood vessels, a fact which may lead to a vicious circle in I
cases where the heart is unable to perform its normal functions and to
empty itself against the resistance of the blood vessels. In this case the
heart dilates more and more, until the slightest increase in the demands upon
it, as by a slight muscular exertion, may suffice to stop its action altogether.
FlG. 478. Simultaneous tracing of arterial
blood pressure and splenic volume from
a rabbit, showing the marked swelling of
the spleen associated with fall of general
blood pressure on stimulation of the cen-
tral end of the depressor nerve. The nerve
was excited between a and b. (Bayliss.)
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1045
Under normal circumstances every part of the body receives just so
much blood as it needs for its metabolic requirements. Hence activity must
be associated with an increased flow of blood through the part. Two
mechanisms are involved in the production of this adaptation. In the first
place, stimuli arising in any part of the body may affect the vascular system
in two directions, causing reflexly dilatation of blood vessels in the part
which is the origin of the impulses and constriction of the blood vessels in
the rest of the body, so that a normal or raised blood pressure is available
for driving an increased supply of blood through the dilated vessels of the
part. Thus, if both hind limbs of an animal be placed in a plethysmograph,
it will be seen that stimulation of the anterior crural or peroneal nerve in
t he left leg causes dilatation of this leg and constriction of the leg of the other
side. At rest the organs of the chest and abdomen contain more than half
of the total quantity of blood in the body, so that very little change in the
rapacity of these organs suffices to furnish the extra supply of blood needed
by any part during a state of increased activity.
THE CHEMICAL REGULATION OF THE BLOOD VESSELS
Another factor, which is possibly involved in the production of the
increased blood flow through active organs, is a chemical stimulation of the
vessels themselves, by means of substances (metabolites) produced as a
result of the chemical changes accompanying activity. The great increase
in the flow through the muscles which accompanies muscular exercise is
probably brought about largely by this means. It has been shown that the
passage of blood containing lactic acid or carbon dioxide (both results of
muscular metabolism) causes a marked dilatation of the blood vessels of a
limb. The Table given below shows the influence of activity on the
blood flow through various organs.
We thus see that carbon dioxide, which is the- universal hormone set
free in the circulation when the activity of the body as a whole is increased,
has a double effect on the blood vessels — a central effect through the
vaso-motor centres, medulla and spinal cord, causing contraction of the
blood vessels, and a local peripheral effect causing dilatation of the blood
vessels. The general result therefore will be to cause dilatation of the
blood vessels of the part where the carbon dioxide is produced and where it
is present in greatest concentration, and vascular constriction elsewhere
under the influence of the sensitive nervous centres.
Flow in Cubic Centimetres fer Minute per 100 Grm. Tissue
Levator labii superioris (of the horse)
Kidney .....
Hind limb ....
Hind limb (after section of nerves)
Thyroid gland ....
Rabbit's brain ....
Heart .....
17-5
85
—
140
3-4
—
9-9
, —
5900
—
1360
—
1010
PHYSIOLOGY
ACTION OF ADRENALINE. This substance, produced by the supra-
renal glands, has a marked influence on the calibre of the blood vessels.
If 1 c.c. of a 1 in 10,000 solution of this substance be injected into the jugular
vein, there is at once a universal constriction of the arterioles with the
exception of those of the brain. If the vagi are cut, we obtain a simultaneous
augmentor action of this drug on the heart and constrictor effect on the
blood vessels, so that the arterial pressure rises to an enormous extent, up
to 300 mm. Hg. or more. The same result occurs after section of the vaso-
Fio. 479. Curve Bhowing the effect of a sudden rise in the arterial resistance on
the output and volume of the ventricles. Systole causes a downward movement
of the lever.
n, heart volume; bp, arterial blood pressure; s, signal Bhowing duration of
stimulation of splanchnic nerve ; T, time marker, 10 sees.
motor nerves or after destruction of the brain and spinal cord, so that there
is no doubt that adrenaline acts directly on the blood-vessel wall. The
action of this drug as a whole is therefore largely to augment the energy of
the circulation. The arterial pressure rises, and the blood will be therefore
travelling at a much greater pace through any part of the body where the
vessels are maintained in a dilated condition, e. g, in an active muscle, or
where there are no vaso-motor nerves, as in the vessels of the brain. It is
therefore not surprising that we have evidence of the secretion of adrenaline
in increased quantities into the blood during any condition of stress. When-
ever the splanchnic nerve is stimulated, there is an increased production of
adrenaline. On this account the rise of pressure produced under these
circumstances shows a stepped curve, the first rise being due to the direct
action of the vaso-motor nerves of the blood vessels, the second being
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1047
brought about by the. stimulation of the suprarenals and the discharge of
adrenaline into the general circulation. Simultaneously with this second
rise of blood pressure, we notice in the curve given in Fig. 479 a diminished
volume of the heart due to more effective contraction of this organ.
This diminished volume of the heart is often associated with a marked
quickening of the heart rate, both effect* being due to the action of adrenaline
on the heart. During asphyxia the rise of arterial pressure is largely brought
about through the intermediation of the splanchnic nerves and is therefore
also associated with the discharge of adrenaline. It is on this account that
Fig. 480. Effect of excitation of splanchnic nerves on tho blood pressure and
on the volume of the denervated hind limb of the cat. (Bayliss.)
in the whole animal, provided that sufficient oxygen is supplied, very large
percentages of carbon dioxide may be inhaled without causing fatal dilata-
tion of the heart, the effect of the adrenaline discharged into the blood stream
serving to counteract the injurious influence of carbon dioxide on the heart
muscle. These two chemical influences, the local production of carbon-
dioxide and the discharge of adrenaline into the general circulation, must
always be kept in mind in trying to account for the behaviour of the blood
vessels under the most various conditions. Thus in Fig. 480 is shown the
effect of temporary stimulation of the splanchnic nerve on the blood pressure
and on the volume of the hind limb of the cat. It will be noticed that the
volume of the hind limb increases passively with the rise of pressure and then
diminishes much below its previous amount. This diminution is due to the
discharge of adrenaline into the blood stream as the result of ■stimulation of
the splanchnic nerve, and is absent if the suprarenals have been previously
destroyed. The curve shown in Fig. 481, which with the foregoing one was
taken by Bayliss to indicate a local adaptation of the blood vessels to their
internal pressure, is probably brought about by the local production of carbon
dioxide (von An rep). Temporary occlusion of the abdominal aorta is here
1018 PHYSIOLOGY
shown to cause first a diminution of the volume of the hind limb, followed
by a marked increase. During the period of obstruction the circulation of
the hind limb was interrupted, and there was thus accumulation of carbon
dioxide in the tissues and around the blood vessels. This caused a relaxa-
tion of the blood-vessel walls and a corresponding increased volume of the
limb when the blood was allowed once more to flow by release of the aortic
obstruction.
Signal
Time 10 sees.
Fig. -181. Effect o£ temporary compression of the abdominal aorta on the volume of
the denervated hind limb. Two compressions, the second not marked by the
signal. Blood pressure taken in the femoral artery of one hind limb, the other
hind limb being in the plethysmograph. (Baymss.)
THE REGULATION OF THE BLOOD FLOW THROUGH THE
CAPILLARIES
Up to the present we have emphasised only two factors as regulating
the blood flow through the peripheral parts of the body, viz. the general
blood pressure, and the state of contraction or tone of the arterioles supplying
those parts. We have regarded the capillaries as a close meshwork of canals,
the calibre of which depends entirely on the extent to which they were
distended by the pressure of blood within them. There is no doubt how-
ever that both the calibre of and the resistance to the flow of blood
through the capillaries are intimately dependent on the nutritive condition
of the cells composing their walls. Certain observers have described spon-
taneous changes taking place in the diameter of the capillaries, and
THE NERVOUS CONTROL OF THE BLOOD VESSELS 1049
have ascribed them to active contraction or change of form of the endo-
thelial cells, which was apparently independent of concomitant arterial
alteration. In a subsequent chapter we shall have occasion to study
in the capillary circulation the impressive changes following slight injury,
chemical, thermal or mechanical, which give the salient features to the
picture of inflammation. But it is certain that nutritive changes of less
degree, falling within normal physiological events, also influence consider-
ably the flow through the capillaries, either by increasing their lumen or by
altering the resistance to the passage of blood through them. Thus during
activity the total capacity of the capillaries of muscle may be increased from
0'02 per cent, to 15 per cent, of the total volume of the muscle (Krogh). The
phenomena of dropsy show us that the capillary wall is very sensitive to the
continued absence of oxygen, oxygen starvation rapidly increasing its
permeability; and it seems that the presence of oxygen is an essential con-
dition of any reactivity to moderate nutritional changes on the part of
the capillaries. The dilator effect we have already studied of carbonic acid
and other weak acids on the arterioles seems to be shared by the capillaries.
In such a case it is difficult to dissociate the effects of arterial dilatation
from those of capillary dilatation. At least one, chemical substance is known
however, which has diametrically opposite effects on the two sets of vessels.
Histamine, the amine produced by the decarboxylation of histidine. has been
3howri by Dale to have a constrictor effect on the arterioles and a dilator
effect on the capillaries. It has been suggested that the production of
histamine or of other substances with a similar action plays an important
part in giving rise to the symptoms of surgical shock. In this condition,
which is found notably after widespread laceration, especially of the
muscles, and consequent destruction of the tissues, there is a continually
increasing depression of the blood pressure due to the ever lessening volume
of blood in circulation. Since this lowering of blood pressure does not
depend on any direct action of the heart nor is it associated with vaso-motor
paralysis, it lias been concluded that the prime factor at work is a general
dilatation of the capillaries, leading to stagnation of the blood in these vessels
and an increased exudation into the tissues, thus causing a constant leak of
Mood fluid from the general circulation.
No evidence has yet been brought forward for a direct action of the
central nervous system on the capillaries. Certain facts however point to
a connection between nerve lesions and the calibre of the capillaries supplied
by the nerves. Thus if in the cat the sciatic nerve be cut on the right side.
Eor t he next few hours the pad of the foot on that side is flushed and warmer
than the left foot. The next day the flush has disappeared, in fact the pad
of the right loot may be paler than that of the left foot. The right foot is
however still a degree or two warmer than the left foot. This condition
may 1 xplained on the assumption that the immediate effect of cutting
the sciatic nerve is to cause dilatation both of the arterioles and of the
capillaries. The capillary dilatation passes oil', so that on the day alter the
seciion. although the arterioles are still dilated and there is a more rapid
L050 PHYSIOLOGY
flow of blood through the pad and a correspondingly higher temperature
than on the sound side, the capillaries are contracted so that the pad contains
less blood and is paler than on the opposite side. These observations
suggest a question whether the whole of the antidromic effects, observed by
Bayliss to follow stimulation of sensory nerves, may not really be confined
to, or have their chief seat in, the capillaries. It is indeed certain that the
closely allied phenomena of herpes zoster and the erythematous eruptions
along the course of a nerve, and having their origin in morbid conditions of
tlic nerve or of the posterior root ganglion, are due to changes in the capil-
laries or in the tissues immediately around them. This question must
however be left for further investigation.
SECTION XI
THE CIRCULATORY CHANGES DURING MUSCULAR
EXERCISE
In the preceeding sections we have studied separately a number of
mechanisms by which the heart or the vessels react to this or that con-
dition, in order to bring about an appropriate modification of the circulation.
In so doing we have analysed somewhat artificially the factors which are
normally involved simultaneously in the adaptation of the circulation to
the necessities of the body, as determined by the exigencies of its
environment. This adaptation is in fact a necessary condition of the
survival of the individual in the struggle for existence. Our view of the
working of the circulation as a whole is imperfect until we can effect a
synthesis of these isolated mechanisms, and trace out the chain of events
Concerned in that intimate co-operation of all parts of the circulation with
all other systems and organs of the body which must be involved in every
act of life. For this purpose we cannot do better than take as an example
the complex of adaptations which are involved in muscular exericse. Though
for purposes of experiment the exercise may be that involved in working a
stationary bicycle, we must remember that it is the same series of processes
as are brought into play in the supreme struggle for life against an enemy
or rival, or in the chase for food which is necessary to avoid death by
hunger. For the analysis of the different events in the circulation, we have
hitherto had large recourse to animal experiments ; but with the facts thus
gained at our disposal, we can proceed to investigate the subject in man
himself, with the added advantages of his voluntary co-operation and of
the absence of abnormal conditions such as anaesthetics, etc.
On initiating such experiments in man we meet at once with a new fact
— viz. that under normal circumstances a reflex and automatic adaptation
of the heart and vessels is preceded and reinforced by the active intervention
of impulses proceeding from the brain. Thus the willed effort, or the emotion
of fear or anger which normally initiates extensive muscular movements,
gives rise at the same time to impulses starting in the brain centres, which
excite changes in the circulatory and respiratory systems of the same character
as those which will be later excited reflexly or automatically as a result of
the exerciseJ.'jThus during muscular movements we find the respiratory
exchanges aha the ventilation of the lungs increased, the blood pressure
raised, and the pulse quickened. With a man seated on a stationary bicycle
the mere question " Are you ready ? " evokes increase of muscular tone in the
act of attention, increased pulmonary ventilation, and a rise of pulse rate
1051
1052
PHYSIOLOGY
and of blood pressure. And these changes are increased as soon as the word
" go " is given and the man starts to pedal, i.e. before the increased metabolic
changes in the muscles can have had time to affect the medullary centres,
or the muscular contractions the vigour of the circulation. The reinforcing
impulses from the cortex, which stimulate the medullary centres and put
these various mechanisms into action, are effective especially at the beginning
of muscular work. In any steady work produced without particular effort
or attention, the subsequent adaptations of the different organs of the body
are probably chiefly automatic, the central reinforcing impulses being of
especial importance when, under emotional stress of any description, the
animal has to put forth its maximum effort.
Fig. 482. Chart showing the effect of increasing amounts
of muscular work on the total ventilation of the lungs V,
on the blood flow BF, and on the oxygen absorption 2 .
(From Means and Newbttrgh )
Increased work means increased metabolism. We have seen that the
oxygen intake and the C0 2 output may undergo a ten or twelve fold augmenta-
tion during violent muscular effort carried out for a short time, and a five fold
increase is not uncommon and may last for many hours. The muscles of a
warm-blooded animal become rapidly fatigued on being deprived of an
adequate amount of oxygen. A necessary condition then of all muscular
exercise is that the muscles shall be supplied with oxygen in proportion to
their requirements. Since the arterial blood is under normal conditions 90 to
95 per cent, saturated with oxygen, no appreciable further amount can be
provided by increasing the saturation of the haemoglobin in the blood ; so
that an eight to twelve fold increase in the oxygen usage by the muscles must
CIRCULATORY CHANGES DURING MUSCULAR EXERCISE 1053
imply a corresponding increase in the blood supplied to these organs. This
increased blood flow to the muscles involves in its turn an increase in the
blood flow through the lungs and in the ventilation of the lungs. Li the next
chapter we shall have occasion to study the method by which the respiratory
centre is enabled to adjust its activity, and therewith the rate at which the
air in the pulmonary alveoli is renewed, in exact proportion to the needs of the
body for oxygen. We are concerned here chiefly with the mechanism l>v
which the circulation through the lungs and muscles can be and is increased
in like proportion. The measurement of the circulation through the lungs is
identical with the measurement of the output of the right ventricle. This
has been investigated by Krogh and Lindhard and by Means and Newburgh
in the healthy man during rest and during exercise. In Fig. 482 are shown
results obtained by the two last-named observers. It will be seen that the
blood flow through the luDgs, or the output of the right ventricle per minute,
increases in a manner almost absolutely proportional to the consumption of
oxygen, and that both increase pari passu with the work done per minute.
How is this admirable adjustment of the activity of the heart and circulation
to the oxygen needs of the muscles effected ? The output of the heart depends
on the inflow into this organ, so that our problem is to determine the
factors which increase the inflow into the heart in proportion to the needs of
the muscles. At or before the onset of muscular exercise, unless this is quite
moderate, there is contraction of the splanchnic vessels, so that the blood is
diverted from the viscera to the muscles and later on also to the skin. Every
muscle as we have seen acts as an accessory heart, the muscular contractions
emptying the capillaries into the veins, and in the latter driving on the fluid
towards the heart in virtue of the valves present in these vessels. The more
active the muscles therefore, the more rapidly the blood which enters them
is passed on with force, tow aids the big veins and the heart. The circulation
through the big veins of the abdomen and chest is aided by the respiratory
movements, which are also augmented in proportion to muscular activity,
each inspiration driving the blood out of the big veins in the abdomen and
aspiring it mto the veins and heart cavities within the thorax. The blood
flow into the heart is thus increased in proportion to the activity of the
muscles. Under resting conditions it seems probable that the filling of the
heart is what Krogh has described as ' inadequate ' — i. e. the amount of blood
entering the heart during each diastole is not sufficient to fill this organ up to
the limits set by the fibrous and inextensible pericardium. The first effect of
muscular exercise will be to increase the filling of the heart and therefore
the output at each beat, and this will go on until the tilling (luring each
diastole has become ' adequate.' The heart therefore, at the beginning of
muscular exercise, automatically reacts by increasing the output per beat.
Whether diastolic tilling of the heart be adequate or inadequate, the pressure
in its cavities just before systole will !»■ approximately zero. If now the
inflow be Mill further increased, the diastolic pressure within the heart and
in the big veins will begin to rise, since the heart cannot lint her increase
appreciably its output per beat. Now comes in the reflex mechanism
1054
PHYSIOLOGY
described by Bainbridge. The increasing tension on the venous side of the
heart evokes reflexly a quickening of the heart rhythm, chiefly by inhibition
of the vagus tone, possibly also by reflex stimulation of the sympathetic
accelerator nerves. Further increase in the inflow into the heart is met by
corresponding quickening of the heart rhythm. Distension of the big veins
is thus prevented, and the output of each ventricle per minute is increased
seven, ten or even twelve times. The part played by increase of output per
beat and by increase of pulse
rate respectively in augmenting
the total output of the heart is
shown in Fig. 483. In this
figure the first rise in pulse
rate from sixty-eight to ninety-
eight and the corresponding
increase in output per beat
can be regarded as associated
with the initial changes origi-
nated by the act of attention
and volition. It will be seen
that between 270 to 600 kilo-
grammetres' work per minute
the pulse rate remains prac-
tically unchanged, while the
output per beat increases
steadily with the work. After
this point there is very little
further increase in the output
per beat, which towards the
end begins to diminish, while there is a steady increase in the pulse rate.
By this means the blood is driven through the lungs at a rate correspond-
ing to the increased needs of the muscles for oxygen. The passage of this
blood through the muscles is provided for by two mechanisms. In the first
place we have the contraction of the splanchnic vessels, so that the blood
pressure is raised and all the available blood can be driven through the
working tissues. In the second place the muscles in their activity produce
lactic acid, C0 2 , and possibly other metabolites, whioh cause dilatation of
the arterioles and capillaries in the muscles themselves. During rest it is
probable that the majority of the capillaries are closed ; during activity
these dilate and are filled with blood, so that the capillary bed in the muscles
ma} r be increased many times in area, and each element of the muscle is
brought into close relation with a dilated capillary through which is flowing
a rapid stream of oxygenated blood. Krogh has shown that the number of
blood-containing capillaries in each square millimetre cross-section of the
muscle may be increased 40 to 100 times during maximal activity of the
muscle. As a result the oxygen tension in the muscle fibres becomes ahnost
equal to that in the capillaries themselves.
Fig. 483 Chart showing the effect of increasing
amounts of muscular work on the pulse rato P,
shown by dots ; on the heart output per beat,
VpB, and on the co-efficient of oxygen utilisa-
tion in the blood, (J. (From Means and New-
BOTtGH.)
CIRCULATORY CHANGES DURING MUSCULAR EXERCISE 1055
This production of acid products in the muscles aids also dissociation of
the oxyhemoglobin passing through the capillaries and therefore sets free
oxygen for the use of the muscles. On this account we find almost invariably
that the utilisation of the oxygen taken in from the lungs is more complete
during exercise. The oxygen utilisation per litre of blood as it flows round
the circulation is known as the ' co-efficient of utilisation.' Thus if 328 c.c.
of oxygen were used per minute and the blood flow were 4-5 litres per minute,
090
— =73 c.c. oxygen would be utilised per litre of blood. If the oxygen
t'.j
capacity of the blood were 193 c.c. per litre, the co-efficient of utilisation
73
would be — = 38 per cent. In Fig. -183 the co-efficient of the oxygen
utilisation is given by the curve 0.
It has been shown by Cannon
that every state of excitement, and
especially fear and anger, is attended
with increased secretion of adrena-
line into the blood stream. During
the violent exercise associated or
caused by emotional stress, there
will be an excess of adrenaline
circulating in the blood, which will
reinforce the activity of the circu-
lation. Thus it will increase the
constriction of the splanchnic area
already excited by the central
effects of the increased CO., or
lactic acid in the. blood. In the
heart the adrenaline will increase
fli.' contractile power and also the
rate of beat, while by its dilator
action on the coronary vessels it
will aid the supply of oxygen to
the heart muscle. At the same
time, as we have seen (p. 844),
adrenaline will cause a rapid con-
version of the glycogen of the liver into sugar, so that the contracting
muscles may be rapidly supplied with the food which they can utilise with the
greatest ease and readiness. It is doubtful whether these adjuvant effects
-of adrenaline are to be reckoned with except in cases of severe emotional
stress.
Training. The muscular efficiency of a man is measured by the extent
to which he can call upon his body for increased efforts, i.e. by his margin
of response. This margin in normal individuals may lie 600 per cent.,
i. c. over a moderate period of time the individual may increase his muscular
wink, his respiratory exchanges, and the rate of his circulation six times
K9.M*t*fS 105
Work per M.nute
Fin. 4:84. ( 'halt showing tho effects of mus-
cular work on the blood flow and oxygen
consumption in a subject with aortic
disease, as compared with a normal indi-
vidual (shown in lighter lines). (From
Means and New-burgh.)
(For oxygen consumption omit the decimal
point and read in c.c.s.)
um
PHYSIOLOGY
above that obtaining during rest. This margin in a normal individual can
be increased by training, the essential features in which are graduated
exercise and healthy diet, so that the muscle grows and becomes free from
interstitial fat, while the fluid parts of the body and of the blood are
diminished so that a larger amount of oxygen can be carried per unit
volume of blood. The well-trained individual may have a margin of as
much as 120 per cent. Disease is marked by a diminution of the margin.
In Fig. 484 is given diagrammatically the response of the circulation and
respiration of a man with heart disease
affecting the aortic and mitral valves. This
man had no discomfort and was able to do
ordinary work without ill effects. On testing
him on measured muscular tasks, it will
be seen that, although at first he reacts like
the normal individual, his margin is dimin-
ished, and when doing only 315 kilogram-
metres of work per minute, the rise in the
oxygen intake and in -the heart output fails
to keep pace with the increase in the work
and loses also the parallelism which is so
marked a feature in normal individuals.
With increasing disease the time would finally
come when the margin was reduced to 50
per cent, or 100 per cent., so that even the
act of changing from a recumbent to an
erect position might be too much for the
enfeebled adaptive mechanisms of the body
and the patient would have to keep his bed .
There is thus no definite dividing fine
between health and disease, the change from
one to the other being but a progressive
Fig. 485. Curved showing the in- diminution of margin or extent of adaptation.
flnenee of exercise on the civcula- 1Ir , ., . ., , .., • ,
tion. The exercise was a six-mile We have seen that tne physiological
run. Ordinates = mm. Hg. pes- condition of the heart is measured by
the degree of dilatation of its cavities, i. e.
the length of its muscle fibres, required
in order that in its beat it may set up a contractile stress adequate
to expel its contents against the arterial resistance. Thus a degree of
filling of the heart, which in a well-trained man may be adequate to excite a
contraction sufficient entirely to empty its cavities, in a weaker heart would
be inadequate, so that blood would accumulate at each diastole until the
stretching of the fibres was sufficient to ensure that the amount entering
during diastole was expelled at each systole. The trained man — i. e. with
a heart in good condition- — will therefore have, a considerable range over
which the output per beat can be increased with increasing inflow without
alteration of rhythm. In the untrained man this margin will be smaller.
sure and rate per minute.
LOWSLEY.)
(O. s.
CIRCULATORY CHANGES DURING MUSCULAR EXERCISE 1057
so that the second mechanism of adaptation, viz. quickening of the heart
beat, will be sooner brought into action to cope with the increased inflow
associated with muscular exercise. Thus one finds a considerable difference
in the effect of exercise on the pulse rate m trained and untrained individuals
respectively, and this is specially shown in the rate of recovery in the pulse
when the exercise comes to an end, the effects lasting much longer in the
untrained. In all cases exercise not carried to exhaustion tends to be fol-
lowed by a prolonged diminution both in pulse rate and in blood pressure
(cf. Fig.' 485).
67
SECTION XII
THE INFLUENCE ON THE; CIRCULATION OF VARIA-
TIONS IN THE TOTAL QUANTITY OF BLOOD
PLETHORA AND HYDREMIC PLETHORA
The effects of increasing the total volume of circulating fluid may be studied
by injecting several hundred cubic centimetres of defibrinated blood or
normal saline fluid into a vein. In the latter case, since the blood is rendered
30GOSZC I I I ' | ' | ' I ' I " I ' I ' I ' I ' I ' I ' I 1"
Imin2 3 44 5 6 7 8 9 10 II 12 13 14 15 IS 17 18 21
Fig. 486. Effects of hydremic plethora on the pressures in the carotid artery (thick
line), portal vein (thin line), and inferior vena cava (dotted line). (Bayliss and
Starling.)
The arterial pressure is in mm. Hg. ; the venous pressures in mm. H 2 0.
more dilute, the condition is called hydrseinic plethora (Fig. 486). On the
arterial pressure the result of such an injection is not very marked. There is
a slight initial increase in the pressure, but the increase is by no means
proportional to the amount of fluid injected, showing that the fluid is not
to any large extent contained in the arterial system. On examining the
pressure in the veins however, we find a very great relative rise of pressure,
and on opening the abdomen it is seen that all the veins are distended and
that the liver is swollen. The effect of increasing the volume of circulating
1058
VARIATIONS IN TOTAL^QUANTITY OF BLOOD
1059
fluid would be to increase the mean systemic pressure, and therefore oue
would expect to find a large increase both in arterial and venous systems.
But the organism prevents the rise on the arterial side by relaxing the
whole system of arterioles, so that the distribution of pressures is altered,
and the venous approximates more closely to the arterial pressure. This
arterial dilatation augments the velocity of the blood : it has been found that
the velocity may be accelerated to six or eight times the normal rate by
Diastole
Fig. 487. Cardiometer tracing from dog's heart to show effect of increasing the
volume of circulating blood (hydraeraic plethora) on the total output and the
volume of the heart. Between the parts a and b 30 c.c. of warm normal salt
solution were injected intravenously, and between B and c 20 c.c. more. It will
bo noticed that both the systolic and the diastolic volume are increased, i. e.
the heart is moro distended during diastole, and does not contract to its
normal size in systole. The contraction volume, and therefore the output,
is very largely increased. (Roy.)
injecting an amount of salt solution equivalent to 50 per cent, of the total
blood.
The high venous pressure causes increased diastolic filling of the ventricles,
and therefore augments the strength of the beat. The'frequency is also
generally raised if the vagi are intact in consequence of the greater
distension of the auricles. Thus the work of the heart is increased in three
ways, viz. by
(1) Rise of arterial pressure.
(2) Greater frequency of beat.
(3) Increased output at each beat (Fig. 487).
These series of changes result in the relief of the vascular system. The
1060 PHYSIOLOGY
heightened pressure in the abdominal veins and capillaries causes a great
leakage of fluid in the form of lymph from the capillaries of the intestines and
liver, while the increased pressure and velocity of the blood in the glomeruli of
the kidney induce a copious secretion of urine, so that within a couple of hours
after the injection of salt solution the volume of the circulating fluid may
have returned to normal.
This recovery is effected with greater difficulty if the plethora has been
brought about by the injection of defibrinated blood, since this fluid cannot
escape rapidly from the capillaries, nor can i t be excreted unchanged by the
kidneys. Hence it is easy to kill an animal by wearing out its heart, if too
large quantities of defibrinated blood be injected. The ultimate fate of the
injected blood is to' be used as food by the tissues, and to be eliminated by
the ordinary channels.
It must be remembered that the blood serum of one animal is often poisonous for
the corpuscles of another. Thus a few cubic centimetres of dog's serum injected into
the peritoneal cavity of a rabbit will cause death. This poisonous action is also shown
by mixing dog's serum with defibrinated rabbit's blood, in which case the red corpuscles
of the latter are broken up, setting free haemoglobin (hemolysis).
THE EFFECTS OF HEMORRHAGE. ANEMIA
Any diminution of the total volume of the blood, as by bleeding, would
tend to lower the pressure on both sides of the system. The vaso-motor
centre however strives to maintain the normal arterial pressure, and so the
circulation through the brain, unaltered. This object is attained by a
general vascular constriction, which diminishes the total capacity of the
system and alters the distribution of pressures throughout the system, so
as to keep the blood as much as possible on the arterial side. Thus a slight
loss of blood has no influence on the arterial blood pressure, but causes a fall
of pressure in the veins, blanching of the abdominal organs, and diminished
flow of urine. The heart beats more frequently, and so aids in emptying the
venous into the arterial system.
The deficiency of circulating fluid caused by bleeding is soon remedied by
a transfer of fluid from the tissues to the blood. This transfer is independent
of the flow of lymph from the thoracic duct into the blood, and is the direct
consequence of the universal fall of capillary pressure which results from
the bleeding. The abstraction of fluid from the tissues is responsible for
the extreme thirst which is the result of haemorrhage, and which directs the
animal to take up by the alimentary canal the fluid which is wanting to the
body. The transfer of fluid from tissues to blood is extremely rapid ; even
during the course of a bleeding it is found that the later samples of blood are
more dilute than those obtained at the beginning. This mechanism suffices
only to make up the supply of circulating fluid. After a bleeding however,
an animal has lost proteins and blood corpuscles, and these constituents of
the blood are but slowly restored, the former directly from the food, the latter
by an increased activity of the blood-forming cells in the red marrow.
CHAPTER XIV
LYMPH AND TISSUE FLUIDS
In no part of the body does the blood come in actual contact with the living
cells of the tissue. In all parts the blood flows in capillaries with definite
walls consisting of a single layer of cells, and is thus separated from the
tissue-elements by these walls and by a varying thickness of tissue. In some
organs, such as the liver and lung, every cell is in contact with the outer
surface of some capillary ; while in others, such as cartilage (which is quite
avascular), a considerable thickness of tissue may separate any given cell
from the nearest capillary. A middleman is thus needed between the blood
and the tissues, and this middleman is the tissue fluid or lymph which fills
spaces between all the tissue elements, so that any tissue can be regarded as
a sponge soaked with lymph.
Throughout these spaces we find a close network of vessels, lined and
separated from the tissue spaces by a layer of extremely thin endothelial
cells, and this plexus communicates with definite channels — lymphatics,
by which any excess of fluid in the part is drained off. The lymphatics
all run towards the chest, where those of the hind limbs join a large vessel
(the receptaculum chyli), which receives the lymph from the alimentary canal,
to form the thoracic duct. This runs up on the left side of the oesophagus,
and after receiving the lymphatic trunks from the left fore lirhb and the left
side of the neck, opens into the venous system at the junction of the left
internal jugular with the subclavian vein. A small vessel on the right side
drains the lymph from the right fore limb and right side of the chest and
neck.
The lymph may be looked upon as a part of the plasma which exudes
through the capillary wall, bathos all the tissue elements, passes between
the endothelial cells into the peripheral lymphatic network, whence it is
laivied liy lymphatic trunks into the thoracic duct, by which it is returned
again to the blood.
It is easy to obtain lymph for examination by putting a cannula (a small
tube of glass or metal) into the thoracic duct, and collecting the fluid that
drops from it in a glass vessel.
We ma}* also tap in a similar way one of the large lymphatic trunks of the
limbs ; but in the latter case we have to use artificial means to induce a flow
of l\ mph, since little or none can be obtained from a limb at rest, the only
pari of the body where there is normally a constant, flow of lymph being the
1001
10C2 PHYSIOLOGY
alimentary canal. And thus we cannot regard the flow of lymph from a
part as any index of the chemical changes going on at that part. In a limb
at rest foodstuffs are being taken up from the blood and burnt up by the
muscles with the production of C0 2 . although we may not be able to obtain
a drop of lymph from a cannula in one of the lymphatics. The lymph
is thus truly a middleman ; as any substance, oxygen or foodstuff, is taken
up by a tissue cell from the lymph surrounding it, this latter recoups itself
at once at the expense of the blood. Thus there would seem to be no need
for lymphatics to drain the limb, were it not that under many conditions
which we shall study directly, the exudation of lymph from the blood vessels
is so excessive that, if it were not carried off at once and restored to the blood,
it would accumulate in the tissue spaces, give rise to dropsy, and by pressure
on the cells and blood vessels affect them injuriously.
PROPERTIES OF LYMPH
Lymph obtained from the thoracic duct of an animal varies in compo-
sition and appearance according to the condition of the animal, whether
recently fed or fasting. From a fasting animal the lymph is a transparent
liquid, generally slightly yellowish, and sometimes reddish from admixture
of blood corpuscles. When obtained from an animal shortly after a meal,
it is milky from the presence of minute particles of fat that have been
absorbed from the alimentary canal. In the latter case, if the intestines be
exposed, the small lymphatics are to be seen as white lines running from the
intestine to the attached part of the mesentery. It is owing to this fact
that these lymphatics have received the special name lacteals, the lymph
in them being called the chyle. The fatty particles form the molecular basis
of the chyle.
On microscopic examination the transparent lymph of fasting animals
presents colourless corpuscles similar to those of blood, or perhaps we ought
to say identical, since the leucocytes of the blood are partly derived from the
corpuscles that have entered with the lymph through the thoracic duct.
All the lymphatics pass at some point of their course through lymphatic
glands, which we may look upon as factories of leucocytes, since these are
much more numerous in the lymph after it has traversed the gland than
before. Leucocytes are also formed in all the numerous localities where
we find adenoid tissues, such as the tonsils, air passages, alimentary canal
(Peyer's patches and solitary follicles), Malpighian bodies of the spleen, and
thymus.
The lymph from the thoracic duct is alkaline, has a specific gravity of
about 1015, and clots at a variable time after it has left the vessels, forming
a colourless clot of fibrin, just like blood plasma. It contains about 6 per
cent, of solid matters, the proteins consisting of fibrinogen, paraglobulin, and
serum albumen. The salts are similar to those of the liquor sanguinis, and
are present in the same proportions.
LYMPH AND TISSUE FLUIDS 1063
THE PRODUCTION OF LYMPH
Many physiologists have thought that, in the transudation of the fluid
which forms the lymph, there is an active intervention on the part of the
endothelial cells forming the capillary wall, and that lymph is therefore
to be regarded as a true secretion. A careful investigation of the known
experimental facts has failed to show that the endothelial cells act otherwise
than passively, as filtering membranes of variable permeability. The factors
which are responsible for the transudation of lymph may be divided into
two classes — mechanical and chemical, the former depending largely on the
pressure of the blood in the vessels, and the latter chiefly on the metabolism
of the ceUs outside the vessels.
According to the views here laid down, the formation of lymph may be
compared to a process of filtration. If this be correct the amount of lymph
formed in any given capillary area must be dependent on the difference
of pressure between the blood in the vessels and the fluid in the extravascular
tissue spaces. This latter pressure is normally extremely low, so that in
attempting to test the truth of this view we must try the effects of altering
the pressure inside the vessels, in the expectation of finding that the lymph
production will rise and fall as the capillary pressure is increased or dimin-
ished. On attempting to carry out such experiments in different parts of
the body, we have to recognise another factor besides the capillary pressure,
viz. the permeability of the vessel wall. Whereas the capillary walls in the
limbs and connective tissues generally present a very considerable resistance
to the filtration of lymph through them, and keep back the larger portion of
the proteins of the blood plasma, the intestinal capillaries are much more
permeable, giving at moderate capillary pressures a continual flow of lymph
and separating off only a small proportion of the proteins. It is in the
iiver however that we find the greatest permeability. Here a very small
pressure sufficies to produce a great transudation of lymph, containing
practically the same amount of protein as the blood plasma from which it is
formed.
The ease with which fluid passes out from the capillaries of the liver is probably due
to the fact that these vessels, unlike most other capillaries of the body, have not a com-
plete endothelial lining. Thus it is impossible to display a continuous endothelial lining
by means of silver nitrate. The cells surrounding the capillaries are large and branched,
and possess marked phagocytic powers, so that after an injection of carmine granules
or bacteria into the blood stream, these bodies are found in quantity within the cells.
Owing to the incompleteness of this investment the liver cells in many places abut
on the lumen of the capillary. On injecting the blood system of the liver the injection
is found to run with ease into channels situated within the cells themselves, and it is
reasonable to conclude that the blood plasma takes the same course through these
intracellular channels, by which it passes into the lymphatics which lie at the periphery
of the lobules.
Li experiments on the lymph production in the limbs, alterations of
capillary pressure have but slight effect. The lymph flow from a limb
lymphatic is practically unaltered by changes in its arterial supply, although
1064 PHYSIOLOGY
a definite increase may be obtained by ligaturing all the veins of the limb
so as to cause a very great rise of capillary pressure. The lymph flow from
the intestines can be measured by collecting the lymph from the thoracic
duct. If the lymphatics which leave the liver in the portal fissure be
previously ligatured, the whole of the thoracic duct lymph in an animal at
rest is derived from the intestines. It will be found that lowering of the
capillary pressure in these organs by obstructing the thoracic aorta stops
the flow of lymph absolutely, whereas a rise of capillary pressure, such as that
produced by ligature of the portal vein, causes a four or five fold increase
of the lymph.
The effect of rise of capillary pressure on the lymph flow is still more
striking in the case of the liver. If the inferior vena cava be obstructed
just above the opening of the hepatic veins, there is a great fall of arterial
pressure but, owing to the damming back of the blood, a rise of pressure
in the liver capillaries to three or four times the normal height. This rise
causes a large increase in the lymph flow from the thoracic duct. The
lymph may be increased eight to ten times in amount, and it contains more
protein than before. If the portal lymphatics be previously ligatured,
obstruction of the inferior vena cava has no effect on the lymph flow,
showing that the whole of this increase is derived from the one region of the
body where the capillary pressure is increased, viz. the fiver.
We must conclude that, in those regions of the body where the capillaries
are fairly permeable, the most important factor in lymph production is the
intracapillary pressure.
In the case of the limbs and connective tissues generally, the pressure
factor is probably under normal conditions of less importance, so that the
second factor, the chemical, comes here more into prominence. The
capillary wall not only permits of filtration under certain pressures but also
allows the passage of water and dissolved substances by diffusion and
osmosis. These osmotic interchanges between blood and cell through the
intermediation of the lymph are constantly going on in the normal life of the
tissue, and are quite independent of the amount of lymph produced. Thus a
gland cell may use up oxygen, calcium, or sugar, and create a vacuum of
these substances in the layer of lymph immediately surrounding the cell.
There is at once a disturbance of the equilibrium, and a flow of these sub-
stances from blood to lymph is set up. In consequence of the wonderful
arrangements in the tissues for ensuring the intimate contact of blood and
lymph without intermingling, these changes can occur with great rapidity.
We find, for instance, that if a very large amount (40 grm.) of dextrose be
injected into the circulation, osmotic equilibrium between blood and lymph
is established within half a minute of the termination of the injection. In
this case the rise of osmotic pressure caused by the injection of the sugar
attracts water from the tissue fluid, and this in its turn from the tissue cells,
until the osmotic pressure inside and outside the vessels is the same. By
this means the volume of the circulating blood is increased at the expense of
the tissues. A process of this character may however work under normal
LYMPH AND TISSUE FLUIDS 1065
circumstances in the reverse direction, and lead to a passage of fluid from
blood to tissues and tissue spaces. Every active contraction of a muscle, for
instance, is attended by the breaking down of a few large molecules into a
number of smaller ones, and this increase in the number of molecules causes
a rise of osmotic pressure in the muscle fibre and surrounding lymph, and
therefore a passage of fluid from blood to lymph. In the same way a cell
of the submaxillary gland, when stimulated by means of its nerve, pours out
a quantity of fluid into the gland duct, and so into the mouth. This fluid
comes in the first instance from the cell itself, but the cell recoups itself from
the surrounding lymph, raising the concentration of this fluid, and the
difference in concentration thus caused at once induces a passage of water
from blood to lymph. Hence salivary secretion is associated with a large
flow of fluid through the capillary walls of the gland. In this passage the
endothelial cells of the capillaries play no part, the whole process being con-
ditioned by changes in the extravascular gland cell. We have only to
paralyse the gland cell by means of atropine in order to see that the active
flushing of the gland, which accompanies activity, produces merely a minimal
increase in the lymph flow from the gland.
The influence of tissue activity in the production of lymph is still better
shown in the case of a large gland, such as the liver. Stimulation of this
organ by the injection of bile salts into the blood stream causes a large
increase in the lymph flow from the organ, and therefore in the lymph flow
from the thoracic duct.
It is important to remember that the relative insusceptibility of the
limb capillaries to pressure holds only for the absolutely normal capillary.
Any factor which leads to impaired nutrition of the vascular wall, such
as deficiency of supply of blood or oxygen, the presence of poisons in the
blood or in the surrounding tissues, scalding or freezing, increases at the
same time its permeability. Under such conditions the limb capillary
reacts to changes of pressure like a liver capillary, the slightest increase
of pressure causing an appreciable increase in the lymph production. This
increased lymph production may be too great to be carried off by the
lymphatic channels, so that the exuded fluid stays in the tissue spaces,
distending them and causing the condition known as oedema or dropsy.
LYMPHAGOGUES- Among the substances which have a direct action
on the vessel wall are a number of bodies which were described by Heiden-
hain as lymphagogues of the first class. As their name implies, these bodies
on injection into the blood stream cause, an increased flow of lymph from
the thoracic duct (Fig. 488). They may be extracted from the dried tissues
of crayfish, mussels, or leeches by simple boiling with water. Commercial pep-
tone has a similar effect. Heidenhain regarded these bodies as direct excitants
of the secretory activities of the endothelial cells. They are however general
poisons, having a special action on the vascular system, and their effect on
lymph production is probably due simply to their deleterious action on the
capillary wall. Although these bodies act chiefly on the liver capillaries, so
that the main increase in the thoracic duct lymph is derived from the fiver,
1066
PHYSIOLOGY
they can be shown also to have some effect in the same direction on the
intestinal and skin capillaries. In fact the injection or ingestion of these
bodies often gives rise to a copious eruption of nettle-rash, i. e. swellings of
the skin due to an increased exudation of lymph into the meshes of the
cutis.
An increased lymph flow from the thoracic duct may be produced also
by the injection of large amounts (10 to 40 grm.) of innocuous crystalloids,
such as dextrose, urea, or sodium chloride, into the circulation. In this
case the lymph becomes much more dilute. The explanation of the action
of these bodies is very simple. We have already seen that injection of
large amounts of dextrose into the circulating blood raises the osmotic pres-
sure of this fluid. The blood therefore imbibes water from the tissues and
O I 2 345678 9 10
Inj of mussel extract
Fig. 488. Changes in lymph flow in portal, inferior cava, and arterial pressures,
resulting from injection of a member of the first class of lymphagogues (extract
of mussels). (Stabling.)
swells up, i. e. a condition of hydraemic plethora is brought about as surely as
if several hundred cubic centimetres of normal salt solution were injected
into the circulation. This increase in the total volume of the blood causes
a rise of pressure throughout the vascular system — arteries, capillaries,
and veins — and the increased capillary pressure, combined with the watery
condition of the blood, induces a great transudation of lymph, especially
in the abdominal organs (Fig. 489). The lymph is more watery because the
blood also is diluted. That the action of these bodies is purely mechanical
is shown by the fact that, if the rise of capillary pressure be prevented by
bleeding the animal immediately before the injection, the increase in the
lymph flow is also prevented (Fig. 489, b), although the concentration of the
sugar or salt in the blood is still greater than in the experiments in which
bleeding was not performed.
MOVEMENT OF LYMPH
In the frog the circulation of lymph is maintained by rhythmically con-
tracting muscular sacs, which are placed in the course of the main lymph
LYMPH AND TISSUE FLUIDS
1067
channels and pump the lymph into the veins. In the higher animals and in
man the onward flow of lymph is effected partly by the pressure at which it
is secreted from the capillaries into the interstices of the tissues, but also to
a large extent by the contractions of the skeletal muscles. In the smaller
lymph radicles the pressure of lymph may attain 8 to 10 mm. soda solution.
H--h^ir-t--~<-+-i-!-!-!-i-+-t--f+4-i--H-t--i-n -
3±j±^L±l±Il:t: ! l+ h ±±tEt^^^Tri^R"tj
78910
r dextrose
ti+FR
'Kl'Hl'TT-Frl Tii"Hj^%^j-J-Tt-i-r
3*S#3~'"Ili"u '"LP" 1 "
01 2345678910
eied to 240 ccm Inj ,
Fig. 489. Effect on lymph flow and on arterial and venous pressures of injection
of concentrated solution of glucose.
In B the animal was bled to 240 c.c. before the injection. The double line
= lymph flow in c.c. per ten minutes ; thin line = portal vein ; thick line =
carotid arteiy ; dotted line = inferior vena cava.
Iii the thoracic duct, at the point where it opens into the great veins of the
neck, the pressure is obviously the same as in these veins, that is to say,
from — 4 to mm. Hg., the negative pressure being occasioned by the aspira-
tion of the thorax. This difference of pressure is sufficient to cause a certain,
amount of flow. It must be remembered however that under normal
circumstances no lymph at all flows from a resting limb. The only part of
the body which gives a continuous stream of lymph during rest is the alimen-
tary canal, the lymph in which is poured out into the lacteals, and thence
1068 PHYSIOLOGY
makes it way through the thoracic duct. Movement, active or passive,
of the limbs at once causes a flow of lymph from them. Since the lymphatics
are all provided with valves (Fig. 490), the effect of external pressure on them
is to cause the lymph to flow in one direction only, i. e. towards the thoracic
duct and great veins. Hence we may look upon muscular exercise as the
greatest factor in the circulation of lymph. The flow of lymph from the
commencement of the thoracic duct in the abdominal cavity to the main
part of it in the thoracic cavity is materially aided by the respiratory move-
ments ; since, with every inspiration, the lacteals and abdominal part of the
duct are subjected to a positive pressure, and the intrathoracic part of the
duct to a negative pressure, so that lymph is continually being sucked into
Hie thorax.
R .B*LBW
FlO. 400. A lymphatic vessel laid open to show arrangement of
the valves. (Testut.)
THE ABSORPTION OF LYMPH AND TISSUE FLUIDS
On injecting a coloured solution or suspension into the connective tissues
of "any part of the body, and gently kneading the part, it is found that
the fluid fills all the lymphatic channels running from the part ; and we can
in this way inject the lymphatics of the limb and trace their course on to
the thoracic duct. The same path is taken by micro-organisms as they
spread in the tissues, or by particles of carmine or Indian ink which have been
introduced in tattooing. It is on account of these facts that the lymphatics
are often spoken of as the ' absorbent system.'
This process of lymphatic absorption, except in the case of the pleural
and peritoneal cavities, is however a slow one unless aided to a large extent
by passive or active movements of the surrounding parts, and cannot therefore
account for the rapid symptoms of poisoning which supervene within two or
three minutes after the hypodermic injection of a solution of strychnine or
other poison. That this absorption is not dependent on the lymphatics is
shown by the fact that the symptoms occur almost as quickly when all the
tissues of the limb have been severed, with the exception of the mam artery
and vein. In the same way, after injecting methylene blue or indigo carmine
into the pleural cavity or subcutaneous tissues, the dyestuff appears in the
urine long before any trace of colour can be perceived in the lymph flowing
from the thoracic duct. The absorption in these cases is by the blood vessels,
and consists in an interchange between blood and extra vascular fluids,
apparently dependent entirely upon processes of diffusion between these
two fluids. So long as any difference in composition exists between the
intra- and extravascular fluids, so long will diffusion currents be set up,
tending to equalise this difference.
LYMPH AND TISSUE FLUIDS 1069
More difficulty is presented by the question of the mechanism of absorp-
tion by the blood vessels of the normal tissue fluids — such an absorption as
we have seen to occur after loss of blood by haemorrhage. It seems probable
that this absorption depends on the small proportion of protein contained in
the tissue fluid as compared with the blood plasma, and is due to the osmotic
pressure of the protein. If blood serum be placed in a bell-shaped vessel
(the mouth of which is closed by a gelatinous membrane which does not
permit the passage of protein), and suspended in normal salt solution, it is
found that the serum absorbs the salt solution until the manometer attached
to the bell-jar indicates a pressure of 25-30 nun. Hg. Thus we may con-
ceive that there is normally a balance in the capillaries between the processes
of exudation and of absorption, the former being conditioned by the capillary
blood pressure and the latter by the difference in protein content, and there-
fore of osmotic pressure between the blood plasma and tissue lymph. A rise
of capillary pressure will upset this balance in favour of transudation and
t he blood will become more concentrated, whereas a fall of pressure will turn
the scale in favour of absorption and the volume of blood will be increased
at the expense of the tissue fluids.
THE PART PLAYED BY THE LYMPH IN THE NUTRITION
OF THE TISSUES
The fact that the tissue cells are separated by the lymph and the capillary
wall from the blood shows that, in all interchanges between the blood and
tissues, the lymph must act as the medium of communication. The lymph
flow plays very little part in this process. The muscles of a resting limb
are taking up nourishment as well as oxygen from the blood and giving off
their waste products — carbonic acid and ammonia, though not a drop of
lymph may flow from a cannula placed in a lymphatic trunk of the limb. In
fact the interchange of material between tissue cell and blood through the
mediation of the lymph is carried out in the same way as are the gaseous
interchanges, viz. by a process of diffusion. This explanation however holds
good only for the diffusible constituents of the blood and will not account
for the supply of the indiffusible protein molecules to the cell. Apparently
the only way in which the tissues can obtain their supply of protein is from
the small proportion of this substance which has filtered through the vessel
wall into the lymph. The increased exudation of concentrated lymph to
1 he 1 issues, which occurs in inflammatory conditions or as the result of injury,
is therefore of advantage, since it furnishes an abundant supply of protein
food to be used up in the regeneration of the damaged cells.
CHAPTER XV
THE DEFENCE OF THE ORGANISM
AGAINST INFECTION
SECTION I
THE CELLULAR MECHANISMS OF DEFENCE
One of the main distinctions, perhaps the most important, between the
animal and vegetable kingdoms lies in the inability of animals to build
up their tissues at the expense of inorganic salts, and especially to synthetise
the various groups necessary for the formation of the protein molecule.
They are thus rendered dependent on the assimilative powers of the vegetable
kingdom, and have to supply their needs by using the members of this king-
dom as food. The protozoa, for example, subsist largely on bacteria. To
obtain a pure culture of any form of amoeba it is necessary to cultivate this
along with some form of bacteria. The power of the unicellular animals to
digest bacteria meets with a response on the part of the latter, many of them
developing, by way of self-defence, the habit of forming and excreting poisons
which will deter the amoeba from taking them up or will injure it after
it has ingested them. There is thus a continuous struggle among the various
grades of unicellular organisms in which sometimes one, sometimes another
type survives. An amoeba placed in contact with most kinds of bacteria,
living or dead, will rapidly englobe and digest them. There is however a
small organism known as microsphera which is taken up by the amoeba, but
is not thereby destroyed. Retaining its vitality, it reproduces itself rapidly
in the body of its host and finally leads to disintegration of the latter. In the
same way the flagellate protozoa are often infected by a species of fungus
known as chytridium, and die in consequence.
The liability of organisms to infection, by others endeavouring to five a
parasitic existence at their expense, extends throughout the whole of the
animal and vegetable kingdoms. In some cases the host and the
parasite arrive at a compromise in which each benefits the other. This
condition is known as symbiosis. We have examples of it in the union of
fungi and algae which occurs in lichens; in the association of nitrogen-
fixing bacteria with many plants, especially those belonging to the natural
order Leguminosae. In herbivorous animals the presence of specific bacteria
in the paunch or caecum causes the breakdown of the cellulose walls of the
food and may indeed lead to a building up of protein from amino-acids or
1070
THE CELLULAR MECHANISMS OF DEFENCE
1071
even from salts of ammonia. It is probable that in these cases the animal is
decidedly benefited from the presence of these bacteria in its alimentary
canal, so that here also we may speak of a symbiosis. Lr most cases invasion
of a higher animal or plant by some lower organism is fraught with danger to
the host, so that special mechanisms have to be provided for the protection
of the tissues from infection. The most primitive means of defence, and
one which is foimd throughout the whole animal kingdom, is exactly ana-
logous to the process by which the amoeba destroys and utilises any bacteria
present in its environment. The prevention of infection is of course the
function of the external layers of the organism, i.e. the epithelial covering,
either of the skin or of the surface of the gut. Protection here may be
of a physical or chemical character. The cells may secrete a horny or
chitinous layer which presents a mechanical obstruction to the entry of
FlO. 401. a, amoeba, infected by Microsphtera : a, early stage.
amoeba, full of parasitic Mkrosphczrw. (Metchmkoit.
bacteria. They may secrete mucin, which entangles and hinders the move-
ments of invading micro-organisms, or they may secrete substances which
actually destroy the life of such organisms. When however a micro-
organism has obtained entrance to the interior of the body, e. g. through a
wound of the surface epithelium, the task of dealing with the invader
becomes the office of a special type of cells belonging to the 'meso blast.
These cells are similar in character to the amoeba. They have the power
of extruding pseudopodia, of wandering from place to place, and of englobing
and digesting particles of food or bacteria with which they come in contact.
On account of these latter properties they have been called by MetchnikofE
phagocytes, and the whole process by which foreign material or the animal's
own dead tissues are got rid of is spoken of as phagocijtosis. The process can
be well studied, as has been shown by MetchnikofE, in the sponge or in the
larva of the echinoderm. At one stage in the development of the latter the
larva consists of a sac which is involuted at one extremity to form the
L072
PHYSIOLOGY
alimentary cavity, while the mesoblast is represented by amoeboid cells
suspended in a semi-liquid substance filling the body cavity. If a particle
of foreign substance be introduced into the body cavity, the wandering
mesoderm cells collect round the particle and fuse into plasmodial masses,
thus forming a wall, as it were, around it. If bacteria be introduced, the
phagocytes may be seen to adhere to and ingest the still living bacteria,
which are then rapidly digested and destroyed. A similar process may be
observed in the transparent crustacean known as the water-flea (Daphnia),
and here it may be noted that the process of phagocytosis is not always
successful in maintaining the health or life of the host. Thus if the spores
of a yeast-like organism, the Monospora, be introduced into the body cavity
of Daphnia, the leucocytes may, if the spores be few in number, lay hold of
Fro. 402. 1, gastrula stage of starfish embryo, with a foreign substance, jH, in its
body cavity ; end, endoderni ; ect, ectoderm ; vies, wandering mcsoblastie
celts. 2, the foreign body of 1, surrounded by a Plasmodium of phagocytes
(highly magnified). (After Metciinikoff.)
the latter and digest them. If the spores be in excess, the phagocytes may
fail to ingest them or may indeed be destroyed as soon as they approach
them. In this case the spores germinate, fill up the body cavity, and
finally lead to the death of the host. The same process of phagocytosis may
be studied in its simple form by injuring or infecting some tissue which
is free from blood vessels. Thus the tail fin of an embryonic axolotl may
be cauterised with silver nitrate, or a small quantity of fluid containing
carmine granules may be introduced by means of a hypodermic syringe. In
either way a certain number of cells are destroyed and the dead tissue there-
upon acts as a foreign body. As a result the wandering mesoderm cells or
leucocytes move from the surrounding tissues towards the seat of the injury,
and the day after the injury has been inflicted a collection of leucocytes
can be seen, many of which contain particles of carmine or debris of the
destroyed tissue which they have taken up. The cells finally wander away
from the part, and the destruction is made good by the proliferation of the
connective tissue cells and of the epithelium immediately adjoining the
injury. In the lowest types of metazoa it is impossible to speak of more
THE CELLULAR MECHANISMS OF DEFENCE 1073
than one type of wandering mesoderm cell. It is probable indeed that the
same type of cell may at one time act as a scavenger and at another as the
chief agent in the formation of connective tissues. Even in Daphnia,
according to Hardy, only one form of leucocyte is present, whereas in the
much more highly organised crayfish, belonging however to the same
family, three different types of leucocyte may be distinguished. These
leucocytes may be present free in the body cavity or they may form an
element of the connective tissues. With the formation of a closed vascular
system many of the wandering mesoderm cells became attached to this
system, so that we may distinguish a group of blood leucocytes or phagocytes
and a group of connective tissue or body -cavity leucocytes. Moreover by
the formation of a blood vascular system, all the tissues of the body are
brought into material relationship with one another, so that many distant
parts may be drawn upon to supply the needs of any one part. It is evident
that injury of a tissue in a higher animal containing blood vessels will involve
more complex consequences than a similar injury or infection of the avascular
tissue of an invertebrate, and that the accumulation of cells for the defence of
the organism against invading microbes will be much more effective if the
blood vessels participate in the process so that, by their means, the phago-
cytic resources of all parts of the body can be drawn upon to ward off a
localised attack. The process of phagocytosis thus in the higher animals
becomes merged into the more complex series of "phenomena to which the
term ' inflammation ' has been applied. This process can be studied by
observing the effects of slight injury to some transparent part of the body,
e. g. the frog's tongue or mesentery or the web of the frog's foot. For this
purpose a small piece of the skin of the frog's web is snipped off with fine
curved scissors, the section being sufficiently deep to remove the skin with-
out causing haemorrhage. The first effect noticed in the immediate neigh-
bourhood of the injury is a dilatation of the vessels, especially of the venules,
with acceleration of the blood flow. In the course of an hour the capill iries
also become dilated, and many capillary channels, previously invisible, are
now occupied with blood. Through the dilated capillaries there is a rapid
blood stream, the corpuscles occupying the axis of the vessel, so that there
is a periaxial layer of plasma. A little later this acceleration gives place
to a slowing of the blood stream, and simultaneously the leucocytes of the
blood are seen to be adherent to the capillary wall. Apparently the latter
becomes what we may call ' sticky,' the effect of the stickiness being to
increase the resistance to the passage of the blood through the vessel and
also to cause the adhesion of the leucocytes to the wall. As the current
becomes still slower, the distinction between axial and peripheral streams
disappears. The corpuscles are closely packed together, the white cor-
puscles being predominant at the margins of the capillary, where they form
a lining to the vessel (Fig. 493). The next stage is the emigration of the
leucocytes. These may be observed to thrust a process through the vessel-
wall (according to Arnold this process of emigration always occurs through
the stigmata, i. e. the points where the endothelial cells come in contact —
1074
1MIYS10LOGY
Fig. 494). The prolongation enlarges on the onter side of the vessel, while
the portion of the leucocyte within the vessel becomes smaller, so that finally
the whole leucocyte passes through and lies in the lymph spaces outside
the capillary. In the course of five or six hours all the capillaries and small
veins in the neighbourhood of the injury may show a crowd of leucocytes
„
Fig. 493. Inflamed mesentery of frog, to show marginatum of leucocytes in the
inflamed capillaries, a ; migration of leucocytes, 6 ; escape of red corpuscles, c :
accumulation of leucocytes outside the capillaries, d. (From Adami after
RlBBERT.) *
along their outer surfaces. The use of this emigration seems to be to
remove the tissue injured by the primary lesion. As soon as this is effected,
regeneration of the injured tissue occurs by a proliferation of the connective
tissue corpuscles and the epithelium, while the leucocytes move away and
disappear. The essential phagocytic character of the inflammatory process
may be shown if the primary lesion be attended with infection. Thus if a
small quantity of the staphylococcus be injected into the subcutaneous tissue
Fig. 494. Emigration of leucocytes through capillary wall. (Arnold.)
of the rabbit, the vessels surrounding the point of injection may within four
hours be found densely filled with corpuscles. In ten hours' time the leuco-
cytes are present in large numbers outside the vessels, while the injected
cocci have spread for some distance along the lymphatic spaces and, while
partly free, have been to a large extent ingested by the leucocytes. In
twenty hours' time the connective tissue fibrils at the point of injection are
found to be widely separated by the aggregation of leucocytes. In forty-
eight hours' time a well-defined abscess is produced. At the centre all
traces of previous connective tissue have disappeared and its place has
been taken by a dense mass of leucocytes, many in a state of degeneration,
THE CELLULAR MECHANISMS OE DEFENCE 1075
mingled with staphylococci, partly within, partly outside the cells. The
margin of the abscess is formed by connective tissue infiltrated with living
leucocytes. A certain number of cocci are to be seen free in the tissue out-
side this layer, but in the course of a day or two these free cocci disappear,
and there is thus a continuous layer of phagocytes surrounding the abscess
cavity and preventing any further invasion of the body as a whole from the
seat of infection. The abscess subsequently discharges on to the exterior
by a process of necrosis of the superjacent skin, and regeneration of tissue
takes place in the same manner as in the more trivial injury. Inflamma-
tion in warm-blooded animals thus, gives rise to dilatation of vessels and
increased vascularity of the part, to alteration of the vessel wall and
therefore to increased effusion of fluid. There are warmth and redness of
the part from the vascular dilatation, swelling from the effusion of lymph,
and very often, as a result of the injury or the swelling and the conse-
quent involvement of sensory nerves, pain. The four cardinal symptoms
of inflammation, namely, rubor, color, turgor, and dolor, which have
been described for generations as typical of this condition, leave out of
account altogether the phenomenon which Waller's and Cohnheim's obser-
vations, in the light of the comparative studies of MetchnikoS, have shown
us to be the essential feature of the process. This is phagocytosis, the
accumulation of wandering mesoderm cells round the seat of injury with
the objects of removing injured tissue, of destroying micro-organisms, of
protecting the body from general infection, and of preparing the way for
reintegration of tissue.
Prior to the work of Metchnikoff, the changes in the blood vessels fettered
the attention of physiologists, and the accumulation of leucocytes was
regarded as secondary to these changes. Though the alteration of the
capillary wall, by permitting the adhesion of the leucocytes, must no doubt
favour their emigration and their passage from all parts of the body into the
inflamed part, we know that the same accumulation of leucocytes occurs
in the entire absence of a vascular system. The movement of the corpuscles
towards dead or injured tissue must therefore have some other explanation.
We have abundant evidence to show that the essential factor in this aggrega-
tion of leucocytes is their chemical sensibility, and that the phenomenon
is simply one of chemiotaxis. A capillary glass tube containing a suspension
of dead micrococci, or peptone, or broth extracted from dead tissue, if
introduced into the anterior chamber of the eye or into the subcutaneous
tissue, is found after a short time to be full of leucocytes. We must assume
that the chemical products diffusing out of the ends of the capillary tube have
acini like the malic acid discharged by the cells forming the female organ, the
archegonium, of ferns. Just as the latter causes a movement of the anthero-
zoids. the male cells, towards the ovule, so the chemical substances diffusing
from the capillary tube have occasioned a positive chemiotaxis on the part
of the leucocytes. It is worthy of note that the positive chemiotactic
influence exerted by any given species of pathogenic bacterium is roughly
inversely proportional to its virulence. A culture lacking in virulence may
1076 J'llYSIOLOUY
cause ;i very pronounced aggregation of leucocytes which speedily ingest and
destroy the micro-organism, whereas if a culture of a more virulent variety
of the same microbe be injected, there may be all the signs of inflammation,
swelling, and large effusion of fluid, but the tissues may contain very few
leucocytes. Under these circumstances the micro-organism rapidly pro-
liferates and spreads from the seat of the lesion, giving rise finally to general
infection.
So far we have spoken merely of leucocytes or phagocytes, and have
nut attempted to distinguish between the parts played by the various types
of leucocyte which are found in the blood and connective tissues. In the
higher animals there are however very many varieties of leucocytes belong-
ing partly to the blood', partly to the connective tissues. The following
Table, modified from Adami, enumerates the leucocytes which may be
concerned with inflammation in a mammal or man :
Polymorphonuclear (polynuclear, finely Originating in adult mammals from the
granular oxyphile, neutrophile, or bone marrow, and migrating from the
amphophile cell). blood into the inflammatory area.
Eosinophile (coarsely granular oxyphile,
macroxycyte).
Lymphocyte ( ? of two types). Originating from lymphoid tissue and from
Plasma cell ( ? histogenous). vascular and other endothelia respec-
Endotheloid leucocyte (mononuclear leuco- tively; present in inflamed area either
cyte, hyaline cell (in part), ' epithelioid by migration from blood or as result of
cell ' (in part). local proliferation.
Connective tissue wandering cell (includ- Originating locally as result of tissue
ing clasmatocyte). proliferation.
The part played by each of these forms is still to a large extent the
subject of discussion. There is no doubt that, in all active inflammations,
the polymorphonuclear leucocyte is the form which is attracted first and
in largest numbers to the seat of injury. It is the characteristic cell from
which pus is formed, and is actively phagocytic. It has nothing to do with
the regeneration of the destroyed tissue. The eosinophile corpuscle is also
present at an early stage arovmd the inflammatory focus, but is never present
in numbers at all comparable with those of the polymorphonuclear leucocyte.
It is especially abundant in chronic inflammations of certain tissues, such as
the skin. According to Kanthack and Hardy, these cells discharge their
granules into the surrounding fluid, rendering this fluid toxic for bacteria.
Although later observations have failed to confirm these views, no other
satisfactory explanation has been given as to the part played by these cells.
They are rarely seen to ingest bacteria and therefore cannot be spoken of as
phagocytic. The lymphocyte predominates in certain chronic inflammations,
especially in those caused by the tubercle bacillus. They do not ingest
bacteria. The histogenous wandering cells appear in the inflammatory
area at a later period than the polymorphonuclear and eosinophile cells.
They are actively phagocytic and are motile. As a rule their phagocytic
properties are exerted, not on bacteria, but on other cells and cell debris.
THE CELLULAR MECHANISMS OF DEFENCE 1077
After an acute inflammation their chief office is to clear away the remains
of the polymorphonuclear leucocytes and dead tissues so as to prepare
the way for subsequent regeneration. It is possible that these cells may
take a part in the formation of new connective tissue. They are indis-
tinguishable from the immature form of connective tissue cells. It is
therefore difficult to be certain whether the wandering and the fixed con-
nective tissue corpuscles are of identical or of different origin. Metchnikoff
speaks of these cells as macrophages, to distinguish them from the polj r -
morphonuclear type, which he terms microphages.
We thus see that several types of the wandering cells of mesoblastic
origin, which take part in inflammation, do not exert active phagocytic
properties and cannot therefore destroy bacteria or other invading organisms
by the process of ingestion and digestion. Yet we have evidence that the
part played by such cells in the defence of the organism is no less important
than that of the actively phagocytic cells. In the alimentation of the more
primitive invertebrata, the cells fining tfie digestive cavity take up the
particles of food directly, and the processes of digestion are carried out in
vacuoles within the cells themselves. In the higher animals this process of
intracellular digestion has almost disappeared, and the cells fining the
alimentary tract have become differentiated into those which secrete
digestive ferments and those which absorb the products of the action of the
ferments on the foodstuffs. Digestion has thus become extracellular. It
seems that a similar modification has taken place to some extent in the
means adopted by the organism for its defence from infection, and that the
leucocytes destroy bacteria, not only by the process of intracellular digestion
but also by the excretion into the surrounding body fluids of substances
which have a deleterious influence on bacteria. Thus normal blood serum
is found to have a strong destructive influence on most species of bacteria,
whether pathogenic or not. Since this property is not shared to anything
like the same extent by the blood plasma, it may be ascribed to the breaking
down of leucocytes in the process of clotting and the consequent liberation
of bactericidal substances. Extracts made from any collection of leuco-
cytes have a similar bactericidal effect, and it has been shown by Wright
that the ingestion of bacteria by normal leucocytes goes on much more
rapidly in the presence of blood serum or if the bacteria have been previously
subjected to the action of blood serum. This adjuvant action of blood
serum on phagocytes is destroyed if the serum be heated to 55° C, so that it
must be due to the presence in the serum of some chemical substance, which
is unstable and destroyed by heat at a temperature far below the coagula-
tion point of the serum proteins. Moreover there are many species of
pathogenic bacteria which cannot infect the animal as a whole. These
nevertheless may multiply on the surface of the body or in an abscess cavity,
and lead to the death of the host, in consequence of the production by
the bacteria of soluble toxins which are absorbed into the blood stream.
Examples of such micro-organisms are those which are associated with
tetanus and diphtheria. The process of intracellular digestion is obviously
1078 PHYSIOLOGY
inadequate to deal with such cases and, since we have the power of resisting
and recovering from these diseases, there must be other mechanisms at the
disposal of the body for the neutralisation of these »toxins. The protec-
tion of the body against destruction by bacterial toxins involves in fact
a whole series of chemical mechanisms, which we must regard as of equal
importance and as co-operating with the phagocytic mechanism.
SECTION II
THE CHEMICAL MECHANISMS OF DEFENCE
IMMUNITY. All infectious diseases are caused by the agency of micro-
organisms. The greater number of these, the bacteria, belong to the class
of fungi or schizomycetes ; a certain number must be classed with the
yeasts, while others are protozoal in character. It is especially in the first
class of diseases, namely, those due to bacteria, that the organism has
developed chemical mechanisms of defence. In the protozoal diseases the
micro-organisms occur for the greater part as intracellular parasites. One
attack of the disease does not as a rule confer immunity, and the treatment
has to be sought along the lines of medication by drugs rather than by the
development of methods of protection normally displayed or developed by
the animal which is the subject of the infection. The diseases due to bacteria
include diphtheria, tetanus, tubercle, anthrax, pyeemia, and many others.
In these diseases we have to deal with a number of phenomena more or less
common to all. The infection in each case is due to the actual transference
of the specific organism from one animal to another. After the micro-
organism has attained entrance into the system there is a period of incuba-
tion before the disease actually breaks out. When this occurs, the specific
microbe is to be found in large quantities either in the blood or in the tissues
of the body. The disease is generally characterised by fever and often by
local lesions, such as the intestinal ulcers of typhoid, or the glandular
swellings of bubonic plague. The micro-organisms may develop in the
animal until its death, or the disease may terminate in recovery and the
total disappearance of the microbes from the body. After recovery it is
found that the patient is protected from reinfection by the bacterium which
was the cause of the disease, and this condition of immunity may last as
[ong as the patient lives. The incidence of these bacterial diseases is not
the same for all animals, so that in the case of many diseases we can speak
of. a natural immunity of certain animals for the diseases in question.
The pathogenic micro-organisms can, in a number of cases, be culti-
vated on artificial media outside the body, ft is then found that they may
be divided into two classes. One class, of which the diphtheria and tetaivus
bacilli are examples, secrete in the surrounding culture-fluid substances
which act as virulent poisons when injected into animals. Other bacteria
do not form such extracellular toxins, but in their case it is found that, if
the bodies of the bacilli be broken up, the injection of the contents of the
bacteria is attended with poisonous effects. The bacteria may be thus
107(1
1080 PHYSIOLOGY
classified according as they produce extracellular or intracellular toxins.
We may deal first with the manner in which the body reacts to the toxins
excreted by the first class. If a culture of diphtheria or tetanus bacilli be
filtered, the clear filtrate free from bacilli is found to exercise as poisonous
results as if the culture itself of the living bacilli had been employed. The
toxins contained in these fluids are extremely potent. Thus five-millionths
of a gramme of tetanus toxin is a fatal dose for a mouse, and -00023 grm.
would kill a man. These weights apply to the mixture obtained by the
evaporation of the solution of toxin, so that the pure toxin must be even
more powerful than is represented in these figures. We have at present no
means of preparing a toxin in a pure condition, nor we do know to what class
of compounds it should be assigned. The toxin is an unstable body and is
destroyed by heating to 65° C. Similar toxins are widely distributed
throughout the vegetable and animal kingdoms. Thus they form the
active constituent of snake venom and of the poison of scorpions and spiders.
They also occur in the seeds of castor oil and of jequirity, the toxins of
which seem to be of protein character and are known as ricin and abrin.
There is a great variability in the reaction of different animals to these
toxins. Thus to the poison of tetanus the rabbit is weight for weight two
thousand times and the hen twenty thousand times more resistant than
the guinea-pig. As in the case of infection by bacteria themselves, a certain
incubation time is necessary after the introduction of the toxin before its
effects are displayed. There is a striking difference in this respect between
the action of these complex bodies and the action of drugs, such as strychnine
or morphine. Thus by increasing the dose of strychnine it is possible to kill
an animal within half a minute. The period of survival after the injection
of a dose of toxin cannot be reduced beyond a certain limit, however much
toxin be injected. Thus a lethal dose of diphtheria toxin kills a guinea-
pig in fifteen hours. If ninety thousand such doses be injected into a
guinea-pig, it is not possible to reduce the time of survival below twelve
hours. Another characteristic of these toxins .is the specificity of their
action. One kind of toxin may act chiefly on the central nervous system,
another on the peripheral nerves, another on the red blood corpuscles.
In this respect of course they resemble ordinary drugs. Associated with,
and apparently a necessary condition of, this specific action is the actual
combination which occurs between the toxin and the organ on which it
exerts its effect. Thus tetanus toxin has a specific affinity for the central
nervous system, and may be removed from a solution by shaking the latter
up with an emulsion of brain. In spite of the excessively fatal character of
these toxins it is possible to render an animal immune to their action. If
a dose of diphtheria or tetanus toxin which is smaller than the fatal dose
be injected into an animal, the latter may show signs of injury from which
it recovers. When recovery is complete, it is found that three or four times
the fatal dose may be injected without producing any evil effects ; and this
process of injection of toxin may be repeated in continually increasing doses
until the animal is able to withstand a dose one hundred thousand times
THE CHEMICAL MECHANISMS OF DEFENCE 1081
as large as that which would have been fatal to it in the firso instance.
When a condition of immunity has been produced in this way, it is found
that the blood serum of the animal has the power of neutralising the toxin.
Thus if the blood serum from a horse, which has been treated with large
doses of diphtheria toxin, be mixed with an equal quantity of the toxin itself,
the mixture may be injected into susceptible animals without the produc-
tion of any effect. It is possible in this way to get a serum, 1 c.c. of which
will neutralise many fatal doses of the toxin ; and this antitoxic serum may
be injected into a susceptible animal and used to confer an artificial immunity
on the latter, or it may be injected into a diseased animal and used thus as a
curative agent. Antitoxin thus plays a great part in modern therapeutics,
especially of diphtheria. In the case of tetanus the toxin has a specific
affinity for the nervous system and apparently travels up the axis cylinders
of the nerves to the central nervous system. By the time that it has arrived
at the central nervous system, and the spasms typical of tetanus have broken
out, the toxin is already so firmly bound to the reacting tissue that the
injection of antitoxin into the blood stream has little or no effect on the
course of the disorder. The use of the tetanus antitoxin is therefore chiefly
as a prophylactic agent.
The question of the manner in which the antitoxin is able to combine
with and neutralise the toxin is one of considerable practical importance.
In this process we have relations presenting marked analogies with the
neutralisation of acids by bases. If we define a unit of toxin as that amount
which possesses a certain power, i. e. which will kill a guinea-pig in so many
days, or will cause the complete haemolysis of 1 c.c. of blood in two and a
half hours, we can find the. amount of anti-body which is just sufficient to
neutralise this effect, and this amount of anti-body can be regarded also as
one unit. If instead of one unit of each we take 100 units, the neutralisation
is effected in the same way. The process is found however to be more
complex when we take 100 units of toxin or lysin and attempt to neu-
tralise them by the fractional addition of antitoxin. In the case of a strong
acid and strong alkali we know that, if 100 c.c. of alkali are just sufficient to
neutralise 100 c.c. of acid, the addition of 50 c.c. of alkali will leave half the
acid unneutralised. If however we try the same experiment in the case of
mixtures of toxin and antitoxin, it will be found that the addition of 50 units
of antitoxin will neutralise much more than half of the toxin, and the same
applies to other bodies of this class. Ehrlich attempted to explain this
result by assuming that in any toxin there is a mixture of substances, some
having a strong affinity for the antitoxin, and others, which he calls toxones,
possessing only a slight affinity. In the 50 units of toxin first added, the
toxins would satisfy all their combining powers, whereas the toxones would
not begin to combine until they were present in large excess. Arrheniu.s
and Madsen have drawn an analogy between the neutralisation of toxin by
antitoxin and the neutralisation of a weak acid, such as boracic acid, by a
weak base, such as ammonia. They show that in this case the general
course of events would be similar to that observed by Ehrlich. At no time
1082 PHYSIOLOGY
would there be complete neutralisation, owing to the fact that hydrolysis
constantly occurs, so that when equivalent quantities of each substance had
been added, the fluid would still contain a certain amount of free base
alongside of free acid, in addition to the salt produced by the combination
of the two. It is impossible however to account in tins simple manner
for all the phenomena presented in the neutralisation of toxin by antitoxin.
Thus seventeen parts of ammonia would neutralise exactly an equivalent
quantity of boracic acid, whether these substances were dissolved in 10 c.c.
or in 100 c.c. of water. If however it be found that 1 c.c. of antilysin
exactly neutralises 1 c.c. of lysin, these two substances will no longer be in
equilibrium when the whole is diluted up to 10 c.c. with water. If a neutral
mixture of lysin and antilysin be taken and filtered under pressure through
a gelatin filter, no lysin or antilysin passes through the filter, so that the
residue on the filter becomes concentrated. On examining this residue it is
found that it has a strong hsemolytic action, and the same is true of the
substance which may be obtained by melting the gelatin out of the pores of
the filter. It is evident that, even in a neutralised mixture, both free lysin
and free antilysin, or free toxin and free antitoxin, are present, and it needs
only the alteration of the physical condition of the mixture in order to
display the action of one or other of these bodies. How then are we to
regard this combination of toxin with antitoxin ? Craw has pointed out
that the combination is in all respects comparable to that which occurs
between absorbing surfaces and many dyestuffs. If we place some filter
paper in a solution of fuchsin or Congo red, the filter paper will take up the
dye substance. The amount taken up by the paper will increase with
increase in concentration of the solution. There will however be a ten-
dency to the formation of false equilibrium points, as in the case of the
reaction of toxin and antitoxin. Thus if two solutions of fuchsin be made
and to each a sheet of filter paper be added, but in one case it be added at
once, and in the other case in three parts at intervals of twelve hours, at
the end of thirty-six hours the paper which has been added in parts will
have removed more dyestuff from the solution than is the case where the
whole amount of paper was added at once. In the same way, when treating
a suspension of bacilli with an agglutinating serum, it is found that the
successive addition of the bacillary suspension to the serum removes more
agglutinin from the solution than when the addition is made at one
time.
The interactions therefore between these bodies must be looked upon as
special examples of the group of phenomena known as adsorption, such as
the adsorption of iodine from solutions by charcoal, of iodine from water by
starch, or of ammonia by charcoal. The exact adsorption which takes place
must be a function of the chemical configuration of the substance forming the
surface, since otherwise it would be impossible to account for the extremely
specific character of the interaction between toxins and their corresponding
antitoxins. The interaction must therefore be assigned to that special
class, in which we have already placed the action of ferments, which is not
THE CHEMICAL MECHANISMS OF DEFENCE 1083
entirely chemical nor entirely physical, but depends for its existence on a
co-operation of both chemical and physical factors.
How are we to account for the production of the antitoxin as a result
of the injection of toxins into the body, a production which is proportional
to, but far transcending in amount, the toxin injected ? In all the specula-
tions on the mode of production and action of antitoxins, an important
part has been played by a conception put forward by Ehrlich in 1885 of the
nature of the living protoplasmic molecule. According to this conception,
which is spoken of as the ' side chain theory,' each unit of living matter
consists of a centrally placed protein group with a number of side-chains
attached to it, on the analogy of the hypothetical configuration of the
benzene ring, to each comer of which may be attached an aliphatic chain.
To explain the phenomena of nutrition and oxidation, Ehrlich regarded some
of these side-chains as corresponding to unoxidised food substances, while
(it hers of the side-chains had a strong affinity for oxygen and might be
regarded, when fully saturated with this substance, as peroxide in character.
Activity in such a unit would be associated with interaction between these
two sets of side-chains. As a result the food chain would be converted to
carbon dioxide and an affinity left unsaturated until it could take up another
food molecule. In the same way the oxygen side-chain, having lost the
greater part of its oxygen, would have a strong affinity for this element and
would re-saturate itself at the expense of the oxygen brought to it by the
blood. Ehrlich regards the toxins as partaking essentially of the same
character as the protoplasmic molecule, as being in fact protoplasmic
fragments differing only from the protoplasm of the cell in the greater
simplicity of arrangement of their side-chains. According to him the central
group, or nucleus, of the toxin possesses two side-chains, one of which by its
stereomeric configuration is peculiarly adapted to fit on to the organ or cell
of thr body which the toxin or active body attacks, and is known as the
haptophore group; and another side-chain, the toxophore group, which is
responsible, when the toxin is once anchored, for the destructive changes
wrought by the toxin on the cell of the body. The antitoxins or antilysins
are thus supposed to act in virtue of their adaptation to the haptophore
group, so us to combine with the toxin or lysin and prevent these from
exercising their injurious effects on the body. Ehrlich has shown that, in
many toxins, the toxophore can undergo weakening or destruction without
any alteration of the haptophore group; such modifications he designates
as ' toxoids.' 1 They have the same combining power for antitoxins as is
possessed by the ordinary toxins, but are cither without physiological effect,
or their poisonous characters are only a fraction of that possessed by ordinary
toxin.
The formation of antitoxins is accounted for (01 rather described) on this
hypothesis in the following manner. When a receptor side-chain of the cell
is occupied by becoming attached to the haptophore group of the toxin,
this side-chain is, so to speak, shut out from the normal activities of the cell.
A defect is thus produced in the cell, to which the latter endeavours to adapt
1084
1MIYKIOLOGY
itself by the product ion of other side-chains of the same character. It
may be regarded as a general rule in living tissues that a reaction tends to
be an over-reaction, so that the compensation by the cell should more than
make good 'the defect produced by the attachment of the toxin. We thus
get, not one, but a number of side-chains produced of the same character
as that occupied by the toxin molecule, and therefore able also to act as
receptors for the haptophore group of the toxin. These new receptor side-
chains, being produced in excess, are supposed by Ehrlich to be thrown off
Fig. 495. Schematic representation of formation of antitoxin as side-chains of pro-
toplasmic molecule. The black bodies are the toxin molecules which fit by
their haptophore end en to the side-chains of the cell. (Ehelich.)
from the cell and to circulate in the body fluids (Fig. 495, 4). A number
of protoplasmic fragments are thus set free which have a specific power of
uniting with the toxin, and it is this excess of side-chains thrown off from
the cell which represents the antitoxin molecules found circulating in the
blood after the injection of toxins. It will be noted that this theory, though
chemical in form, is really purely biological. It does not explain the
phenomena by reference to the known laws of chemistry, but is a manner of
viewing the biological phenomena, which facilitates their description and
discussion and enables us to classify the very complex phenomena of
immunity in a more or less imperfect fashion.
The property of giving rise to anti-bodies on injection into an animal
is not confined to toxins, a large number of substances, e.g. egg albumin,
THE CHEMICAL MECHANISMS OF DEFENCE 1085
serum, proteins, ferments, albumoses, partaking of the same property. All
snch • substances are classed together as antigens. Thus human serum
injected into a rabbit produces in the rabbit's serum some body which will
give a precipitate when mixed with human serum even in minute traces.
This precipitin formation is specific, so that it may be used as a test for the
origin of any unknown specimen of serum. In the same way rennet fer-
ment when injected gives rise to the production of an anti-rennin which will
neutralise the action of this ferment on milk. Antigens are all colloidal in
character and probably optically active. Ordinary drugs do not give rise
to the formation of anti-bodies, a necessary condition being apparently
some similarity in the molecular structure of the antigen to the proto-
plasm of the animal on which it acts and to which it becomes finked by
its haptophore group.
CYTOLYSINS. The bacteria of tetanus and diphtheria cannot exist in
the body, infection by them being limited to a surface or abscess cavity.
When a disease involves infection of the tissues themselves by living micro-
organisms, somewhat more complicated mechanisms are brought into play
for the defence of the organism. We have already seen that normal blood
serum may exert a paralytic or destructive action on bacteria. Light has
been thrown on the factors involved in this destruction by a study of the
phenomenon of liwmolysis, i. e. the destruction of red blood corpuscles.
Normal goat's serum may be mixed with the red blood corpuscles of the
sheep without any injury to the latter. If however sheep's corpuscles,
previously washed in normal saline, be injected at intervals of a few days
into a goat, the goat's serum is found to have accpiired the power of rapidly
dissolving the red blood corpuscles. This hemolytic power can be
proved by mixing the serum and the w-ashed blood corpuscles together
and allowing the mixture to stand in a narrow tube. The corpuscles
rapidly sink to the bottom, leaving the colourless serum above, unless
haemolysis has occurred, in which case the serum will be of a transparent
red colour. If the hsemolytic serum be heated to 55° C. it is found to have
lost its power of dissolving sheep's corpuscles. This power is at once restored
if to the heated serum be added any normal blood serum, even of the sheep
itself. It seems therefore that two substances are involved in the haemolysis,
namely, (a) a substance present in most normal sera which is destroyed at
i temperature of 60° C. and has been called the complement, and (b) a
substance present in the serum only as a result of the previous injection of
some species of red blood corpuscle, which is resistant to the action of heat
and is called the amboceptor. The reason for these names will be at once
apparent from the following experiment. Hsemolytic goat's serum is
mixed with sheep's red blood corpuscles and the whole mixture kept at 0° O,
at which temperature hsernolysis is indefinitely delayed. After some time
the corpuscles are separated by means of the centrifuge. On testing the
supernatant fluid it is found to have no action on sheep's corpuscles, though
it still possesses the power of activating another specimen of serum which
has been heated. The serum separated from the corpuscles has thus lost the
1086 PHYSIOLOGY
amboceptor, but retained the complement. The amboceptor is found to have
attached itself to the red blood corpuscles. If these be washed and then
added to normal sheep's serum, i. e. serum containing the complement, they
are rapidly dissolved. When solution has taken place, both complement and
amboceptor are found to have disappeared. The function of the amboceptor
thus seems to be to enable the complement already present in normal serum
to act upon the red blood corpuscles. We may regard the amboceptor
therefore as having two haptophore groups, one of which anchors on to the
red blood corpuscle, while the other attaches itself to the complement
(Fig. 496, 7). The amboceptor plus the complement thus comes to resemble
the toxin molecule, having a free haptophore group at one end and a toxo-
phore group (the complement) at the other end. The reaction to the injec-
tion of the red blood corpuscles consists in the formation of the amboceptor,
which is essentially the anti-body of the red blood corpuscle (Fig. 496, 8).
Fia. 496. Diagram to show the relation of amboceptor and complement
to the animal cell (7) and to red corpuscles (8). (Ehklich.)
Similar specific anti-bodies effecting the dissolution of cells or organisms
may be produced by the injection of various species of bacterium or of
animal cells, such as leucocytes, spermatozoa, liver cells, etc., and there can
be no doubt that bacteriolytic substances play a considerable part in acquired
immunity.
OPSONINS. In some cases the anti-bodies produced by the injection
of living or dead micro-organisms do not bring about actual destruction of
the bacteria, but alter them in such a way as to make them more susceptible
to the action of the phagocytes. If washed white blood corpuscles be mixed
with micrococci, such as those found in an ordinary boil, they are found to
take up the micro-organisms in considerable numbers. The numbers taken
up are much increased in the presence of serum derived from an individual
who has received repeated minute injections of the dead micrococci in ques-
tion. To the substances in the serum, which thus prepares the micrococci
for ingestion by the phagocytes, Wright has given the name of opsonins.
The opsonic index of the leucocytes of any individual, in reference to a given
species of microbe, is determined by observing the number of the microbes
THE CHEMICAL MECHANISMS OF DEFENCE 1087
taken up by the leucocytes after treatment with the serum of the individual,
and then comparing it with the number taken up by the same leucocytes when
the bacteria have been treated with the serum of an average individual.
We thus see that immunity, whether innate or acquired, is extremely
complex in character and may depend on one or more of many factors.
The immunity of an animal to any given infection may be determined by
the absence of receptor groups in his body for the toxin excreted by the
microbe responsible for the infection, or by the fact that the receptor groups
an- present but are confined to tissues on which the toxophore group can
have no influence. Thus e.g. an attachment of the tetanus toxin to a
connective tissue cell would be without effect on the health of the bod)-.
Again, immunity may be due to the efficacy of the phagocytes, either of the
fluids or the connective tissues, in ingesting and destroying the micro-
organisms, and this, as we have seen, may again be dependent on the presence
or absence in the body fluids of substances which, while not destroying the
micro-organisms, render them more accessible to the action of the phago-
cytes. In those cases where the infecting organism secretes a specific toxin,
the mam line of defence and the main factor in the production of immunity
is the formation of specific antitoxins to the poison in question. Finally
there may be produced as a result of the excess of micro-organisms substances
such as the amboceptors, which render the micro-organisms susceptible to
destruction by the complements or cytases normally present in the circu-
lating fluids and possibly themselves derived from the activity or destruction
of the leucocytes and other phagocytes of the body.
fn this short description we have been able to touch only upon the most
salient features of the immunity problem. The question enters strictly into
physiology since, as we have seen, it involves adaptations on the part of
the organism to change in itself or its environment. For the practical
application of these facts, as well as the consideration of the minuter details
and exceptions, we must refer the student to works especially dealing with
the subjects of infectious diseases and immunity.
CHAPTER XVI
RESPIRATION
SECTION I
THE MECHANICS OF THE RESPIRATORY MOVEMENTS
In unicellular animals the interchange of gases, %. e. the intake of oxygen and
the output of carbon dioxide, is as a rule carried out by processes of diffusion
occurring at the surface of the cell. With increased size of the organism
the surface becomes insufficient for this purpose, and special organs make
their appearance for presenting a large extent of surface to the surrounding
medium. In the multicellular animals the actual process of tissue respira-
tion is carried out between the internal medium, lymph, blood, etc. and
the individual cells; and the use of the special organ of respiration is to
bring the circulating internal medium in intimate relation over a large area
with the surrounding fluid, whether air or water. In insects we find a large
branched svstem of tubes, the trachea?, which contain air and are distributed
to the finest tissues, renewal of the air in the tubes being provided for by
special respiratory movements. In most water animals the respiratory
organ is known as the gills, and presents a large surface well supplied with
circulating blood over which a continual stream of the surrounding water
is kept up. In all these animals therefore we can distinguish two processes,
viz. (1) the interchange of gases between the tissue cells and the surrounding
lymph, ' internal respiration ' ; (2) the interchange of gases between the
circulating fluid and the external medium, ' external respiration.' In all
air-breathing vertebrates the organs of external respiration, the lungs,
arise as paired diverticula of the anterior part of the alimentary canal.
The renewal of the air in the air sacs formed from these diverticula is
effected by alternate increase and diminution in their size caused by the
movements of respiration, while a rapid circulation of blood is carried out
through a fine meshwork of capillaries just underneath the surface of
the sacs.
In man the organs of external respiration, the lungs, are built up in the following
way : The trachea or windpipe, a wide tube about 44 inches long, divides below into
two main branches — bronchi ; and these subdivide again and again, becoming gradually
smaller. The terminal ramifications or bronchioles open into rather wider parts — the
iiifumlibuki, the walls of which are beset with a number of minute cavities, the alveoli.
The larger tubes are kept patent by rings or plates of cartilage in their walls. The
1088
MECHANIC'S OF THE RESPIRATORY MOVEMENTS
1089
smaller tubes have no cartilage, their walls being composed of fibrous and elastic tissue
and a coating of unstriated muscular fibres, which are able by their contraction to
occlude the passage. The whole system of tubes is lined with a layer of epithelium —
ciliated columnar in the trachea, bronchi, and bronchioles, and cubical over the parts
of the infundibulum not occupied by air cells. The alveoli are the special respiratory
parts of the lung. Their walls are composed of connective tissue containing a large
number of elastic fibres, and are covered internally by a single layer of extremely thin
large flattened cells. The alveoli are closely packed
together, so that in a section of the lung an alveolus is
seen to be in contact with others on all sides. Imme-
diately below the squamous epithelium ramify blood-
capillaries derived from the pulmonary artery. These
form a close network, and the blood in them is in
proximity to air on two sides, being separated from
the air in the alveoli only by the thin endothelial cells
of the capillary wall and the flattened cells fining the
alveoli.
The lungs in their development grow out from the
fore part of the alimentary canal into the front part
of the body cavity on each side — the pleural cavity. The
surrounding body walls become strengthened by the
formation of the ribs, so that the lungs are suspended
in a bony cage-work, the thorax. Their outer surface
is covered with a special membrane, the pleura, which
is reflected on to the wall of the thorax from the roots
of the lungs, and completely lines the cavity in which
they lie. The surface of the pleura facing the pleural
cavity is lined with a continuous layer of flattened
endothelial cells, and is kept moist by the secretion of
lymph into the cavity. Thus, being attached to the
thorax only where the bronchi and great vessels enter,
the lungs are able to glide easily over the inner surface
of the thorax, with which under normal circumstances they are in intimate contact.
Vi :
■■■■m
Fig. 497. Diagrammatic re-
presentation of the struc-
ture of the lungs. The
trachea branches into two
bronchi, which subdivide
again and again before
ending in the infundibula.
(From Yeo.)
A constant renewal of the air in the lungs is secured by movements of
the thorax, which constitute normal breathing. With inspiration the cavity
of the thorax is enlarged, and the lungs swell up to fill the increased space.
The capacity of the air passages of the lungs being thus increased, air is
sucked in through the trachea. The movement of inspiration is followed
by that of expiration, which causes diminution of the capacity of the thorax
and expulsion of air. At the end of expiration there is normally a slight
pause. The number of respirations in the adult is about 17 or 18 a minute.
This is however much influenced by various conditions of the body, and
also by the age of the individual. Thus a newborn child breathes about 14
times a minute, a child of five about 26 times, a man of twenty-five about 16,
and of fifty about 18. The frequency is increased by any muscular effort,
so that even standing up increases the number of respirations. These
movements arc much affected by psychical activity; they are to a certain
extent under the control of the will, although they can occur in an animal
deprived of its brain, and are normally carried out without any special act
of volition. We can breathe fast or slow at pleasure, and can even cease
breathing for a time. It is impossible however to prolong this respiratory
69
1090 PHYSIOLOGY
standstill for more than a minute ; the need of breathing becomes imperative,
and against, our will we are forced to breathe.
With every inspiration the cavity of the thorax is enlarged in all dimen-
sions, from above downwards by the contraction of the diaphragm, and
in its transverse diameters by the movements of the ribs. 1
The diaphragm is a sheet separating the cavity of the chest from that
of the abdomen. It consists of a central tendon which forms an arched
double cupola, to the circumference of which are attached muscle fibres.
The diaphragmatic muscles present two main divisions, namely, (1) the
spinal or crural part, the fibres of which arise from the upper three or four
lumbar vertebrae and from the arcuate ligaments and are inserted into the
posterior margin of the central tendon ; and (2) the
sterno-costal part, which arises by a series of
digitations from the cartilages and adjoining bony
parts of the lower six ribs and from the back of the
ensiform process. These latter fibres pass backwards
as they ascend. In the cavity of the larger dome on
the right side lies the liver, while the smaller dome
on the left side is occupied by the spleen and
stomach. These viscera in the normal condition
are pressed against the under-surface of the
diaphragm by the elasticity of the abdominal walls.
F t g Zo^r^Z: The central part of the diaphragm is thus pressed
pliragm in respiration. up into the chest, partly by the intra-abdominal
i i, inspiratory position; pressure and partly bv the elastic traction of the
e e, expiratory position. -,.,,-,, „' . . ,, , ,
(Yeo.) distended lungs, ihe upper surface of the central
tendon is united to the pericardium. This part,
during expiration, is the deepest part of the middle portion of the diaphragm.
Towards the back of the pericardial attachment the central tendon is pierced
for the passage of the inferior vena cava. In expiration the lateral muscular
zone of the diaphragm lies in contact with the lower part of the thoracic
wall. During inspiration the muscle fibres contract and draw the central
tendon downwards, so that the lower surface of the lungs descends. The
enlargement of the lungs at the lower part of the thorax is aided by the
abduction of the floating ribs, produced by the contraction of the quadralus
lumhorum and deep costal muscles. In this contraction the diaphragm
presses on the contents of the abdomen, so that the abdomen swells up
with each inspiratory movement. The middle of the central tendon, where
the heart lies, moves less than the two domes, and the part where the vena
cava passes through the tendon is practically stationary during normal
respiration. In deep inspiration however both this part as well as the rest
of the pericardial attachment is forcibly depressed towards the abdomen.
In quiet breathing, when observed by the Rontgen rays, the mean descent
1 The student is advised to consult the article by Keith on the " Mechanism of
Respiration in Man " for a fuller account of this subject (L. Hill's " Further Advances
in Physiology," 1909).
MECHANICS OF THE RESPIRATORY MOVEMENTS 1091
of the right dome m inspiration has been found to be about 12-5 mm., and
of the left dome 12 mm. We may say, roughly, that the average descent
of the diaphragm during normal respiration is about half an inch. The
viscera and the intra-abdominal pressure play an important part in
determining the movement of the diaphragm, and especially in preserving
the abduction of the lower ribs and so furnishing a fixed point for the
muscular fibres of the diaphragm. If the contents of the abdomen are
removed from a living animal the ribs are drawn inwards every time the
diaphragm contracts. In children with weak chest walls and with respira-
tory obstruction we may often see a depression round the lower part of the
chest corresponding to the lower border of the lungs. It corresponds to
the hue at which the diaphragm leaves the chest wall, so that the distending
force of the abdominal pressure on the bony walls of the thorax abruptly
gives place to the pull of the distended lung. The contraction of the
diaphragm lasts four to eight times longer than a simple contraction or
muscle twitch. It may be regarded therefore as a short tetanus.
The enlargement in the other diameters is effected by an elevation of the
ribs. Each pair of corresponding ribs, which are articulated behind with
the spinal column and in front with the sternum, forms a ring directed
obliquely from behind downwards and forwards. With each inspiratory
movement the ribs are raised, the obliquity becomes less, and the horizontal
distance between sternum and spinal column is therefore increased. More-
over the ribs from the first to the seventh increase in length from above
downwards, so that when they are raised, the sixth rib, for instance, occupies
the situation previously taken by the fifth, and the transverse diameters of
the thorax at this height are increased. With each inspiration there is a
rotation of the ribs. In the expiratory condition they are so situated that
their outer surfaces are directed not only outwards but also downwards.
As they are raised by the inspiratory movements, they rotate on an axis
directed through the fore and hind ends of the rib, so that their outer
surfaces are turned directly outwards. In this way a certain enlargement
of the thorax cavity is produced. As the thorax is raised there is always
some stretching of the rib cartilages.
In expiration the processes are reversed, and the cavity of the thorax
is diminished in all three dimensions.
The movements of the thorax are effected by means of muscles. Inspira-
tion is performed by the following muscles :
The diaphragm, which is the most important, and almost suffices alone
to carry out quiet respiration.
The external intercostal muscles, which shorten and so raise the ribs.
The serratus posticus superior.
It is probable that an important part is played even under normal
eircumstances in the respiratory movements by the extension of the spinal
Column. This movement, which is specially marked at the upper part of
the thorax, causes an increase on all three diameters of this cavity. The
leoatores costarum, which are often included in the inspiratory muscles, arc
1092 PHYSIOLOGY
so inserted into the ribs as to be unable to influence their movements.
They are concerned, not in respiration, but in lateral movements of the
spine.
These muscles are the only ones normally engaged in carrying out in-
spiration. When, in consequence of muscular exertions or from any other
cause, the inspiratory efforts become more forcible, a large number of
accessory muscles are brought into play. These are :
The scaleni,
Sterno-mastoid,
Trapezius,
Pectoral muscles,
Rhomboids, and
The serratus anticus.
Normal expiration is chiefly effected passively. When the inspiratory
muscles cease to contract, the lungs, which were stretched by the previous
inspiration, contract by virtue of the elastic tissue they contain, and the
thorax itself sinks by its own weight, and by the elastic reaction of the
stretched costal cartilages.
It must be remembered however that in a position of rest the elasticity
of the thorax is opposed to the elasticity of the lungs. Elasticity of the
chest wall would therefore tend to produce inspiration. This factor would
tend to make inspiration easier at its onset, but would also present an
impediment to the carrying out of expiration, so that towards the end of this
act there is need for the active co-operation of muscular contractions. It
seems possible that more or less muscular activity of the expiratory muscles
is alternated with that of the inspiratory muscles. In fact Sherrington's
results on the co-ordination of muscular movements would tend to make us
assume inhibition of the tone, e. g. of the abdominal muscles, during inspira-
tion, and active augmentation of their tone during expiration. Where the
tone of the muscles is entirely lost, e.g. in the condition of viscero-ptosis,
it has been observed that the diaphragm is thrown out of action, breathing
being chiefly carried out by an elevation of the upper part of the thorax.
Probably under normal circumstances the internal intercostal muscles also
contract with each expiration.
Although the action of the intercostal muscles has been a subject of debate, physio-
logical experiments serve on the whole to confirm the view first put forward by Hani-
ber^er and based on a consideration of the direction of the fibres. The external inter-
eostals pass from one rib to the next below downwards and forwards. Hence if a pair of
ribs be isolated from the rest of the chest wall, leaving the vertebral and costal attach-
ments intact, contraction of these muscles will cause a rise of both ribs. This result will
be evident from a consideration of Fig. 499, where ab is a fibre of the external intercostal
muscles, passing from the rib vs to be attached to the rib v's' at b. When ab contracts,
the tension it exerts on its two attachments can be resolved into two components ac acting
downwards and bd acting upwards, bd however acts at the end of the long lever bv',
whereas ac acts at the end of the short lever av. Hence the raising effect will overcome
the depressing effect, and both ribs will rise,
The fibres of the internal intercostals run in the opposite direction to the external
MECHANICS OF THE RESPIRATORY MOVEMENTS
1093
muscles, and from a consideration of Fig. 500 it is evident that their effect will be to
depress any pair of ribs, thus acting as expiratory muscles.
Owing to the fact that the costal cartilages make an angle with the bony ribs, the
fibres of prolongation of the internal intercostals, musculi intercartilaginei, have the
same relation to their attachments that the external intercostals have to the bony ribs.
Their action therefore must be to raise the cartilages and flatten out the angle between
the cartilaginous and bony ribs so that they must act with the external intercostals as
inspiratory muscles.
In forced expiration a large number of muscles may take part — such
as the serratus posticus inferior and the muscles forming the wall of the
abdomen, i. e. the rectus, obliquus, and transversus abdominis muscles.
As the lungs are distended with each inspiration their position changes
in relation to the thoracic wall. All parts are not equally distensible in the
normal position of the lungs. There are three areas which are in contact
with the nearly stationary parts of the thoracic wall and cannot therefore
be directly expanded. These are (1) the mediastinal surface in contact with
Fro. 499.
the pericardium and structures of the mediastinum ; (2) the dorsal surface in
contact with the spinal column and with the spinal segments of the ribs;
(3) the apical surface lying in contact with the deep cervical fascia at the
root of the neck. The roots of the lungs move with inspiration somewhat
forwards and downwards. The front parts of the lungs move downwards
and inwards, so that their inner borders in front approach one another.
The extent and boundaries of the lungs can be easily ascertained in the
living' subject by means of percussion. On tapping the finger laid on the
chest a sound is emitted which varies with the nature of the subjacent tissues.
If this is lung tissue filled with air, a clear resonant tone is obtained; where
it is solid tissue, such as the heart, or a lung consolidated with inflammatory
products, or the liver, a dull sound is obtained. It is easy to show that the
resonant area of the chest increases with each inspiration. The apices of
the lungs extend about one inch above the clavicle anteriorly and behind
reach as high as the seventh spinous process. During moderate expiration
the lower margin of the lungs extends in front from the upper border of the
sixth rib at its insertion to the sternum, and runs obliquely downwards to
the level of the tenth rib at the back of the chest. During the deepest
inspiration the lungs descend in front to the seventh intercostal space
and behind to the eleventh rib, while during deepest possible expiration the
1094 PHYSIOLOGY
lower margins of the lungs are elevated almost as much as they descend
during inspiration. In the front of the chest a triangular space can lie
always marked out over the heart where the note obtained on percussion
is dull. This space is bounded on the right by the left border of the
sternum and extends out as far as the cardiac apex, being bounded above
by the fourth costo-sternal articulation and below by the sixth costal
cartilage.
BREATH SOUNDS. If the ear be applied to the chest wall, either directly
or through the medium of a stethoscope, each inspiration is found to be
accompanied by a fine rustling sound, the ' vesicular murmur.' It is
thought to be caused by the sudden dilatation of the air vesicles during
inspiration or perhaps by the current of air passing from the narrow terminal
bronchioles into the wider infundibula. It is important to remember that
this sound is heard only during inspiration and over healthy lungs. On
listening over the larger air passages, i. e. the larynx, trachea, and bronchi,
we hear a much louder sound which accompanies both expiration and
inspiration and may be compared to a sharp whispered hah. This is known
as the ' bronchial murmur.' It can be heard also at the back of the chest
between the scapulae at the level of the fourth dorsal vertebra, where the
trachea bifurcates. In all other parts of the chest the healthy lung prevents
the propagation of this sound to the chest wall. If however the lung is solid,
as occurs in pneumonia, it conducts the sound easily from the large air tubes
to the chest .wall. Bronchial breathing at any part of the chest other than
that immediately over the air tubes is therefore a distinctive sign of con-
solidation of the lung. Absence of breath sounds at any part of the chest
implies either that air is not entering that part of the lung, or that the lung
is separated from the chest wall by effused fluid.
INTRATHORACIC PRESSURE. Even at the end of expiration the lungs
are in a stretched condition. This is shown by the fact that if in an animal
or in the corpse an opening be made into the pleural cavity, air rushes into the
opening and the lungs collapse, driving a certain amount of air out through
the trachea. Since the lungs are always tending to collapse, it is evident that
they must exert a pull on the thoracic wall. This pull of the lungs gives rise
to a negative 'pressure in the pleural cavity. If we connect a mercurial
manometer with the pleural cavity, we find that the pull of the lungs amounts
in the corpse to 6 mm. of mercury. If the lungs are fully distended, as after
full inspiration, the elastic forces are more brought into play, and the negative
pressure in the pleura may amount to 30 mm. Since the lungs are always
tending to collapse, respiration becomes impossible directly free openings
are made into the pleural cavities on both sides. With each inspiratory
movement air rushes in through these openings, so that the thoracic move-
ments can no longer exert any influence on the volume of the lungs. The
negative pressure in the thorax is diminished by any factor decreasing the
elasticity of the lung tissue. Thus in an old man, where the elastic tissue is
degenerated and the alveoli are enlarged, giving rise to the condition known
as emfhysema, the lungs may collapse only slightly or not at all on opening
MECHANICS OF THE RESPIRATORY MOVEMENTS 1095
the chest. The lungs do not collapse on making an opening in the chest
of a new-born mammal ; but this is owing to the fact that they completely
fill the thorax in the expiratory position, and it is only later that, with the
growth of the ribs, the thorax gets, so to speak, too large for the lungs which
are therefore stretched to fill it.
The force exerted by the inspiratory muscles is nearly all spent in over-
coming the elastic resistance of the lungs and costal cartilages. A free access
of air is provided for by contractions of certain accessory muscles of respira-
tion. With each inspiration the glottis is widened by abduction of the vocal
cords. When the glottis is observed by means of the laryngoscope, a
rhythmical separation and approximation of the vocal cords are observed,
synchronous respectively with inspiration and expiration (Fig. 312, p. 622).
When inspiration is laboured, the alee nasi are dilated by the action of the
dilator nasi. This movement of the nostril, which is constant in many
animals, becomes very marked in children suffering from any respiratory
trouble.
If a manometer be connected with one of the nostrils, so as to register the
pressure in the air cavities, it is found that there is a negative pressure of
— 1 mm. Hg. with inspiration, and a positive pressure of 2 or 3 mm. with
expiration. With forced inspiration the negative pressure may amount
to — 57 mm. Hg., and with forced expiration there may be a positive pressure
of -f 87 mm.
PULMONARY VENTILATION. Under no circumstances can we by forced
expiration empty the lungs of air. At the end of the most forcible exe
piration, if the pleura were perforated, the lungs would collapse and driv-
more air through the trachea. When breathing quietly a man takes in and
gives out at each breath about 500 c.c. of air, measured dry and at 0° C. If
measured moist and at the temperature of the body, viz. 37° C, the
volume would be about 000 c.c. This amount is known as the tidal air.
By means of a forcible inspiratory effort it is possible to take in about 1500
c.c. more (complemental air). At the end of a normal expiration a forcible
contraction of the expiratory muscles will drive out about 1500 c.c. more
(supplemental air). These three amounts together constitute the ' vital
capacity ' of an individual. This total may be determined by means of the
instrument known as the spirometer, which is merely a small gas-meter with
a gauge by which the amount of air in it can be at once read off. The person
to be tested fills his lungs as full as possible, and then expires to the utmost
into the spirometer. The air left in the lungs after the most vigorous
expiration is known as the residual air.
The residual air may be determined by letting a person expire to the utmost extent
and then connecting with his mouth or nose a bag of known capacity filled with hydrogen.
The subject of the experiment then inspires and expires into the bag two or three times,
ending in the same state of forced expiration as he began. Any diminution of the total
volume of gas in the bag will represent the gas lost during the experiment by diffusion
into the blood vessels. By analysis of the gaseous mixture in the bag, it is possible to
determine the amount of air in the lungs at the beginning of the experiment. Supposing,
for example, the bag held 4000 c.c. hjdrogen, after two respirations the total volume is
1096 PHYSIOLOGY
unaltered, but the gas is found to consist of 3000 c.c. hydrogen and 1000 c.c. oxygen>
nitrogen, and C0 2 , i. e. pulmonary gases. Since the gas in the lungs must have the same
composition and 1000 c.c. hydrogen have disappeared from the bag, it is evident that the
lungs will contain 1000 c.c. hydrogen and ' ' T) "°, i. e. 330 c.c. pulmonary gases. Thus
the total volume of gas left in the lungs at the end of the forced expiration was 1330
c.c, which is the residual volume for the individual.
The above example is purely imaginary. As a result of actual deter-
minations carried out, we may assume the residual air in the lungs as
something between 600 and 1200 c.c.
Of the 500 c.c. of tidal air taken in at each inspiration, only a certain
part reaches the alveoli, part being required to fill the air tubes, trachea,
bronchi, and bronchioles which lead to the air cells. The volume of the
air tubes has been reckoned to amount to 140 c.c, so that of the 500 c.c. about
360 c.c. reach the alveoli. For the same reason the expired air represents
the air from the alveoli (360 c.c.) diluted with 140 c.c. of air which has
remained in the air tubes and undergone very little change, other than the
elevation of temperature and saturation with aqueous vapour. We have
therefore to allow for this air contained in the so-called ' dead space ' of the
lungs when we seek to arrive at the composition of alveolar air from an
analysis of expired air.
THE BRONCHIAL MUSCULATURE
Both the large and smaller air tubes have a coating, consisting of un-
striated muscle fibres, which in the bronchioles is complete. Contraction
of these fibres must have the following effects : (1) a constriction of the
bronchi and bronchioles; (2) a diminution of the air space of the lungs and
therefore of the volume of the lung; (3) an increased resistance to the
passage of the air into and out of the alveoli. Changes in the condition of
contraction of these muscle fibres may be studied in two ways. In the first
method artificial respiration is carried out, a constant volume of air being
blown in and sucked out at each respiration. Any diminution in the
calibre of the bronchioles must increase the resistance to the incoming
current of air and so cause a rise of pressure in the tracheal tube. Einthoven,
in investigating this subject, has made use of an arrangement by means of
which a mercurial manometer is connected with the trachea for a brief
space of time during one part of the inspiratory phase. Any resistance
to the current of air raises the pressure during the whole inspiration and
therefore at the moment at which the manometer is put into connection
with the tracheal tube, and a rise of the mercury in the manometer is thus
produced. By this method was obtained the tracing shown in Fig. 501.
By the second method artificial respiration at a constant pressure is made
use of. Any changes in the bronchioles will in this case affect the volume
of air entering the lungs at each stroke of the pump, and can be measured
by recording either the passive respiratory movements of the chest or the
changes in volume of a lobe of the lung enclosed in a plethysmograph
MECHANICS OF THE RESPIRATORY MOVEMENTS 1097
(Brodie and Dixon). By both these methods it has been shown that
stimulation of the peripheral end of either vagus causes constriction of the
Fig. 501. Tracings of blood pressure (middle curve) and of intra -tracheal pressure
(upper curve) taken by Einthoven's differential manometer. Between Q and Q'
the peripheral end of one vagus was stimulated. Time marking = seconds.
bronchioles (vide Figs. 502 and 503). As a rule there is little tonic action of
the vagi, section of both vagi leaving the respiratory pressure curve unaltered
or lowering it slightly by 2 to 10 mm. H 2 0. It is very easy to bring about
Fig. 502. Tracings of the volume changes of tho lung, with constant variations of'
tracheal pressure. (Bkodie and Dixon.) T.P t r.i. h.-al pressure. L.V. Iuiil'
volume. B.P. blood pressure (Zero B.P. 17 mm. below time marker). Showing
constriction of bronchial musculature as a result, of vagus excitation.
a vagus tonus by allowing the animal to inhale air containing 3 to 4 per
nut. carbon dioxide. A peripheral tonus may also be produced by ad-
ministration of muscarine or pilocarpine. In the latter case Brodie and
Dixon have shown that stimulation of the vagus may cause relaxation
1098
PHYSIOLOGY
of the bronchioles, so that this nerve appears to contain both motor and
inhibitory fibres to the bronchioles.
THE EFFECTS OF BRONCHIAL CONSTRICTION : ASTHMA. Under
the influence of vagal stimulation or of carbon dioxide, the pressure neces-
sary to drive the normal amount of air into the lungs may be raised in the
dog from 125 to 300 mm. H 2 0. We should therefore expect that, in cases
where bronchial constriction is present, there would be difficulty both in
inspiration and expiration. There is however a difference in the mechanical
conditions of the bronchi during the two phases of a respiratory move-
ment. Normally the elastic structure of the lungs is drawing upon the
bronchial wall, tending to maintain it patent, and so opposing the action of
Tracing showing inhibitory effect of vagus on the bronchial tonus pro-
duced by O'Ol grm. pilocarpine.
the bronchial muscle. During inspiration this expanding force is in-
creased, so that in the presence of bronchial constriction the access of air
is rendered the easier, the more powerful the contraction of the inspiratory
muscles. In expiration all parts of the lung collapse, drawing with them
the chest wall ; the pull of the lung tissue on the bronchial wall is lessened,
but is still present. If however the expiratory muscles contract vigorously,
the intrapleural pressure becomes positive, and the pull of the lung tissue
on the bronchial walls is changed into a pressure tending to obliterate their
lumen and so impede the outflow of air.
It is evident therefore that, in the presence of a spasmodic contraction
of the bronchial muscles, the inspiration will be forcible and rapid, but all
contractions of muscles must be avoided so far as possible during expiration,
which must be left to the elastic reaction of the lungs and becomes slow
MECHANICS OF THE RESPIRATORY MOVEMENTS 1099
and prolonged. Moreover it will be of advantage to keep the lung as
nearly as possible in the inspiratory position, so as to reinforce the elastic
forces which dilate the bronchioles and aid expiration. We thus get the
typical breathing which occurs in man in cases of spasm of the bronchial
muscles, known as asthma nervosum. This type of breathing is often
described as being marked by expiratory dyspnoea. This description is
however erroneous. It is the inspiratory muscles, which in these cases are
contracted to their uttermost; the expiratory muscles, such as the
abdominal, will be found to be quite flaccid even during expiration.
SECTION II
THE CHEMISTRY OF RESPIRATION
The energy of the body is derived almost entirely from the oxidation of the
carbon and hydrogen of the foodstuffs. An adult man during the twenty-
four hours produces on the average 250 c.c. of carbon dioxide per kilo, per
hour. A man of 70 kilos, will therefore excrete 250 X 70 X 24 = 420,000 c.c.
carbon dioxide in the course of twenty-four hours. During sleep the output
of carbon dioxide is lowered with the diminution in all the metabohc pro-
cesses of the body and amounts, to only 160 c.c. per kilo, per hour. If we
assume that eight hours of the twenty-four are given to sleep, this will leave
295 c.c. per kilo, per hour as the average excretion of carbon dioxide during
the waking hours. Since the access of oxygen to the body and the removal
of carbon dioxide is effected by the pulmonary ventilation, the expired air
will differ from the inspired air in containing more carbon dioxide and less
oxygen. The oxygen intake is not however absolutely proportional to
the carbon dioxide output. This is owing to the fact that carbon is not
the only element which leaves the. body hi an oxidised condition. Fats, for
example, contain a number of unoxidised atoms of hydrogen, which in the
metabohc processes of the body are fully oxidised, to be excreted as water.
Oxygen will also leave the body in combination with carbon and nitrogen
in the urine, so that a certain amount of oxygen which is taken in does not
reappear as carbon dioxide in expired air. There is thus an absolute
diminution in the volume of expired air as compared with that of inspired
air. This diminution, due to loss of oxygen, is greater in carnivora whose
food consists mainly of proteins and fats, than in herbivora which feed
principally on carbohydrates, and depends on the respiratory quotient, i. e.
, , , . CO, expired.
the ratio — -. — -.
2 inspired.
In man the average respiratory quotient can be taken as 0-85. On this
basis the amount of oxygen which will be taken in during the waking hours
will be 347 c.c. per kilo, per hour. Taking round figures, we may say that,
when awake, a man takes in 350 c.c. oxygen and gives out 300 c.c. carbon
dioxide per kilo, per hour. From these figures we can calculate the normal
composition of expired air when a man is breathing quietly. Under these
conditions the tidal air amounts to 500 c.c. If he breathes seventeen times
a minute, the total pulmonary ventilation during the hour will be 500 x 17
X 60 = 510,000 c.c. per hour. If the man weighs 70 kilos., his expired air
1100
THE CHEMISTRY OF RESPIRATION 1101
will contain 300 x 70 c.c. = 21,000 c.c. carbon dioxide. Hence the per-
centage of carbon dioxide in the expired air will be 4-1 per cent. In the
same way we can reckon the percentage of oxygen in the expired air at 16-4
per cent. Exact experiments have shown that the volume of nitrogen is
unchanged durmg respiration, this gas taking no part in the ordinary
metabolic processes of the body. We may therefore compare the ordinary
composition of inspired and expired air as follows :
Inspired Air
Oxygen . . . . . . .20 - 96 vols, per cent.
Nitrogen (including argon) . . . 79 - 00 „ „
Carbon dioxide ..... - 04 „ ,
Expired Air
Oxygen . . . . , . 16 - 4 vols, per cent.
Nitrogen . . . . . . 79'5 „ „
Carbon dioxide . . . . . 4 - 1 „ „
The increase in the figure for nitrogen refers of course only to the per-
centage amount, shice the total volume of air breathed is decreased by the
disappearance of a certain amount of oxygen without the production of a
corresponding amount of carbon dioxide, so that the relative amount of
nitrogen is slightly increased. These figures for the composition of inspired
and expired air refer to dry air at a temperature of 0° C. and a pressure of
760 mm. Under normal circumstances inspired air contains a variable
amounij of aqueous vapour and has a variable temperature corresponding
with, the time of year. Expired air is fully saturated with aqueous vapour
and has the temperature of the body, 37° C. The aqueous vapour at this
temperature is by no means negligible. Its tension amounts to 50 mm. Hg.
Thus when a man is breathing dry air at a pressure of 760 mm. Hg., the
pressure of the mixture of gases in the alveoli of his lungs will be only
760 — 50, i. e. 710 mm. Hg.
Only. a certain percentage of the 500 c.c. of tidal air reaches the alveoli,
100 to 140 c.c. being required to fill the trachea and bronchial tubes. Hence
the alveolar air must contain more carbon dioxide and less oxygen than the
tracheal air ; and it is found that, if we take the air from the alveoli instead
of that expired through the mouth or nose, the differences between it and the
inspired air are much more pronounced.
A sample of alveolar air may be obtained for analysis in the following way (Haldane) :
A piece of india-rubber tubing is taken of about 1 inch diameter and 4 feet long. Into
one end (Fig. 501) is fitted a mouthpiece, the other being left open or connected with a
spirometer. About 2 inches from the mouthpiece is fixed a gas sampling-bulb, which is
provided with three-way taps at the upper and lower ends. Before an experiment tin-
bulb is tilled with mercury, if the lower end is open, or else it is completely exhausted.
The subject of the experiment, after breathing normally a few times, at the end of a
normal inspiration puts his mouth to the tube, expires quickly and deeply, and closes
the mouth-piece with his tongue. The tap of the sampling-bulb is then turned, and the
air last expelled from the lungs (wliich is therefore pure alveolar air) rushes into the bulb.
The tap of the bulb is then turned off, and the gas may be removed for analysis. A
1102 PHYSIOLOGY
similar sample is then taken, in which the subject expires deeply at the end of a normal
expiration. This sample will, of course, contain more CO., and less O a than that obtained
at the end of inspiration. The mean of the two samples is taken as the average >■
position of alveolar air.
The difference between the composition of expired air and alveolar air
is determined by the dilution of the alveolar air with that contained in the
(had space. Hence with shallow breathing there will be a large difference,
but this will decrease with increased depth of respiration. Thus, if the
alveolar air contained 6 per cent. C0 2 and the dead space amounted to
150 ox., the expired air would contain only 3 per cent. C0 2 when the person
was taking in only 300 c.c. at each respiration. If however he was breath-
ing slowly and deeply so as to raise the tidal air to 1500 c.c, only one-tenth
of this would be represented by the dead space, and the expired air would
contain nine-tenths as much C0 2 as the alveolar air, i. e. 5- 1 per cenl .
Mour/Y-f/£C£.
Sampung tube.
The changes in the composition of alveolar air with respiration are by
no means so marked as those ■ produced in the tidal air, since the latter
forms only a small proportion of the total air in the lung alveoli. Thus
at the end of a normal expiration the alveoli still contain 2500 c.c. of gases.
In inspiration 360 c.c. atmospheric air is taken into this space and mixed
with the 2500 c.c. already there. The ' ventilation coefficient ' in quiet
breathing is therefore only one-seventh, and the change in the oxygen and
carbon dioxide content of the alveolar air produced by this access of 360 c.c.
will amount to less than one-half per cent. This is illustrated by the follow-
ing figures from Haldane, giving the alveolar content in carbon dioxide at
the end of inspiration and at the end of expiration respectively.
Alveolab CO., Tensions
Alveolar CO^ at
inspiration. (M
twelve observations)
inspiration. ~ (Mean of \ C ° 2 XB £a5on' f
tiv.lv,. niK,.rvntim>i.i expiration
J. S. H. 5-54 5-70 5-62
J. G. P. 6- 17 6-39 6-28
We can thus speak of an average jcomposition of alveolar air which, in
spite of the constant ventilation, differs from the external air in containing
an excess of carbon dioxide and a relative lack of oxygen. Lavoisier, who
was the first to study the chemical changes in respiration accurately, regarded
the lungs as the seat of the formation of carbon dioxide and the consump-
tion of oxygen. This view was generally accepted until it was shown by
THE CHEMISTRY OF RESPIRATION
1103
Magnus, in Heidenkain's laboratory, that the blood passing to the lungs
contained more carbonic acid gas and less oxygen than that passing away
from the lungs. The effects of this discovery were to transfer the chief seat
of oxidation to the tissues of the body, and to show that the blood acts
simply as a carrier of the oxygen from the lungs to the tissues, and of the
carbon dioxide from the tissues to the lungs. We thus learnt to distinguish
between external and internal respiratory processes. A consideration of the
^ ^
1'IQ. 5(J5. Barorofts modification of the Topler pump.
chemical mechanisms, involved in the process of external respiration, in-
cludes therefore an investigation of the manner in which gases are held by
the blood and of the factors which are responsible for the transfer of oxygen
and carbon dioxide from blood to alveolar air, and from alveolar air to blood.
If blood be exposed to a Torricellian vacuum at the ordinary tem-
perature, the whole of its contained gases is given off. For the purpose of
extracting the blood gases, a great variety of pumps have been devised. In
every case a glass vessel is evacuated by means of the mercury pump, and
is then put into connection with a reservoir containing blood which has been
dehbrinated, or has been prevented from clotting by the addition of oxalate
1104 PHYSIOLOGY
or citrate. In all these pumps the main difficulty arises in the exclusion of
atmospheric air, and it is therefore important to dispense so far as possible
with taps. One of the best modifications of the Topler mercury pump is
that employed by Barcroft (Fig. 505), which differs little from the pump
devised by Bohr.
The construction of the pump is shown in the diagram. The actual pump consists
of the parts a, b, c, d. The buJb b is prolonged below by a wide tube dipping into the
mercury in the Woulf bottle A. The upper part of the bottle is filled with water and
connected by two taps at w with the water-supply and with a sink. The water being
turned on, mercury is forced up into B ; as it rises into Y it carries before it a glass valve
which prevents its further passage, so that it can escape only by the tube C, driving
before it all the air previously contained in B. The water-supply is now turned off, and
the tap to the sink turned on. The mercury runs back. Air cannot enter by c, since
this tube is sealed by mercury. The valve y therefore sinks and allows the air in the
blood receivers G, g and the rest of the apparatus to escape into B. The process is re-
peated many times until a high vacuum is produced in the whole apparatus. A measured
quantity of blood is now let into the lower bulb G. F is a condenser through which cold
water is constantly flowing (to prevent all the blood boiling away), while warm water
circulates round the bulbs G, G to facilitate the giving off of the blood gases. The blood
boils in the vacuum, and the gases escape into B, and may be driven off and collected
over mercury in a cylinder D by raising the mercury in B. The process of exhaustion is
repeated until no more bubbles rise into D on filling the bulb B with mercury. E is a
sulphuric acid chamber for drying the gases as they pass from the blood to the bulb B.
In this way, from 100 c.c. of blood, about 60 c.c. of mixed gases may be
obtained, consisting of oxygen, carbon dioxide, nitrogen, and argon. Argon
is present only in insignificant quantities, about -04 volume per cent. The
nitrogen also forms only between one and two volumes per cent, and is
present in the same proportion in both arterial and venous blood. The
amounts of oxygen and carbon dioxide in these two kinds of blood differ
however within wide limits. The following Table represents the average
composition of the gases obtained from an artery and a vein of the dog :
From 100 vols. May be obtained
Of oxygen Of carbon dioxide Of nitrogen
Of arterial blood . . 20 vols. . 40 vols. . 1 to 2 vols.
Of venous blood . 8 to 12 vols. . 46 „ . „ „
Measured at 760 mm. and 0° C.
The principle introduced by Haldane (vide p. 902) for the determination of the
oxygen combined in the form of oxyhemoglobin may be successfully applied to small
quantities of blood, such as 1 c.c. or even 0"1 c.c, and in the same sample of blood the
carbon dioxide may also be determined. In this way it becomes practicable to make
blood-gas analyses in a patient, or in experiments on small organs where it is desired
to determine their gaseous metabolism by comparing the arterial with the venous
blood. Barcroft's apparatus for dealing with 1 c.c. of blood is shown in Fig. 506 A.
The apparatus consists of two bottles of identical size (about 30 c.c.) attached to a
manometer, the tubing of which is 1 mm. bore. The manometer is filled with clove oil
of known specific gravity. To fill it take out the centre tube, pour in clove oil at A, put
in the centre tube with the glass tube B open and some pressure on the rubber tube C.
The oil should stand about half way up each tube. Seal B in a flame. The constant
of the apparatus must be determined, viz. the capacity of the bottles and with their
connections.
THE CHEMISTRY OF RESPIRATION
1105
It is determined by finding what rise of pressure in the apparatus is produced by
the liberation of a known volume of oxygen from hydrogen peroxide, which is placed in
the bottle, the liberation being effected by the addition of potassium.
To determine the oxygen capacity of a sample of blood. Place 2 c.c. of ammonia solution
(made by adding 4 c.c. of strong NH 3 to a litre of water) in one of the bottles and add
1 c.c. of blood. Thoroughly lake the blood. Rub vaseline on the large and small stoppers.
Put 0'2 c.c. of a saturated solution of potassium ferricyanide in the small tube in
the stopper of the bottle containing the blood (this is best done with a fine pipette
which goes down this tube). Insert the small stopper. Place the apparatus on the
side of a large water bath (such as a pail) with both taps open. In about five minutes close
the tap on the side of the blood and rotate the bottle on the stopper till the ferricyanide
trickles into the laked blood. Shake thoroughly, replace in the bath, ancj repeat this
several times till a constant difference of level is obtained. By means of the screw clamp
Fig. 506. Barcroft's blood-gas apparatus.
a, for 1 c.c.; B, for 0"! c.c. blood.
bring the column of oil on the side of the blood to its original level, and then measure
the difference of level between the two sides. Let this difference of level be y mm.;
let p be the height of the barometer in millimetres of clove oil, and x the volume of
oxygen given off in cubic millimetres; then x = y[ - ). Except in the most exact work
V
p may be taken as 10,000 mm., in which case the expression may bu determined once
for all and called C, the constant of the apparatus : then x = y x C.
To determine the gaseous contents of a given blood. If we wish to determine the actual
amount of oxygen as oxyhsemoglobin in the sample, the blood must be carefully intro-
duced so as to he below the ammonia and not to come in contact with the air. The
stopper is then replaced in the bottle and immersed in the bath, with both taps open
until it has attained a constant temperature. The tap is then closed and the height of
the column of oil noted. The blood is then laked by rotating the apparatus, and after
allowing five minutes for complete laking the ferricyanide is run in. The rest of the
determination is carried out as aboVc.
The carbon dioxide may be determined in the same sample of blood by adding
tartaric acid in the same way as potassium ferricyanide was previously added. It is
necessary always to determine the oxygen before the carbon dioxide, since the mere
70 *
1106
PHYSIOLOGY
acidification of the blood causes the evolution of a certain amount of oxygen. The
results obtained for carbon dioxide are not so accurate as those for the oxygen, owing to
the larger error introduced by the increased solubility of this gas in watery media.
The same apparatus may be used as a differential blood-gas manometer, where it is
desired to compare the oxygen contents of two samples of blood, e. g. of arterial and
venous blood. For this purpose 1 c.c. of the arterial blood is introduced into one bottle
and 1 c.c. of the venous blood into the other bottle, in each case under 1£ c.c. of weak
ammonia. The bottles are then placed on the apparatus and immersed in the water
bath until no change occurs in the height of the column of oil. The two taps are then
closed and the apparatus is vigorously shaken. The blood on each side is laked and, in
contact with the air in the bottles, becomes completely saturated with oxygen. No
carbon dioxide is given off, since this combines with the weak ammonia. If the two bloods
contain the same amount of oxyhemoglobin, no difference will be produced in the level
of the oil in the two tubes. If however one be arterial and the other venous, the venous
blood will absorb more oxygen from its bottle than the arterial blood from its side of the
apparatus, so that the oil will rise in the tube on the side of the venous blood. From
the degree of rise the difference in the amount of oxygen taken up by the blood on the
two sides can be reckoned, and this figure will express the relative saturation of the
luvmoglobin in the two samples of blood.
For clinical purposes it is possible to work with 01 c.c. of blood. Fig. 506 B represents
the form of apparatus devised by Barcroft for dealing with these minute quantities.
The principle of the apparatus is the same as that of the larger type.
The condition of the gases in the blood can be judged by the amount of
gas which the blood will take up when exposed to different pressures of the
gas. If a gas is in simple solution the amount of it dissolved varies directly
with the pressure. Thus, if water takes up a certain bulk of a gas at a given
temperature and pressure, it will take up twice as much if the pressure of
the gas be doubled. Since the volume of a gas varies inversely as the
pressure, we may say that a fluid will dissolve the same volume of gas
whatever the pressure. The absorption coefficient of a liquid for a gas is
expressed by the number of cubic centimetres of gas which will be taken
up at 0° C. by 1 c.c. of the liquid when the gas is at a pressure of 760 mm.
Hg. The absorption coefficient diminishes with rise of temperature. The
following Table represents the absorption coefficients for oxygen, carbon
dioxide, carbon monoxide, and nitrogen, in water at various temperatures
between 0° and 40° C. :
Temperature
Oxygen
Carbon dioxide
Carbon monoxide
Nitrogen
0-0489
1-713
00354
00239
10
00380
1194
0-0282
0-0196
20
00310
0-878
0-0232
00164
30
0-0262
0-665
00200
0-0138
40
00231
0-530
00178
00118
From this Table we see that 100 c.c. of water at 0° C. will absorb 4-89 c.c.
oxygen at 760 mm. Hg., i. e. at one atmosphere. If the pressure be raised
to two atmospheres, the volume of gas absorbed will be the same, but if
these gases be measured at the original pressure, i. e. at one atmosphere,
the amount dissolved will be 9-78 volumes. If therefore we plot out the
THE CHEMISTRY OF RESPIRATION 1107
absorption of the gas on a curve of which the ordinates represent the amount
of gas dissolved and the abscissa the different pressures of the gas, we shall
find that the curve is a straight line. The relation between the amount
absorbed is not altered by the presence of other gases at the same time.
The pressure of the whole atmosphere is 760 mm. Since the atmosphere
consists roughly of four parts of nitrogen with one part of oxygen, the
atmospheric pressure is due as to one-fifth to the oxygen and as to four-
fifths to the nitrogen. If we shake up water at 0° C. with the atmospheric
air at the ordinary pressure, 100 c.c. of water will absorb 4-89 c.c. x * of
oxygen, and of nitrogen 2-39 c.c. x f. We may therefore extend our
statement as to the solubility of gases in fluids and say that the amount of
gas dissolved in a fluid is proportional to the partial pressure of the gas.
When water is shaken up with a gas until it will take up no more, i. e.
until it is saturated for that pressure, a state of equilibrium exists between
the gas dissolved in the fluid and the gas in contact with the fluid. In
this state of equilibrium the number of molecules of the gas entering the
fluid is exactly equal to the number of molecules of the gas leaving the
fluid. If we remove the liquid after saturation, say, at one atmosphere, to a
vessel where it is in contact with gas at a pressure of half au atmosphere, the
liquid will give off gas until the amount left in solution is diminished to one-
half. The gas dissolved in a liquid thus has a pressure or tension which
tends to make it escape from the liquid. The Only way in which we. can
measure this tension is by finding what pressure of gas is in exact equilibrium
with the liquid. Thus if we take some water containing carbon dioxide in
solution, divide it into two parts, and shake up one part- with a gaseous
mixture containing 4 per cent, of carbon dioxide and the other part with a
mixture containing 5 per cent, of carbon dioxide, and find that the solution
loses gas to the fcrmer and takes up carbon dioxide from the latter, we
may conclude that the tension of carbon dioxide in the original fluid was
something-between 4 and 5 per cent, of an atmosphere. It is by some such
means that the tensions of gases in the blood are measured, the instruments
for this purpose receiving the name of aerotonmneters.
The solvent power of water for gases is diminished if the water contains
other solid substances in solution. Blood plasma or blood corpuscles will
therefore have a smaller solvent power for gases than has pure water. It
has been shown by Bohr that the depression of solubility caused by the
presence of proteins or salts in solution is the same for all gases. The absorp-
tion coefficient of blood plasma for gases is reduced to 97-5 per cent, of pure
water, and of blood to 92 per cent., that of the blood corpuscles being as low
as 81 per cent. We may thus reckon the absorption coefficient of blood
plasma, blood, and blood corpuscles for oxygen, nitrogen, and carbon
dioxide.
From the following Table we see that 100 volumes of blood at 38° C. might
contain 2-2 c.c. of oxygen in solution if the blood had been exposed to.
oxygen at a pressure of one atmosphere. The blood in the lungs is however
exposed to air which contains only about one-sixth of its volume of oxygen,
I I OK
PHYSIOLOGY
so that the total amount of oxygen present in arterial blood in .solution
cannot be more than one-sixth of 2-2, i. e. about 0-36 c.c. per cent. Since
arterial blood, or blood saturated with oxygen by shaking with air, wdll
yield as much as twenty volumes per cent, of oxygen to a Torricellian
vacuum, the oxygen cannot be in simple solution, but must be in some form
of combination with some of the constituents of the blood. Of this oxygen
practically the whole is contained in the red blood corpuscles in combina-
tion with hsemoglobin, the plasma containing no more than can be accounted
for by simple solution.
Blood plasma .
Blood
Blood corpuscles .
Oxygen
Nitrogen
Carbon dioxide
15°
38°
15°
38°
15°
38°
0033
0031
0-025
0023
0-022
0-019
0017 0012
0-016 0011
0-014 0010
0-994
0-937
0-825
0-541
0-511
0-450
One gramme of crystallised ha3moglobin can absorb 1-31 c.c. of oxygen.
If a solution of oxyhemoglobin be subjected in an air-pump to gradually
diminishing pressure at the temperature of the body, very little oxygen
is given off until the partial pressure of the oxygen is diminished to about
30 mm. Hg. (Fig. 508). At this point a large evolution of gas begins,
and continues at falling pressure until at mm. pressure all the oxy-
hemoglobin is dissociated and converted into haemoglobin. The same
observation may be made in a reverse direction. If a solution of reduced
hsemoglobin be exposed to gradually increasing pressures of oxygen, it will
be found that the greatest absorption takes place between and 30 mm. Hg.
After this point the oxygen is more slowly absorbed up to the point of
complete saturation.
Since there is no direct proportion between the partial pressure of the
oxygen and the amount absorbed, it is evident that the oxygen combines
with hsemoglobin to form an unstable chemical compound, and that this is
not a mere question of solution. This is further proved by the fact that
we can displace the oxygen (0 2 ) from the oxyhaemoglobin by equivalent
amounts of CO or NO. Haemoglobin is also supposed to form an unstable
combination with carbon dioxide, since it takes up much more of this gas
than the corresponding bulk of water or salt solution would do. Although
carbon dioxide combines with haemoglobin, it does not displace oxygen from
the oxyhemoglobin molecule. Thus we may have haemoglobin saturated
at the same time with oxygen and with carbon dioxide. The presence of
carbon dioxide does however alter the ease with which oxyhaemoglobin
dissociates.
The relation between the partial pressure of oxygen and the amount
of oxyhaemoglobin formed under varying conditions can be investigated in
the following way (Barcroft) :
tup: chemistry of respiration 1109
A large glass globe with a stop-cook at one or both ends (Fig. 507) is filled with a
gaseous mixture of known composition containing oxygen. Into it are introduced 2 or
3 c.c. of blood or of haemoglobin solution. It is then tightly stoppered and immersed in a
horizontal position in a pail of water kept at a constant temperature. In the pail it is
suspended between its two ends, so that it can be slowly revolved by means of a piece of
string passing round its neck. In this way the blood is continually spread in a thin layer
over the sides of the vessel. At the end of a quarter to half an hour it will have attained
equilibrium with the gaseous mixture. It is then turned into an erect position so that
the fluid can run down into the neck closed by a stop-cock, whence 1 c.c. may be drawn
off for analysis in a Barcroft apparatus. A further portion of the same blood may be
shaken up with air so as to saturate it completely, and the saturation of the two samples
may be compared in the differential gas apparatus.
Frc-507. Barcroft 's apparatus for dotcnnininr; the curve of absorption of
oxygen by haemoglobin.
Barcroft has shown thnt the dissociation curve of haemoglobin is largely
altered by slight variations in the fluid in which the haemoglobin is dissolved.
The most important of these conditions are (1) the saline content of the
fluid, (2) the reaction of the fluid. Under this latter heading must be classed
the amount of carbon dioxide present, since its action on the dissociation
carve is similar to that produced by the presence of weak acids such as
lactic acid. The influence of dissolved salts on the dissociation curve is
shown in Fig. 508.
It is interesting to note that the differences between the dissociation
curve of blood and of haemoglobin solution, as well as between bloods of
different animals, have been shown by Barcroft and Camis to be dependent
on the saline content of the solution in the various cases. Thus human
haemoglobin solution, with a concentration of salts similar to that of dogs'
blood, gives the same dissociation curve as normal dogs' blood.
More important is the effect of reaction since, as we shall see, it is the
reaction of the blood, controlled especially by carbon dioxide tension, that
determines the activity of the respiratory centres. In Fig. 509 is repre-
sented the influence of varying tensions of carbon dioxide, and in Fig. 510
the effect of slight additions of lactic acid on the dissociation curve. It
will be seen that the more acid the blood, or the greater tension of carbon
dioxide it contains, the more readily does it undergo dissociation. This is
especially marked at the very high tension of 420 mm. carbon dioxide. It
1110
PHYSIOLOGY
plays an important part in the lower tensions such as 40 and 80 ram. Hg.
carbon dioxide. It must be remembered that 40 mm. carbon dioxide repre-
,, ' k ,u ^.i-i-i4-r-' — Ht^-iizt."
• + " — " B * : -i jijjS 1 '* r .'-*1-** rt 'Ti-*— ■""
_ , — ^__,- j_ - ^-'" r "^
i -j* ^'TfT h
r] i,'/
Z.A "
n~ tVw'?
«t - • - -
t . it _
t f t^ r ~
t-,-^
-, 17
lilt
It
-i^U
lit
jit
..lb
¥j
X t-
j
Fig. 508. Dissociation curve of haemoglobin in various solvents.
I, in water; II, in - 7 per cent. NaCl; III, in 0'9 per cent. K.C1.
(Bahcroft.)
Sntm CC 2
« -'" _g — := = S- "^ J "'"'* "
-' ^'" 2 "" , '""'''•'"'' ^j"""
* h^/ ^^ / s'' s^*
^y%Y^ s ^
L r Z4/y.^ Z?
jtj-7^^7 ^
U-> /--, -?£ -^
Jtl-i 7- Y +'
^LtZ-t-/ S
-ii-4-/ <— Z y
tit-/- 4 s
in 7 *
4 jft~/ ^
JLTTT, y<
WfL _,i, s> Total surface
Capacity of
capillaries
in 100 c.c.
muscle
Rest .
Massage
Work
Maximum eircula-)
tion . . 1
0-5
0-5
0-5
0-5
5
10
31
85
270
1400
2500
3000
45
12
3
•04
1-4
1-2
3 cm. 2
8 „
32 „
200 „
390 „
750 „
002 c.c.
0-06 ..
0-3 ..
2-8 „
5-5 „
15-
The first thing that strikes us in this Table is the enormous difference
between the capillary circulation of resting and that of active muscle. In
the resting muscle the majority of the capillaries are empty and collapsed,
so that large areas of muscle intervene between the few capillaries in which
the circulation of blood is proceeding. Under these conditions the pressure
difference necessary to supply the total oxygen consumed by the muscle,
e. g. 45 mm. Hg., may fall below the venous oxygen tension, so that in parts
of the muscle the oxygen tension may be zero, as maintained by Verzar.
After massage a number of capillaries open, and the number is still further
increased by work, so that there may be a hundredfold increase in the
number of capillaries in every square millimetre of a cross-section of the
muscle. Under these conditions the passage of oxygen from the capillaries
is so facilitated that the oxygen pressure in the muscle tissues becomes
practically equal to that of the blood. It would appear that, so far as the
supply of oxygen to the muscle is concerned, the increase in the capillary
area during muscular exercise is far ahead of the actual needs of the muscle.
1114
PHYSIOLOGY
Krogh suggests that this enormous increase in the number of patent capil-
laries may be brought about to meet requirements of the muscle other than
those for oxygen. These observations afford further support for the view
already put forward that the capillaries do not play a merely passive role
in the circulation, but by active dilatation or constriction are largely respon-
sible for determining the actual blood supply to . each tissue in accord with
its metabolic requirements.
Under normal circumstances a blood corpuscle never stays long enough
in the proximity of the tissues to lose its whole store of oxygen. If however
the further supply of oxygen to the blood be prevented, as in asphyxia,
the last traces of oxygen disappear from the blood. The enormous avidity
of the tissues for oxygen under these circumstances is shown by the following
experiment (Ehrlich). If a saturated solution of methylene blue be injected
Fig. 511. Curves showing the rate at which arterial blood is reduced on bubbling
through a gas free from oxygen, and the effect on the rate of the presence of
C0 2 and of lactic acid. Ordinates = percentage saturation of oxyhaemoglobin.
Abscissae = time in minutes. (Mathison.)
into the circulation of a living animal and the animal be killed ten minutes
later, it is found on first opening the body that most of the organs present
their natural colour, although the blood is a dark blue colour. On exposure
to the atmosphere all the organs acquire a vivid blue colour. These pheno-
mena are due to the production in the tissues of reducing bodies, whose
avidity for oxygen is so great that they are able to decompose the methylene-
blue molecule, with the formation of a colourless reduction product, which
on exposure to the air undergoes oxidation again and re-forms methylene
blue. If the tissues are able to effect the reduction of a comparatively
stable body like methylene blue, it is easy to understand their power of
THE CHEMISTRY OF RESPIRATION 1115
reducing oxyhemoglobin, which is so unstable that it is decomposed by
simple physical means such as exposure to a vacuum.
It was long debated whether the chief processes of oxidation take place in the
blood or in the tissues. Our experiences with muscle would alone serve to convince
us that, in some tissues at any rate, processes of oxidation take place, and the methylene-
blue experiment shows that these processes of oxidation are intense in all the chief organs
of the body. It has been found moreover that it is possible to keep a frog alive after
substituting normal saline solution for its blood, if it be placed in absolutely pure
oxygen, and that in this case indeed the metabolism of the animal goes' on as actively
as before. As the frog has no blood, it is evident that its metabolic processes, consisting
of the taking up of oxygen and the giving out of carbon dioxide, must have their seat
in the tissues.
As a result of the oxidative changes in the tissues, carbon dioxide is
produced, and the tension of this gas in the tissues therefore rises. As
Barcroft has pointed out, in cold-blooded animals the dissociation of oxy-
hemoglobin with the setting free of oxygen must be largely conditioned
by the rise of carbon dioxide tension in the tissues, since at the normal
temperature of these animals the evolution of oxygen from haemoglobin
is extremely slow. The alteration in reaction of the blood, caused by a rise
in C0 2 tension or by the presence of small amounts of lactic acid, markedly
quickens the rate at which oxyhemoglobin gives up its oxygen, as is shown
in Fig. 511. The carbon dioxide tension in the tissues may be approximately
measured by taking the tension of this gas in fluids such as the bile or urine.
Here it may amount to 8 or 10 per cent, of an atmosphere, and since the
carbon dioxide in venous blood is rarely above G per cent, of an atmosphere,
there is a descending scale of tensions from tissue to blood, just as there is
an ascending scale in the case of oxygen. This gas therefore passes from
the tissues through the lymph into the blood by a simple process of diffusion.
The carbon dioxide carried by the blood is, like the oxygen, chiefly in a
state of chemical combination. From dogs' venous blood we may obtain
by means of the pump about 50 c.c. of carbon dioxide per 100 c.c. blood.
Water at the temperature of the body, if shaken up with an atmosphere of
carbon dioxide at a pressure of 760 mm. Hg., would take up about 50 per
cent, of the gas, and the plasma as a mere solvent would take up slightly
less. The tension of carbon dioxide in the blood is however much less than
1 atmosphere. Shaken up with pure carbon dioxide at a pressure of 1
atmosphere, the blood would take up as much as 150 per cent. If we
determine the tension of the carbon dioxide in the blood by one of the
methods to be described later, we find that in venous blood this gas is at a
pressure of only about 5 to 6 per cent, of an atmosphere (about 40 nun.
Hg.). Taking the pressure of the carbon dioxide as .?,-,- of an atmosphere,
and knowing that at a pressure of 1 atmosphere the blood might dissolve
50 volumes per cent., it is evident that at /„- of an atmosphere the blood
would dissolve only ],',' volumes per cent., i.e. about 2.V volumes. All the
rest of the carbon dioxide in the blood must therefore be in combination
(cp. Fig. 512).
1UG
PHYSIOLOGY
The carbon dioxide is contained chiefly in theplasma, though a certain
amount is also in combination in the corpuscles. Part of the carbon dioxide
must be in combination with some constituent common to both plasma
and corpuscles. When blood plasma is calcined, the ash is found to be
distinctly alkaline and to contain an amount of sodium greater than is
necessary to combine with
the other acid radicals, e. g.
CI, S0 4 , and P0 4 , and this
excess becomes greater if we
consider that a large part of
the P0 4 and S0 4 is derived
from the oxidation of the
sulphur and phosphorus pre-
sent in organic combination
in the plasma. We may
therefore conclude that acon-
siderable part of the carbon
dioxide exists in the plasma
as sodium bicarbonate.
The question arises
whether the whole of the
combined carbonic acid of
the blood can be regarded
as existing in the form of
sodium bicarbonate. Ac-
cording to the analyses of
Carl Schmidt given on page
909, the blood contains
4-31 x Kr 2 N sodium. On
saturating blood with car-
bonic acid and making
allowance for the amount
/
s
+' *'
^t ^
/I y
/ ' / ^i'
/- ^^ -^
/ ~7f .■'
/ y'
~7_7~ /
Z. '
~1_ , '
' ,'
30 40 50 60 70 80 9<
Fig. 512. Curve of C0 2 tension in blood.
(Christiansen, Douglas and Haldane.)
This curve shows the influence of the saturation of
the haemoglobin with oxygen on the amount of C0 2
taken up by the blood at various pressures.
Upper curve = absorption of C0 2 by human blood in
presence of hydrogen and C0 2 .
Middle curve = absorption of C0 2 by human blood in
presence of air and C0 2 .
Lower curve = absorption of C0 2 in blood of ox and
dog in presence of air.
The thick line A-B represents the absorption of C0 2 by £ this radicals takes place between the corpuscles and the
plasma on exposure of blood to varying tensions of C0 2 . According to
Hamburger, when carbon dioxide is passed into defibrinated blood, the
THE CHEMISTRY OF RESPIRATION
111!)
alkaline reserve of the plasma increases while the chlorides diminish, and
the reverse change must take place when the carbonic acid tension in the
blood is diminished as on exposure of the blood to a vacuum.
EXCHANGE OF GASES IN THE LUNGS
A fluid gives oft" gas to or takes up gas from any other medium with
which it is in contact, according to the relative pressures' of the gas. The
question arises whether the physical conditions in the lungs are such as to
account for the absorption of oxygen and the evolution of carbon dioxide
by the blood in its passage through these organs. In order to answer this
question we must know the partial pressures or tensions of oxygen and of
•carbon dioxide in the alveolar
air. in the venous blood coming
to the lungs, and in the arterial
blood leaving the lungs. In the
alveoli the pressures are given
by the analysis of alveolar air.
The determination of the gaseous
tensions in the blood presents
however considerable difficulty.
It is necessary to bring the blood
in contact with gaseous mixtures
containing various proportions
of the gas whose tension in the
blood it is desired to measure.
By making various experiments
a gaseous mixture will be found
with which the blood is in
equilibrium. If we know before-
hand the amount of gas in this
mixture, we know its tension and therefore the tension of the gas in the
liquid.
Pfliiger's aerotonometer (Fig. 514) consists of two glass tubes, r and b, contained in
a vessel filled with water at the temperature of the body. The upper ends of the tubes
are connected by the tube a with the artery or vein in which it is desired to estimate
the tension of the blood gases. If, for instance, we wish to determine the tension of
C0 2 in venous blood, where we expect the tension to amount to about 4 per cent, of an
atmosphere, one tube R is filled with a gaseous mixture containing 3 per cent. C0 2 , and
the other tube K with a mixture containing 5 per cent. C0 2 . a ia now connected with
the distal end of the jugular vein or with the central end of the carotid artery, and
blood is allowed to flow in a thin stream down the walls of the tubes R and R, thus
presenting a large surface to the contained gases. The blood collects in the lower
narrower portions of the tubes, and runs out into the vessels 6, 6, whence after defibrina-
tion it is returned at intervals into the veins of the animal.
In all such instruments the main difficulty is in obtaining a sufficient
surface of the blood exposed to the gaseous mixture. The interchange of
Fig. 514. Pfliiger's aerotonometer.
1120 PHYSIOLOGY
gases is thus very slow, and it is difficult to be certain at any time that
the blood and the gas with which it is in contact are really in equilibrium.
Krogh therefore adopted an ingenious device of limiting the volume of air
to a small bubble, the superficial area of which is large in proportion to
its bulk. This bubble, after it has been in a stream of blood for some minutes,
is transferred to a special capillary tube in which its analysis can be carried
out with a fair degree of accuracy.
The performance of a tonometer may be expressed by the ratio of the surface of
blood exposed to the volume of the air used. The ' specific surface ' of an aerotonometer
, , area in so. cm. ' .„ ' , _„.. , . . ,
is represented by . . The specific .surface of Pfluger s instrument is only
volume m c.c.
3*3 and of Bohr's only 5 - 2. In Krogh's microtonometer the absolute volume of air
employed is reduced to a bubble of about 2 mm. in diameter, having a volume of -004 c.c.
and a surface of 0*125 sq. cm., so that its specific surface is 30. In such a bubble the
equalisation of the tensions takes place with extreme rapidity and only a minute
quantity of fluid is necessary. The microtonometer consists of the tonometer proper
and the apparatus for tho micro-analysis of the gas bubble. In the latter the measure-
ment of the gas bubble is carried out in a capillary tube, the absorption of carbon dioxide
and of oxygen being effected in the usual way with potash and with pyrogallic acid.
The tonometer is represented in Fig. 515. It is kept in a small water-bath at the tem-
perature of the blood to be examined. The tonometer is filled with saline solution and
contains the gas bubble 2, winch can be drawn up by means of the screw 4 into the
narrow graduated tube 3, where its volume is measured. The blood from the artery or
vein, in which we wish to examine the tension of the gases, passes by a cannula through
the tube 1, and enters the tonometer as a fine jet. It forces its way up above the gas
bubble, which is pressed a little down by the current, and kept oscillating with great
rapidity. From the tonometer the blood flows back through the tube 7 and is collected
in a vessel where it can be measured and afterwards drawn off and reinjected into the
animal if necessary. Since the total pressure of the gases in the blood is nearly always
negative, it is necessary to keep the pressure in the tonometer also negative. 1 This is
accomplished by means of a mercury valve and can be regulated to any desired pressure.
During the course of a tonometric experiment the volume of the gas bubble is
measured from time to time by drawing it up into the graduated tube, and the pressure
is regulated until the volume of the bubble remains constant. After five minutes
gaseous equilibrium will have been established between the gas bubble and the sur-
rounding blood, and it is necessary then only to draw it up into the graduated tube
and analyse it in order to determine the tension of the gases in the blood. Clotting
of the blood is prevented by the injection of hirudin.
In these experiments the tension of the air in the alveoli of the animal's
lungs or in the bifurcation of the trachea was determined by taking samples
of the air. The results of the experiments show that the tension of the
gases in arterial blood follows closely the tension of the corresponding gases
in the alveolar air. The tension of carbon dioxide in arterial blood is either
identical with or very slightly above the tension of the gas in the alveolar
air. The oxygen tension of the blood is always lower than the alveolar
oxygen tension, and the difference is generally 1 to 2 — even 3 to 4 — per cent,
of an atmosphere. The results of a series of determinations of the tensions
of the gases in the blood and alveolar air respectively are given in Figs. 516
1 Otherwise the whole bubble would gradually go into solution and disappear.
THE CHEMISTRY OF RESPIRATION
1121
and 517. In Fig. 517 a and b (Krogh) the composition of the alveolar air
artificially altered by increasing the percentage of carbon dioxide and of
oxygen respectively. It will be seen in each case that there was a corresponding
alteration of the tension in the arterial blood, the tension of carbon dioxide
being higher and that of oxygen lower in the blood than in the air through-
out the experiment. We have no direct determinations of the tensions of the
gases in the blood of man, though an approximate valuation of these tensions
Fib. 515. a, Krogh's microtonoineter. b, upper part of niicrotononieter showing
capillary tube into which the bubble is returned for measurement and analysis.
can be obtained by knowing the degree to which the arterial and venous
blood respectively is saturated with oxygen or carbon dioxide. An indirect
method may be employed to measure Hie gaseous tensions in the venous
blood coming to the lungs. It is possible, as Loewy has shown, to block the
right bronchus in man by introducing a cathether through the larynx and
trachea, so that the renewal of air in the right half of the lung is entirely
stopped for some time. A sample of air in the blocked lung can be taken
at any time by means of the catheter. The interchange of gases between
alveolar air and blood will go on until the tension of gases in the air is the
same as that coming to the blocked portion of lung. By this means the
tension of the oxygen in the venous blood was found to be 5-3 per cent. = 37
mm. Hg., and that of the carbon dioxide 6 per cent. = 46 mm. Hg.
71
1122
PHYSIOLOGY
The tensions in the alveolar air of man may be taken as follows :
Oxygen 107 mm. Hg.
Carbon dioxide . . . . . 40 „ „
As the. venous blood enters the lungs there is thus a difference of. pressure
f 107 — 37 = 70 mm. Hg., which will tend to cause a flow of oxygen from
Fig. 516. Tensions of 2 and C0 2 in alveoli compared with those in arterial
blood of rabbit.
The dottod lines represent the tensions in the alveolar air, the uninterrupted
lines the tensions of the gases in the arterial blood. (Kboqh.)
tto
ioas
ftr x %
.
• 1
in inspired
\\
f
l:
\ ' ■ : -
\ * '■
*.-.
1
\v.
■
0j
*»5
CO*.
' -t-
+
Fig. 517. Tensions of gases- in alveolar air and in arterial blood.
A, during artificial increase of oxygen tension in alveoli; B, during artificial
increase of CO, tension in alveoli.
alveolar air to blood and a difference of 46 — 40 = 6 mm. Hg., tending
to cause a flow of carbon dioxide from blood to alveolar air. Is this differ-
ence sufficient to account for the amount of gas given off or taken up by
the blood in its passage through the lungs ? In a state of medium distension
the 3000 c.c. of air contained by the lungs have been estimated to occupy
seven hundred million alveoli, each of which has a diameter of 0-2 mm.,
so that the total surface over which the blood is exposed to the alveolar
THE CHEMISTRY OF RESPIRATION 1123
air amounts to 90 square metres. This is a minimal figure, since no account
in the calculation is taken of the augmentation of surface caused by the
fact that the capillaries project into the lumen of the alveolus; and by
Hiifner the total surface exposed is estimated at 140 square metres. The
former figure however amounts to about 1000 square feet and is equivalent
to the floor-space of a room 50 feet long by 20 feet wide. It is important
to realise that the blood passing through the pulmonary artery suddenly
spreads out into a layer which is uot more than one blood corpuscle thick,
and is exposed to the air over this huge area, whence it is picked up again
and collected into the pulmonary veins. Such a means of facilitating rapid
interchange of gases between the blood and a given volume of air we cannot
possibly imitate artificially. The thickness of the tissue separating this
layer of air from the alveolar air is on the average -004 mm. Loewy and
Zuntz have directly determined the velocity of diffusion of carbon dioxide
and nitrous oxide through the frog's lung, and have calculated therefrom
the rate at which oxygen would diffuse through a similar layer of tissue,
taking into account the much greater solubility of carbon dioxide as com-
pared with oxygen. They estimate that, under a constant difference of
pressure of 35 mm. Hg., 6-7 c.c. of oxygen would pass in a minute through
each square centimetre of the alveolar wall. Through the whole surface
of the lung this would amount to an absorption of 6083 c.c. oxygen. The
oxygen actually absorbed by a man at rest amounts to about 300 c.c. per
minute, so that the physical conditions allow an ample margin for any increase
in the consumption of oxygen ; in fact, a difference of pressure of a couple
of millimetres would suffice to cause a passage of the 250 c.c. per minute
which is required by the resting man. In the same way it is 'easy to account
for the passage of carbon dioxide in the reverse direction. This gas diffuses
through a wet membrane about twenty-five times as rapidly as oxygen,
so that a difference of pressure between the blood and the alveolar air
amounting to only -03 mm. Hg. would suffice to cause a passage outwards
of the 250 c.c. normally expired per minute.
It is evident that the only limitation for the absorption of oxygen is
given by the power of the haemoglobin to combine with the oxygen which
passes through the alveolar wall into the blood plasma.
U we look at the dissociation curve of the oxyhemoglobin in mammalian
blood given on p. 1110, we see that the amoimt of oxygen which can be taken
up by hsemoglomh in the presence of the normal tension of carbon dioxide,
i. e. 40 mm. Hg., begins to diminish very rapidly when the pressure of the
oxygen falls below 50 mm. Hg. Thus at 40 mm. oxygen pressure and a
carbon dioxide tension of 40 nun., oxyhsemoglobin is about 65 per cent,
saturated, and at 30 mm. it is only 50 per cent, saturated. Under normal
circumstances the blood leaves the lungs over 90 per cent, saturated with
oxygen. If the saturation falls to 60 per cent, we should expect to obtain
evidence of failure of oxygen supply to the tissues. According to Loewy
the oxygen tension in the alveoli can sink to between 30 and 35 mm. Hg.
before any signs of oxygen lack make their appearance. These results were
L124 PHYSIOLOGY
obtained by exposing a man in a state of complete rest to reduced pressure
in an air-chamber. Under these conditions the slightest muscular exertion
would at once tend to cause distress from deficient oxygen supply. The
exact percentage of oxygen in the inspired air, which would give an alveolar
oxygen tension of 30 to 35 mm., varies with the depth of respiration. Thus
with shallow respiratory movements the pressure may sink to 35 mm.Hg.
when the inspired air contains as much as 12 per cent, oxygen. If the
movements be deeper, the oxygen content of inspired air may be reduced
to 9 or 10 per cent, before respiratory distress is observed.
The view that, in the interchange of gases in the lungs, the membrane between the
blood and the alveolar air play's simply a passive part was till recently by no means
universally accepted. In Bohr's experiments on the tension of oxygen and carbon
dioxide in the blood as determined with his aeroto'nometer, oxygen tensions were often
found considerably higher in the blood than in the air of the alveoli, and in the same
way the carbon dioxide tension of the blood leaving the lungs was found to be less than
the carbon dioxide tension of the alveolar air. Krogh's experiments show conclusively
however that these results are not reliable, and that the difference between the tensions
in the alveoli and in the blood respectively is always such as to allow of the passage by
diffusion of oxygen inwards and carbon dioxide outwards from the blood. Moreover,
as Krogh points out, the structure of the pulmonary epithelium lends no support to
the view that it acts as a secreting membrane. In mammals the cells are of two kinds,
viz. small granular nucleated cells lying in the interstices of the capillaries, and larger
extremely thin structureless plates, without nuclei, covering the capillaries. In birds,
where the gaseous exchange is of all animals the most rapid and efficient, the existence
of a lung epithelium has never been demonstrated, and the capillaries appear to be
almost completely free and to be surrounded with air on both sides.
Bohr's view as to the secretory function of the pulmonary epithelium was supported
as concerns the intake of oxygen by Haldane. This observer has devised a method of
determining the oxygen tension of the blood in the lungs founded on the use of carbon
monoxide. It has already been mentioned that carbon monoxide has the power of dis-
placing oxygen from oxyhemoglobin to form a much more stable compound, carboxy-
hernoglobin. If blood be shaken up with a mixture of oxygen and carbon monoxide,
the haemoglobin distributes itself between the two gases. In order however to get an
equal distribution, it is necessary to take a very small percentage of carbon monoxide,
owing to its greater avidity for hemoglobin. Thus, if haemoglobin solution be shaken
up with air containing ;07 per cent, of CO, the result is a mixture of equal parts of oxy
and carboxyhsemoglobin. The affinity of CO for haemoglobin would thus appear to be
21
about — = 300 times the affinity of oxygen for hemoglobin.
Carbon monoxide is not destroyed in the body, so that if a mixture containing a
small proportion of CO be breathed, this gas will be taken up until a certain percentage
of haemoglobin is converted into CO-hernoglobin and the tension 'of CO in the tissues
and fluids of the body is equal to that of the inspired air. The amount of haemoglobin
which is converted into carboxyhsemoglobin will serve as a measure of the relative
tensions of CO and oxygen in the lungs. If the oxygen tension of arterial blood were
the same as that of the alveolar air,' we should expect that, with a given percentage of
CO in the air breathed, the final saturation with CO of the blood within the body would
be the same as the saturation of blood when shaken outside the body with air con-
taining the same percentage of CO as in the air breathed. It was found by Haldane
however that in all cases the percentage of CO hemoglobin formed was much less in the
body than outside the body. Thus in blood shaken up with air containing 20'0 per cent.
oxygen and - 045 per cent. CO, the amount of carbon monoxide hemoglobin formed was
31 per cent, of the whole hemoglobin. When the same mixture was inhaled for three
or four hours by a man, the percentage of CO hemoglobin in his blood rose only to
THE CHEMISTRY OF RESPIRATION 1125
20 per cent., at which figure it remained stationary. This would correspond to an
oxygen tension of about 25 per cent, of an atmosphere, whereas we have already seen
that the oxygen tension in the alveoli cannot be greater than 15 per cent. He therefore
concluded that the epithelial cells of the alveoli play an active part in the respiratory
interchange, taking up the oxygen on one side at a tension of 15 per cent, and piling it
up on the other until the pressure in the blood is much higher than that in the alveolar
air. Theoretically there is no reason to deny the possibility of such powers to the
pulmonary epithelium. We knew that the secreting cells of the kidney take up urea
from the blood which contains only about - 02 per cent, of this substance, and excrete
it into the renal tubule, into a medium containing about 2 per cent. ; and if the data
given by Haldane are correct we must ascribe an analogous function to the pulmonary
epithelium. These data however were obtained by a colorimetric method working
with very minute quantities of blood, and lacked the support of control experiments.
As a result of further experiments, Haldane has modified his position so far as to allow
that under normal conditions the absorption of oxygen from the alveolar air takes place
in accordance with the difference of pressure, i. e. by a process of diffusion. He is still
of opinion that under abnormal conditions, when the oxygen tension in the alveolar
air is very low, there is an active absorption and transference of oxygen to the blood
on the part of the pulmonary epithelium. Why animals should evolve a function
which can be brought into play only on climbing mountains seems difficult to under-
stand, and it does not seem probable that a reinvestigation of the tensions of oxygen
in the blood under such conditions by Krogh's method will lend any confirmation to
Haldane's conclusions.
An analogy has been drawn between the processes of gas interchange in the lungs
and that in the swim bladder of the fish. Bohr has shown that the gas obtained by
puncturing the bladder often contains considerable excess of oxygen. If the bladder
be punctured and the fish then left in the water, the gas rapidly reaccumulates, and it
is found, on tapping a second time, that the percentage of oxygen is largely increased,
and may amount to between 60 and 80 per cent, of the total gases. This reaccumulation
of the gases does not take place if both vagi are cut, and is therefore ascribed to a direct
secretory activity on the part of the epithelium lining the swim bladder under the
influence of the vagus nerves. Bohr, as the result of experiments by himself and some
of his pupils, is inclined to endow the vagus nerves in the higher vertebrates, including
mammals, with an analogous regulatory influence on the gaseous exchanges in the lungs.
As regards the evolution of carbon dioxide, the facts elucidated by Haldane himself
would make one hesitate in ascribing any special secretory activity to the pulmonary
epithelium. We find, namely, that the respiratory centre reacts immediately to the
slightest increase in the tension of the carbon dioxide in the alveolar air. Since this
behaviour of the respiratory centre is independent of any nervous connections between
the lungs and the brain, it seems to indicate, as indeed Krogh has found, that the tension
of the carbon dioxide in the blood follows closely the tension of the carbon dioxide in
the alveolar air. Ii the carbon dioxide were secreted by the pulmonary epithelium, we
should expect the lungs to react to increased carbon dioxide in the alveoli by simply
increasing their work so as to maintain the tension of carbon dioxide in the blood at a
constant level. This at any rate is the way in which the kidney would behave under
analogous circumstances. Moreover there is no likeness between the thick typical
secreting cells of the ' red gland,' which is the gas-secreting part of the swim bladder,
and the thin structureless plates which separate the capillaries of the lungs from the
alveolar air.
SECTION III
THE REGULATION OF THE RESPIRATORY
MOVEMENTS
Each movement of inspiration involves the co-ordinated activity of a large
number of muscles. Thus the . diaphragm and the intercostal muscles
must come into action at the same time, and the extent to which they
contract will determine the depth of the inspiration. Similarly, they must
cease to act simultaneously if the act of expiration is to take place. The
rhythm and extent of the alternate contractions and relaxations of the
respiratory muscles are determined, as we have seen, by the needs of the
organism as a whole. These respiratory movements are regulated so that
the total ventilation of the alveoli shall be sufficient to meet the gaseous
exchanges of the body. Whether the organism consumes 250 or 1000 c.c. of
oxygen per minute, the respiratory movements keep the composition of the
gas in the alveoli at a practically constant level.
The muscles involved both in inspiration and expiration can be thrown
into activity only by the intermediation of nerves. Each act of inspiration
involves a discharge along a number of nerves, e. g. the facial to the muscles
moving the alse nasi, the vagus to the muscles of the larynx, the branches
of the cervical and brachial nerves to the muscles of the neck, the phrenic
nerves to the diaphragm, and the dorsal nerves to the intercostal muscles.
The fibres making up these nerves are derived from nerve cells of the anterior
horn, situated at various levels in the medulla and spinal cord. In each act
of inspiration or expiration the activities of all these groups of cells must be
brought into relation among themselves, as well as with the needs of the
organism for oxygen and for the elimination of carbon dioxide. It is
conceivable that the co-ordination of the activities of the various motor
nuclei might be attained by the provision of communicating nerve paths
joining the centres among themselves, and by a sensibility of all these centres
to the gaseous contents of the blood as well as to the influence of afferent
impressions from the periphery. A much more efficient co-ordination
however would be effected by the subjection of these motor nuclei to the
action of some specialised portion of the central nervous system, which
would act as a receiving centre for afferent impressions from the lungs and
surface of the body, and would be endowed with a special sensibility to
changes in the composition of the blood circulating through its vessels.
Experiment shows that the latter method is employed in the organism for
the regulation of the respiratory movements. If the spinal cord be cut across
1126
REGULATION OF THE RESPIRATORY MOVEMENTS 1127
below the seventh cervical nerve roots, the action of the intercostal and
abdominal muscles in respiration ceases permanently, although respiration
is still continued by the rhythmic activity of the diaphragm and the other
muscles supplied by nerves leaving the central nervous system above the
point of section. Division of the cord at the first or second cervical nerve
abolishes the action of the diaphragm, though the movements of the muscles
supplied by the facial, vagus, and spinal accessory nerves continue. A
section of the brain stem through the mid -brain leaves the respiratory
movements unaltered, and the same absence of effect as concerns these
movements may often be obtained when a section is carried across the upper
part of the medulla about the level of the striw acoustical. We must con-
clude from these experiments that the motor nuclei of the cord are subject
to and normally thrown into activity by impulses originating in the medulla
oblongata and transmitted therefrom down the spinal cord.
Many experiments have been made with the idea of locating the position
of the medullary respiratory centre more accurately. The first experiments
on this point were made at the beginning of last century by Legallois, whose
observations were confirmed and extended by Flourens. These observers
described the respiratory centre as limited to a small area at the level of the
apex of the calamus serif tortus , which they designated nceud vital on account
of the fact that destruction of this area was at once fatal by paralysis of
respiration. Later experiments have shown that the centre is not quite so
circumscribed. .In the first place, it is bilateral, each centre presiding more
especially over the muscles of the same side of the body, so that longitudinal
section in the middle fine does not destroy the respiratory movements.
Other observers have located the centre in the situation of the solitary
bundle (' respiratory bundle of Gierke '), which is made up of the descending
branches of the vagus nerve after they have entered the medulla, while,
according to Gad-, the respiratory centre is diffused over a considerable
area of the formatio reticularis on either side of the medulla. There is no
doubt that this centre is in close connection with the central terminations
of the vagus nerves.
From the centre on each side the efferent impulses to the motor nuclei
of the respiratory muscles pass down in the deeper portions of the lateral
columns of the cord. Hemisection of the cervical cord, e.g. on the right
side, causes cessation of the contractions of the diaphragm on the same side.
There must however be commissural fibres joining the motor nuclei on the
two sides. If the right phrenic nerve be divided, after hemisection on the
left side, the left half of the diaphragm at once commences to contract
rhythmically with each respiration (Porter). It is evident that the cessation
of respiration after section of the cord is not due to a condition of shock of
the lower spinal centres, since it is possible for impulses to pass down the
cord and to cross over to the contra-lateral diaphragm nucleus immediately
after hemisection of the cord on the side of the nucleus.
THE QUESTION OF SPINAL RESPIRATORY CENTRES. Several physiologists
c. g. Brown-S^quard, Langcndorff, and Wertheimer, have described respiratory centres
1128 PHYSIOLOGY
in the spinal cord. There is no doubt that, if the cord be cut across in the upper cervical
region and artificial respiration maintained for some time, cessation of the respiration
may be followed by rhythmic contractions of the respiratory muscles. These are
especially marked in young animals and if the activity of the cord has been heightened
by the injection of small doses of strychnine. Careful observation of the movements
shows however that they cannot be spoken of as respiratory, since although rhythmic,
they are not co-ordinate. The diaphragm may contract either simultaneously or in
alternation with the intercostals, and muscles which are essentially expiratory at the
same time as those which we are wont to regard as inspiratory. These experiments
show merely that the motor centres of the cord can enter into rhythmic activity under
the influence of asphyxial conditions. The movements affect the muscles of the limbs
as well as those essentially respiratory in function.
THE AUTOMATICITY OF THE RESPIRATORY CENTRE
We have now to inquire what it is that keeps the respiratory centre in
activity. Is the rhythmic discharge of inspiratory impulses from the centre
due to rhythmic or continuous stimulation of afferent nerves, or is the centre
so constructed that under the normal conditions of its environment the
metabolic activity of its constituent parts tends, like that of the heart cells,
to assume a rhythmic character? In other words, is the activity of the
centre reflex or automatic ? It has been found by Rosenthal that rhythmic
respiratory movements are maintained even after complete section of the
brain stem at the level of the superior corpora quadrigemina, section of the
cord at the level of the seventh cervical nerve, and division of both vagi and
of the posterior roots of all the cervical spinal nerves. It is true that if the
sections of the brain stem be placed as low as the strice acousticce, the re-
spiratory movements are profoundly modified and give place to a series of
inspiratory spasms. We might argue from this that the centre was capable
of a very imperfect degree of automatic action, but needed the stimulus of
afferent impulses from the vagi or from the higher parts of the brain to
render these actions adequate for the respiratory needs -of the organism.
In the above experiment the centre cannot be regarded as free from all afferent
stimuli, since the mere closure of the demarcation current in the cut ends of the nerves
would cause a certam amount of excitation, and the animal does not survive sufficiently
long to allow this condition to pass off. Hering has shown that in the ' spinal cord
frog ' (?'. e. one in which the brain has been destroyed) section of all the posterior roots
absolutely abolishes all mobility, the injection of strychnine being without effect. A
typical spasm however can be at once produced by exposing and stimulating the
stump of one of the cut posterior roots. We might suppose that the respiratory centre
would be similarly devoid of automatism if absolutely free from afferent stimuli. It
must be mentioned however that, according to Sherrington, it is possible to excite
strychnine or asphyxial spasms in a dog or cat with isolated spinal cord, in which all
the afferent roots below the transection have been divided six or seven hours previously.
He therefore is of opinion that in the mammal the motor nervous mechanism can be set
into activity apart from the incidence of afferent impressions. The respiratory centre
tends to respond to all stimuli, continuous or rhythmic, by means of rhythmic discharges,
and there can be no doubt that, if we take the medulla in connection with the rest of
the hind- and mid-brain, we are justified in regarding its activity as automatic.
The automatic activity of the heart is intimately dependent on the
saline constituents of the blood. It may be abolished or diminished by
REGULATION OF THE RESPIRATORY MOVEMENTS 1129
modifying these constituents, and can be maintained for a considerable length,
of time by perfusing the heart, with solutions containing inorganic salts in
the concentration in which they exist in the blood plasma. When we
speak of the automatic activity of the respiratory centre, we imply in the
same way that its activity is dependent on the normal composition of
the blood circulating through its vessels. In this case however it is the
gaseous contents of the blood which are of supreme importance. If the
normal ventilation of the lungs be prevented, as by ligature of the trachea
or opening both pleural cavities, the blood becomes more and more venous.
As this venous blood circulates through the medulla, the activity of the centre
is continually increased, until finally the impulses discharged from the
centre may set into activity practically every muscle of the body, producing
asphyarial convulsions. On the other hand, the activity of the respiratory
centre can be diminished or even abolished if, by an artificial ventilation of
the alveoli, we maintain an over-arterialisation of the blood, so that the
fluid passing to the brain contains more oxygen and less carbon dioxide
than is the case under normal circumstances. What are the factors involved
in this chemical regulation of respiration?
THE CHEMICAL REGULATION OF THE RESPIRATORY
MOVEMENTS
If, the nervous centres being intact, the proper aeration of the respiratory
eenl re be interfered .with in any way, the respiratory movements increase in
ill and frequency, and if the disturbing factor be not removed the
animal dies, presenting a train of phenomena which are classified together
under the term ' asphyxia.'
The phenomena of asphyxia may be divided into three stages :
(1) In the first stage, that of Ityperpncea, the respiratory movements
are increased in amplitude and in rhythm. This increase affects at first both
inspiratory and expiratory muscles. Gradually the force of the expiratory
movements becomes increased out of all proportion to the inspiratory, and
the first stage merges into :
(2) The second, which consists of expiratory convulsions, in which almost
every muscle of the body may be involved. Just at the end of the first
consciousness is lost, and almost immediately after the loss of con-
sciousness we may observe a number of phenomena extending to almost all
the functions of the body, some of which have been already studied. Thus
the vaso-motOT centre is excited, causing universal vascular constriction.
There is often also secretion of saliva, inhibition or increase of intestinal
movements, constriction of the pupil, and so on.
(3) At the end of the second minute after the stoppage of the aeration of
the blood, the expiratory convulsions cease almost suddenly, and give way to
slow deep inspirations. With each inspiratory spasm the animal stretches
itself out and opens its mouth widely as if gasping for breath. The whole
stage is one of exhaustion : the pupils dilate widely, and all reflexes are
1130 PHYSIOLOGY
abolished. The pauses between the inspirations become longer and longer,
until at the end of four or five minutes the animal takes its last breath.
If we increase the activity of the centre and therefore its gaseous inter-
changes, by warming the blood in the carotid arteries, there may be a
considerable quickening of respiration unaccompanied by any deepening, a
condition which is spoken of as tachypncea. On the other hand, we may slow
the respiratory movements by placing a small piece of ice on the floor of the
fourth ventricle.
In the production of the phenomena of asphyxia two factors must be at
work. In the first place, there is an accumulation -of carbon dioxide in the
blood bathing the centre, or an increased tension of this gas in the centres
themselves, either as a result of deficient excretion or increased production.
On the other hand, the centre is deprived of oxygen, either by failure of
renewal of the oxygen supply or by increased using up of this gas in the
metabolism of the centre. The question arises, which of these two changes
is responsible for the different physiological events which characterise
asphyxia ? At various times these phenomena have been ascribed either to
the increased tension of carbon dioxide or to the diminished tension of
oxygen in the centre. The view, that the normal stimulus to the respiratory
centre in asphyxia was the lack of sufficient oxygen and that the normal
activity of this centre was determined by the tension of oxygen in the blood
circulating through the brain, was first put forward by Rosenthal. When
sufficient oxygen was present, the centre, according to this observer, would
cease to. act, so that a condition of apncea would be produced. According
to Traube, on the other hand, the special respiratory stimulus was the
excess of carbon dioxide in the blood, and this view was supported strongly
by Miescher. The tendency of recent work, especially by Haldane and
his pupils, has been to show that there is an element of truth in both views
— that indeed the respiratory centre can be excited either by excess of
carbon dioxide or by lack of oxygen, but that its sensitivity to carbon
dioxide is by far the more important factor in the determination of the
increased respiratory movements in asphyxia, and is the only chemical
factor which can be regarded as playing any part in the regulation of the
respiratory movements under normal conditions. This factor is well brought
out if we investigate the effect on the respiratory movements of altering the
tensions of the two gases' in the air breathed . If by this means we succeed
in altering the tension of the two gases in the alveolar air, we may assume that
the tensions of the gases in the arterial blood leaving the lungs are altered in
the same ratio. The results of such experiments are very striking. Even
a slight increase in the percentage of carbon dioxide in the air causes an
increase first in the depth and later on in the rhythm of respiration (Fig. 518).
This is shown in the following Table by Haldane, which represents the average
depth and frequency of the respirations when the subject was breathing
normal air and air charged with varying percentages of carbon dioxide.
A rise of carbon dioxide in the atmosphere to 2 per cent, increases the depth
of respirations by 30 per cent., and the total alveolar ventilation by 50 per
REGULATION OF THE RESPIRATORY MOVEMENTS 1131
cent. A rise of carbon dioxide to 3 per cent, increases the total ventilation
of the alveoli by 126 per cent. An amount of carbon dioxide equivalent
to 6 per cent, increases the depth of each respiration by 272 per cent., and
the total alveolar ventilation by 757 per cent.
Fig. 518. Effect of CO a on respiratory movements of rabbit. (Scott.)
Upper line, tracing of diaphragm slip iHead's method). Lower tracing, carotid
pressure. During the first period indicated on tho signal line the animal breathed
9-fi per cent. CO, in air, and during the second period 10 per cent. C0 2 with 33 per
cent, oxygen. Time tracing = 2 sees. Scale = mm. Hg. blood pressure.
Percentage COo .
in inspired air
Average depth
of respirations
Average
frequency of
respirations
per minute
Ventilation of alveoli
with inspired air
(normal = 100)
CO, percentage
in alveolar air
004
673
14
100
5-6
0-79
739
14
(6-60 litres per min.)
116
5-5
202
864
15
153
5-6
307
1216
15
226
5-5
5- 14
1771
19
498
6-2
6-02
2104
27
857
6-6
If we examine the last column of figures in this Table, representing the
percentage of CO, in the alveolar air, it will be seen that, in spite of the very
large variations in the air breathed, the alveolar content in C0 2 remained
practically constant until the C0 a in the atmosphere was increased to such
;ui extent that the processes of compensation were no longer efficient. We
must conclude therefore that the respiratory centre is so arranged as to
react to the slightest increase of C0 2 tension in the blood, any increase in
this gas giving at once a compensatory increase in depth and frequency of
respiration, so that the alveolar C0 2 content may be maintained almost
constant.
That it is the tension of C0 2 in the alveolar air and therefore in the blood
bathing the centres, and not the percentage amount of this gas which is the
determining factor, is shown by a comparison of the composition of the
1132
PHYSIOLOGY
alveolar air under different atmospheric pressures. Thus, when the subject
of the experiments from which the above Table was derived, was placed in
an air-chamber compressed to a pressure of 1261 mm., the mean percentage
of C0 2 in the alveolar air was 3-42, corresponding however to a tension of
3-42 X - = 5-6 per rent, of an atmosphere, a figure almost identical
with those given in the last column of this Table. At the top of Ben
Nevis, where the barometric pressure was 646 mm., the percentage of C0 2 in
the alveolar air was 6-6, corresponding to a tension of 6-6 X — = 5-2 per
760 '
3000 2600 2200
Fio. 519. Effects of alterations in the barometric pressure on the alveolar CO,
tension, the al'veolar C0 2 percentage, and in the alveolar O, tension. Note
that the excitant effects of O. lack are not seen until the pressure falls below
500 mm. Hg. (Boycott and Haldane.)
cent, of an atmosphere, i. e. of 760 mm. Thus the pressure of C0 2 in alveolar
air remains practically constant with widely varying limits of atmospheric
pressure and with very different percentages of C0 B in the inspired air,
showing that the reactions of the organism are directed so as to maintain,
by alterations in the respiratory depth and rhythm, a constant tension of this
gas in the alveoli and therefore in the arterial blood.
Very different are the phenomena observed on alteration of the partial
pressure of oxygen (Fig. 519). Here, within wide limts, the partial pressure
of oxygen in the alveolar air is determined by its pressure in the inspired air.
Thus, if we take the same series of observations with a pressure of 646 mm.,
the percentage of oxygen in the alveolar air was 13-19, corresponding to a
tension of 13-19 X — = 10-4 per cent. At an atmospheric pressure of
755 mm. the percentage of oxygen in the alveolar air was 13-97, corresponding
to a tension of 13-06 per cent., which we may take as the normal figure at the
REGULATION OF THE RESPIRATORY MOVEMENTS 1133
sea-level. In air compressed to a pressure <>f 1261 mm. the percentage of
1261
oxygen was 16-79, corresponding to a tension of 16-79 X — — = 26-8 per
cent, of an atmosphere of 760 mm.
Similar results are obtained by altering the percentage of oxygen in the
air breathed. The oxygen tension or percentage in the inspired air can be
lowered from its normal of 20-93 to 12 or 13 per cent, without altering
in any way the depth or rhythm of respiration, and in fact without any
change being noticed by the individual who is the subject of the experiment.
A percentage of 13 per cent, of oxygen corresponds to an alveolar content in
Fig. 5:20. Effects of oxygon lack. (Scott.)
Upper tracing, diaphragm slip; lower tracing, carotid blood pressure. During
time indicated by signal, 5 per cent, oxygen in nitrogen was inhaled. C = eon-
vulsion.
oxygen of 8 per cent., and with a further reduction of the oxygen content
there is increased pulmonary ventilation (Fig. 520), but the diminution in
oxygen may be pushed to such an extent that the patient becomes blue from
the deficient aeration of his haemoglobin, without any considerable distress
being caused. In fact in many cases the subject of such an experiment may
lose consciousness suddenly before he has been aware of any serious deficiency
in his aeration.
The difference in the sensitiveness of the centre to increase of carbon dioxide and
lack of oxygen respectively is well shown by an experiment of Haldane's, in which the
same person breathed in and out of a bag, in the first place allowing the carbon dioxide
produced in respiration to accumulate, and in the second removing the carbon dioxide
In means of soda lime, so that the sole effect of respiration was to produce a continual
diminution in the percentage of oxygen. In the first case, when the carbon dioxide was
il.'.l PHYSIOLOGY
allowed to accumulate, it was found that extreme and intolerable hyperpneca was pro-
duced when the gaseous content of the bag consisted of 56 per cent, carbon dioxide
with 14 - 8 per cent, oxygen. When the carbon dioxide was absorbed, it was possiblo
to breathe in and out of the bag for a much longer period. No hyperpncea was pro-
duced, and the experiment was stopped as soon as the subject was becoming blue in
the face and experienced slight throbbing in the head. The pulse frequently had gone
up from 80 to 108. The bag was found to contain no carbonic acid and only 8' 7 per
cent, oxygen. In another similar experiment the oxygen had been reduced to 6' 7 per
cent, before it was necessary to stop the experiment.
We must conclude that the respiratory centre possesses a specific sensi-
bility for carbon dioxide, which determines the normal depth and rhythm
of the respiratory movements. Although the respiratory centre, in com-
mon with the rest of the central nervous system, is sensitive to and can be
excited by lack of oxygen, this quality is rarely brought into play. Under
all ordinary circumstances, an increased need for oxygen is associated with
an increased production of carbon dioxide in the oxidative processes of the
body, and the augmentation of respiration, produced by the excitatory
effect of a small excess of carbon dioxide tension in the blood, suffices to
provide fully for the increased' needs of the organism for oxygen. The
reactions of the organism have not been evolved in order to adapt it to
balloon ascents or experiments in respiratory chambers. As an example of
a normal adaptation, we may take the changes in respiration which occur
in an animal as the result of muscular exercise. During their activity a
large amount of carbon dioxide is produced in the muscles. The blood
passing from the muscles to the heart will not be able to get rid of the excess
of the carbon dioxide in passing through the lungs, and will reach the
respiratory centre more highly charged with this gas, the tension of which
will be raised. The respiratory centre is thus stimulated, and the increased
pulmonary ventilation thereby produced lowers the alveolar carbon dioxide
pressure, until a point is reached at which an equilibrium is maintained
between the effect of the increased production of carbon dioxide in raising
the arterial carbon dioxide tension and that of the increased respiratory
activity in lowering it. Under these circumstances it is found that the
increased consumption of oxygen in the contracting muscles is more than
compensated, so that the oxygen tension in the alveoli and in the arterial
blood is rather above than below normal.
In certain experiments Zuntz and Geppert foimd that, during muscular
exercise, the respiratory movements were increased to such an extent as
to bring the tension of carbon dioxide in the arterial blood below normal.
In these experiments the muscular contractions were produced by tetanis-
ing, through the spinal cord, the lower linibs of an animal. Under these
circumstances the activity of the muscle would be associated with a
diminished blood flow, so that the contractions would be carried out in the
absence of a sufficient supply of oxygen. In the absence -of sufficient
oxygen, muscular contractions result in the production, not of carbon
dioxide but of lactic acid ; and it is highly probable that in the experiments
in question there was a discharge of acid substances into the blood, diminish-
REGULATION OF THE RESPIRATORY MOVEMENTS 1135
ing the alkalinity of this fluid and therefore lowering its carrying power for
carbon dioxide. As a matter of fact, one can produce dyspnoea by diminish-
ing the alkalinity of the blood by the injection of acids; and attacks of
dyspnoea are observed in the later stages of diabetes, when the alkalinity
of the blood is decreased in consequence of the production of such bodies
as oxybutyric acid. This dyspnoea has been ascribed to the fact that a
diminished carrying power of the blood for carbon dioxide will raise the
tension of this gas in the tissues where it is formed, so that a diminished
alkalinity of the blood may cause a higher tension of carbon dioxide around
the respiratory centre. It has been shown by Ryffel that even a short
period of sufficiently violent muscular exercise, i. e. one giving rise to
dyspnoea, causes a subsequent increase of lactic acid in the urine, and that
the blood itself at the close of the period of exercise contains a demonstrable
amount of this acid. Thus in one case the urine, passed thirty minutes
after running one-third of a mile in two minutes, contained 454 mg. lactic
acid as against a normal excretion of between 3 and 4 mg. lactic acid
per hour. In another experiment blood was obtained from the fore-arm
before exercise, immediately after exercise, and three-quarters of an hour
later. The exercise, which consisted of running rapidly, lasted two minutes
forty-five seconds. The following Table represents the results obtained :
Lactic acid per 100 c.c.
Blood before starting ..... 12'5 mg.
Blood immediately after stopping . . . 708 „
Blood 45 minutes later ..... 15*9 „
The production of lactic acid during muscular exercise may thus be
regarded as a second line of defence for the organism, tending to maintain
the increased ventilation of the lungs even when the supply of oxygen is
insufficient to oxidise completely the materials consumed in the production
of the muscular energy. This acid mechanism is however employed only
when the supply of oxygen lags behind the respiratory needs of the body
(cp.'Fig. 521). Ordinary exercise, even when considerable {e.g. a twenty-
four hours' track walking race), does not cause, as Ryffel has shown, any
appreciable increase in the ehmination of lactic acid by the urine. Under
normal circumstances the depth and rhythm of respiration depend on the
carbon dioxide pressure in the respiratory centre, a rise of 0-2 per cent, of
an atmosphere in the tension of this gas in the alveoli being sufficient to
double the amount of alveolar ventilation during rest.
The first phase in the phenomena of asphyxia is thus conditioned simply
by the changes in the carbon dioxide tension. A little later the gradual
exhaustion of oxygen in the blood round the centre begins to make itself
felt. The respiratory centre shares with the rest of the central nervous
system a sensitiveness to the absence of oxygen, deprivation of oxygen
having first an excitatory and later a paralytic effect. In asphyxia the
first centres to feel this effect are those of the cortex, and during the first
stage there is mental excitation terminating rapidly in abolition of con-
sciousness. During the second stage there is a discharge of energy, which
1136
PHYSIOLOGY
spreads throughout the whole nervous system, beginning in the bulbar
centres and causing a great rise of blood pressure with slowing of the heart,
and extending thence to all the spinal centres with the production of muscular
spasms. At this stage too, there is a discharge of impulses giving contraction
of the pupil, and a discharge along the whole sympathetic system, producing
the various phenomena of vasoconstriction, erection of hairs, sweating,
salivation, which are generally brought about by stimulation of different
parts of this system. The phenomena of the third stage are due to
exhaustion of the nerve centres, accompanied or preceded by exhaustion
and dilatation of the heart, the circulation failing before the excitation of
the lower centres has entirely come to an end. In this third stage it is
impossible bv the strongest stimuli to evoke any reflex.
^-■^ ..-- — ."
^Itfj*^ ■' '
7^ ,•' ,1
sL ' =s " ~~ *—
~i / •' 'l'''"
J-£rs
Tl : -7
-Et : j
%V -f
•ttrt
-44't-i
Tt r L
rriy
/ '" ; /
o / / , A/, \
~/* ,' ^'■ 7>
_SZz>^'
4 '& ''
Fio. 521. Dissociation curve of oxyhemoglobin in defibrinated cats' blood.
1, cat I, after partial occlusion of trachea and fifteen minutes breathing of gas
of increasing poverty in oxygen; 4, cat II, at beginning of experiment; 3, cat II,
after fifteen minutes gas respiration ; 2, after twenty-one minutes ditto.
Considerable discussion has taken place as to the exact nature of the stimulation
brought about by want of oxygen. The blood of animals, which have been killed by
asphyxia, is known to contain reducing substances, so that oxygen added to it disappears
and cannot be recovered in a vacuum. Pfliiger therefore suggested that it was these
reducing substances themselves which were effective exciting agents. It was shown
many years ago by Hoppe-Seyler and his pupils that in conditions of chronic oxygen
starvation there was an excessive production of lactic acid in the body, and we have
seen that the same is true for the isolated muscle, and that to these substances has been
ascribed the excitation of the respiratory centre which takes place in violent muscular
exercise (Zuntz and Geppert). Haldane has suggested that in the hyperpncea and con-
vulsions, which occur as the result of breathing mixtures with very low percentages of
oxygen, the effective stimulus is also lactic acid. Experiments were carried out by
Ryffel on individuals who had been subjected in a respiratory chamber to very low
oxygen tensions, sufficient to cause C3"anosis, so that their oxygen alveolar tension was
only about 6 per cent. After an experiment lasting four hours, there was a definite
increase of lactic acid in the blood of the forearm (up to 23"6 mg. lactic acid per 100 c.c.).
After one lasting only fifteen minutes, in which the oxygen shortage became very
marked, no increase could be detected. When we expose an animal such as a rabbit to
low percentages of oxygen, the hyperpnoea so produced disappears almost immediately
REGULATION OF THE RESPIRATORY MOVEMENTS 1137
when a larger percentage of oxygen is supplied to the animal, whereas that produced by
carbon dioxide excess dies awa}' slowly on exposure to normal conditions. It would seem
that, when the exposure to low oxygen tensions is of short duration, no lactic acid is pro-
duced in the blood. If therefore we ascribe the hyperpneea to the production of lactic
acid, we must locate the production of this acid in the respiratory centre itself. There
are no inherent improbabilities in such an assumption, but it is difficult at present to
see how it can be put to the test of experiment.
In dealing with the question of the blood alkalinity we denned neutrality as a con-
dition in which there were equivalent concentrations of H and OH ions. In the blood
the H ion concentration is about 0'3 X 10~ 7 N. The alkalinity is expressed by
. The acids and bases of the blood serum and of the tissue fluids
concentration H ions
lly are in such proportions as to maintain the approximate neutrality of these
fluids even a"er considerable additions of acid or alkali. Thus hydrochloric acid may
be added to the extent of 025 N, or NaOH to the extent of "005 N, without causing
any marked alteration in the reaction of the blood. Although the change produced
by the addition of acids or alkalies is so minute, it is appreciable by electrical
methods, and it may still more readily be appreciated by and act as a stimulus for the
pells of the body themselves. Thus we have not yet succeeded in determining electric-
ally the change in hydrogen ion concentration caused by the change from arterial to
venous blood. If however blood serum be saturated with carbon dioxide at a full
atmosphere, the concentration of the hydrogen ions rises to 1"4 X 10 -7 N, while after
removing the greater part of the carbon dioxide from the same serum by the passage of a
stream of air, the concentration of the hydrogen ions sinks to - 008 x 10 "" 7 N. As the
respiratory centre responds to such minute changes of concentration as would be
expressed by a difference of 02 per cent, of an atmosphere in the carbon dioxide tension
of the circulating blood, it must possess a sensitivity greater than any of our physical
means for measuring the concentration of hydrogen ions in a fluid. We may approach
this delicacy of reaction by using a large molecule as our indicator. Thus, as we have
seen, the dissociation curve of haemoglobin is sensitive to the change in reaction caused
by raising the tension of carbon dioxide in the hemoglobin solution by 10 mm. Hg.
(cp. Fig. 509).
The regulating factor in the blood is probably not carbon dioxide nor any special acid,
but the concentration of hydrogen ions in this fluid or in the cells of the centre itself.
Such a conclusion brings under one head all the several factors which we know to act
upon the respiratory centre, namely, tension of carbon dioxide, presence of acids in the
blood — especially lactic — and considerable diminution of oxygen supply to the cells.
The respiratory centre would then not differ qualitatively from any other part of the
central nervous system. Its special function would be determined simply by the evolu-
tion to a marked degree of a sensibility to hydrogen ions which is already possessed by
the whole of the central nervous system and indeed by practically every tissue of the body.
We may conclude that mere lack of oxygen is not to be regarded in
itself as an excitatory agent. Its influence will be rather to paralyse all
activity. On the other hand, excitation is caused by the products of
metabolism, which vary according as the oxygen supply is ample or
insufficient for the needs of the cells. In the former case activity results
in the production of carbon dioxide, in the latter of lactic acid, and perhaps
other substances. Both these are acid substances and their production
will therefore raise the concentration of the hydrogen ions in the cells
where they are produced as well as in the blood. The nerve centres are
extremely sensitive to minute changes in the hydrion concentration either
in themselves or in the fluids surrounding them, and are thrown into activity
by excess of these ions and inhibited, or put to rest, by relative deficiency
1138
PHYSIOLOGY
of the ions. In their relation to H and OH ions respectively the
medullary centres have a sensibility five times as great as the spinal
centres. The condition of apnoea, which is associated not only with
cessation of respiratory movements but also with fall of blood pressure,
may be ascribed to relative increase in the OH ions or diminution in the
H ions.
Since the animal has developed a mechanism by means of which changes
in the reaction of the blood can be rapidly adjusted by varying the excre-
tion oi carbon dioxide, whilst the excretion of other acids is relatively sloW
carbon dioxide may be regarded as the normal respiratory hormone ; and
so far we may agree with Henderson in regarding carbon dioxide as maintain-
ing the activities of the various nerve centres at their normal level. But it is
the bydrion concentration which appears to be the essential factor, and the
acid substances produced during oxygen lack are equally efficacious, but not
Fia. 522. Normal tracing of diaphragm slip (Head's method).
so convenient. Thus their production is not a steady process like that of
carbon dioxide but, as Mathison pointed out, commences suddenly at a time
when the executive side of the nerve cell is feeling the effect of oxygen
starvation, so that the cell may be too much disorganised to respond to
stimulation. " The broad margin of safety protecting the organism against
paralysis of its cells by oxygen starvation is assured by the sensitiveness of
the medullary centres to hydrogen ion concentration and therefore to carbon
dioxide in common with other acids."
On the other hand, it must be remembered that excessive production of
hydrogen ions may finally result in a condition of paralysis, which in the
nervous centres is expressed by narcosis. These effects can be removed only
by a free supply of oxygen. The concentration at which these results occur
varies, as we have seen, in different parts of the nervous system and also in
different tissues. Thus on the heart a slight increase in H ion concentration
causes diminished tone, which may lead to dilatation and failure of this organ.
The same effect is produced on the unstriated muscle fibre of the blood
vessels. Since in the heart and blood vessels the reverse effect is produced
by increasing the OH ion concentration, it is evident that the fine of
' physiological ' neutrality, at which neither stimulation nor paralysis
results, must vary in different tissues.
REGULATION OF THE RESPIRATORY MOVEMENTS 1139
It is an interesting question whether the electrical excitation of nerves
may not be due to a similar alteration in the hydrion concentration at the
cathode which is the seat of stimulation. If this were so, all the activities
of protoplasm might be regarded as determined by the relative concentration
of the H and OH ions within the cells or in the medium surrounding the cells.
THE REFLEX NERVOUS REGULATION OF RESPIRATION
Although the specific sensibility of the respiratory centre to C0 2 is the
most important factor in determining the depth and rhythm of the respiratory
movements, these movements and the condition of the respiratory centre
itself are modified in a large degree by impulses arriving at the centre along
both vagi. Through other sensory nerves of the body the respiratory
movements can be altered 'reflexly, but it is only through the vagi that a con-
tinuous stream of impulses passes to the centre under normal circumstances,
so that every respiratory movement is modified by these impulses.
In studying the nervous mechanism of respiration, it is necessaiy to have some
accurate method of recording the respiratory movements. They may be registered by
means of a tambour applied to the chest, communicating with another tambour provided
with a lever, which is arranged to write on a blackened surface; or a side tube to a
cannula in the trachea may be connected with the registering tambour. In the first
case movements of the thorax are registered ; in the second changes of intra-pulmonary
pressure. These methods are obviously useless when it is wished to study the effects
of artificial distension or collapse of the lungs. In this instance we may use the method
described by Head. In the rabbit a slip of the diaphragm on either side of the ensiform
cartilage is so disposed that the end of it may be freed and attached by a thread to a
lever without injury to its blood- or nerve-supply. It is found that this slip contracts
synchronously with the rest of the diaphragm, so that it serves as a sample of the
diaphragm, the contractions of which may be recorded uninfluenced by passive move-
ments of the chest wall or artificial increase of intra-pulmonary pressure.
If, while the respiratory movements are being recorded in one of the
a line-mentioned ways, both vagi be divided, 1 a marked change in the
respirator}' rhythm is at once seen. The first effect is an increased
inspiratory tonus, but this rapidly disappears, and the respiratory move-
ments become less frequent and are increased in amplitude. If now the
central end of one of the vagi be stimulated with an interrupted current, the
inspiration may be quickened or, as is more commonly the case, the in-
spiratory movements may be increased at the expense of the expiratory so
that finally a condition of inspiratory standstill is produced, and the slip of
the diaphragm enters into prolonged contraction.
1 The division of the vagi is best effected by putting them on a hooked copper wire,
of which the upper end is inserted in a freezing-mixture. In this way complete func-
tional division of the nerves is obtained without any excitation. If the nerves be cut,
a certain amount of stimulation takes place in consequence of the closure of the demarca-
tion current produced by the cross-section.
1140
PHYSIOLOGY
With a very weak stimulus it is sometimes possible to produce augmenta-
tion of the expiratory movements or rather inhibition of the inspiratory, and
this is the invariable result of passage of
a constant current through the vagus in
an ascending direction. This effect may be
more strikingly brought about by stimu-
lation of the central end of the superior
laryngeal nerve, which produces first an
inhibition of inspiration, so that the re-
spiratory muscles come to a standstill in
the position of expiration, and then a
forcible contraction of the expiratory mus-
cles. This illustration of the presence of
expiratory fibres in the superior laryngeal
nerve is not confined to laboratory experi-
ence, but is constantly occurring in every-
day life. The superior laryngeal nerve
supplies sensory fibres to the mucous
membrane of the glottis, and we know
that the slightest irritatiou of these fibres
— the presence of a crumb or a particle of
mucus— causes forcible expiratory spasms,
with spasmodic closure of the glottis, which
we term a cough. 1
So we see that the vagus nerve con-
tains two kinds of afferent fibres, or at
any rate afferent fibres with two distinct
functions. Stimulation of the one kind
stops inspiration and produces expiration ; stimulation of the other stops
expiration and produces inspiration. Since section of both vagi causes
slowing of respiration, impulses which exert some influence on the re-
spiratory centre and quicken respiration must travel up the vagi from the
lungs. The respiratory movements cause an alternate distension and con-
traction of the lungs, and it has long been thought that it is these changes
in the volume of the lungs which start the accelerating impulses that travel
up the vagus nerves. To test the truth of this hypothesis it is necessary
to study the two phases of respiration separately; that is, to see first the
result on the ' respiratory impulses of distension of the lungs, and secondly
the result of a sudden collapse or a contraction caused by sucking air out
of the lungs. The effects of distension or collapse of the lung may be shown
by simply closing the trachea at the end of inspiration or of expiration. The
results of such an experiment are shown in Fig. 523.
1 It must not be imagined that the fibres of the superior laryngeal nerves are con-
cerned in the reflex maintenance of the normal respiratory rhythm. They are cited here
merely because the result of their stimulation resembles that which would be caused
by stimulation of the analogous expiratory fibres which rim in the trunk of the vagus
from the lungs to the respiratory centre.
Fig. 523. Effects of distension and
collapse of lung. Both curves are
described by a lever attached to a
slip of the diaphragm of a rabbit.
A contraction of the diaphragm
(inspiration) raises the lever; dur-
ing relaxation of the diaphragm
the lever falls.
In A, the trachea is closed at x,
the height of inspiration ; a pause
follows, during which the lever
gradually sinks until an inspiration
(a very powerful one) sets in.
In B, the trachea is closed at the
end of expiration, x; there follow
powerful inspirations. (Foster.)
REGULATION OF THE RESPIRATORY MOVEMENTS 1141
A still more marked effect is produced if the kings, by means of a tube
in the trackea, be artificially inflated or if air be sucked out of them. The
inflation produces an instantaneous and complete relaxation of the dia-
phragm (Fig. 524) which by clamping the tracheal tube may be prolonged
for several seconds, while sucking air out of the lungs causes a tonic contrac-
tion of the diaphragm (Fig. 525). Somewhat similar results may be obtained
by repeatedly inflating or deflating the lungs (positive and negative ventila-
tion). The effects here are complicated by the fact that one is dealing in
both cases with alternating movements of the lungs, viz : — expansion and
contraction, both of which will have an influence on the respiratory centre.
Pos. ventilation
Fio* 524. Positive ventilation. (Head.)
Under the influence of positive ventilation, the inspiratory contractions of the
diaphragm become less and less till they disappear completely.
>■<■'„'. ventil >i urn
FlG. 525. Negative ventilation. (Head.)
At a negative ventilation was commenced. The expiratory relaxation of the
diaphragm is seen to become more and more incomplete, until it finally enters into
continued contraction.
Moreover repeated forcible inflation of the lungs increases the ventilation
of the pulmonary alveoli, thus lowering the normal carbon dioxide tension
of the lungs. As a result of repeated ventilation we may obtain a condition
of respiratory standstill. In this condition however, as we shall see later,
the determining factor is rather chemical than mechanical.
These inhibitory and augmentor effects of changes in the volume of
the lung must also result from the normal movements of these organs in
respiration. Let us consider, for instance, what will happen if the influence
of the two vagi could be suddenly thrown in after these nerves have been
divided. (This experiment can, in fact, be realised more or less completely
if the functional division of the vagi be effected by cooling or by ether
narcosis.) The animal would be breathing slowly and deeply. If at the
beginning of an inspiration the vagi became functional, the expansion of the
lungs caused by the inspiratory movement would send inhibitory impulses
1142
PHYSIOLOGY
up to the vagus centre, which would stop the movement of inspiration.
The movement of expiration would then begin, and the collapse of the lungs
thereby produced would itself send impulses up the vagi which would tend
to excite an inspiratory movement. Both inspiration and expiration would
therefore be shortened, and the successive movements would follow one
another at a shorter interval than if the vagi were not functional. In this
way, under normal circumstances, the rhythm of the respiratory centre
must be determined reflexly through the agency of the vagi, while the chief
factor in determining the total pulmonary ventilation is, as we have seen,
the carbon dioxide tension ot the blood.
R T Lung
artif resp app.
L T Lun
Fig. 526. Diagram to illustrate Head's experiment on the effect of collapse of the
lung. R.c, respiratory centre; R.v, L.v, right and left vagi.
In the foregoing account we have spoken of the expiratory and inspiratory effects
of the vagus as if they were of equal importance. It seems probable however that the
inhibitory or expiratory impulses started by the inspiratory movement, the only or
the more active part of normal respiration, play a more prominent part in the regulation
of respiration than do the inspiratory impulses ; and one observer (Gad) goes so far as
to deny altogether the existence of two kinds of respiratory fibres in the vagus. Accord-
ing to Gad, the vagus, as regards the respiratory centre, is a purely inhibitory nerve.
Hence the primary effect of dividing both vagi is an increased inspiratory tone. This
view at first seems paradoxical, in that it explains the final slowing of respiration after
section of the vagi as due to the cutting off of previous inhibitory impulses. But inhi-
bition in all tissues has a twofold effect. Although the immediate effect is diminution
of activity, yet the diminished disintegration necessarily associated with lowered
activity means an increase of the anabolic at the expense of the catabolic processes of
the tissues. In this way we explained the diminished excitability occurring in a nerve
at the anode of a constant current, and it will be remembered that the secondary result
of anelectroronus was increased irritability and consequent excitation at break of the
constant current. The same sort of process must occur in the respiratory centre. A
continued restraint of its rhythmic activity must lead to a heaping up of its irritable
material, so that the final result is a state of hyperexcitability in which the centre, so to
speak, boils over on the slightest provocation.
In this condition a cutting off of the inhibitory impulses must at first increase the
REGULATION OF THE RESPIRATORY MOVEMENTS 1143
activity of the centre, leading to the' increased inspiratory tonus already described.
But unchecked by any reigning impulses, the centre enters upon a career of spendthrift
activity. Each inspiratory contraction is maximal, but the centre, exhausted by the
effort, has to wait a considerable time before it can accumulate sufficient energy for
the next; hence the final result of section of both vagi is deepening and slowing of
respiration.
Although Gad has rendered great service in emphasising the importance of the
inhibitory or expiratory impulses which ascend the vagi, there is no doubt that he went
too far in denying the existence of inspiratory fibres in the vagus. This is shown by the
following experiment of Head. According to Gad's view, collapse of both lungs implies
simply a removal of the normal inhibitory impulses ascending the vagi, and is therefore
equivalent to division of these two nerves. If in the rabbit the left vagus be divided, a
tube can be introduced into the left bronchus, and artificial respiration can be performed
by alternate inflation and collapse of the left lung, without in any way affecting the
respiratory centre, all connections with the latter being destroyed (v. Pig. 526). Mean-
while the animal carries out normal respiratory movements, which can be recorded by the
diaphragm slip method. While the slip is contracting regularly, the right pleura is
Fn;. 527. Effect of 10'6 per cent. C0 2 in a mixture containing 233 per cent. 0„ on a
rabbit with both vagi divided. The gas was administered between the arrows.
Zero line of blood pressure is 32 mm. below bottom of tracing. Compare this
Figure with Fig. 518, p. 1131. (F. H. Scott.)
opened and the right lung allowed to collapse. The effect of this collapse, carried up by
the right vagus to the centre, is an extreme contraction of the diaphragm, and since the
onset of asphyxia is prevented by the artificial respiration carried out on the left lung,
the tonic standstill of the diaphragm may last over a minute. In this case therefore
the effect of collapse of one lung is enormously greater than that produced by section
of both vagi, showing that the effect is due, not to abolition of the ordinary tonic inhibi-
tory stimuli, but to excitation of special inspiratory fibres in the vagus by the collapse
of the lung.
By means of the string galvanometer it is possible to show definitely that a collapse
of the lungs does set up a nervous impulse travelling up the vagus nerves. This impulse
must be inspiratory in character, so that there is no reason to deny the existence of both
kinds of fibres in these nerves. The effect of electrical stimulation, especially with an
ascending constant current, is also strong evidence in the same direction.
After division of both vagi the total pulmonary ventilation does not as
a rule undergo any marked changes, and in the absence of anaesthesia the
aeration of the blood may be carried out almost, if not quite, as well as in
the intact animal. The importance of the vagus action for the organism is
shown however if we put an increased strain on the respiratory mechanism,
as for instance by increasing the percentage of carbon dioxide in the air
breathed. In the intact animal this procedure leads first to increased depth
and later to increased frequency of respiration, the total ventilation being
1144
PHYSIOLOGY
thereby augmented to such an extent as to'keep the alveolar tension of carbon
dioxide almost constant. If the same percentage of carbon dioxide be
administered to an animal after section of both vagi, the effect is deepening
of respiration but not quickening (Fig. 527). Each inspiratory movement
however is already considerable so that the margin by which increase of
pulmonary ventilation is possible, by increase of depth of respiration alone,
is not so great as in a normal animal. Moreover, since no quickening of
respiration takes place, the increased ventilation rapidly becomes inadequate
for the maintenance of the normal alveolar carbon dioxide tension. In the
following Table the total amounts of pulmonary ventilation, obtained on
administration of mixtures containing carbon dioxide to a rabbit before
and after section of the vagi, are compared.
Rabbit, 3 kilos.
Respiration with air ....
„ 4-2 per cent. C0 2
„ 8-6 per cent. C0 2
„ air ...
Respirations Vol. of each
per minute respiration
Total ventilation
per minute
e.c.
72 19
96 25
97 29
72 20
1368
2400
2813
1440
Vagi Divided
Respiration with air .
4-2 per cent. C0. 2
„ 8-6 per cent. CO,
45
45
42
29
34
38
1305
1530
1596
Whether we assume that the prevailing impulses travelling up the
vagi are purely inhibitory or are both inhibitory and augmentor, the re-
sultant effect, by reining in the activity of the centre, is to economise its
energy and the energy of the respiratory muscles. The result of the vagal
impulses will therefore be to increase the excitability of the respiratory
centre and make it more susceptible to slight changes in the carbon dioxide
tension of the blood, while maintaining a sufficient margin of energy to
meet the increased needs thrown on the respiratory mechanism by augmented
metabolism, such as occurs in violent muscular exercise.
The important part played by the vagi in the regulation of normal
respiration is shown still more strikingly if the respiratory centre in the
medulla be separated from the higher parts of the brain before the section
of the vagi is carried out. Separation of the medulla from the higher parts
of the brain, as by section just behind the corpora quadrigemina, has
practically no influence on the respiratory rhythm. If now both vagi be
divided, the normal respiratory movements cease entirely, being replaced
by a series of inspiratory spasms, each of which lasts several seconds and
is followed by a pause of half to one minute's duration. These spasms are
REGULATION OF THE RESPIRATORY MOVEMENTS 1145
inadequate for the proper oxygenation of the blood. They become gradually
less and less frequent, and in about half an hour the animal dies of asphyxia.
We must conclude 'therefore that the medullary respiratory centre "with
the help of the vagi is able to carry out normal respiratory movements. If
both vagi are cut. impulses arrive at the centre from the higher parts of the
brain, regulating its activity and enabling it to carry out modified but
sufficient respiratory movements. Removed from both these sources of
afferent impulses, the centre discharges only a series of spasms which are
totally inadequate for the renewal of the blood gases, so that the animal
dies.
We may summarise these results as follows :
Respiratory centre with vagi — normal respiration.
Respiratory centre with brain — modified respiration.
Respiratory centre alone — inadequate spasmodic contractions of
respiratory muscles, and death of animal.
The nature of the supplemental action of the mid-brain on the medullary respiratory
centre has not yet been made out. It is apparently not dependent on afferent impulses
arriving at the brain, since section of no cranial nerve affects in any way the activity of
the centres. Certain observers have described ' accessory respiratory centres ' in the
mid-brain, in the region of the posterior corpora quadrigemina. Stimulation of this
part causes increase in the rate of inspiratory movements and finally tonic spasm of the
diaphragm. Expiratory effects have been produced by stimulation of the anterior
corpora quadrigemina, and it would seem that a section has to pass through or behind
these bodies in order to produce the results, already described, of cutting off the higher
centres from the medulla oblongata after division of the vagi. Other localised spots in
the brain from which effects on respiration have been obtained are the inner wall of the
optic thalamus and the root of the olfactory tract. Further experiments are necessary
before we can regard any of these centres as normally involved in the maintenance or
regulation of the respiratory movements.
APNCEA. If artificial respiration be maintained so as to produce a
somewhat greater ventilation than is effected by the normal respiratory
movements of the animal, a standstill of respiration is brought about. This
condition is called apnoea. The first explanation of this standstill was that
it was due to over-oxygenation of the blood. The fact that it could be
produced by artificial ventilation with inert gases, such as hydrogen and
nitrogen, as well as the discovery of the inhibitory influence of distension
of the lungs on the respiratory centre, led Head to ascribe it to the summation
of a series of inhibitory stimuli. In these experiments however the fact
was forgotten that forced ventilation of the lungs with air or any inert gases
will reduce the carbon dioxide tension in the blood circulating round the
pulmonary alveoli and therefore round the respiratory centre. A respiratory
pause will thus ensue and last until the increasing accumulation of carbon
dioxide in the blood raises its tension to the normal height, at which the
respiratory centre is 'set,' so to speak, to respond by a respiratory dis-
charge. If the carbon dioxide content of inspired air be increased to about
4-5 per cent., it is impossible to produce an apnoeic pause, however rapidly
the respiratory movements be carried out. It would seem therefore that
1146 PHYSIOLOGY
ordinary apnoea is entirely due to deficiency of carbon dioxide tension in the
respiratory centre, and that although the vagus nerve is inhibitory of
respiration, it is impossible to summate a series of vagus inhibitions by
artificial respiration so as to produce a lasting cessation of respiratory
movements. The chief use of the vagi in respiration seems to be for main-
taining, by frequent inhibitions, the excitability of the respiratory centre
at a maximum.
Miesoher distinguished three types of apnoea, viz. :
Apncea vera, due to the washing out of C0 2 from the lungs, and the consequent
reduction of the tension of this gas in the blood.
Apncea vagi, a stoppage of respiration caused by stimulation of the inhibitory fibres
of the vagi. This stoppage is limited, as we have seen, to the immediate duration of .
the stimulus (whether electric or produced by distension of the lungs).
Apncea spuria. Stoppage of respiration by stimulation of other nervous or sensory
surfaces. Thus when a duck plunges there is immediate stoppage of respiration,
which may last four or five minutes if the animal remains so long under water. The
same stoppage may be produced by pouring water on the beak.
Fig. 528. Forced breathing of air for two minutes, followed by apnrea for two
minutes, and periodic (' Cheyne-Stokes ') breathing for about five minutes.
At A, sample of alveolar air contained 2 , 11 "44 per cent.; C0 2 , 5'58 per cent.
Second sample at b, 2 , 13 - 55 per cent. ; C0 2 , 5 - 57 per cent. (Douglas and
Haldane.)
• CHEYNE-STOKES ' BREATHING
If a man desires to hold his breath for some time he takes first a series
of deep breaths. The result is to dimmish the carbon dioxide tension in the
alveoli and therefore to take away the need and the desire to breathe until
the carbon dioxide tension rises to normal as the result of the continued
formation of carbon dioxide. By continuing forced respiratory movements
for a minute or two, the carbon dioxide tension both in the alveoli and in
the blood may be brought down to a very considerable extent. As a result
there is a prolonged period of apncea. During this period of cessation of
respirations however, the oxygen is being used up, and the tension of this
gas in the alveoli may fall to such an extent that the respiratory centre is
excited by lack of oxygen before the carbon dioxide tension in the alveoli
has risen to its normal value. As a result of the excitation by oxygen lack, a
few breaths are taken, the carbon dioxide tension is once more lowered
tod the stimulation due to the oxygen lack disappears. There is thus
again a cessation of respiration. These periods of cessation alternate with
periods of respiration, so that we get a condition of periodic breathing which
is spoken of as Cheyne-Stokes respiration. During the period of apncea
REGULATION OF THE RESPIRATORY MOVEMENTS 1147
resulting on forced breathing, the great diminution of oxygen tension in
the alveoli is shown by the fact that the subject of the experiment becomes
blue, and may indeed lose consciousness. There are at the same time
rhythmic changes in the blood pressure, which rises towards the ends of
the periods of the apncea. falling during the periods of respiration. The first
respiration after forced breathing is due to oxygen lack. The period of
apncea may therefore be considerably prolonged, if the onset of oxygen
lack be postponed b) 7 increasing the tension of this gas in the alveoli at
the commencement of the apnceic period. By forcibly breathing for a
period of two minutes in an atmosphere of oxygen, men have succeeded in
holding their breath for as long a period as eight minutes (Vernon).
' Cheyne-Stokes ' breathing is almost invariably observed as one of the effects of
exposure to high altitudes, and is then especially marked during sleep. It is often present
when the activity of the respiratory centre is depressed, as in cases of uraemia or per-
nicious ansemia. Under these circumstances *it may be temporarily' removed by
administering cither oxygen or carbon dioxide (in small percentage) to the patient.
The oxygen improves the condition of the centre: the carbon dioxide acts as an added
Stimulus and louses its activity.
SECTION IV
THE EFFECTS ON RESPIRATION OF CHANGES IN
THE AIR BREATHED
We have already seen that a moderate increase in the carbon dioxide per-
centage of the air breathed (e.g. np to 4 per cent.) causes a proportional
increase in the ventilation of the lungs, so as to maintain the tension of this
gas in the alveoli at the normal level. The same effect is observed whether
the mixture breathed contains 18 or 50 per cent, of oxygen, showing that the
slight diminution in oxygen content caused by mixing the air with carbon
dioxide is in no way responsible for the effect. If the amount of carbon
dioxide be increased to 12 or 15 per cent., it becomes almost impossible to
continue the inhalation owing to the spasm of the glottis produced by the
irritant effects of the carbon dioxide. If these high percentages be ad-
ministered to an animal by a tracheal tube, violent dyspnoea is produced
which gradually diminishes, and the animal passes into a condition of
narcosis in which the respiratory movements become less, and the oxygena-
tion of the blood is ineffectively carried out even hi the presence of excess of
oxygen. The administration of larger percentages, such as 30 or 40 per
cent., causes rapid death and failure of the circulation and respiration, often
preceded by convulsions. Coincident with the increased respiration brought
about by moderate percentages of carbon dioxide, there is a rise of blood
pressure determined by vascular constriction. With high percentages of
carbon dioxide the curve of blood pressure obtained resembles that produced
by lack of oxygen.
Oxygen itself exercises no excitatory effects on the respiratory move-
ments. At the normal atmospheric pressure the tension of oxygen in the
alveoli is about 107 mm. Hg., a pressure which, as we have seen, is amply
sufficient to saturate the haemoglobin passing through the vessels of the
lungs. Since the depth and frequency of respiration are determined by the
carbon dioxide tension in the alveoli, no alteration in respiration will be
produced by increasing the tension of oxygen in the air breathed above its
normal amount. The respiratory movements in an atmosphere of pure
oxygen will, in the normal individual, remain unchanged.
This statement is true only for the healthy individual. If from failure of the heart
and circulation, from diminished oxygen tension, or from severe loss of blood, the oxy-
1148
EFFECTS ON RESPIRATION OF CHANGES IN AIR 1149
genation of the blood is already insufficient, marked amelioration of the symptoms may
be produced by inhalation of pure oxygen. Especially is this noticeable where there is
failure of the heart. In these cases the heart, already affected, is unable to keep up an
adequate circulation and to supply itself with sufficient oxygen. A vicious circle is thus
established in which the heart tends to get steadily worse. By administration of oxygen
an adequate supply of this gas to the heart muscle is assured; the heart beat therefore
becomes more effective and the whole circulation is improved and therewith the provision
of oxygen to the body at large.
If a warm-blooded animal be immersed in a chamber and submitted to
pure oxygen at a pressure of four atmospheres, it dies as rapidly as if it were
in an atmosphere of pure nitrogen. At this pressure the oxidative processes
of the body as well as the intake of oxygen into the lungs are absolutely
abolished. It is interesting to note that certain other oxidative phenomena,
e. g. the spontaneous oxidation of phosphorus, also cease if the tension of the
oxygen be sufficiently high. Exposure of an animal over a considerable
period of time to a pressure of oxygen of two atmospheres may, as Haldane
and Lorrain Smith have shown, set up severe inflammation of the lungs and
thereby cause death indirectly.
CHANGES IN TENSION OF OXYGEN. If a man breathe a mixture of
nitrogen and oxygen free from carbon dioxide, and the oxygen be gradually
diminished, no feeling of 'want of breath' may be experienced. With
percentages of oxygen as low as 12 per cent, there may be no change in the
respiration, even though the deficient oxygenation of the blood may be
shown by the blueness of the lips and face. If the oxygen be reduced still
lower, a certain amount of hyperpncea may occur, but in many cases the
individual experimented on may not feel any ill effects until he suddenly
becomes unconscious from lack of oxygen. If fresh oxygen be not supplied
this unconsciousness may be followed by convulsive movements and death.
If the administration of low percentages of oxygen, e. g. about 10 to 12
per cent, of an atmosphere, be continued for some time, the subject of the
experiment may suffer considerable discomfort. One of the signs of oxygen
lack is often severe headache, and this may be accompanied by vomiting or
nausea and by a feeling of discomfort in the precordial region. Many
experiments have been made both on animals and man by submitting them
to a lowered atmospheric pressure in chambers specially built for the
purpose. The limit to which the pressure may be reduced varies in different
individuals, the variations being determined by the type of respiratory
movement of the individual in question, since on the depth of respiration
depends the relation between the tension of oxygen in the alveoli and that
in the inspired air. The lowest limit at which life is possible corresponds
to an oxygen tension in the alveoli of 27 to 30 mm. Hg.
MOUNTAIN SICKNESS. The phenomena, just described as ensuing on
exposure of an animal to low oxygen tensions in a respiratory chamber for
some length of time, are exactly similar to those which are regarded as
characteristic of mountain sickness. The following Table shows the
diminution in the atmospheric pressuie at varying heights above the level
of the sea :
1150
PHYSIOLOGY
Height above sea level,
Barometer
Per cent, of au
in metres
mm. Hg.
atmosphere
760
100
1000
670
88
2000
593
78
3000
524
69
4000
463
61
5000
410
54
6000
357
47
7000
320
42
At a height of 5000 metres the pressure of the air is reduced to little
over half an atmosphere, and the oxygen tension is therefore only about
11 per cent, of an atmosphere. It must be remembered that in most cases
of mountain sickness, in addition to this absolute oxygen lack, there is
increased consumption of oxygen, owing to the muscular exercise involved
in climbing. Moreover a greater volume of the alveolar air must consist
of Carbon dioxide if the tension of this gas is to be kept constant (cp. Fig. 519,
p. 1132). Since, diminished oxygen tension, within fairly wide limits, does
not excite any corresponding increase in the respiratory movements, there
must, at these heights, be an actual diminution in the oxygen tension in the
alveoli. This diminution in tension is shown by a series of observations
carried out by Zuntz on himself and fellow- workers at different localities.
It may be noted that on Monte Rosa, where the oxygen tension in the
alveoli was reduced to between 37 and 57 mm. Hg., as against the normal 101
to 105 nun. Hg., all the members of the party were suffering from mountain
sickness.
Height
Ub'ivr sra
level,
in metres
2
tension
of air
Alveolar O-j tensior
A
B
c
D
1
F
104
Berlin .
54
157
105
101
105
103
Brienz .
500
148
84-5
94
80
88
86
91
Brienzer Rothorn .
2130
121
68
66
64
62
66
71
Col d'Olen .
2900
110
57
—
—
60
68
68
Monte Rosa .
4560
89
—
46
49
61
37
57
As a result of the oxygen starvation there is inadequate supply of this
gas to the heart, so that the circulation tends to fail, especially on making
the slightest muscular movements. At the same time the oxygen starva-
tion of the brain produces failure of judgment and inability to carry out or to
co-ordinate muscular movements properly. The symptoms as a rule do not
increase until death results, so that, although there is an oxygen starvation
of the body, there must be some means by which the respiration is modified
so as to obtain a sufficiency of this gas for the lowered requirements of the
body. That the adaptation is effective is shown by the fact that most
EFFECTS ON RESPIRATION OF CHANGES IN AIR 1151
individuals, if they remain at a height, gradually recover from the mountain
sickness and may finally be able to carry out muscular movements with
almost as great precision and force as they could previously on the plains.
The mechanism, by which increased ventilation of the lungs is attained, is
that already mentioned (p. 1136) in dealing with the effects of lack of oxygen,
namely, the production of acid substances in the body. The respiratory
centreisthus stimulated by these acid substances, especially lactic acid, as well
as by the carbon dioxide tension of the blood ; and the joint action of these
two substances (which probably co-operate in raising the hydrion concen-
tration of the blood) determines the marked increase in the lung ventilation.
Since the carbon dioxide is no longer the sole factor responsible for the
ventilation, the tension of this gas in the alveolar air is diminished.
ACAPNIA. This diminution of carbon dioxide tension in the blood and alveolar air
has been regarded by Mosso as the essential factor in the causation of mountain sickness
and has been designated acapnia. It may be absent however in the most marked
cases of mountain sickness, where the respiratory centre has failed to respond to the
additional acid stimulation ; and it may be present to a marked degree in individuals
who are experiencing none of the ill-effects of this "disorder.
Another important means of rapid adaptation is by means of the circula-
tion. This is noticeable even in the case of persons, sitting quietly in a
gas chamber, who are subjected to gradually lower pressures. It is evident
that a deficient passage of oxygen from the alveoli to the blood may, so
far as the tissues and heart are concerned, be accommodated for by in-
creasing the rapidity of the circulation, and this is effected by a quickening
pulse rate. The following Table shows the changes in the pulse rate
caused by exposure to varying pressures in a gas chamber :
Pui.se in Gas Chamber
Pres*nre PuLse
720 64
650 72
424 84
This quickening of the pulse is to be observed also in the trained mountain
soldier, in individuals in whom there is no lowering of the alveolar carbon
dioxide tension, so that apparently in such cases the whole adaptation to
altered conditions is by means of the circulation. In cases where adaptation
fails, it is in the circulation that the failure is most marked, so that the
symptoms of severe mountain sickness resemble closely those produced by
rapid heart failure. Dilated heart, cyanosis, muscular weakness, vomiting,
mental torpor, inco-ordination, delirium, may all be observed in both cases.
The disturbance of the central nervous system is shown by the almost
invariable occurrence at great heights of Cheyne-Stokes breathing.
If the animal is able to withstand the immediate effects of exposure to a
rarefied atmosphere, a process of adaptation comes into play which finally
fits him for discharging his functions normally even at the high altitude.
From the lack of sensibility of the respiratory centre to small changes in
1152
PHYSIOLOGY
oxygen tension, any diminution in oxygen tension must cause a corresponding
diminution in the degree of saturation of the haemoglobin of the blood. This
change in oxygen saturation is at once felt by the blood-forming organs.
As an immediate effect of change to a region of low atmospheric pressure,
there is a relative increase in the blood corpuscles due to a concentration
of the blood and a diminution of its plasma. Simultaneously however
the blood-forming organs enter into a condition of increased activity, so
that after a stay of four or five weeks' duration at a height, both corpuscles
and haemoglobin are considerably increased in total amount. The following
Table shows the average number of red corpuscles contained in one cubic
millimetre of blood from the inhabitants of regions at varying altitudes :
Height above sea
level,
in metres
Red corpuscles
Cliristiauia .
4,970,000
Zurich
412
5,752,000
Davos .
1560
6,551,000
Arosa .
1800
7,000,000
Cordilleras .
4392
8,000,000
There is of course a limit to the power of adaptation, a limit which varies
in different individuals. Thus for some men it is impossible to stay any
length of time in the high settlements in the Andes, while others, after two
or three weeks' discomfort, become perfectly inured to their new conditions.
It seems doubtful however whether any of the present race of men could
become adapted to permanent residence at a height over 5000 metres, and
though for a certain length of time by bringing into play the reserve
mechanisms already described, they may raise themselves to a height
considerably above 5000 metres, it seems questionable whether without
artificial means, such as the inhalation of oxygen, it will be possible for
any man to attain the highest points on the earth's surface, or at any rate
to arrive there by his own unaided efforts. The highest summits in the
Himalayas have a height approaching that attained by Tissandier with his
two companions in his famous balloon ascent, namely, 8600 metres. In this
ascent, although oxygen inhalation was used (somewhat ineffectively), two
of the party succumbed.
The stimulating effect of oxygen lack on the blood-forming organs
extends also to the muscular system, so that one of the effects of a residence
in high altitudes is increased assimilation of nitrogen. For a time the
nitrogen output is less than the nitrogen intake, and there is an actual
building up of new tissue. The condition of the individual is similar to that
of a growing animal, a fact which may explain the admirable results of a
mountain holiday. We can hardly imagine that the power of the organism
to react in this way was evolved through generations of mountain climbing.
We are probably here making use of an adaptation which has been evolved
for the purpose of retrieving loss of blood by haemorrhage, such as must have
EFFECTS ON RESPIRATION OF CHANGES IN AIR 1153
been of continual occurrence in the struggle of individual against individual,
which has resulted in the survival of the animals of to-day.
ALTERATIONS IN THE NITROGEN TENSION. The nitrogen of the
atmosphere plays no part in the metabolism of the body, and must be
regarded as a purely inert gas. It is a matter of indifference whether under
normal atmospheric pressure we breathe an atmosphere of pure oxygen or
one containing one-fifth part of this gas diluted with four-fifths of nitrogen.
The very inertness of nitrogen may be of danger to the body under certain
conditions. If a man or an animal be exposed, as in a diving-bell, to a
pressure of three, four, or six atmospheres, the respiratory functions are
unaffected, but the amount of nitrogen dissolved in the fluids of the body
is increased in direct proportion to the pressure. If the pressure be now
suddenly released, the nitrogen, which cannot be used up by the tissues, is
given off from the body fluids in the form of bubbles, just as carbonic acid
gas rises in bubbles from soda-water when the pressure is removed by with-
drawing the cork from the bottle. These bubbles occurring in all the
capillaries obstruct the flow of blood, and therefore, if the evolution of gas is
sufficiently large, the animal dies in convulsions. A similar evolution of gas
may occur in the spinal cord, giving rise to destruction of the cord and
paralysis (' divers' palsy '). In order to prevent this sudden evolution of
gas it is necessary that the change from the high pressure to the ordinary
atmospheric pressure should be carried out gradually, so as to give the
blood plasma, supersaturated with nitrogen, time to get rid of its excess of
nitrogen without the formation of bubbles.
OTHER GASES. Hydrogen and methane are, like nitrogen, indifferent
gases. They may be respired if mixed with 20 per cent, of oxygen, and
either of the gases may be used instead of nitrogen to dilute the oxygen that
we breathe, without harm or inconvenience.
Carbon monoxide is rapidly poisonous by its action on the red corpuscles.
It combines with haemoglobin, forming CO-haemoglobin, a compound which
is much more stable than oxyhaemoglobin. The blood is therefore deprived
of its oxygen carrier, and the animal dies of asphyxia. We have seen
however that the displacement of oxygen by CO is not absolute, but only
relative. Hence, although the avidity of CO for haemoglobin is 140 times
that of oxygen, we can convert the CO back into oxyheemoglobin by in-
creasing the mass influence of the oxygen. This may be done by giving the
poisoned animal pure oxygen to breathe, or even oxygen under pressure.
In pure oxygen at a pressure of two atmospheres an animal can breathe and
live, even though the whole of its haemoglobin is converted into CO-haemo-
globin, the amount of oxygen which is simply dissolved by the blood plasma
being sufficient at this pressure for the respiratory needs of the animal
(Haldane).
Other gases which have special poisonous properties are hydrocyanic
acid, sulphuretted hydrogen, phosphuretted hydrogen (PH 3 ), arseniuretted
hydrogen, etc.
IRRESPIRABLE GASES are those which are so irritating that they
73
1154 PHYSIOLOGY
produce spasm of the glottis. Such are ammonia, chlorine, sulphur dioxide,
nitric oxide, and many others.
VENTILATION
A point of practical importance is the securing to each individual of
sufficient fresh air, so that he may always have a plentiful supply of oxygen,
and may be relieved of his waste products. It is found that a dwelling-room
becomes unpleasant and stuffy when the percentage amount of C0 2 has
reached 0-1 per cent. This stuffiness is supposed to be due to organic
exhalations from the skin, lungs, and alimentary canal, some of which have
a poisonous effect, giving rise to headache and sleepiness. Since these
cannot be measured, it is taken as a cardinal rule in ventilation that the
amount of C0 2 should never rise above 0-1 per cent.
Since in questions of ventilation we have generally to deal with trades in
which the metric measure is not used, it may be convenient to give the data
as to carbon dioxide production and the amount of air required in cubic feet.
An adult man gives off about 0-6 cubic foot of C0 2 every hour Hence
in that time he raises the amount of C0 2 in 1000 cubic feet of air from "04
per cent, (the normal amount in the atmosphere) to 0-1 per cent. He must
therefore be supplied with 2000 cubic feet of air per hour in order to keep
the amount of C0 2 down to -07 per cent.
(Ordinary air contains -04 per cent. CO,, therefore 2000 cubic feet would
contain 0-8 cubic foot C0 2 , which with the 0-6 cubic foot given off by the
man would be 1-4, which is -07 per cent.)
In order that the air may be easily renewed without giving rise to exces-
sive draught, a certain amount of cubic space must be allotted to each man.
Each adult should have in a room 1000 cubic feet of space, and be supplied
every hour with 2000 to 3000 cubic feet of air.
SECTION V
THE MECHANISMS OF OXIDATION IN THE TISSUES
The blond in its passage through the capillaries takes up carbon dioxide
from the tissues, giving oxygen to the latter in exchange. This interchange
is determined by the differences in tension of the gases on the two sides of
the capillary wall. Whereas the tension of oxygen in the plasma varies
from loo mm. Hg. in arterial to 25 mm. Hg. in venous blood, the tension of
oxygen in the tissues outside the vessels in most cases approaches 0, as is
shown by Ehrlich's methylene-blue experiment described on p. 111-1. On
the other hand, the tension of carbon dioxide in the tissues, as judged from
the examination of fluids such as bile and urine, varies from 6 to 10 per cent,
of an atmosphere. The continuous flow of oxygen into, and of carbon
dioxide away from, the tissues points to the constant occurrence of oxidative
changes in the tissue cells. By the blood the tissues receive not only oxygen
but also foodstuffs, namely, proteins or amino-acids, fats, and sugars,
derived from the alimentary canal or, in starvation, from other parts of the
body. The activity of the tissues, whether motor as in the case of muscle,
or secretory as in the case of glands, is derived from the energy set free in
the partial or complete oxidation of these foodstuffs, which occurs within
the active cells themselves. A study of the mechanism of oxidation in the
body involves therefore a consideration of the processes which take place
within the confines of each cell. The question is by no means an easy one.
Although we speak of the 'burning' of foodstuffs, and compare the pro-
in the body to those which take place in combustion, e.g. in a candle-
flame, the analog} is after all a very rough one. In the first place, the food-
stuffs, even after absorption, belong to a class of substances which have been
led as dysoxidisabh, since they present no tendency to combine with
ordinary atmospheric oxygen. Thus sugars, proteins, or fats, if guarded
from microbial infection, may be kept for years exposed to the air without
irgoing any change. It is true that in certain eases, e.g. in alkaline
solutions of sugar, we may obtain slow absorption of oxygen and oxidation
of the sugar. The changes are however slight and limited in extent. All
these foodstuffs are susceptible of combustion if raised to a sufficiently high
temperature, but in the animal body the processes of oxidation have to go
.mi at a temperature varying between 5° and 40° C, and in a solution which
is almost neutral in reaction. It might be said that at the temperature of
an ordinary flame th.' combustion of tin' foodstuffs is immediate and
Complete, whereas in the body the oxidation takes place by stages. Recent
1155
1156 PHYSIOLOGY
research has tended to remove this point of distinction by pointing out that
even in an explosion of a mixture of methane and oxygen there is a series
of intermediary products, and that the whole process, if analysed, is made
up of stages in which hydrolysis and oxidation go on simultaneously, so
that on this account it is difficult to cause a combination, even of hydrogen
and oxygen, in the complete absence of any watery vapour. The oxidations
in the body are strictly limited both in nature and extent. The mere fact
that a substance is readily or even spontaneously oxidisable (autoxidisable)
affords no guarantee that it will undergo oxidation in the animal body.
Thus phosphorus or pyrogallol taken by the mouth can be recovered in an
unoxidised form from the urine. Carbon monoxide is excreted unchanged.
There must apparently be some definite relationship between the molecular
structure of the foodstuffs and that of the cells of the body. Thus ordinary
proteins, which undergo complete oxidation, contain large quantities of
leucine. This substance is laevorotatory and is designated Meucine. If
Meucine be administered to rabbits it is completely oxidised. If its isomer
(Z-leucine, resembling it in every particular, so far as we can see, except in
its relation to polarised light, be administered to a rabbit, the greater part
of the substance passes through the body unchanged. In the same way
there are sixteen sugars of the formula C 6 H 12 6 . Of these only four, namely,
glucose, fructose, galactose, and mannose, can be oxidised in the animal
body. Other sugars differing in so slight a degree from these four as,
e. g., Z-glucose or Z-fructose, camiot be utilised by the body. Not only must
there be a distinct relation between the structure of the cell and the molecular
structure of the foodstuff supplied, but there must be different mechanisms
for the foodstuffs and their derivatives. Thus in certain cases of disease
or of abnormal nutrition the body may lose absolutely the power of utilising,
%. e. of oxidising, a whole class of foodstuffs. In severe diabetes, or after
destruction of the pancreas, glucose behaves in the body as if it were one
of the artificial unassimilable sugars. The normal oxidation of fats probably
proceeds by stages in each of which two atoms of carbon undergo oxidation.
The penultimate stage in the oxidation of any of the higher fatty acids is
thus oxvbutyric acid. In complete carbohydrate starvation, for some
reason or other the body loses its power of completing this last stage, so
that the oxybutyric acid undergoes no further oxidation, and either accumu-
lates in the body or is excreted combined with bases in the urine. In the
normal individual tyrosine, whether administered separately or in combina-
tion in protein, is completely oxidised, the benzene ring being broken up.
In certain rare cases of disordered metabolism the patient, who is otherwise
apparently well, is unable to effect the total oxidation of tyrosine, which
is therefore excreted as homogentisic acid, after undergoing only the first
stage of its normal transformation in the body. These various mechanisms
are adjusted in each case to the functional activity of the cell and are limited
therefore, not by the supply of oxygen or of foodstuff to be oxidised, but
by the necessities of the cell, i. e. the adaptations induced in it by its environ-
mental changes. In discussing the mechanism of intracellular oxidation
THE MECHANISM OF OXIDATION IN THE TISSUES 1157
we have therefore to consider in the first place how the dysoxidisable
foodstuffs are made to combine with the molecular oxygen diffusing into
the cells from the blood in the capillaries; in the second place the means
by which these oxidative changes are strictly limited in accordance with
the necessities of the cell ; and finally the nature of the specific oxidative
mechanisms for each land of foodstuff and for the various stages in the
oxidation of each foodstuff.
We are very far as yet from being able to give a definite answer to any
one of these questions. Even in the first problem, namely, the oxidation
of dysoxidisable substances, we have to confine ourselves almost exclusively
to speculation on possibilities. Although these substances will not unite
with the oxygen of the air, in which the combining activities of the oxygen
are satisfied by the combmation of two atoms to form one molecule, many
of them readily undergo oxidation if subjected to the action of ' atomic '
oxygen or ' active ' oxygen ; and it has been suggested that the problem of
the oxidation of the body is really bound up with the question as to the
mode of activation of the molecular oxygen derived from the oxyhemoglobin.
Thus Hoppe-Seyler suggested that the activation of oxygen might occur
through the intermediation of reducing substances. He supposed that
reducing substances might be formed under the influence of ferments by
hydrolytic splitting of the foodstuffs. A reducing substance is one that
has sufficient affinity for oxygen at the ordinary temperature to tear asunder
the bonds which unite two atoms of oxygen to form one molecule, and to
combine with one or both of the atoms so set free. If the combination is
with only one atom, the other atom of the oxygen molecule is set free in an
active form, and is therefore able to oxidise dysoxidisable substances which
may be present. Thus, when a mixture of ammonia and pyrogallol is
exposed to the atmosphere, the oxygen is rapidly absorbed, forming a dark
brown solution, pyrogallol being therefore a reducing agent. But at the
same time a certain amount of the ammonia (a dysoxidisable substance)
undergoes oxidation with the formation of nitrite. In the slow spontaneous
oxidation of phosphorus, which occurs on exposing this substance to the
atmosphere, ozone, 2 0, is always formed. As a type of the formation of
reducing substances in hydrolytic fermentations may be adduced the butyric,
acid fermentation, in which sugar is converted into butyric acid, carbonic
acid, and hydrogen :
C 6 H 12 6 = C 4 H 8 2 + 2C0 2 + 2H 2 .
The hydrogen produced in this process would act as a reducing agent.
There is no doubt that reducing substances are formed under normal circum-
stances in the tissues, as is shown by the methylene-blue experiment, and
it is possible that such reducing substances may aid in activating oxygen
and in bringing about certain oxidative processes. The activation of
oxygen would however not explain the specific character of the various
oxidations, and the accurate gradation of these oxidations to the necessities
of the cell. In many cases reducing substances may themselves act as
1158 PHYSIOLOGY
carriers of oxygen, and their action be more or less specific. If for instance
glucose be boiled with an ammoniacal solut inn of cupric hydrate, it undergoes
oxidation, the cupric being reduced to cuprous hydrate. Cuprous hydrate
in ammoniacal solution is a reducing .substance; it absorbs oxygen from
the air and is reconverted to cupric hydrate. A small amount of cupric
hydrate therefore, in the presence of air, may act as a carrier of oxygen from
the air to the sugar and may thus oxidise indefinitely large quantities of
sugar. In the same way, if indigo in alkaline solution be boiled with sugar,
it undergoes reduction with the formation of a colourless compound. On
shaking the decolorised solution with air, it absorbs oxygen with the reproduc-
tion of indigo, so that here again minute quantities of indigo blue may servo
to oxidise large, quantities of glucose. The mode of action of these oxygen
carriers resembles closely that of the various ferments which effect the
transference of water from the menstruum to the substrate {e.g. trypsin.
invertase, etc.). These hydrolytic ferments differ from ordinary hydrolytic
agents, such as dilute acids, in the specific character of their action. Trypsin,
for instance, will hydrolyse polypeptides of a type corresponding to those
which make up the ordinary food products, but is powerless to hydrolyse
polypeptides composed of artificial amino-acids which are the optical isomers
of those occurring in the body. It seems possible that we might explain the
specific oxidations occurring in the cell by assuming the presence of a number
of ferments, oxidases, which would act as oxygen carriers, but each of which
would be able to act only on a certain type of foodstuff or on molecules
of a given configuration.
Such oxidative ferments have been described as existing in many animal
and vegetable extracts. Many species of fungus contain a ferment known
as tyrosinase, from the fact that, when it is added to solutions of tyrosine in
the presence of air, the tyrosine is oxidised with the formation of a brown
pigment. The same ferment is able to effect the oxidation of other aromatic
substances. The browning of a freshly cut potato or apple on exposure to
the air is similarly ascribed to the oxidation of a chromogen by the oxygen
of the air, through the intermediation of an oxidase present in the cells.
If benzyl alcohol or salicyl aldehyde be added to a suspension of liver cells
in blood, and air be allowed to bubble through the mixture for some time,
the alcohol or aldehyde is oxidised to the corresponding acid. In the same
way xanthine (C 5 H 4 N 4 2 ) added to a mixture of spleen pulp and defibrinated
I ili K >d is converted into uric acid (C 5 H 4 N 4 3 ).
Bach and Chodat have shown that in many cases the oxidase is not a
single substance, but a mixture of an organic peroxide with a ferment,
peroxidase, which has the property of splitting off atomic, i. e. active oxygen,
from the peroxide. These peroxidases have the same effect on hydrogen
peroxide. They must be distinguished from the ferment caialase, which is
present in almost all animal and vegetable tissues, and which effects a rapid
decomposition of hydrogen peroxide with the formation of molecular
oxygen :
2H 2 2 = 2H 2 + 2 .
THE MECHANISM OF OXIDATION IN THE TISSUES 1159
In the case of a peroxidase the equation would be represented :
H 2 0„ = H 2 + O'.
In chemistry many reactions are known in which the part of a peroxidase
is played by an inorganic catalyst. Thus hydrogen peroxide effects a slow
oxidation of many organic substances, but the oxidation is enormously
hastened- if to the mixture be added a trace of a ferrous salt (Fenton's
reaction). The same part may be played by salts of manganese, and it is
interesting to note that manganese forms an essential constituent of the
peroxidase laccase, which is present in many plants and is responsible for
the formation of the Japanese lacquer. It effects a specific oxidation of
hydroquinone and pyrogallol. The oxidations carried out by the use of
hydrogen peroxide, with or without a catalyst or peroxidase, present a
close resemblance to the oxidations' occurring in the animal body. Thus
Dakin has shown that saturated fatty acids, even the higher members of
the series, are gradually oxidised if warmed gently with hydrogen peroxide
in the presence of ammonia; and the course of the reaction resembles in
many respects that which, on other grounds, we have assumed to take place
in the normal metabolism of the body.
We have no evidence that hydrogen peroxide is formed at any time in
the body, though there is some reason to assume its formation in the process
of carbon assimilation -in the green leaf. If we adopt the views of Bach and
Chodat, we must assume that every animal cell contains organic peroxides
as well as peroxidases, or else that it can under physiological conditions
form these substances. Since there is also evidence of the presence of
reducing substances in the cells, we may conveniently assume, with Ehrlich.
that distinct side-chains of the protoplasmic molecule have specific affinities
for oxygen. When all these affinities are saturated, these side-chains will
act as peroxides, parting with their oxygen with extreme ease, whereas
when the greater number are imsaturated, the resultant effect will be that
of a reducing agent. The same protoplasmic molecule may therefore,
according to its state of saturation with oxygen, act either as an oxidising
or reducing agent, and can effect, probably through the intermediation of
specifically adapted oxidases, the oxidation of the various foodstuffs stored
up as the paraplasm of the cell. Since the oxidative processes are deter-
mined, not by the presence of oxygen but by the functional activities of
the tissue, welmust assume that the peroxidases are not preformed in the
cell, but exist as precursors, zymogens, from which they can be set free in
accordance with the necessities of the cell.
It is probable that many of the foodstuffs or other proximate con-
stituents are not directly accessible to oxidation, and that the first step in
their utilisation is a process of cleavage or hydrolysis, which itself involves
the presence of specific ferments. Thus, so far as we can tell, the amino-acids
undergo deamination before oxidation. They can thus be stored up in the
cell either free or in the form of protein, and present no point of attack to
oxygen until the process of hydrolysis and deamination has taken place. This
course of events is certainly true for some of the members of the purine group.
CHAPTEE XVII
RENAL EXCRETION
SECTION I
THE COMPOSITION AND CHARACTERS OF THE URINE
The main product of the oxidation of carbon, namely, carbon dioxide, is
discharged by the lungs and to a slight extent by the skin. Water, taken
as such with the food but also derived to a slight extent from the oxidation
of hydrogen, is got rid of by the lungs, skin, and kidneys. The salts of
heavy metals, e.g. iron, bismuth, mercury, when administered, are excreted
for the most part by the alimentary canal. A certain proportion of the
pigmentary waste products of the body, derived from the breakdown of the
blood pigment, is also eliminated with the faeces. With these exceptions,
practically all the waste products resulting from metabolism are excreted
in the urine by the kidneys. We have thus to seek in the composition of
this fluid the last chapter in the metabolic history of a large number of the
constituents of the body. Since moreover the kidneys may excrete almost
any substance which circulates through their blood vessels, many of the
intermediate metabolites may be found in minute quantities in the urine
and may be isolated by working up large quantities of this fluid.
Under pathological conditions these metabolites may appear in the
urine in larger amounts and serve then as an index to some inter-
ference with the later stages in the metabolism of fats, carbohydrates, or
proteins.
The composition of the urine must therefore be a variable one, according
to the activity of the body, the quantity and nature of the food taken, and
the relative amount of water escaping by the kidneys, lungs, and skin
respectively. But just as we can describe a normal diet for an adult man
of average weight, so we can describe an average composition for the urine.
The history of the urinary constituents has been given for the most part in
the chapter dealing with the metabolism of the proximate constituents of
the food. It will be useful however to enumerate in this chapter the various
constituents of the urine and to summarise their properties, preparation,
and normal significance.
The urine of man is a clear yellow fluid which froths when shaken. On
standing, a cloud of mucus is deposited, consisting of a very small amount
of nucleoprotein derived from the epithelial lining of the bladder and urinary
1160
THE COMPOSITION AND CHARACTERS OF THE URINE 1161
passages. In concentrated urine a deposit occurs on cooling. This deposit
dissolves when the urine is warmed, and consists of urates. Under
certain circumstances urine is turbid as it is passed, but in this case the
turbidity generally consists of earthy phosphates and is not cleared up
by heating.
The colour of the urine varies with its concentration. After severe
sweating the amount of water excreted by the kidneys is small, and the
urine is therefore concentrated and of high colour. After copious draughts
of liquid the urine may be very pale and dilute.
Ordinary urine has an aromatic odour, but this varies largely with the
character of the food. Many food substances give characteristic odours,
which may depend on alterations undergone by them in their passage
through the body.
The specific gravity of the urine is proportional to its concentration.
Normally it is 1016 to 1020, though it may rise as high as 1040 or sink as
low as 1002.
The molecular concentration of the urine is almost always greater than
that of the blood. Its osmotic pressure may be measured by determining
the depression of freezing-point. The A of urine normally varies between
0-87 and 2-71 (A of blood = 0-56). After copious draughts of water the
depression of freezing-point in the urine may be less than that of serum, and
may be as small as 0-25.
The reaction of urine is generally described as acid. It is acid to litmus
and to phenolphthalein. This is due to the fact that neutral constituents
of the food give rise to acid end-products in metabolism. The sulphur of
proteins is converted into sulphuric acid and the phosphorus of lecithin
into phosphoric acid. . There is thus a predominance of acid radicals over
bases in ordinary urine. This statement however applies only to man and
to carnivora. In the food of herbivora there is a predominance of alkaline
bases. Vegetable acids, e.g. tartaric, malic, and citric acids, midergo
oxidation to carbonic acid in the body, so that their bases leave the body as
alkaline carbonates. The urine of such animals therefore contains- an
excess of alkaline carbonates, and is alkaline in reaction and froths on the
addition of an acid. If a herbivorous animal be starved so that it has to
live on its own tissues, it becomes for the time, so to speak, carnivorous,
and its urine becomes clear and acid. The urine of man can be made
alkaline by the ingestion of large quantities of vegetables or fruits. Under
such circumstances the urine as passed is generally turbid from the presence
of precipitated earthy phosphates. In determining the reaction of urine it
is usual to adhere to one indicator, e.g. phenolphthalein, and to give the
acidity in terms of decinormal acid, naming the indicator used. The
acidity (i. e. the concentration of H ions) can also be determined by the
electrical method. In this way Hoeber found the acidity of human urine
to vary between 4*7 x 10 ~ 7 and 100 X 10 ~ 7 . On the average it was
49 X 10 _7 in the litre.
THE AVERAGE COMPOSITION OF THE URINE. Several analyses
1162 PHYSIOLOGY
of the day's urine under varying conditions of food have already been given
(v. pp. 802, 823). The following may be taken as a fair average for an adult
man on ordinary mixed diet :
Total amount of urine = 1500 c.c.
This contains about 60 grm. of solids, of which 25 grm. are inorganic and
35 grm. organic. These are distributed as follows :
Inorganic Constituents
Organic Constituents
Sodium chloride .
15'0 grm.
Urea .....
300 grm
Sulphuric acid
. 2-5 „
Uric acid ....
0-7 „
Phosphoric acid .
. 2-5 „
Creatinine ....
1-0 „
Potassium .
• 3-3 „
Hippuric acid
0-7 „
Ammonia
. 0-7 „
Other substances
2-6 „
Magnesia
• 0-5 „
Lime ....
• 0-3 „
Other substances .
• 0-2 „
The quantity of urine will naturally vary with the water leaving the
body by the kidneys, and therefore according to the habit of the individual
with regard to the intake of fluids and with his occupation. Thus after
copious sweating the total amount may fall to 400 c.c. in the course of the
day. If large draughts of liquid be taken it may rise to 3000 c.c. or more.
There are also diurnal variations in the amount secreted, depending probably
largely on the circulation through the kidneys. The secretion is at a mini-
mum during sleep, and especially between 2 and 4 o'clock in the morning.
It is at its maximum during the first hours after rising, and increases generally
after each meal. Muscular exercise may also give an initial increase owing
to the greater vigour of the circulation associated with exercise. If the
exercise is severe enough to cause sweating or is carried to fatigue, there
may be a consequent diminution in the amount of urine secreted.
THE INORGANIC CONSTITUENTS OF THE URINE
(«) ACID RADICALS. The chlorides of the urine are derived almost
entirely from the chlorides of the food. Though essential constituents of
the body fluids, it does not seem that the chlorides enter into organic com-
bination with the constituents of the cells. The output of chlorides, which
normally varies from 6 to 10 grm. CI. in the course of the day, will therefore
depend on the amount of chlorides taken in with the food. If these be
withdrawn altogether, the chlorides may almost disappear from the urine,
although the circulating blood contains practically the same amount of
chlorides as in the normal individual, showing that the body retains the
chlorides necessary for the proper carrying out of the vital processes as
long as possible. Chlorides may also disappear from the urine temporarily
under various pathological conditions. This is especially marked in cases
of acute pneumonia.
THE COMPOSITION AND CHARACTERS OF THE URINE 1163
Sulphates. The salts of sulphuric acid do not form an important con-
stituent of the food. The sulphates of the urine are derived almost entirely
from the oxidation of the sulphur of the protein molecule. The output of
sulphates is therefore, like that of urea, an index of protein metabolism.
As the nitrogen of the urine goes up, so the sulphates will increase. On an
average diet the ratio of urinary nitrogen to S0 3 is about 5:1; though,
owing to the varying content of different proteins in the sulphur, this ratio
will alter with the nature of the protein taken as food. The daily
output of sulphuric acid varies between 1-5 and 3 grm. S0 3 . The greater
part of the sulphate is present as sulphates of the alkaline metals. A certain
proportion, about 10 per cent., is present in the form of conjugated or
ethereal sulphates, chiefly indoxyl sulphate. A small proportion of the
sulphur excreted in the urine is present in unoxidised form as so-called neutral
sulphur. The neutral sulphur probably includes a number of different
bodies, among which sulphocyanates and cystine are the best known.
Inorganic sulphates can be precipitated from the urine by the addition of hydro-
chloric acid and barium chloride. On filtering off this precipitate, the filtrate contains
the ethereal sulphates. On boiling, the hydrochloric acid decomposes these substances,
setting free sulphuric acid, which combines with the excess of barium present and is
precipitated as barium sulphate. This second precipitate therefore, when weighed,
gives the amount of ethereal sulphates present. To determine the neutral sulphur, the
fluid after the separation of both kinds of sulphates is treated with sodium carbonate
to precipitate the barium, filtered, and the filtrate evaporated to dryness. The residue
is then ignited with potassium nitrate, cooled, and extracted with water. By this
treatment all the neutral sulphur is converted into sulphates, which can be thrown down
from the solution with barium chloride and weighed in the usual way.
Phosphates. The phosphates of the urine are derived partly from the
phosphates of the food, partly from the oxidation of the organic phosphorus-
containing constituents of the food and of the tissues, e.g. nuclein, lecithin,
etc. If the food contains much calcium and magnesium, the amount of
phosphates excreted by the urine diminishes, since these substances are
excreted with the faeces as calcium and magnesium phosphates. According
to the diet therefore, phosphoric acid may be excreted either by the intestine
or by the kidneys. The amount of phosphates, reckoned as P»0 5 , excreted
in the course of the day may vary between 1 and 5 grm. In the urine the
phosphates exist as a mixture of the mono- and di-sodium phosphates, the
relative amounts of the two varying with the acidity of the urine. If the
urine is neutral or alkaline there is very often a deposit of earthy phosphates.
Whether this deposit is present or not. depends on the varying solubility of
the different calcium and magnesium phosphates. Thus the mono-mag-
nesium phosphate MgH 4 (P0 4 ) 2 and the mono-calcium phosphate CaH 4 (P0 4 ) 2
are both fairly soluble in water, and their solubility is increased by the
presence of neutral salts. With increased acidity of the urine the proportion
of the two bases present in these forms is diminished. The di-magnesium
and di-calcium phosphates are only slightly soluble in water, and the latter
would, if present in the urine, be deposited. One may indeed, in slightly
acid urine, find the di-calcium phosphate occasionally present as a crystalline
1164 PHYSIOLOGY
deposit. On heating the urine the di-calcium phosphate breaks up into a
mono-calcium phosphate and a tri-calcium phosphate, while the acidity of
the urine is increased by the solution of the mono-calcium phosphate.
Alkaline urine will always present a precipitate of tri-calcium phosphate
Ca 3 (P0 4 ) 2 . When normal urine is allowed to stand, the urea is converted
by the presence of micro-organisms into ammonium carbonate, and the
urine becomes alkaline. Under such conditions we may often find a
crystalline precipitate of ammonium magnesium phosphate, NH 4 MgP0 4 ,
the so-called ' triple phosphate.'
(b) THE BASES OF THE URINE. The bases include potash, soda,
ammonia, magnesia, and lime.
The amount of potash excreted in twenty-four hours varies between 1-9
and 3-2 grm., according to the nature of the food taken. With a large meat
diet, which contains considerable quantities of potassium, the output of
this base is increased. In fasting there is also an increase in the output of
potash, owing to the utilisation of the tissues of the body which themselves
are rich in potassium.
The amount of sodium excreted in the twenty-four hours varies on
the average between 4 and 5 grm., but depends very largely on the quantity
of sodium chloride taken with the diet.
The alkaline earths, lime and magnesia, are invariably present in urine,
but in much smaller quantities than the alkaline metals. The average
amount of these two bases in the twenty-four hours varies in each case
between 0-1 and 0-2 grm. Their output by the urine is no criterion of
the amount taken in with the food or absorbed from the intestines, since
both these bases may be re-excreted into the gut and appear as insoluble
phosphates in the faeces.
Normal human urine always contains a small amount of ammonia, on
an average between 0*6 and 0-8 grm. in the twenty-four hours. As we
have already seen, in dealing with the origin of urea in the body, the quantity
of ammonia in the urine is an index to the excess of acids over bases which
have to be excreted by this fluid. Thus it is easily possible to increase the
proportional amount of ammonia in the urine by the administration of
mineral acids. An increase of the proportion of nitrogen excreted as
ammonia, apart from the administration of acids with the food, is an
important indication of the formation of abnormal acid substances in meta-
bolism. Thus in diabetes, when the last stages of fat oxidation are in
default, so that the oxy-fatty acids, /?-oxybutyric and aceto-acetic acids,
accumulate in the body, there is always a considerable rise in the ammonia
of the urine.
It is usual to reckon iron among the bases which may be excreted by the
urine. The amount of this substance in the urine is extremely small, as a
rule less than 5 mg. in the day. It affords no clue to the iron metabolism
of the body, since the main channel of excretion of this substance is the
intestine.
THE COMPOSITION AND CHAEACTERS OF THE URINE 1165
ORGANIC CONSTITUENTS OF THE URINE
Almost all these constituents contain nitrogen, which in man is dis-
tributed anion" the various urinary constituents as follows :
Urea
Ammonia
Creatinine
Uric acid
85-90 per cent.
2-4
3
1-3
About 6 per cent, of the urinary nitrogen is in the form of other substances,
such as hippuric acid, pigments, etc.
UREA or CARBAMIDE, C0 \ N tt" can be
./OH
regarded as derived from
carbonic acid, CO^ ^^ by the replacement of each OH group by an NH 2
group. It is isomeric with ammonium cyanate, NH 4 CNO. If a solution
of potassium cyanate and ammonium chloride be warmed together and
evaporated, crystals -of urea may be
obtained in long colourless prisms
(Fig. 529) without any water of
crystallisation. It is soluble in water
and alcohol, and insoluble in ether.
Its solutions are neutral in reaction,
but it forms crystalline salts with
strong acids. Thus urea nitrate.
which is produced by treating strong
solutions of urea with concentrated
nitric acid, forms microscopic rhombic
plates which are extremely insoluble,
so that their formation may be used
as a test for urea (Fig. 530). With
oxalic acid urea solutions yield an
insoluble oxalate, also in typical
crystals. Urea when heated melts
at about 130° C. On further heating
it undergoes decomposition, giving
off ammonia and forming biuret, as
follows :
("Kg
co<^
co CO
(HO)C C— NHs
II II
N— C — N /
>C(OH)
Uric acid forms small rhombic crystals. The crystalline form varies
considerably in the presence of impurities. The different forms of uric
acid crystal which may occur in the urine are shown in the accompanying
figure (Fig. 532). It is extremely insoluble in pure water, one part of uric
acid requiring 39,000 parts of water at 18° C. for its solution. It is easily
soluble in concentrated sulphuric acid and alkalies.
It may be prepared from human urine or from guano, which consists almost entirely
uf urates. In order to prepare it from guano, this is dissolved with the aid of heat in
dilute sodium carbonate, filtered, and the filtrate treated with a few drops of concen-
trated hydrochloric acid and boiled. On allowing to cool, the uric acid crystallises out.
1168 PHYSIOLOGY
From urine uric acid may be obtained by adding one-fiftieth of its volume of concen-
trated hydrochloric acid and allowing to stand for two days. The uric acid is thrown
down in small dark red or brown crystals. They can be collected on a filter, dissolved
in alkali, decolorised by boiling with animal charcoal, and the pure acid thrown down
as before by means of hydrochloric acid.
A more convenient method of preparation from human urine is based on the fact
that ammonium urate is insoluble in concentrated solutions of ammonium chloride
(Hopkins). The urine is saturated with crystals of ammonium chloride and a few drops
of strong ammonia added. A gelatinous precipitate of ammonium urate is produced.
This is collected on a filter, washed off with a minimum amount of hot water into a
beaker, and a few drops of hydrochloric acid added. The mixture is boiled and then
allowed to cool, when the pure acid crystallises out.
TESTS FOR URIC ACID
(1) MUREXIDE TEST. If a small quantity of uric acid be treated with a little
strong nitric acid and the whole evaporated to dryness on the water-bath, an orange-
red residue is obtained, which on treatment with ammonia yields a fine purple colour.
If a drop of sodium hydrate be now added the purple changes to blue. Instead of nitric
acid, bromine water may be employed.
(2) SCHIFF'S TEST. If uric acid be dissolved in a little soda and a drop be placed
on filter paper previously moistened with silver nitrate, a yellow or brown spot is
produced.
(3) On boiling urie acid with Fehling's solution for some time, a yellowish precipitate
of cuprous hydrate is produced.
(4) An alkaline solution of uric acid on treatment with a few drops of a solution of
phosphomolybdic acid gives a dark blue precipitate with a metallic lustre, consisting
of microscopic prismatic crystals.
(5) With sodium hypobromite uric acid is decomposed, giving off about half of its
nitrogen as the free gas.
URATES. Of the four hydrogen atoms in uric acid, two can be replaced
by metallic radicals. Uric acid thus acts as a weak dibasic acid. It forms
three orders of salts, namely, the neutral urates, the bi-urates, and the
quadri-urates. The neutral urates, M' 2 U, are very unstable, and exist only
in the presence of caustic alkalies. They are decomposed even by the
carbonic acid of the atmosphere. The bi-urates, MHU, are the most stable
of the urates. They may be prepared by dissolving uric acid with the aid
of heat in weak solutions of the alkaline carbonates, from which they
separate, on cooling, in stellar crystals.
The quadri-urates have the formula H 2 U, MHU. They may be pre-
pared by boiling uric acid with dilute solutions of potassium acetate. On
cooling the mixture the quadri-urate separates as an amorphous precipitate
or in crystalline spheres. The quadri-urates are extremely unstable, and in
the presence of water are broken up into the bi-urates and free uric acid.
It is probable that under normal conditions the greater part of the uric acid
in the urine is present in the form of a quadri-urate (Roberts), and the so-
called lateritious deposit, the brick-red amorphous precipitate of urates
which occurs in concentrated urine on cooling, consists of these quadri-
urates. The exact condition of the urate however will depend on the
reaction of the urine. A bi-urate, with acid sodium phosphate, is decom-
posed with the formation of uric acid in the following way :
MHO + MH 2 P0 4 = H 2 U + M 2 HP0 4 .
THE COMPOSITION AND CHAKACTERS OF THE URINE 1169
Thus the quadri-urates present in the urine immediately after its secre-
tion will tend to undergo spontaneous decomposition into uric acid and the
bi-urate, and the latter itself may be decomposed with the formation of
uric acid and alkaline phosphate. We thus see that when the urine is acid,
i. e. when there is a predominance of acid phosphates, there will be a tendency
to the precipitation of uric acid in the urinary passages. If however the
di-sodium phosphate be in excess, the uric acid may be kept in solution as
the quadri-urate or even as the bi-urate.
The uric acid of the urine is derived almost entirely from the purine
metabolism of the body. The uric acid may be endogenous or exogenous,
i. e. may be derived from the breaking down of the nucleins of the cells or
by a direct transformation of the nucleins contained in the food. The
amount passed daily varies between 0-4 and 1 grin., according to the nature
of the diet. It is not absent from the urine even during complete starvation.
It is increased when foods are ingested rich in nucleins, such as liver or sweet-
breads, or in any other precursors of uric acid, e.g. hypoxanthine, such as
meat or meat extract. We have no evidence that the urinary uric acid
in the mammal is formed by synthesis, though this is the manner in which
the greater part of the uric acid excreted by birds and reptiles is
formed.
Small traces of purine bases also occur in urine, namely, xanthine, hypo-
xanthine, and adenine. When tea and coffee are taken the methyl-prxrines
may occur, namely, caffeine, theobromine, and their derivatives.
HIPPURIC ACID is a frequent, though not a constant, constituent of
human urine. It is derived from benzoic acid or from an aromatic sub-
stance which on oxidation can give rise to benzoic acid. In the kidneys
the benzoic acid is conjugated with glycine to form hippuric acid. The
amount of hippuric acid excreted in the day may vary between 0-1 and
1 grm. After a diet rich in fruit or vegetables its amount may rise to 2 grm.
It is present in considerable quantities in the urine of herbivora and may be
most easily prepared from horses' urine. Hippuric acid has the formula :
C 6 H 5 CO
I
HNCH 2 COOH
It can be obtained in niilk-white crystals (Fig. 533), which are only slightly
soluble in cold water, but easily soluble in alcohol, ether, and acetic acid.
It is insoluble in petroleum, ether, and benzol. On heating, it is broken up
into benzoic acid and glycine. On heating with concentrated nitric acid,
it forms nitro-benzol, which can be recognised by its characteristic smell of
bitter almonds.
In order to extract it from the urine, the urine is made alkaline with sodium car-
bonate, filtered, and the filtrate evaporated to a syrupy consistence. This is then treated
with alcohol, the alcohol evaporated, and the residue repeatedly extracted with acetic
ether. The acetic ether is collected, evaporated to dryness, and the residue repeatedly
extracted with petroleum ether to remove the benzoic acid and fat. What is left behind
is hippuric acid, which can be purified by recrystallisation from alcohol or ether.
74
1170
PHYSIOLOGY
AMINO-ACIDS. According to Levene and van Slyke, amino-acids are
always present in the urine, and contribute about 1-5 per cent, of the total
nitrogen.
OTHER AROMATIC SUBSTANCES. The chief of these is the so-called
' urinary indican ' or potassium-indoxyl-sulphate. This is derived from the
indol produced in the intestines from the tryptophane contained in the
proteins of the food, the change being effected by the influence of the micro-
organisms of putrefaction. The amount of the conjugated sulphates in
the urine is thus an index of the extent
of putrefaction in the intestines. In
dogs, when the intestine has been
disinfected by repeated doses of calo-
mel, the conjugated sulphates entirely
disappear from the urine. Urinary
indican has the formula :
■COSO,OK
Fig. 533. Hippuric acid. (Funke.)
HC C CH
C N
H H
In addition to the tests for conjugated sulphates mentioned earlier, the indoxyl-
sulphate can be detected by various methods dependent on the formation of indigo blue.
The urine is treated with an equal volume of concentrated hydrochloric acid and
several cubic centimetres of chloroform added. A solution of chloride of lime is
now added drop by drop, shaking after the addition of each drop. A bluo colour is
produced which is extracted by the chloroform. It is important not to add too much
chloride of lime, as otherwise the blue colour first produced will be destroyed by further
oxidation.
THE URINARY PIGMENTS. Normal urine gives no definite absorption
bands. It owes its colour to the presence of a yellow pigment, urochrome.
In order to separate urochrome from urine, the urine is saturated with
crystals of ammonium sulphate and filtered. The filtrate, which still
contains nearly all the colour of the urine, is shaken up with alcohol, which
withdraws the greater part of the colouring matter. On concentrating the
alcohohc solution and pouring it into an equal volume of ether, an amor-
phous brown precipitate falls, which is the urochrome. Urochrome, on
treatment with aldehyde, yields a pigment closely similar to urobilin. On
the other hand, urobilin, treated with potassium permanganate, is converted
into a substance practically identical with urochrome. Urochrome must
therefore be derived from the same source as urobilin.
Urobilin is rarely present in normal urine, and then only in the form of
a chromogen, from which it must be set free by acidification. In certain
pathological conditions, especially in cirrhosis of the fiver, urobilin may
occur in the urine in considerable quantities.
THE COMPOSITION AND CHAKACTERS OF THE URINE 1171
In order to extract urobilin from such urine, the urates are first precipitated by
saturation with ammonium chloride, and the filtrate is then saturated with ammonium
sulphate and a drop of sulphuric acid added. On shaking the fluid up with a mixture
of two parts ether and one part chloroform, the urobilin is taken up by the latter.
The ether-chloroform solution is separated off and shaken up with caustic soda, when
the urobilin passes entirely into the alkaline solution.
Urobilin in solution gives a single absorption band between the lines b
and F, i. e. at the junction of the green and blue of the spectrum. On
treating with zinc chloride and ammonia its solutions show a well-marked
green fluorescence. The urobilin of urine is identical with stereo bilin, the
colouring matter of the foeces. It is formed from bile when the latter
decomposes, and is probably produced in the intestines by the action of
mioro-organisms on bile pigment.
Other pigments which may occur in urine are uroerythrin and hsema-
toporphyrin. Uroerythrin gives the pink colour to urate sediments. Its
chemical nature is not known. It is distinguished by the fact that on
addition of caustic soda the pink colour is changed to green. On suspending
the red-coloured precipitate of urates in hot water and extracting with amyl
alcohol, a pink solution is obtained which shows two absorption bands in
the green part of the spectrum.
Hwmatoporphyrin is present only in very small amounts in normal urine,
but under certain conditions, especially after poisoning with sulphonal, it
may occur in such large quantities as to give the urine a deep purple colour.
Under these circumstances it is found in the form of alkaline haematopor-
phyrin and gives the characteristic absorption bands of the latter.
Urorosein is a name that has been given to a pigment which is formed
when the urine is treated with strong mineral acids. It is probably an
indol derivative. It gives a single absorption band between the lines
d and e.
ABNORMAL CONSTITUENTS OF THE URINE
A very large number of substances occur in the urine in minute traces and may be
detected when large quantities of this fluid are worked up at one time. Most of the
so-called pathological constituents may be detected in this way in normal urine. It is
only when they occur in easily detectable amounts that their presence becomes of any
significance.
COAGULABLE PROTEIN. Under normal circumstances urine is free from any
coagulable protein except the small traces of mucinous material, nucleoprotein, which
uivts the cloudiness to the urine. If the kidney cells are damaged by disease, by inter-
ference with their blood supply, or by circulating poisons, the glomerular epithelium
permits the passage of a certain amount of the proteins of the plasma. Under these
circumstances, if small pieces of the kidney be plunged into boiling water, the coagulated
protein may be seen in Bowman's capsule. The presence of coagulable protein (generally
spoken of as albumin) in the mine is significant of the pathological conditions of the
kidney associated with Bright's disease. A small trace will generally be found in
the urine which is passed shortly after taking muscular exercise. Under this condition
the presence of albumin in the urine has no pathognomonic significance.
The proteins generally found are identical with those of the blood plasma and con-
sist of serum albumin and serum globulin. Their presence in the mine may be detected
by the precipitate produced on boiling. In carrying out this test a few cubic centi-
1172
PHYSIOLOGY
Fig. 534. Glucosazone.
metres of saturated salt solution should be added and one or two drops of dilute acetic
acid. A more delicate test is that known as Heller's. Some strong nitric acid is placed
in a test-tube and the urine is poured carefully down the side of the tube so as to form a
layer on the surface of the nitric acid. If albumin be present, a white ring is formed at
the junction of the two liquids.
SUGAR. Normal urine eon-
tains about one part per thousand
of glucose. In diabetes the power
of assimilating carbohydrates is
diminished or destroyed. The
amount of sugar in the blood is
increased, and sugar appears in
large quantities in the urine. The
sugar is practically always glucose.
Lactose may occur in the urine of
mil sing women even in conditions
of health. Since both these sugars
will reduce Fehling's solution, it
becomes important to be able to
distinguish between them.
The following tests are used for
the detection of abnormal amounts
of sugar in the urine :
(1) FEHLING'S TEST. The
urine is boiled with Fehling's solu-
tion (an alkaline solution of copper
sulphate to which Rochelle salt has been added to keep the cupric hydrate in solution).
Under the action of glucose or lactose the cupric hydrate is reduced to an insoluble
cuprous hydrate, which forms a yellow or red precipitate.
(2) The phenylhydrazine test may be carried out as follows : 2 c.c. of 50 per cent.
acetic acid, saturated with sodium
acetate, and two drops of phenylhy-
drazine are added to 5 c.c. of urine.
The mixture is evaporated down to
3 c.c, rapidly cooled, and again
warmed in a water bath. It is then
allowed to cool slowly. Crystals of
the corresponding ozazone separate
out in the hot liquid in the case of
glucosazone, on cooling in the case
of lactosazone (Figs. 534, 535).
(3) The most convenient way of
distinguishing between lactose and
glucose is by adding a little yeast
to the urine in an inverted trst-
tube. If glucose be the sugar pre-
sent, it is fermented by the yeast
with the production of carbon
dioxide, which collects at the top
of the test-tube.
In rare circumstances fructose or
laevulose, or pentose may be found
in the urine. The former would be detected by the fact that it rotates polarised
light to the left instead of the right, as is the case with glucose.
GLYCURONIC ACID. Small traces of this are present in normal urine. It occurs
as a conjugated acid after the administration of various substances, e. g. camphor and
chloral. If phenol, indol, or scatol be given to an animal which is receiving very little
Fig. 535. Lactosazone. (Plimmek.)
THE COMPOSITION AND CHARACTERS OF THE URINE 1173
protein in its diet, these substances will leave the body conjugated, not with sulphuric
acid, but with glycuronic acid. Glycuronic acid may be regarded as the first product
of oxidation of glucose, having the formula :
COOH
I
(CHOH) 4
I
CHO
It reduces Fehling's solution and rotates the plane of polarised light to the left.
OXY-FATTY ACIDS AND ACETONE. These substances occur often associated
with glucose in diabetes, especially towards the end of the disease. They represent the
penultimate stages in the oxidation of the fats. Their relation to one another is seen
from their formula" :
CHo CHg • CHg
I I
CO
I
CH,
CHOH
1
CO
i
CH 2
I
CH 2
1
COOH
Oxybutyric acid
COOH
Aceto-acetic acid
They may also occur in any condition of carbohydrate starvation, relative or absolute.
Thus they are found in the urine during absolute starvation as well as in individuals
on a pure fat and protein diet. The two acids are generally found associated in the
urine.
The presence of aceto-acetic acid may be detected as follows :
(1) To some urine add ferric chloride as long as a precipitate of ferric phosphate con-
tinues to form. Filter this off and to the filtrate add a few more drops of ferric chloride.
If the acid be present a claret colour is produced.
(2) On heating with dilute alkali, aceto-acetic acid is decomposed, with the pro-
duction of acetone. This may be detected by its odour or by distilling off a small
proportion of the fluid and testing the distillate in the following ways :
(a) On the addition of sodium hydrate and iodine and warming, iodoform is formed.
(6) Legal's test. A few drops of freshly prepared sodium nitroprusside solution is
added and the 7nixture rendered alkaline with sodium hydrate. A deep red colour is
formed. On acidifying with acetic acid this colour is changed to a reddish purple.
CYSTINE. This substance, which is a normal product of the hydrolysis of proteins,
is found as a constant constituent to the amount of half a gramme a day in the urine of
certain individuals. The condition of cystinuria represents, like alcaptonuria, an inborn
error of metabolism. It is found in the child and persists throughout life. In such
cases the cystine may give rise to urinary deposits or even to a urinary calculus.
HOMOGENTISIC ACID. This is an aromatic acid having the composition of
dioxyphenyl acetic acid. Its formula is as follows :
OH
/\
I I CH 2 .COOH
OH
It occurs as a constituent of the urine of certain individuals, who are said to be
affected with alcaptonuria. The urine of these cases is remarkable for its resistance to
putrefactive changes. It slowly darkens on exposure to the air, and on the addition of
alkali and shaking with air it becomes rapidly brown or black. It reduces Fehling's
solution, so that the presenco of sugar may be suspected. Such urine contains homogen-
1174
PHYSIOLOGY
tisic acid in a quantity of 3 to 6 grm. per day. The amount of the acid excreted varies
with the protein food taken. It seems that in these cases the power of the organism to
break up tyrosine and phenylalanine is entirely absent. If either of these substances be
administered by the mouth, it is converted almost quantitatively into homogentisic acid,
which appears in the urine. Individuals with alcaptonuria continue to secrete homo-
gentisic acid during starvation, so that the tyrosine and phenylalanine set free in the
course of tissue disintegration undergo the same fate as when they are derived from the
food. Alcaptonurics apparently suffer no ill effects as a result of their abnormal
metabolism. The tyrosine and phenylalanine can be absorbed and play their part
in building up the proteins of the tissues,
but the process or ferment is wanting which
is responsible for the further break-up
of the first product of their oxidation,
namely, homogentisic acid.
URINARY DEPOSITS
In addition to formed elements,
such as blood corpuscles, bacteria, or
pus cells, which may occur in abnor-
mal urine, the following deposits may
be found :
(a) In Acid Urine. (1) Amorphous urates occur generally as a brick-
red amorphous deposit thrown down as the urine cools. It is redissolved
on warming the urine, and consists generally of the quadri -urates. The
crystals. (Fbey
Fig. 537. Urinary deposit, containing uric
acid, sodium urate, and calcium oxalate.
Fio. 538. Deposit of ' triple ' phosphate
and ammonium urate. (Ftjnke.)
acid urate of sodium and of ammonium may occasionally occur in star-
shaped clusters of needles or as spherules with small crystals adhering to
them.
(2) Uric acid. Whetstone, dumb-bell, or sheaf -like aggregations of
crystals, generally deeply pigmented so as to resemble cayenne pepper
(Fig. 536).
(3) Calcium oxalate (Fig. 537). Colourless, transparent, highly refrac-
THE COMPOSITION AND CHARACTERS OF THE URINE 1175
Insoluble in acetic acid, soluble
The
five octahedral crystals (envelope-shaped),
in hydrochloric acid.
(4) Ammonium magnesium phosphates (in faintly acid urine),
crsytals have been compared to
knife-rests or coffin-lids (Fig. 538).
They are soluble in acetic acid.
(5) Calcium hydrogen phosphate.
CaHP0 4 . These are rare. They
form large prismatic crystals often
arranged in rosettes. Easily soluble
in dilute acetic acid. On adding a
solution of ammonium carbonate, the
crystals are eaten away and form an
amorphous deposit.
(6) Tyrosine, fine needles in star-
shaped bundles, and cystine, in
regular hexagonal plates, ma)'' occur
under very rare circumstances.
(b) In Alkaline Urine. (1) The commonest precipitate consists of
earthy phosphates, amorphous, easily soluble in dilute acetic acid.
(2) Ammonium magnesium phosphate or triple phosphate is common
in mine which has undergone ammoniacal fermentation.
(3) Acid ammonium urate (Fig. 539) may also occur in alkaline urine.
On treatment with HC1 it is dissolved and uric acid in crystals slowly
separates out.
Fig. 539. Ammonium urate.
QUANTITATIVE ESTIMATION OF THE CHIEF URINARY
CONSTITUENTS
It may be useful here to summarise the most trustworthy methods which are employed
for the estimation of the chief urinary constituents. 1
The TOTAL ' ACIDITY ' of the urine is measured by titrating it against decinormal
alkali in the presence cf an indicator, such as phenolphthalein. The indistinctness of
the end-point is due to the presence of calcium salts and ammonium salts. Folin there-
fore recommends that the titration be carried out in the presence of potassium oxalate,
which diminishes the error.
Method. To 25 c.c. urine add 15 to 20 grm. potassium oxalate and 1 to 2 drops of
phenolphthalein. Shake thoroughly for one or two minutes, and whilst the solution
is still cold from the effect of the oxalate, titrate with NaOH until a permanent pink
remains.
TOTAL NITROGEN. In all metabolic experiments, the determination of the total
nitrogen of the food, the mine, and the faces is indispensable. In each case Kjeldahl's
method is employed. This method depends on the fact that all the nitrogenous sub-
stances met with in the body, when heated for a considerable time with concentrated
sulphuric acid, undergo oxidation, the nitrogen being finally converted into ammonia.
On adding alkali to the mixture, the ammonia is set free from its combination with the
1 Fuller details will be found in Plimmer's Practical Physiological Chemistry, from
which most of the methods here given are taken.
L176 PHYSIOLOGY
sulphuric acid and can be distilled off and received into a vessel containing a known
amount of deeinormal acid. By titrating this acid after the operation we can determine
the quantity of ammonia which has been produced. To carry out this method 5 c.c.
of urine are heated with 20 c.c. sulphuric acid and a small quantity of copper sulphate
and potassium sulphate. The copper sulphate is to aid the oxidation of the organic
substances, the potassium sulphate is to raise the boiling-point of the mixture. The
boiling is continued for half an hour. The flask is then cooled and half filled with dis-
tilled water. A special form of distillation tube (Fig. 540) is now attached by a rubber
cork which fits tightly, but just before this is done an excess of strong caustic soda
sufficient to neutralise the concentrated sulphuric acid is run in under the acid. The
other end of the distillation tube is at once arranged to dip under the surface of a
measured quantity of standard acid (e. g. 10 c.c. H 2 S0 4 ), diluted with water, and con-
tained in a fiOO c.c. Erlenmeyer flask. The flask is then shaken and heated. In about
a quarter of an hour the ammonia is completely distilled off, and its amount can be
determined by titrating the acid in the flask with NaOH, methyl orange being used
as indicator.
UREA. The method usually adopted for estimating the urea is that devised by
Hiifner. It depends on the fact that urea is decomposed by an alkaline hypobromite
with the production of CO; and nitrogen. In the presence of an excess of alkali the C0 2
is absorbed, and the nitrogen may be collected and measured, and serves as an index
of the amount of urea present. The reaction which occurs is as follows :
CO(NH 2 ) 2 + 3NaBrO + 2NaOH = 3NaBr + N 2 + Na 2 C0 3 + 3H 2 0.
60 grm. 22-4 litres = 28 grm.
1 grm. 372 c.c.
Actually however only 354-33 c.c. nitrogen are evolved by 1 grm. urea.
The disadvantage of this method is that other substances, such as ammonia, creati-
nine, and uric acid, give off a certain amount of their nitrogen with sodium hypobromite,
so that the method is not strictly accurate, though enough so for most clinical purposes.
In actually carrying out the method 5 c.c. cf urine are treated with 25 c.c. of freshly
prepared solution of sodium hypobromite, and the nitrogen evolved is coDected in a
graduated tube over water.
Urease Method. A still simpler method is to employ urease, a ferment contained
in soy bean, which splits urea with hydrolysis into ammonia and carbonic acid. Five c.o.
of urine with 25 c.c. of water, and half a grm. of powdered soy bean are placed in a
cylinder, which is kept at about 40° C. Air is drawn through the mixture and then
through 25 or 50 c.c. of sulphuric acid for half to one hour. One grm. anhydrous
sodium carbonate is then added to break up any ammonium salts, and air drawn through
as before for another half hour. Titration of the acid then gives the amount of ammonia
liberated, from which, after subtraction of the ammonia originally present in the urine,
the percentage of urea may be calculated.
Folin's Method. In Kjeldahl's method all the nitrogenous constituents of the urine
are converted into ammonia by boiling with strong sulphuric acid. This conversion
occurs with extreme readiness in the case of urea, so that by using a weaker acid and
carefully regulating the temperature the hydrolysis may be confined practically to the
urea itself. This is the principle of Folin's method of estimating urea.
Five cubic centimetres of urine are measured into a 200 c.c. Erlenmeyer flask. Five
cubic centimetres of concentrated hydrochloric acid, 20 grm. crystallised magnesium
chloride, a piece of paraffin the size of a small hazel nut, and finally 2 or 3 drops of a
1 per cent, solution of alizarin red in water are added. A special safety tube is then
inserted into the neck of the flask and the mixture boiled until each returning
drop from the safety tube produces a very perceptible bump. The heat is then
THE COMPOSITION AND CHARACTERS OF THE URINE 1177
reduced somewhat, and the heating is continued for a full hour. The alizarin red is used
in order to ensure that the contents of the flask do not become alkaline. At the end
of an hour the contents of the flask are put into a litre flask with about 700 c.c. water
and 20 c.c. of a 10 per cent, sodium hydrate,
and the ammonia is then distilled off into a
measured quantity of acid. The results obtained
in this way will give us the total amount of
urea together with any ammonia which was
preformed in the urine. It is therefore neces-
sary also to determine the amount of this pre-
formed ammonia.
ESTIMATION OF AMMONIA. In Folin's
method for the estimation of ammonia, this is
set free by the addition of weak alkali (sodium
carbonate) and is then removed from the urine
at ordinary room temperature by passing a strong
current of air through the liquid. The issuing
current of air carrying the ammonia passes
through a measured quantity of decinormal
acid. If the air current be strong enough,
one and a half hours is sufficient to remove the
whole of the ammonia from 25 c.c. of urine. The
decinormal acid is then titrated and the amount
of the ammonia reckoned. In carrying out the
method 25 c.c. of urine is measured into a
cylinder 30 to 40 cm. high, and about a gramme
of sodium carbonate and some petroleum (to prevent foaming) are added. The upper
end of the cylinder is then closed by a doubly perforated rubber stopper through which
pass two glass tubes, only one of which is long enough to reach below the surface of
the liquid. The shorter tube, about 10 cm. in length, is connected with a calcium
chloride tube filled with cotton, and this in turn is attached to a glass tube
extending to the bottom of a wide-mouthed bottle, capacity about 500 c.c, which
contains 20 c.c. decinormal acid in 200 c.e. of water.
A more convenient method for the estimation of ammonia is that originally pro-
posed by Schiff and recently worked out by Malfatti. It depends on the fact that, when
a neutral solution of an ammonium salt is treated with formaldehyde, combination
occurs with the formation of hexamethylene tetramine (urotropine) and the liberation
of a corresponding amount of acid, which can be estimated by titrating with decinormal
alkali. The reaction which occurs is as follows :
Fig. 540.
6CH,0 + 2(NH 4 ) 2 S0 4
Formaldehyde
6H 2 + N 4 (CH 2 ) 6 + 2H 2 S0 4 .
Hexamethylene tetramine
In carrying out this method 25 c.c. of urine are measured by means of a pipette into a
flask or beaker and diluted with five times its volume of water. Four or five drops of
phenolphthalein are then added and decinormal sodium hydrate is run in until there is
a slight permanent pink colour. The amount of alkaline solution necessary to produce
this colour is a measure of the acidity of the urine. Ten cubic centimetres of formalin,
diluted with three volumes of water and previously neutralised to phenolphthalein
with decinormal alkali, are then added. The colour disappears owing to the setting
free of the acid radicals previously combined with ammonia. Decinormal alkali is then
run into the mixture until a permanent pink colour is again obtained. The number of
cubic centimetres of the decinormal alkali required in this second case corresponds to
the amount of decinormal ammonia previously present in the 25 c.c. of urine. .
This method gives somewhat higher figures than the method of Folin just described,
owing to the fact that the small traces of amino-acids, which may be present in the urine,
react to formalin in a very similar way. The difference does not exceed 10 per cent.,
so that the method is amply delicate for clinical purposes.
1178 PHYSIOLOGY
CREATININE. In Folin's method for the determination of creatinine, which is
now universally employed, advantage is taken of the colour reaction given by creatinine
(and by no other normal urinary constituent) with picric acid in alkaline solution
(Jaffre's reaction), the colour being compared with that of a standard potassium
bichromate solution. The reagents employed are decinormal potassium bichromate
containing 24 - 55 grm. per litre; saturated picric acid solution containing about 12 grm.
per litre ; and a 10 per cent, solution of sodium hydrate. For the comparison of the
colours a Duboscq colorimeter is employed.
Ten cubic centimetres of urine are measured into a 500 c.c. flask; 15 c.c. of picric
acid and 5 c.c. of sodium hydrate are then added and the mixture allowed to stand for
five minutes. Some of the potassium bichromate solution is placed into one of the
cylinders of the colorimeter and its depth accurately adjusted to the 8 mm. mark.
At the end of five minutes the contents of the 500 c.c. flask are diluted up to 500 c.c.
with water, and some of the mixture placed into the other cylinder of the colorimeter,
and the two colours are then compared. The calculation of the results is very simple.
If, for example, it is found that it takes 9-5 mm. of the unknown urine picrate solution
to equal the 8 nun. of the bichromate, then the 10 c.c. of urine contains
10 X = 8 - 4 me. creatinine.
ESTIMATION OF URIC ACID. The best method for this purpose is a slight modi-
fication by Folin of the method devised by Hopkins.
For this method the following reagents are required :
(1) A solution of ammonium sulphate, uranium acetate, and acetic acid, made up as
follows : 500 grm. ammonium sulphate, 5 grm. uranium acetate, and 60 c.c. 10 per
rent, acetic acid are dissolved in 650 c.c. water. The volume of this solution is
almost exactly 1000 c.c.
(2) Ten per cent, ammonium sulphate solution.
n
(3) r- potassium permanganate solution made by dissolving 1 - 581 grm. pure potassium
permanganate in one litre of water; 1 c.c. = '00375 grm. uric acid.
Measure 200 c.c. urine with a pipette into a 500 c.c. flask and add 50 c.c. of the
ammonium sulphate and uranium acetate reagent. Mix the solutions and allow to
stand for about half an hour so as to let the precipitate settle. This precipitate
contains a mucoid substance (and phosphates) which, if not thus removed, renders the
subsequent filtration and washing of the ammonium urate precipitate very slow. Filter
off the supernatant liquid through a dry filter into a dry vessel, and measure out 125 c.c.
( = 100 c.c. urine) of this with pipettes into a beaker. Add 5 c.c. concentrated ammonia,
mix well, and allow to stand covered with paper for twelve to twenty-four hours.
Carefully decant the supernatant liquid upon a filter, wash the precipitate of ammo-
nium urate on to the filter with 10 per cent, ammonium sulphate, and wash this once
or twice with the same reagent to remove the chlorides as completely as possible.
Remove the filter from the funnel, open it, and with a fine stream of water wash
the ammonium urate precipitate into a beaker. To the ammonium urate precipitate,
suspended in about 100 c.c. water, add 15 c.c. strong sulphuric acid and titrate at once,
without cooling, with the potassium permanganate solution. At first every small
addition of the permanganate is decolorised before it diffuses through the liquid, but
towards the end the decolorisation is slower, and the permanganate should be added
two drops at a time until a faint pink colour is seen throughout the whole solution.
The amount of uric acid can then be calculated, 1 c.c. of the permanganate solution being
equivalent to "00375 grm. uric acid.
CHLORIDES. The chlorides of urine are estimated by Volhard's method. The
principle of this method consists in precipitating the chlorides by excess of a standard
solution of silver nitrate in the presence of nitric acid. The excess of silver is then
estimated in an aliquot part of the filtrate with a solution of potassium or ammonium
THE COMPOSITION AND CHARACTERS OE THE URINE 1179
sulphocyanate which has been previously standardised against the silver solution, a
ferric salt being used as indicator.
The following solutions are required :
(1) Standard silver nitrate solution either or so that 1 c.c. corresponds to -01 grm.
NaCl. '
(2) Potassium sulphocyanate solution (8 grm. per litre).
(3) Pure HN0 3 free from chlorides.
(4) A saturated solution of iron alum.
The potassium sulphocyanate solution must be standardised against the silver nitrate
solution. This is carried out as follows : Place 10 c.c. AgN0 3 solution with a pipette
in a beaker, add 5 c.c. pure HN0 3 , 5 c.c. iron alum solution, and 80 c.c. water. Now
run in the sulphocyanate solution from a burette until a permanent red tinge is obtained.
Note the amount required for the 10 c.c. AgN0 3 solution.
The method of analysis is carried out as' follows: Place 10 c.c. urine in a 100 c.c.
measuring flask with a pipette. Then add about 4 c.c. pure nitric acid and 10 or 20 c.c.
with a pipette of the standard silver nitrate solution. Now fill up to the mark with
distilled water, mix thoroughly, and filter into a dry vessel through a dry paper. Take
exactly 50 c.c. of the filtrate with a pipette and titrate with the sulphocyanate solution
until a permanent red colour is obtained, iron alum having been added before the titra-
tion is commenced. Calculation of results :
50 c.c. filtrate = 8 c.c. KCNS
.-. 100 c.c. „ = 25 c.c. „
Now a: c.c. KCNS = lOc.c. AgN0 3
.-. 25 c.c. „ = 10 x — AgNO,
x i
This is the excess not utilised to precipitate the chlorides
10 x 25\
.•. (20 — 1 = amount of AgN0 3 solution used.
F^om this the amount in grammes of NaCl passed in the urine in twenty-four hours
can be calculated.
ESTIMATION OF PHOSPHATES. The method depends upon the precipitation
of all the phosphates by a standard solution of uranium acetate or uranium nitrate in
the presence of sodium acetate and acetic acid as (Ur0 2 )HP0 4 . The determination of
the end-point, when soluble uranium salt is in solution, is shown by means of potassium
ferrocyanide, or by cochineal tincture which becomes green.
The following reagents are required :
(1) Acid sodium acetate solution (100 grm. NaAc, 30 grm. HAc, 1000 c.c. H 2 0).
(2) Cochineal tincture (5 grm. cochineal extracted for several days with 150 c.c. alcohol
and 100 c.c. water and then filtered).
(3) Standard uranium solution (1 c.c. = '005 grm. P 2 5 or 5 mg.).
This must be prepared by standardising against a standard phosphate solution.
Generally sodium phosphate is employed ; about 12 grms. are weighed out and dissolved
in 1000 c.c. watei ; 50 c.c. of this solution are evaporated to dryness, incinerated, and
weighed as pyrophosphate. From the weight of this the amount of P 2 5 in 50 c.c. can
be calculated and the remainder of the solution can be diluted, so that 50 c.c. contain
0'1 grm. P 2 6 . It is simpler to use acid potassium phosphate, KH 2 P0 4 , which can be
weighed directly and dissolved in water, so that 50 c.c. contain 0T grm. P 2 5 . Fifty
cubic centimetres of this solution are titrated with the uranium solution (30 grm. in
one litre) in the manner described below, and the uranium solution is then diluted so
that 1 c.c. = 5 mg. P 2 5 .
The method of analysis is carried out as follows : Place 50 c.c. urine with a pipette
1180 PHYSIOLOGY
in a 100 c.c. beaker, add 5 c.c. acid sodium acetate solution and a few drops of cochi-
neal tincture. Heat the urine to boiling and run in slowly the standard uranium
acetate solution from a burette as long as a precipitate is formed. Again heat to
boiling and add the uranium solution drop by drop, until the red colour is changed to
green. This end-point can also be tested by taking out a drop and placing it in contact
with a drop of potassium ferrocyanide solution or on a little heap of this substance
finely powdered on a white piece of porcelain. A brown colour or precipitate is
formed when excess of soluble uranium salt is present in the solution. (A few more
drops may be required to reach this point than to turn the cochineal green.)
The principle of the estimation of sulphates has already been described (p. 1163).
It is not advisable to attempt this volumetrieally.
SECTION II
THE SECRETION OF URINE
With the single exception of hippuric acid, all the constituents of the urine
are formed in parts of the body other than the kidneys. * Extirpation of
both kidneys leads to an accumulation of these specific urinary con-
stituents in the blood and tissues. The work of the kidney is therefore
confined to an excretion of preformed constituents. Considered from a
broad standpoint, the function of this organ is the preservation of the normal
composition of the circulating blood.
Whenever the latter contains an abnor-
mal constituent or any of its normal
constituents are present in abnormal
quantities, the kidney excretes the sub-
stance in question until the composition
of the blood is restored. We have to
determine the conditions which influence
the quantity and quahty of the urine
secreted by the kidneys, and to ascribe
to each element in these organs its proper
share in the total work of the kidney.
In no other organ of the hody are our views
as to function so intimately dependent on our
knowledge of structure as in the kidney. This
organ is a branched tubular gland consisting
in man of ten to fifteen nearly equal divisions,
known as the Malpighian pyramids. In certain
animals, such as the rabbit and rat, only one
pyramid is present. It is divided into an outer
portion or cortex, an inner portion, the medulla,
and between these the ' boundary layer,' con-
taining the larger branches of the renal blood
vessels (Fig. 541). From the outer boundary
of the Malpighian pyramids of the medulla, a
number of processes, the medullary rays, pass out into the cortex towards the surface
of the kidney. All parts of the kidney are made up of branched tubules embedded m
scanty connective tissue and richly supplied with blood vessels. Each tubule begins
by a blind dilated extremity in the cortex, known as Bowman's capsule, which surrounds
a bunch of capillary blood vessels, the glomerulus, the two together formmg the Mal-
pighian body From Bowman's capsule a short neck leads into a proximal convo-
luted tubule, and this into a y-shaped portion which passes down in a medullary ray
1181
'ia. 541. Section of human kidney.
(Cadi at.)
a, cortex; b, medulla or Malpighian
pyramids; c, papilla; d, ureter;
e, e, boundary zone.
1 182
PHYSIOLOGY
into the underlying portion of the medulla, and consists of straight descending and
ascending limbs and the loop of Henle. The ascending limb passes into a distal convo-
luted tubule, and this by a ' junctional tubule ' joins with a number of others to form a
straight ' collecting tubule.' Several of these unite to form the papillary ducts, which
open on the surface of the papilla in the expanded part of the renal duet or ureter
(Fig. 542). The whole tubule consists of epithelium lying on a basement membrane;
the epithelium varies in structure in different parts of the tubule. The bunch of
glomerular capillaries is covered with a very thin layer of endothelial cells, and a similar
layer forms the lining of Bowman's capsule. The convoluted tubules contain cells
which are roughly cubical or cylindrical in cross-section, but do not present very
definite cell outlines. These cells, which are similar in the two sets of convoluted
tubules, have long been distinguished as ' rodded epithelium ' (Fig. 543) on account of
the ease with which a radial disposition of rods or granules is demonstrated in their
protoplasm. As ordinarily prepared, the free margin of these cells, where they abut
/ Boundary zone
Diagram showing courso of urinary tubules, and the distribution
of blood vessels. (From Yeo.)
on the lumen, is irregular. This appearance is due to the readiness with which the
cells undergo alteration under the influence of different fixing reagents, especially of
such as contain water. When properly fixed it is seen that the rodded structure, as
described by Heidenhain, is due to rows of granules arranged vertically to the basement
membrane. Moreover the free margin of the cells, instead of being irregular, consists of
a well-marked striated border, formed of a number of very fine hairs closely set together
and springing from a row of granules in the peripheral part of the cell (Fig. 544). The
hairs, which make up the striated border (sometimes called the ' brush border '), have
not been observed to present ciliary movement, and are probably comparable with the
similar structures found clothing the free border of the epithelium of the intestinal
villus. Such cells are characteristic features of the epithelium lining the urinary organs
in all types of animals, and are well marked in the nephridia of worms. Besides these
rows of granules, other granules are found, especially towards the free margin of the cell
and round about the nucleus. Some of the granules appear to be of a fatty, others of
a protein character.
The descending limb of Henle's loop is narrow, and possesses flattened epithelial
cells, while the ascending limb presents an epithelium similar to that of the convoluted
tubules, but with less marked striation. The junctional and collecting tubules are
THE SECRETION OF URINE 1183
lined with cubical or columnar cells with a clear protoplasm. The marked differences
between the structure of these various parts point to a differentiation of function and
division of labour among them in the preparation of the fully formed urine. This con-
clusion is borne out by a study of the blood supply of the kidney. The large renal
r
Fie. 543. A portion of convoluted tubule with ' rodded ' epithelium.
(Heidenhain.)
artery divides in the pelvis into four or fivje branches, which pass up to the boundary
zone and there give off arteries in different directions; those which run towards the
surface are the interlobular arteries. Each of these, which is an end artery presenting
no anastomoses with its fellows, gives off on all sides short wide branches, which pass
to the glomeruli and constitute the vasa afferentia of these bodies. Each vas afferens
has a thick muscular wall. The glomerulus itself consists of a number of anastomosing
A
^■1 >v>
k>
/•;%;
13
A&$
•->>& *
^H
FlG. 544. C - ion ol convoluted tubules from kidney of rat. (Sauek.)
a, during Blight secretion; b, during maximal secretion.
wide capillaries invested by an extremely thin wall, which is sometimes said to consist
simply of a protoplasmic film devoid of nuclei. The glomerular capillaries are collected
together to form an efferent vessel, the vas efferens, which is narrower than the vas
afferens but, like the latter, presents a well-marked muscular coat. The vas efferens
breaks up again into a second set of capillaries, which ramify round the tubules of the
cortex and communicate with a similar network round the tubules of the medulla. The
medullary pyramids are also provided with blood by a plexus of capillaries taking their
origin from little bunches of vessels, the vasa recta (v. Fig. 542), which leave the concave
side of the arterial arches of the boundary zone to run towards the papilla, and receive
also a few vessels which spring from the vasa afferentia of the cortical vessels. From the
1184 1'IIYSIOLOGY
capillaries of the tubules the blood is collected again into veins, which leave the kidnej
partly by the cortex and capsular vessels, partly by lame venous trunks which join to
form the renal vein at the hilurn of the kidney. The kidney is richly supplied with
nerves, which arc chiefly distributed to the muscular walls of its blood vessels. Some
ant hois have, described a fine nerve- plexus surrounding the tubules and sending branches
between and into the cells of the convoluted tubules themselves.
The main points in the above description of the structure of the kidney
were made out by Bowman in 1840, and suggested the theories of urinary
secretion both of Bowman and of Ludwig (1844), theories which have
furnished the basis of all our subsequent investigation of the subject. Both
observers appreciated the great difference between the membrane covering
the glomerular loop and the lining membrane of the tubule, and both drew
attention to the difference in the circulation in these two portions of the
kidney. The glomerular capillaries, supplied with blood through a short
wide artery and drained by an efferent vessel smaller than the afferent,
would represent a region of very high capillary blood pressure, whereas the
pressure in the capillaries surrounding the tubules must be low and similar
to that in other capillary regions. Bowman therefore suggested that the
urine consisted of two parts, namely, one part containing the water and
salts produced by a process of filtration through the walls »f the glomerular
capillaries, and another part, containing the specific urinary constituents,
urea, uric acid, etc., secreted by the cells probably of the convoluted tubules.
To Ludwig, on the other hand, it seemed possible at first to account for the
whole process of formation of urine without the assumption of any active
intervention on the part of the cells of the tubules. He imagined that the
whole of the urinary constituents passed from the blood to the urinary
tubule in the glomerulus by a process of filtration. The glomerular transu-
date would represent therefore a very dilute urine containing the crystalloids
of the blood in the same concentration as in the blood and with no more
urea than the blood itself contained. The great difference in urea content
between the blood and the fully formed urine he ascribed to a process of
concentration takmg place in the fluid in its passage through the tubules, in
which water and certain of the salts were reabsorbed, a process of reabsorp-
tion conditioned by the difference hi protein content between the urine within
the tubules and the lymph under low pressure on the outside of the tubules.
We know now that in its original form the theory of Ludwig is untenable.
If a process of concentration occurs within the tubules, it must invobre^
the performance of work by the cells lining these tubules, and could not take
place as a result of mere differences of colloid content between the two fluids.
It was shown long ago by Hoppe-Seyler that, if urine be dialysed against
serum, there is a passage of water, not from urine to serum, but from
serum to urine, i. e. the latter is much more concentrated than the former.
The movement of water from one fluid to another through a colloid mem-
brane depends on the relative osmotic pressures of the two fluids, and this
in turn is determined by the molecular concentration of the two fluids. It
is easy to estimate the molecular concentration of any sample of serum <>r
urine. The method which is most convenient is to determine the depression
THE SECRETION OF URINE
1185
of freezing-point in the two fluids. Whereas senim ordinarily freezes at
— 0-56° C. to — 0-59° 0., the freezing-point of urine is generally lower and
may vary from this figure to as much as — 4-5° C. For the production
therefore of urine from blood plasma, a certain amount of work has to be
done, and the seat of this work we can locate only in the cells of the kidney.
We may determine the rmnmvm work, necessary to form a certain amount of
urine of a given concentration, by measuring the amount of heat that must
be imparted to the blood plasma in order to reduce it to the same concentra-
tion and volume, or we can calculate it if we know the freezing-points of the
two fluids. A depression of freezing-point A = — 1° C. corresponds to an
osmotic pressure of 122-7 metres of water. To concentrate 100 c.c. of a
saline fluid, such as urine, so as to halve its bulk and double its depression of
freezing-point, e.g. from — 1° C. to — 2° C, would therefore require the
expenditure of work equivalent to that which would be required to compress
100 c.c. of a gas at a pressure of 122' 7 metres of water to half its bulk.
In this way can be determined the work necessary to change a fluid of A = — 0-56
(such as plasma) to one of — 2-3 (urine). The work done in forming 200 e.c. of urine
of this concentration from fluid plasma would amount to 42-9 kgm. metres. But the
c mcentration in the kidney does not occur in this simple fashion. If we compare the
c imposition of blood plasma with that of urine, we see that almost every constituent is
changed in different proportions.
Relative Compositions of Blood Plasma and Normal Urine in Man (Cushny)
Blood plasma
per cent.
Urine per cent.
Change in
concentration
in kidney
Water .....
90-93
95
Proteins, fats and other colloids
7-9
—
—
Dextrose ....
01
—
Urea
0-03
2
60
Uric Acid
0002
005
25
Na .
0-32
0-35
1
K .
002
0-15
7
NH 4
0001
0-04
40
Ca .
0008
0015
2
Mg .
00025
0006
2
CI .
0-37
0-6
2
PO,
0009
0-27
30
so 4
0003
0-18
60
If we added up the work required to produce the change in concentration of each
constituent, we should arrive at a figure probably ten times as great as that given above.
The large amount of work done under some conditions by the kidneys in the formation
of urine is indicated by measurements of the oxygen consumption of this organ. This
may amount to -04 to -06 c.c. per gramme per minute, and in some forms of diuresis may
rise to as much as -28 c.c. per gramme per minute. It is worthy of note that this rise
in oxygen consumption is found when the diuresis is caused by the intravenous injection
of urea, sodium sulphate, or phlorhizin, but not when the diuresis is brought about by
the injection of water, Ringer's solution or sodium chloride.
75
IJ86 PHYSIOLOGY
The abandonment of Lud wig's view as to the mechanism of the concentra-
tion does not however place his theory out of court. The question will
still have to be discussed whether the chief object of the tubules is the con-
centration of the fluid produced in the glomeruli, or whether they add to this
fluid by a further secretory process, or whether they may not possibly
possess both functions and in their various parts alter the fluid flowing
through them either by addition or by withdrawal of water or dissolved
constituents. The common point in the two theories is the sharp distinc-
tion which is drawn between the nature of the glomerular activity and the
nature of the activity of the tubules. The questions which we have to
decide by experiment are :
(1) The nature of the glomerular activity and the conditions which
determine the amount of fluid formed by the glomeruli, and especially
whether the energy required for the formation of the glomerular fluid is
furnished by the heart through the blood pressure within the capillaries or
by the endothelium covering these capillaries.
(2) The function of the tubules, whether they secrete or absorb, and
what part is played in these processes by the various segments of the tubules,
which differ so widely in their histological characters.
FUNCTIONS OF THE GLOMERULI
It is generally assumed, as the best explanation of known facts with
regard to the secretion of urine, that a watery exudation free from protein is
formed in the glomeruli, and that this becomes concentrated on its way
through the tubules, either by the absorption of water and certain salts or by
the secretion and addition of urea, uric acid, etc. as well as such salts as
acid phosphates. As to the nature of the glomerular functions two opinions
have been held. According to the Ludwig school, the process is one simply
of filtration, in which, under the pressure of the blood in the glomerular
capillaries, the water and crystalloid constituents of the plasma are filtered
through the glomerular epithelium, leaving behind the protein constituents.
According to Heidenhain, the process cannot be regarded as one simply of
filtration, but involves the secretory activity of the glomerular epithelium.
If the glomerular urine is a filtrate, it must resemble blood plasma in practi-
cally all particulars except its protein content, since the blood pressure, which
is the only force causing filtration, is too small to effect any appreciable
separation of salts. On the other hand, a certain nunimum difference of
pressure between the two sides of the membrane must be present in order to
separate the colloids from the other constituents of the plasma. We have
seen in Chapter iv (p. 141) that, in order to produce a filtrate containing only
water and salts from serum, a minimum difference of pressure of 30 mm. Hg.
is necessary, corresponding to the osmotic pressure of the colloidal con-
stituents of the blood plasma or serum. Thus in order to produce a filtrate,
free from protein, from the blood plasma circulating through the glomerular
capillaries, the pressure of the urine in the tubules and ureter must always
THE SECRETION OF URINE U8F-
be at least 30 mm. lower than the pressure of the blood in the glomeruli. A
direct determination of the latter figure is not possible. The anatomical
arrangements are such as to bring this pressure up to a high point. Not only
are the vasa afferentia very short, but the vasa efl'erentia are only two-
thirds of the diameter of the vasa afferentia. Moreover the sudden increase
of bed, which ensues as the blood passes from the vas afferens to the bundle
of capillaries, must itself cause a rise of pressure in the latter, due to the
transformation of the kinetic energy of the moving fluid into the statical
energy represented by pressure on the walls of the vessels.
This point can be rendered clearer by the following considerations. If fluid is flowing
in a tube of continuous bore ab (Fig. 5-45) there will be a continuous fall of pressure
from a to b. If however in the tube abc the segment b be of much greater diameter
than the segments a and c, although while the fluid is at rest the pressures will be equal
at all points of the system, as soon as the fluid moves from a to c, although there is a fall
of pressure between a and c, a manometer attached to 6 may show an actual greater
pressure than a manometer inserted at a. Fluid is flowing from a place of lower to a
place of higher pressure. The apparent paradox is due to the fact that the energy
pressure
1 pressure
causing the fluid to move from a to b is of two kinds. It equals fmi' 2 -f- P> »• e. repre-
sented by the kinetic energy of the moving mass of fluid as well as the difference of
pressure between any two points of the tube. The total energy will diminish con-
tinuously from a to c, and is used in overcoming the resistance of the system. We may
say then that the sum of these two, namely, %mv 2 -f- P, is greater at a than b, and is
greater at 6 than c ; but as the fluid passes from the narrow tube a into the wide tube b,
there is a sudden fall of its velocity and a consequent diminution of the factor \rriv 2 -.
In order to provide for a continuous fall in the total energy of the fluid, namely, \mv % -f-
P, the diminution in the factor \mv % must cause a corresponding increase in the factor
P, i. e. in the lateral pressure exercised by the fluid on the vessel wall. As the total
diameter of the bed of the stream in the capillaries may be twenty times that of the bed
in the vas afferens, the velocity of the blood in these capillaries will be only one-twentieth
of that in the artery and the kinetic energy of the blood only one four-hundredth. It
is possible therefore that the pressure exercised by the blood on the walls of the capil-
laries may be even greater than that in the interlobular arteries, and this effect will be
still further aided by the narrow diameter of the vas efferens. Although therefore the
pressure in the ordinary capillaries of the body is probably not greater than 20 to 30 mm.
Hg., the glomerular capillaries might present a pressure little inferior to that in the main
arteries of the body.
The pressure in the ureter is under normal circumstances approximately
nil, whereas that in the glomerular capillaries is probably not more than
20 mm. Hg. below that in the main arteries of the body, so that there is a
difference of pressure on the two sides of the membrane more than sufficient
to cause a constant filtration of a protein-free fluid from the blood plasma
1188 PHYSIOLOGY
coursing through these capillaries. On raising the pressure on the tubule
side, the filtration ought to come to an end when t lie pressure approaches
a figure which is 30 to 40 mm. Hg. below that in the glomerular capillaries.
A number of observers have found that urinary secretion ceases when the
blood pressure falls to between 40 and 50 mm. Hg. The urinary secretion
can be stopped by raising the pressure in the tubules by means of ligature
of the ureter. On applying the ligature the secretion continues for a time
until the pressure in the ureter rises up to a certain point, when the secretion
comes to an end. In one experiment the following pressures were obtained
in a dog which was secreting urine copiously under the action of diuretin.
Manometers were connected both with the carotid artery and with the
ureters so that no outflow of urine was possible.
Arterial pressure . Ureter pressure
140 72
138 92
133 88
In this experiment therefore secretion came to an end with a difference
of pressure between ureter and arteries of between 40 and 50 mm. Hg.
The absolute pressure attained within the ureter in any given experiment after liga-
ture of these tubes will vary with several factors. In the first place, if the minimum
secreting pressure is really conditioned by the colloid content of the blood plasma, it
will be less the smaller the proportion of colloids in the plasma. In some experiments
(.Magnus) a flow of urine was observed with a blood pressure as low as 18 mm. Hg., but
in this case the blood was extremely dilute as the result of the continuous injection into
the blood vessels of normal salt solution. Barcroft and Knowlton have shown that the
diuresis brought about by injection of saline (Ringer's) solution is inhibited by mixing
with the saline fluid colloids, such as gelatin and gum, which possess an osmotic pressure.
Colloids such as starch, with no measurable osmotic pressure, have no such effect.
On the other hand, the ureters, or at any rate the urinary tubules, cannot be regarded
as absolutely water-tight. Not only are the cells of these tubules capable of taking up
fluid, but it is probable that at high pressures a certain amount of actual filtration takes
place between these cells. This process of reabsorption will tend to diminish the actual
pressure of the fluid in the ureters, so that the secretion of urine may apparently come
to a standstill when there is still a difference of pressure between blood and urine con-
siderably over 50 mm. Hg. Under such circumstances the ureter pressure will be higher,
and the difference of pressure between urine and blood less, the more rapid the formation
of urine by the glomeruli. In a number of experiments by V. E. Henderson, it was
found that the figure B.P. — U.P. tended to approximate 40 mm. Hg. the more rapid
the secretion of urine was. With a slow secretion the flow of urine apparently ceased
when there was as much as 80 mm. Hg. difference of pressure on the two sides of the
glomerular membrane.
We may conclude that, for the production of any urine by the kidney,
a certain minimum difference of pressure is necessary between the blood in
the glomeruli and the urine in the tubule, and that this difference becomes
less the smaller the protein content of the blood. Since the only work
required in the formation of a protein-free filtrate from the blood is that due
to the osmotic pressure of the proteins themselves, and the observed difference
of pressure during secretion is greater than this osmotic pressure, we are
justified in concluding, provisionally at any rate, that the mechanical factors
THE SECRETION OF URINE 1189
present at the upper end of the urinary tubule are sufficient to account for the
production of a glomerular transudate free from protein, but containing the
same proportion of water and salts as the blood plasma circulating through
the capillaries.
If the process occurring in the glomeruli is simply one of filtration, three
conditions must be realised :
(1) The amount of filtrate, so long as the ureter pressure is constant,
must depend on the pressure and rate of flow of the blood in the glomerular
capillaries, and must fall or rise with the lattet.
(2) The constitution of the fully formed urine as it appears in the ureters,
after modification by addition or subtraction on the part of the tubular cells,
must approximate more closely to the supposed glomerular transudate,
containing the same proportion of salts as the blood plasma, the more rapidly
the formation of the glomerular transudate takes place : i. e. the quicker the
flow of urine the more nearly must its composition, reaction, and osmotic
pressure resemble those of the blood serum.
(3) The total quantity of solids excreted in any given time must be
increased with any increase in the urinary flow. For, whatever the activity
of the tubules, the glomeruli must blindly turn out a certain proportion of
solids with every cubic centimetre of fluid that they form.
We may deal first with the. influence of alterations in the renal blood
supply on the flow of urine. Ligature of the renal vein diminishes and soon
stops the flow altogether. Since this procedure must cause a large rise of
pressure in the capillaries of the kidney, this result was regarded by Heiden-
hain as disproving any possibility of the glomerular process being of the
nature of a filtration. At any given time however, the glomeruli contain but
little blood. With total cessation of the renewal of this blood, their contents
will rapidly become so concentrated that they will be little more than a mass
of red corpuscles. No filtration of water and salts can take place unless there
is a continual renewal of the fluid on the blood side of the filter.
On the other hand, alterations in the blood supply to the kidney,
determined by changes on the arterial side, have pronounced effects on the
amount of urine formed. The pressure in the glomerular capillaries and the
rate of flow through these capillaries can be increased in either of two ways :
fa) By increase of the driving force, i. e. the general blood pressure ;
(b) By a diminution of the resistance to the flow of blood through the
kidneys, as by dilatation of the vessels of this organ.
The blood flow through the kidney can be investigated, either by record-
ing the total volume of this organ, or by determining the amount of blood
which leaves it through the renal vein, according to the methods described
in Chapter xiii.
It is necessary at the same time to take a record of the arterial blood
pressure by means of a mercurial manometer. It is evident that an expan-
sion of the kidney may be caused by a rise of general arterial pressure or,
the latter remaining constant, by a dilatation of the kidney 'vessels; and,
conversely, a fall of kidney volume may be due either to a fall of general
1190
PHYSIOLOGY
blood pressure or to a constriction of the renal blood vessels. By taking
these two records it is possible to tell whether a given increase of blood flow
through the organ is of local or of general causation, i. e. is active or passive.
Thus the volume of the kidney gives us an indirect clue to the pressure in
and the flow through the kidney vessels. The flow through the vessels
can be determined directly either by a cannula in the inferior vena cava, all
veins other than the renal being clamped, or by Brodie's method, already
described (p. 1037).
The results of the experiments carried out by these methods can be
represented in the following tabular form :
Procedure
General blood
pressure
Eenal vessels
Kidney volume
Urinary flow
Division of spinal cord in
Falls to
Relaxed
Shrinks
Ceases
neck ....
40 mm.
Stimulation of cord
Rises
Constricted
Shrinks
Diminished
Stimulation of cord after
Rises
Passively
Swells
Increased
section of renal nerves
dilated
Stimulation of renal nerves
Unaffected
Constricted
Shrinks
Diminished
Stimulation of splanchnic
Rises
Constricted
Shrinks
Diminished
nerve
Division of one splanchnic
nerve : . . .
(a) In dog
Unaffected
Dilated
Swells ( ?)
Increased
(6) In rabbit .
Falls
Relaxed
Shrinks ( ?)
Diminished
Plethora
Rises
Dilated
Swells
Increased
Haemorrhage
Falls
Constricted
Shrinks
Diminished
It will be seen that in every case, where an increased blood flow attended
with a rise of blood pressure in the glomerular capillaries is brought about,
the urinary flow is at the same time increased.
Another factor, altering the ease with which filtration of watery fluid
and salts would take place through the glomerular capillaries, would be the
composition of the blood plasma. Any dilution of this plasma must render
filtration more easy, while a concentration would make it more difficult.
As a matter of fact hydremia, and especially hydraemic plethora caused by
injection of normal saline into the circulation, evoke an increased flow of
urine. A smaller effect is produced by injection of defibrinated blood, and
if the blood has been previously concentrated by depriving the animals of
water, there may be little or no increase in flow, in consequence of the high
osmotic pressure of the proteins of the plasma injected.
If the glomerular function is that of mere filtration, we should expect
that the more rapidly the process occurs, the more nearly would the urine
which is turned out into the ureters resemble the blood plasma in com-
position, reaction, and osmotic pressure, since the glomerular filtrate hurried
through the tubules would have very little time to undergo any changes
resulting in its concentration. If, on the other hand, the diuresis produced
by salt or sugar solutions is to be ascribed to a stimulation of the renal
THE SECRETION OF URINE 1191
epithelium, the differences between blood plasma and urine should be
greatest at the height of the diuresis, when the concentration of the specific
stimulant is also at its highest. The following experiment shows that the
more rapid the secretion of urine, the more closely does its concentration,
as indicated by its osmotic pressure and depression of freezing-point (A),
approximate that of the blood plasma.
A dog received 40 grm. of dextrose dissolved in 40 c.c. of water. The
following Table represents the relative concentrations of urine and blood
serum at different stages in the diuresis thereby produced :
Time
TJriDe
Rate of flow
A of urine
A of blood-serum
11.30-12
10 c.c.
3-3
2-360
0-625 (at 12.0)
From 12.0 to 12.7 injected 40 grm. dextrose into jugular vein
12.7 -12.15
35 c.c. 45
1-210
12.16-12.20
20 c.c. 50
0-975
0-700 (at 12.16)
12.20-12.30
52 c.c. 52
0-835
—
12.30-12.40
45 c.c. 45
0-825
0-700 (at 12.30)
12.40-12.50
22 c.c. 22
0-830 J
0-675 (at 12.40)
0-675 (at 12.50)
A still closer approximation of the concentration of the urine to that of the
plasma was obtained by Galeotti in some experiments in which the modifying
influence of the tubular epithelium on the glomerular transudate had been
prevented by poisoning the animal with corrosive sublimate, which causes
destruction of the epithelium but is said to leave the glomeruli intact.
Since the glomerular transudate must have a concentration approxi-
mately identical with that of the blood plasma, it would be impossible for
a urine formed by mere filtration to have a concentration less than that
of the blood plasma. It is however of frequent occurrence that, after
copious potations of tea or light beer, urine is passed with an osmotic pressure
and a molecular concentration considerably below that of the blood. In
one case Dreser obtained a urine with a freezing-point of A = 0-16 O, and
the same result has been obtained on one or two occasions when the diuresis
has been produced by the administration of caffeine. If we assume that this
hypotonic fluid is formed by the glomeruli, we must at once give up any idea
of the process in these structures being essentially one of filtration. But
the fine adaptation of the kidney to slight changes in the composition of
the blood is apparently an endowment of the tubular epithelium; and in
those cases where large quantities of hypotonic urine are passed, there is
not at any time any appreciable change either in the composition of the
blood or in its total volume. Water is absorbed from the alimentary canal
and is almost immediately excreted by the kidneys. When we attempt to
produce the same effect by infusion of large quantities of water or hypotonic
solutions into the blood stream, we get a flow of urine apparently deter-
mined entirely by the circulation through the kidney and having a con-
centration not inferior to that of the blood. The passage of hypotonic urine
1192 PHYSIOLOGY
can be ascribed to a modification of the glomerular transudate as it passes
through the tubules, a modification which may be due either to the absorption
of salts from the fluid, or to a secretion of water or extremely dilute salt
solution by the cells of the tubules themselves. Possibly both processes are
involved.
Certain other observations accord with our hypothesis that in Bowman's capsule a
fluid is transuded having the same molecular concentration as blood plasma, and there-
fore considerably less concentrated than normal urine. Ribbert succeeded in extir-
pating the whole of the medullary portion of the kidney in the rabbit, leaving the cortex
intact, and found in this case that during the survival of the animal the urine passed was
much more dilute than normal. In cases where, while the glomeruli remain intact,
there is destruction of the tubular epithelium either in consequence of disease or, as
in Galeotti's experiments, as a result of poisons, we are accustomed to obtain a dilute
copious urine; and the continual passage of such urine is in man regarded as a sign of
one form of renal disease.
The experimental facts which we have passed in review do not therefore
negative the view that the glomerular epithelium plays the part of a passive
filter in the formation of tirine, and that the energy of the process by which
' urine ' is produced in Bowman's capsule is entirely furnished by the heart
in driving the blood at a high pressure through the glomerular capillaries.
It is important however to remember that, however passive it may be
in the formation of urine, the filtering membrane is composed of living cells,
which may alter and lose their powers of filtration or their powers of retaining
the colloid constituents of the blood plasma under any influences which
impair their vitality. Thus obstruction of the renal artery for half a minute
may suppress the formation of urine in the kidneys for half to several hours,
and the urine, when again formed, is found to contain coagulable protein
(' albumin ') which can be shown to have transuded through the glomerular
epithelium. The filtering properties of the membrane may be impaired to
a lesser degree by slowing the circulation of the blood through the kidneys.
In the venous congestion of heart disease, the presence of albumin in the
urine is of frequent occurrence. The same effect on the permeability of the
epithelium may be produced by many kinds of poisons, mineral or microbial,
circulating in the blood.
FUNCTIONS OF THE RENAL TUBULES
Whatever the nature of the glomerular activity, it is evident that the
multiform epithelium of the tubules may alter the glomerular transudate,
either by the absorption or by the secretion of water or solid constituents.
We may deal with the evidence for the occurrence of these two processes
separately.
SECRETION BY THE RENAL TUBULES. Although it is impossible
to collect the secretion of the glomeruli apart from that of the tubules, the
arrangement of the blood vessels in certain animals enables us to influence
separately the circulation to these two parts of the kidney. The amphibian
kidney receives a blood supply from two sources. A number of renal
THE SECRETION OF URINE
1193
Test-
Kidney
Renal pgrral
ArU abdom.v-
Aorfa
Vena cava
Renal arteries
Femoral
Fid 546.
arteries leaving the aorta enter the kidney and supply the whole of the
glomeruli, the vasa eSerentia from which pass, as in the mammalian kidney,
into the intertubular capillaries. These are also supplied with blood of
venous character by the renal portal vein. If all the renal arteries be divided
or ligatured, the glomeruli, as was shown by Nussbaum, are entirely cut out
of the circulation, though the tubules continue to receive venous blood
through the renal portal vein. Nussbaum stated that ligature of all the
renal arteries caused cessation of the urinary secretion, which could be
reinduced by injection of urea.
He concluded that urea with F a f bod
water was secreted by the
tubules, whereas peptone, sugar,
and haemoglobin were turned
out by the glomeruli. Beddard
showed that these results of
Nussbaum must have been due
to the. fact that he had not
obstructed the whole of the renal
arteries. One or two of these
small vessels will suffice to
supply blood to a considerable
number of the glomeruli. After
complete obstruction of the
arteries, no urinary flow could be
induced even with subcutaneous
injection of urea. But the cutting off of the arterial blood supply from the
tubules caused a rapid destruction of the tubular epithelium, so that the
result of the experiment could not be taken as negativing the possibility of
this epithelium having, when in a normal state of nutrition, some secretory
power. He therefore carried out, with Bain bridge, another series of ex-
periments of the same description, in which the frogs, after ligature of the
renal arteries, were kept in an atmosphere of pure oxygen. Under these
circumstances sufficient oxygen diffused into the blood of the renal portal
win to maintain an adequate supply of this gas to the tubules. No desquam-
ation of the epithelium resulted, and injection of urea produced a small
flow of urine even when, by subsequent injection of the blood vessels, it was
proved that every glomerulus had been cut out of the circulation.
In the cells of the convoluted tubules various kinds of granules and of vacuoles may
be distinguished. Gurwitsch divides these vacuoles into three classes;
(1) Large granules staining densely with osmic acid, and probably rich in lecithin.
(2) Smaller very numerous granules consisting of some form of protein material.
(3) Large vacuoles lying close to the free margins of the cells, whose contents do
not undergo coagulation with the ordinary fixing reagents, and therefore are free from
protein, fat, or mucin. These vacuoles are especially marked in kidneys which are
secreting at a great rate, in consequence of the injection of saline diuretics or of large
quantities of normal salt solution. They have been regarded as excretory vacuoles, and
as containing water or saline fluids which have been collected by the cells and are
being passed on by them to the lumen of the tubules.
The vascular supply to the kidney
in the frog.
1194 PHYSIOLOGY
In a secreting gland such as the parotid, there is a marked change in the appearance
of the granules according as the gland is resting or actively secreting. No such changes
have been discovered in the granules of the renal cells, and the vacuoles that have been
described might be either in process of secretion or might be evidence of copious absorp-
tion of watery fluids from the lumen of the tubule.
As a rule it is impossible to trace any definite constituent of the urine
on its way through the cells of the tubules. But if massive doses of uric acid
in piperazin be injected intravenously into a rabbit, the kidneys, taken
twenty to sixty minutes after the injection, present tubules full of uric acid
concretions. In the medullary portion of the kidney this uric acid precipitate
is confined to the lumen of the tubules, but in the convoluted tubules granules
of uric acid are to be found in the epithelial cells, especially towards their
inner border.
Under the same circumstances masses of uric acid crystals are also
found in the connective tissues between the tubules. It is therefore impos-
sible to be certain that the granules observed within the epithelial cells
are in process of excretion or are being absorbed from the lumen. Modem
methods have failed to substantiate the older observations as to the occur-
rence of uric granules under normal conditions in the cells of the convoluted
tubules of the bird's kidney.
Heidenhain has attempted to throw light on the excretive functions of
the kidney by studying the mechanism by means of which it excretes certain
dyestuffs, such as sulphindigotate of soda (' indigo carmine '). If the
indigo be injected into the veins, it is excreted in a concentrated form,
both by the liver and by the kidney, so that the urine assumes a dark blue
colour. If the animal be killed when the excretion of the pigment is at
its height, and the kidneys be rapidly fixed with absolute alcohol (which
precipitates the dyestuff), all parts of the kidney present a blue colour,
which is especially marked in the medulla. Under these circumstances the
urine, which is being excreted by the glomeruli, rapidly carries down the
dyestuff, wherever it may be turned out, into the tubules of the pyramids.
In order to discover the exact locality of the cells involved in its excretion,
we must stop the glomerular transudate by some means or other. This
stoppage of the urinary flow can be effected in two ways, viz. by section of
the spinal cord in the neck, so as to reduce the blood pressure to about
40 mm. Hg., i. e. below the minimum necessary for the production of urine,
or by cauterising portions of the surface of the kidney by means of silver
nitrate. If the indigo be injected into the veins after section of the cord,
and the animal be killed half an hour later, and the kidneys fixed with
absolute alcohol, they are found to be of a bright blue colour, although no
urine has been secreted. On cutting into the kidneys the colour is seen to
be confined to the cortex, and on making microscopic sections granules of
the pigment are found within the lumen and in the epithelial cells of the
convoluted tubules. If the kidneys have been cauterised, the stain is
confined to the convoluted tubules of the cortex only under those areas
which have been cauterised, and where the glomerular functions have been
abolished.
THE SECRETION OF URINE 1195
All these appearances are susceptible however to another explanation.
If indigo carmine is turned out by the glomerulus it will be so dilute that
unless very large doses are injected the glomerulus will not be stained. As
the glomerular transudate descends the tubules it undergoes concentration.
The precipitation of the dyestufl in the tubules may be simply a result of this
concentration, and the granular deposit in the cells may be evidence not
of secretion but of absorption of the dyestufi by the cells. In fact we
must acknowledge that the evidence for secretion by the cells of the con-
voluted tubules is very defective. Since all the microscopic appearances
observed after the injection of dyestufi are susceptible of two explanations,
there remains only the experiment of Nussbaum, as repeated by Bainbridge
and Beddard, as evidence of secretion on the part of the tubular epithelium ;
and this evidence would lose its weight if one or two glomeruli in the operated
kidney still received some blood supply, even though they failed to be
injected with the injection mass used at the end of the experiment for conr
trolling the completeness of occlusion of the renal arteries.
ABSORPTION BY THE RENAL TUBULES. The experiments of Ribbert,
mentioned above, in which removal of the medullary portion of the
kidney led to the formation of an increased quantity of a more watery urine,
points to the possession by the tubules of a power of absorbing water. We
have other evidence that this power of resorption is not confined to water,
but may affect also the dissolved constituents of the glomerular transudate.
It was pointed out by Meyer that, if two salts such as sodium sulphate and
sodium chloride were present at the same time in the glomerular transudate,
any process of resorption should'afiect chiefly the more diffusible salt, namely,
sodium chloride. Such a differential resorption would account for the much
greater diuretic power of sodium sulphate as compared with sodium chloride.
In certain experiments Cushny produced a diuresis by the injection of
equal parts of equivalent NaCl and Na 2 S0 4 solutions into the veins of a
rabbit. An increased flow of urine was produced which lasted two hours
and a half. The chlorides of the urine rose with the diuresis and reached
their maximum at the height of the urinary flow. They then sank, and hi
some experiments had practically disappeared from the urine towards the
end of the observation. The concentration of the sulphates however con-
tinued to rise in the urine to the end of the experiment. Thus in the first of
two identical experiments, when the rabbit was killed at the height of the
diuresis, the serum contained 0-547 per cent, chlorine and 0-259 per cent,
sulphate, while the urine contained 0-372 per cent, chlorine and 0-546 per
cent, sulphate. In the second, in which the rabbit was killed when the rate
of the urinary flow had considerably diminished, the serum contained 0-493
per cent, chlorine and 0-191 per cent, sulphate, while the urine contained
■094 per cent, chlorine and 2-0 per cent, sulphate. 'These results are illus-
trated in Fig. 547.
The difference between the two salts can be made still more striking if
the process of secretion be slowed by increasing the pressure within the
tubules by partial obstruction of one ureter. Thus in one experiment,
1190
PHYSIOLOGY
where diuresis was produced by the injection of 30 c.c. of a solution con-
taining 5-85 per-cent. NaCl + 14-2 per cent. Na 2 S0 4 , the right ureter was
partially clamped so as to make the right kidney secrete against a pressure
of 31 mm. Hg. The following results were obtained :
Urine c.c.
Cl. grm. SOj grm.
4.37 till 4.47
| Left kidney ....
I Right kidney
Difference (absorption) .
24
8
16
00809 ! 0-1080
0-0142 00667
00677 00413
We must conclude that the tubular epithelium possesses the power of
modifying the glomerular transudate, not only by the absorption of water
but also by the absorption of dissolved constituents, and that the relative
1,
'1 A
J V
| Y
i
/
1
1 1
\ \
\
/
\
O
s
\
\
N
V
^4—
—
-..
I* -1U 4-5 60 75 50 IOS ISO 135
Fig. 547. Curves showing excretion of urine (thick line), of sulphate molecules
( ' „\ thin line), and of Cl molecules ( - , dotted line), after injection of 50 c.c.
of a solution containing 1-775 grm. Cl and 4-8grm. S0 4 per 100 c.c. The black
line along the base marks the duration of the injection. (Cttshny.)
permeability of the cells to the constituents is at any rate one factor in deter-
mining the substances absorbed. It is not however the only factor. The
function of the kidney is to preserve the normal constitution of the body
fluids by turning out those substances which are abnormal or present in too
great an amount. The behaviour of the tubule cells with regard to any «iven
substance will therefore depend to a certain extent on the previous nutritive
history of the body.
If for instance, in consequence of the administration of sodium chloride
THE SECRETION OF URINE 1197
in large quantities to the animal during the few days preceding the experi-
ment, the body is overloaded with this salt, it becomes an abnormal con-
stituent and the kidney secretes a urine far richer hi sodium chloride than is
the blood plasma. Moreover, when diuresis is produced in such an animal
by the injection of equivalent quantities of sodium chloride and sodium
sulphate, there is no diminution of the NaCl hi the urine towards the end of
the diuresis, but its percentage rises steadily as the rate of urinary flow
diminishes. On the other hand, a total deprivation of sodium chloride
extending over several days, although not altering to any large extent the
percentage amount of this salt in the blood plasma, leads to a total dis-
appearance of the salts from the urine, the whole of the sodium chloride
present in the glomerular transudate being absorbed on its way through the
urinary tubules.
It has been suggested that the effects of certain diuretics on the kidney,
such as caffeine, diuretine, or theocine, may be largely conditioned not so
much by their influence on the glomerular circulation as by a paralytic effect
on the absorptive functions of the tubules. According to Loewi, on injec-
tion of caffeine or diuretine, the increase of total amount of urine is not
accompanied by any diminution in the percentage amount of NaCl. Perhaps
however the strongest evidence in this direction is afforded by an experi-
ment of Pototzky. A rabbit had been fed on a diet almost totally devoid
of chlorides, and was therefore excreting a urine containing only -08 per
cent. NaCl. Under the influence of diuretine the urine was increased and
the concentration of the NaCl rose to 0-64 per cent. The same increase in
the percentage amount of sodium chloride in the urine has also been observed
after the injection of theocine, which has therefore been specially recom-
mended as a diuretic in cases of dropsy, where a diminution of the salt
content of the body is a valuable means for the diminution of the dropsical
Hi rid present iu the tissue spaces.
THE RENAL MECHANISM
What conclusions can we draw from this mass of experimental data
as to the functions of the kidney as a whole, and as to the part played by
its various constituent elements in the secretion of urine? The amazing
adaptability of its functions to the needs of the organism has been abund-
antly illustrated in the facts with which we have dealt. Its ordinary activity
is determined by the production, as a result of the normal processes of meta-
bolism, of soluble non-volatile substances in every cell of the body. These
substances, together with the excess of water taken in with the food above
that lost by respiration and cutaneous transpiration, arc turned out by the
kidney as urine. The activity of this organ must therefore be determined in
the first place by chemical stimuli. If we accept a secretory function for
the tubules, we may assume that the kidney reacts to the slightest deviation
from normal of the blood composition in two directions :
(1) Under the influence of certain substances, such as urea, uric acid,
1198 PHYSIOLOGY
or water, the cells of the convoluted tubules may take up the substance,
which is in excess, from the surrounding lymph and accumulate it in vacuoles,
which are discharged on the inner surface of the cells into the lumen of the
tubules.
(2) Besides this specific secretory activity of the cells of the convoluted
tubules, the tubules as a whole are certainly endowed with the power of
absorbing both water and dissolved substances from the fluid in their lumen.
Whether this absorptive power is limited to the cells of Henle's loop, as
was first suggested by Ludwig, or occurs also in the cells of the convoluted
tubules, as might be imagined from the close analogy between the structure
of these cells and that of the intestinal epithelium, we have not sufficient
evidence to decide. We do know however that the quality of the absorp-
tion is strictly regulated according to the needs of the organism, so that the
constituents which are precious are reabsorbed for service in the body, while
those which are in excess or are of no value to the organism are allowed to
pass out into the ureters. The process of resorption is indeed, as is shown
by Cushny's experiments, largely dependent on the physical qualities of
the substances undergoing absorption, and especially on the permeability
of the renal cells to these substances. The physical conditions are however
subordinated to the physiological, so that a salt so diffusible as potassium
iodide is left in the fluid, while sodium chloride may be reabsorbed in large
quantities.
The necessity for the endowment of the tubular epithelium with a resorp-
tive function as well as any secretory function it may possess is determined
by the presence at the beginning of the tubule of a mechanism — the glo-
merulus, devoid of the fine selective power or chemical sensibility which
characterises the cells of the convoluted tubules. The production of urine by
the glomerulus is regulated entirely by the pressure and velocity of the blood
through its capillaries and by the colloid content of the blood plasma. We
may assume that in Bowman's capsule there is under normal conditions a
constant production of a fluid, free from protein but having the same
crystalloid concentration as the blood plasma. With any rise of general
blood pressure the amount of this transudate is increased ; with any fall it is
diminished. The small qualitative changes, which are constantly occurring
in the blood as the result of the taking of food or the activity of different
organs, probably produce but little effect on the amount of glomerular fluid.
Only indirectly, as the result of these events on the general blood pressure,
or possibly in consequence of the production of substances having a vaso-
dilator effect on the renal vessels, will the amount of the urine turned out
by the glomeruli be affected. These structures therefore have the twofold
fimction of regulating the total amount of circulating fluid and of providing
an indifferent fluid which will, so to speak, flush the kidney tubules and
carry down any constituents excreted in a concentrated form by the cells
of these tubules. The constant production of a glomerular transudate
might result, especially in terrestrial animals, in the loss to the organism of
water or, under certain nutritive conditions, of substances indispensable
THE SECRETION OF URINE
1199
as normal constituents of the serum, such as sodium chloride, which could
not be made good at the expense of the food. It is for this reason that an
absorptive mechanism sensitive to and reflecting the nutritive condition
of the whole body, especially as concerns water and salts, should be present
in the tubules.
According to Cushny, the whole of the changes by which the glome-
rular transudate is transformed into urine may be ascribed to processes
of absorption occurring in the tubules, there being no need to assume the
possession of any secretory functions by this part of the kidney. He would
indeed deny any fine discrimination to the kidney, since the fluid absorbed
is always the same whatever the needs of the organism at the moment. In
the following Table are given the changes which must be effected in the
glomerular transudate in order to transform it into urine.
67 litres plasma
contain
62 litres
filtrate
contain
in all
61 litres re-absorbed
fluid contain
1 litre urine
contains
cent. ™ aI
Per
cent.
Total
Per-
cent.
Total
Water
'92 62 1.
62 1.
_
611.
95
950 c.c.
Colloids .
8 5360 gr.
Dextrose
01 67 gr.
67 gr.
011
67 gr.
—
—
Uric Acid
0002 1-3 „
13 „
00013 0-8 „
005
0-5 gr.
Sodium .
0-3 200 „
200 „
0-32
196 „
0-35
3-5 „
Potassium
002 13-3 „
13-3 „
0019
118 „
015
15 „
Chloride
Urea
0-37 248 „
003 20 „
248 „
20 „
0-40
242 „
0-6
20
60 „
20 „
—
—
Sulphate
0003 1-8 „
18 „
—
—
018
1-8 „
It will be seen that, while there is no absorption of urea and of sulphate,
the whole of the dextrose is absorbed, a portion of the uric acid and the
greater part of the sodium, potassium and chloride. The absorbed fluid thus
resembles strongly Locke's fluid. According to this view the constituents
of the glomerular transudate, i. e. the diffusible constituents of the blood
plasma, may be divided into two classes, 'threshold substances' and
' no-threshold substances,' the former being only excreted in the urine so
far as they exceed a certain threshold value, while the others are excreted
in proportion to their absolute amount in the plasma. Thus, of the threshold
substances, the dextrose of the plasma is normally below the threshold,
and is therefore not present in normal urine. The sodium chloride also
comes within the threshold class, but its threshold is more frequently
exceeded in normal conditions, and the excess is then ehminated. When
the sugar of the plasma rises, as in diabetes, to 0-3 per cent., it appears in
the urine and then undergoes concentration just as urea does. Thus, so far
as concerns the cells of the tubules, the no-threshold substances are nut
absorbed and must all escape by the ureter, whereas the threshold bodies
1200 PHYSIOLOGY
arc absorbed in different proportions determined by their normal values in
the plasma. The tubules absorb from the glomerular filtrate a slightly
alkaline fluid containing sugar, amino-acids, chlorides, sodium and potassium
in approximately the same proportions as they are present in normal plasma.
" Thus the tubules, out of the glomerular filtrate, return to the blood the
fluid best adapted for the tissues, and allow the rest to escape. If the plasma
is too rich in sugar or chloride, the filtrate also contains those substances
at or above the threshold value. The tubules however return them at the
optimal or threshold concentrations and the remainder passes into the
ureters. If much water has been ingested and the filtrate is correspondingly
dilute, the subtraction of the optimal solution leaves the excess water in
the urine along with the urea and other waste products " (Cushny).
The power of absorption possessed by the cells of the tubules is not
indefinitely large, and the urine can therefore never exceed a certain con-
centration at which its osmotic pressure just equals the absorptive power
of the cells. This hmiting concentration differs in different animals, the cat
being able to absorb against a resistance of fifty to sixty atmospheres, while
the human kidney cannot concentrate against a resistance of more than
twenty-five atmospheres. The presence of any inabsorbable substance in
the glomerular fibrate, e.g. urea, sodium sulphate, or phosphate, must
therefore limit the absorption owing to the osmotic resistance they offered
to the absorptive powers of the cells. These substances will therefore act
as diuretics. In the same way the threshold substances will act as diuretics,
provided that they are present in the plasma in proportions above the
plasma, so that they can no longer be absorbed by the cells of the tubules.
It has been objected by Heidenhain and others to this view that, if we
exclude the occurrence of secretion by the cells of the tubules, we must
assume that, of the seventy litres passing the glomeruli in the course of
twenty-four hours, no less than sixty-eight litres must be reabsorbed in the
tubules in the formation of two litres of urine. But Cushny points out that
we have many analogies to this process in the body. Thus the hver throws
into the duodenum 500 c.c. of fluid in twenty-four hours, all of which is re-
absorbed with the exception of a little pigment. The urine of birds passes
down the ureter as a clear fluid, but in the cloaca almost all the water is
absorbed, leaving a thick paste of urine. Nor is the work out of proportion
to the mechanism provided. In a cat fed on meat, 100 c.c. of urine con-
tained as much solids as twelve litres of plasma filtrate, so that for twelve
litres filtered through the glomeruli 11-9 were reabsorbed in the tubules.
Since each kidney contains about 16,000 glomeruli, the amount of fluid
filtered by each glomerulus would amount to about -055 c.c. per hour. Of
this more than "0144 c.c. was absorbed in passing along 3 cm. of tubule,
leaving less than 1 mg. per hour from each capsule to enter the collecting
tubule (Cushny). This cannot be regarded as too severe a task either for
tha glomeruli or for the tubules.
THE SECRETION OF URINE 1201
ACTION OF DIURETICS
Attempts have been made to solve the problem of renal secretion by
studying the action of diuretics, i.e. substances which, injected into the
blood stream or absorbed from the alimentary canal, increase the secretion
of urine. These attempts have generally ended in trying to explain the
action of diuretics by the theory preferred by the experimenter. A large
increase in the urinary flow can be brought about by the intravenous injection
of saline diure tics such as sodium sulphate or potassium nitrate, of neutral
crystalloids such as urea or sugar. An increased production of urine may
be due to augmented glomerular transudation or to increased secretion, or to
diminished absorption in the tubules ; and in many cases both mechanisms
may be involved.
Three factors might' be concerned in promoting an increased glomerular
transudation. These are:
(1) A rise of pressure in the glomerular capillaries.
(2) Acceleration of the blood flow through the capillaries.
(3) Diminution of the amount of proteins in the blood plasma.
When a concentrated solution of salt is injected into the circulation, the
osmotic pressure of the plasma is . raise d and water passes from the tissue
cells into^the blood stream, in consecnience of the osmotic differences
between the blood and cells so induced. As a result the total volume of the
circulating fluid is increased by the addition to it of water derived from the
tissues, i. e. a condition (if hydraemic plethora is set up, just as if a large bulk
of normal saline fluid had been injected into the circulation. So long as
tliis hydraemic plethora continues, so long is there a rise both in arterial and
venous pressures and in the velocity of the circulating blood. The
kidney placed in an oncometer shows a gre at increase in volume. While
the plethora lasts there are mechanical conditions at work in the kidneys,
i. e. rise of pressure, greater rate of flow r , and diminished concentration
of plasma — all of which would concur in producing an increased glomerular
transudation. With certain salts, such as sodium chloride, the diuresis
may be coterminous with the hydraemic plethora, but with other members
of this class, such as grape sugar, the diuresis always outlasts the plethora, so
that the continued augmentation in the secretion of urine leads to an actual
concentration and diminution of the volume of the circulating blood, as is
shown in Fig. 548. If the kidney be placed in an oncometer, it is found that
the dilatation of the kidney outlasts the plethora, and comes to an end only
with the cessation of the increased urinary flow. Since however increased
secretion of urine involves dilatation of the tubules, and therefore
swelling of the whole kidney, the rise of the oncometer during diuresis
is no proof that there is still a greater circulation through the kidney.
In fact, however much glomerular change may be concerned in the initial
increase in the urinary flow, the terminal increase must be ascribed to the
effects of the injected substances on the tubules. As we have already seen,
every substance which is not absorbed by the tubules from the glomerular
7<;
1202
PHYSIOLOGY
filtrate must act as a diuretic, since it will oppose osmotic resistance to the
absorbing powers of the cells. Thus the no-threshold substances, urea,
and sodium sulphate, nitrate, and phosphate, will act as diuretics in any con-
centration. The threshold substances will act as a diuretic so long as their
concentration in the plasma surpasses their normal threshold value.
i
^
Ar
+
t. HP
mm
Hffi
Haeiii
--
Percent.
1
\ /
,'\
K
t *
0*
V
a>
\
1
o
-
c
_|
1
Urine
1
SO LW luij 1 10 UV 130 U0
Fig. 548. A comparison of the effects of intravenous injection of 30 grm. glucu.se
in concentrated solution on the arterial blood pressure, the concentration of the
blood, the kidney volume, and the urinary flow. Abscissa = time in minutes.
With regard to the specific diuretics, such as caffeine, the question is
not quite so clear. In most cases injection of caffeine in the rabbit brings
about a dilatation of the kidney and a proportional increase in the secretion
of urine. But cases have been recorded in which expansion of the kidney
occurred without any increase in urinary flow, and, on the other hand,
augmented urinary flow without any increase in the kidney volume or
even in the rate of blood flow through the kidney (as determined by Brodie's
method). The general rule however is that a greater rate of blood flow is
obtained pari passu with, the increased urinary flow ; and a consideration
of certain peculiarities in the renal circulation must prevent us from laying
THE SECRETION OF URINE
1203
too much stress on apparent exceptions to the rule. To the blood entering
the kidneys by the renal arteries two ways are open. The blood may pass
through the vasa afferentia, through the glomeruli and tubular capillaries,
back to the renal vein. On the other hand, it may escape the glomeruli
altogether, and pass through the vasa recta directly into the intertubular
capillaries and so into the renal veins. It is a common experience, in
injecting the blood vessels of the kidneys •post-mortem, to find the renal
arteries, intertubular capillaries, and veins filled to distension with the
injection mass, but hardly any in the glomeruli. One must assume in such
a case thai there has been spasmodic contraction of the muscular coats of
the vasa afferentia (cp. Fig. 549). The normal amount of blood might
5= ^§^
Via. f>4'J. Diagram (after Morat) to illustrate the effect of active changes in the
\.i ;a afferentia and efferent ia on the pressure in the glomerular capillaries.
If the vas afferens constricts, the pressure will be represented by the lower
dotted line. On the other hand, constriction of the vas efferens would raise
the pressure in the glomerulus till it almost equalled that in the renal artery,
as is shown by the upper dotted line.
A, arteries; o, glomerular capillaries ; c, tubular capillaries ; v, vein.
therefore circulate through the kidney without any flowing through the
filtering apparatus, i.e. the glomeruli. On the other hand, a dilatation of
the afferent vessels and a slight constriction of the efferent vessels would
cause a considerable rise of pressure in the glomerular capillaries, and a
consequent increased transudation, without necessarily altering to any
marked extent the total circulation of blood through the whole organ. The
changes hi the afferent and efferent vessels of the glomeruli are however
beyond our control or powers of observation, so that it is impossible to
devise at the present time any crucial experiment which might decide the
nature of the process occurring in the glomeruli.
On the other hand, it seems probable that many diuretics — of which
ca Heme may be i me — act by altering the activity of the tubules. If we accept
the idea that the main function of these structures is that of secretion, we
may assume that the diuretics increase their secretory power. It is more
simple however to assume that any action these substances possess on the
tubules is one of paralysis, complete or partial, of their powers of absorption.
Thus the action of phlorhizin may be assumed to paralyse the absorptive
powers of the tubular cells for glucose — i. e. to reduce glucose for this par-
ticular kidney to the state of a no-threshold substance. The glucose in the
J204 PHYSIOLOGY
glomerular transudate, in passing through the tubules, may thus be con-
centrated sixty to a hundred times. Since glucose is made in the body
and supplied to the circulating blood in proportion to the needs of the
body, so as to maintain its concentration in the plasma at a definite height,
the loss of sugar in the urine will be continued, and the percentage in the
plasma will not tend to diminish progressively with the increased secretion
of urine, as would occur for example in the case of urea. We may assume
that different diuretics have similar powers of paralysis on the absorptive
mechanisms of the tubules, either general, or confined as in the case of
phlorhizin to one or other of the normal constituents of the plasma.
SECTION III
THE PHYSIOLOGY OF MICTURITION
The urine as it is formed passes through the ureters to the bladder, where
it gradually accumulates, and is voided at intervals.
The ureters are muscular tubes lined by transitional epithelium. The
muscular coat is composed of three layers of unstriated fibres, a middle
circular coat lying between external and internal longitudinal coats. If
the ureter be exposed in the living animal, contraction waves are seen to
pass along its muscular coat from the pelvis of the kidney to the bladder,
driving the contained fluid in front of them. The frequency of the con-
tractions is increased by warming the ureter, and to a certain extent by
distension, so that the waves are more frequent when the secretion of urine
is profuse. The ureters enter the bladder at or near its base, at the two
posterior angles of the region known as the trigonum. Their entrance is
oblique, so that a valvular orifice is formed, which effectively prevents
reflux of urine from "bladder to ureter. Khythmic waves of contraction are
observed also in the excised ureters, when these are kept warm in normal
siiline solution. By Engelmann they were regarded as myogenic, since they
were present in the middle third of the ureter, which he imagined to be
entirely free from ganglion cells. As a matter of fact ganglion cells are
found throughout the ureter, though in larger numbers at its two ends. The
ureters are supplied with nerve fibres from the splanchnic nerves by way
of the renal plexus, and at their lower ends from the hypogastric nerves.
Stimulation of the latter as a rule increases the rhythm of the contraction
presented by the lower end of the ureter. The splanchnic nerves have been
-luted to produce either acceleration or inhibition of the contractions at the
upper end; their action is however uncertain. It is by the rhythmic
advancing waves of contraction of the ureter that the urine is continuously
passed on to the bladder, so that the pelvis of the kidney is kept empty of
fluid whatever the position of the animal.
The bladder is lined by transitional epithelium, closely adherent to the
underlying muscular coat. It is usual to describe in the latter three layers
of muscular fibres :
(1) An outer layer composed of bundles running longitudinally from
the neck, of the bladder to the fundus, sometimes distinguished by the
name of the detrusor urince. At the neck of the bladder these bundles send
some fibres to be attached to the pubes as the pubo-vesical muscles. On
t he dorsal surface some bundles in the male pass mi to t he prostate and the
1205
]206 PHYSIOLOGY
urerlira, while in the female I hey end in the tough connective tissue in the
met liio-vaginal septum.
(2) The middle layer, which is the thickest of the three, is composed
of fibres arranged circularly and forming a continuous layer.
(3) The inner layer is thin and incomplete, and is composed of anasto-
mosing bundles of fibres with meshes in between them which are covered
by the folds of the mucous membrane. The bundles of fibres run freely
from one layer to the other, and there is no doubt that the name of detrusor
ought physiologically to be applied to
the whole of the three coats, which act
as one in diminishing the capacity of
the bladder. At the base of the blad-
der the structure of the wall is modified
over the triangular region lying between
the orifices of the ureters and of the
Ureter-- '\^f y/ urethra (the trigonum) by the differen-
tiation here of fibres which serve as a
sphincter and prevent the escape of
Prostate- -^W s ,-» ,i , • ,.
-j&Sz^^Smssu^ urine. Over the trigonum the mucous
8l^ membrane of the bladder is smooth
\ and closely adherent to the subjacent
Fio. 550. muscular fibres, which themselves are
much more closely packed than the rest
of the bladder wall. From these muscular fibies the most important
sphincter, the sphincter trigoni, is formed. Bandies of muscle fibres pass
from the trigonal muscle obliquely forwards and downwards (the individual
being considered in the civet posture), and form a loop around the orifice
of the bladder, lying on the ventral side of the bladder below and quite
distinct from the thick coat of circular fibres belonging to the bladder itself
(ss, Fig. 550).
This sphincter is the most important mechanism for the retention of
urine. If a catheter be passed into the urethra no urine escapes until its
orifice has actually entered the bladder. The wall of the urethra is sur-
rounded by circular muscular fibres which, by their tonic contraction, will
also tend to prevent the escape of urine along the canal. This urethral
muscle is strengthened by two sphincter muscles which are voluntary and
composed of striated fibres. The chief one, which has been named by
Kalischer the sphincter urogenitalis but is better known as the compressor
urethras, forms a flat ring around the second part of the urethra, extending
in the male from the prostate to the bulb, where its function is taken up
by the bul bo-cavern osus.
The bladder is therefore supplied with a powerful muscular wall, the
contraction of which will cause its evacuation, and with sphincters of two
kinds, one involuntary, the sphincter trigoni, at the upper neck of the
bladder, and two voluntary, the sphincter urogenitalis and buJbo-cavernosus
muscles, which can empty the lower parts of the urethra.
THE PHYSIOLOGY OF MICTURITION
1207
The nerve supply of the bladder (Fig. 552) is derived from two main
sources, namely, from the upper four lumbar nerves through the sympa-
thetic svstem, and from the second and third sacral nerves by means of
>n\><;< t iiUili<
Circular coat
T-ongitudinal coat
Sphincter trigoni
Circjlar coat
Longitudinal coat
Sphincter Iriga
l 'ircular coat
Longitudinal coat
Sphincter trigoni
l-ougitudiual muscle
I'ig. 561. Sagittal sections through neck of bladder.
(Metznkr after Kalischer.)
\. in middle line (male); B, slightly to left of middle lino (male);
C, ditto (female).
the pelvic viscera] nerves or nervi erigenles. The upper lumbar nerves
send white, rami communicantes to the lateral chain of the sympathetic,
and thence to the collateral ganglia, which are grouped round the inferior
mesenteric artery to form the inferior mesenteric ganglion. Most of the
fibres end in this collection <>i ganglion cells, and a, new relay of axons passes
1208
PHYSIOLOGY
by two main trunks, the hypogastric nerves, into the pelvis on each side of
the rectum and ends in a plexus, the hypogastric plexus, at the base of the
bladder. From this plexus fibres pass to the bladder wall. The pelvic
visceral nerves are derived from the second and third sacral nerves. They
make no connection with the sympathetic system, but pass directly to the
3rd lamb pert.
Sup. mes. nerves . .
Median mes. nerves
Inf. mes. nerves ..
Inf. mes. ganglion ,
Hypogastric nerves
Fig. 552. Nerve supply to bladder of eat. (Nawrocki and Skabitschewsky.)
hypogastric plexus and are carried with branches of this plexus to the neck
of the bladder. The fibres do not run directly from the spinal cord to their
ending in the bladder wall, but make connection with cells situated peri-
pherally, partly in the hypogastric plexus, but chiefly in the walls of the
bladder itself. Both sets of fibres supply also the rectum and the colon,
and carry efferent impulses to the bladder. Afferent impulses from the
bladder travel chiefly in the pelvic visceral nerves.
THE PHYSIOLOGY OF MICTURITION 1209
THE FILLING OF THE BLADDER
Under normal circumstances the sphincters at the neck of the bladder are
in a state of tonic contraction, presenting a resistance to the emptying of
tins organ which will vary according to their degree of contraction. Thus it
requires a considerably greater pressure in the bladder to overcome the
resistance of the sphincters during life than after death of the animal. In
some cases after death they may permit the passage of urine when the
pressure of the bladder is only about 20 mm. water, whereas in the normal
animal the pressure has as a rule to be at least 160 mm. of water before any
escape takes place. The urine therefore as it is secreted must accumulate
and distend the bladder. The bladder wall reacts to a distending force
in the manner which is characteristic of all muscular tissue, especially
lmstriated. An extending force applied to an unstriated muscle fibre has
a double effect. In the first place, if the stretching force is applied very
slowly, a considerable increase in length of the muscle may occur with the
U 3
20" ►
Fig. 553. Tracings of rhythmic contractions of urinary bladder.
('Sherrington.)
application of a very small amount of force. If however the force be
applied more rapidly, the sudden increase of tension acts as a direct excitant
to the muscle, causing it to enter into contraction, which may be tonic or
rhythmic. The effect of the entry of urine into the empty bladder on the
tension in this organ will depend therefore on the rapidity with which the
kidneys are secreting. Under normal circumstances micturition occurs
in man when the intravesical pressure has risen to about 150 mm. water.
Under these conditions the bladder will contain between 230 and 250 c.c.
of urine. If however the secretion of urine has occurred very rapidly, the
same pressure may be attained with a much smaller bladder content, and if
the bladder be artificially distended by the injection of fluid through a
catheter, 50 c.c. of fluid may suffice to raise the pressure to this level. As the
urine is slowly secreted, the bladder wall at first gives to the incoming fluid,
so that a considerable amount can be stored without any marked rise of pres-
sure Later on the pressure begins to rise more rapidly, and finally attains
a pressure of between 120 and 150 mm. water. At this point the second
effect of the stretching of the muscular wall makes its appearance. A mano-
meter connected with the bladder shows a series of rhythmic contractions
of the muscular wall (Fig. 553^, each lasting about a minute, at first slight
1210 PHYSIOLOGY
in extent, but becoming more marked as the distension of the bladder
augments. In a bladder entirely cut off from its connection with the
central nervous system, these automatic rhythmic contractions gradually
increase in force until one of them suffices to overcome the resistance pre-
sented by the tonically contracted sphincter. A partial emptying of the
bladder therefore takes place, but the pressure falls below that necessary to
overcome the resistance of the sphincter before the bladder has been quite
emptied, so that there is always under these circumstances a certain amount
of residual urine left in the bladder. This is the condition found in animals
where the lower part of the spinal cord has been extirpated, or in man where
the same part of the central nervous system has been destroyed as the result
of accident or disease.
THE MECHANISM OF EVACUATION OF THE BLADDER
In the denervated bladder the factor finally causing partial evacuation
is the gradual increase in the intravesical tension from the accumulation of
fluid in this viscus. The same factor is prepotent in determining the onset
of normal micturition in an animal with the nervous connections of its
bladder intact. Apart from the control of the higher centres, micturition
will take place each time that the tension in the. bladder has reached a
certain height, i. e. about 15 cm. water, the amount of fluid in the bladder
at the time depending on the one hand on the rate at which the fluid has
entered this organ from the ureters, on the other hand on the irritability
of the bladder wall itself and of the nervous centres concerned with its motor
innervation. The effect of the gradual accumulation of fluid and rise of
tension is twofold. In the first place, it acts on the bladder wall, causing
rhythmic contractions of ever-increasing intensity; in the second place, the
mere stretching of the bladder originates impulses in the sensory nerve-
endings in its wall, which are reinforced at every rise of tension caused
by the rhythmic contractions. These impulses travel up to the spinal
centres, and are summated until they result in a sudden discharge of efferent
impulses of two kinds, namely :
(1) Motor impulses to the whole musculature of the fundus of the
bladder (the detrusor in its widest sense) ;
(2) An inhibition of the tonic contraction of the sphincter. This in-
hibition may be determined by inhibitory impulses travelling to the sphincter
and causing its relaxation, or by the central inhibition of the impulses
normally going to the sphincter and maintaining its tonic contraction. The
resultant of these two processes, the contraction of the detrusor and the
relaxation of the sphincter, is a complete emptying of the bladder, and the
act is completed by the contraction of the involuntary and voluntary
muscles surrounding the urethra and causing complete expulsion of the
contents of this tube.
THE PHYSIOLOGY OF MICTURITION 1211
THE INNERVATION OF THE BLADDER
ACTION OF THE PELVIC VISCERAL NERVES. In all animals ex-
citation of the peripheral end of one pelvic visceral nerve causes a strong
contraction of the same side of the bladder, involving all its coats and some-
thnes extending to a slight extent to the contralateral half of the bladder.
When both pelvic nerves are stimulated simultaneously, contraction of both
sides of the bladder causes a considerable rise of pressure in its interior
(Kg. 554) which is always sufficient to overcome the resistance of the
sphincter and to cause a complete emptying of the bladder. There is no
doubt therefore that these nerves are the most important for the act of
micturition. As to the action of these nerves however on the sphincter, the
results of different experimenters are somewhat at variance. In the cat
there seems 1" !><• no doubt thai inhibition of the sphincter may result from
Fig. 554-. Curve showing rise of pressure in tin: bladder caused l>\ .stimulation
of S, sacral nerves ; h, hypogastric nerves. ( Fagck.)
The scale indicates centimetres of water.
stimulation of the pelvic visceral nerves. On the other hand Fagge,
working on the dog, found that, although micturition was excited by the
stimulation of these nerves, the expulsion of urine did not occur until the
intravesical tension had reached the point at which the resistance of the
sphincter could be overcome without any alteration of its state of con-
traction, i. e. the point at which fluid injected into the bladder through
the ureter began to escape from the urethra without stimulation of any
nerves whatever.
Observation:; on man would support the view that an active relaxation of
the sphincter trigoni is a necessary part, of the act of micturition. Thus in
experiments by Reyfisch a rigid catheter was introduced into the bladder,
which was fully distended with fluid. On withdrawing the catheter until its
opening lay just outside the bladder in the posterior urethra, the flow of
urine stopped. The man however was able to micturate directly he was
told to, and, to stop again at will. It was impossible in this case for
any of the urethral muscles to be concerned, since the rigid catheter
1212 PHYSIOLOGY
impeded their action. The relaxation of the sphincter must therefore
be brought about by impulses descending the pelvic visceral nerves,
which we may regard as motor to the detrusor and inhibitory to the
sphincter of the bladder.
Section of the nerve on one side causes no abnormality in micturition.
After three weeks, stimulation of the intact nerve causes contraction of the
whole bladder, owing to the outgrowth of preganglionic fibres from the sound
trunk to the decentralised ganglia of the opposite side (Elliott). Section of
both nerves paralyses micturition, but power of partial evacuation of the
bladder may return in a few weeks. If now the hypogastrics be cut, or
even the sacral cord extirpated, the bladder is not completely paralysed, but
its evacuation becomes unconscious and incomplete.
ACTION OF THE HYPOGASTRIC NERVES. These nerves, which
are derived from the sympathetic system, show marked differences in their
action, according to the animal which is the subject of investigation. In
the dog the hypogastric nerves cause a strong contraction of the muscle
fibres at the base of the bladder, especially of the trigonum and of the
sphincter trigoni. When these nerves are stimulated simultaneously with
the pelvic visceral nerves, a great rise of intravesical tension may be induced
without any flow of urine taking place. In some cases prolonged stimulation
of these nerves in the dog causes apparently an active relaxation of the
sphincter of the bladder. On the other hand, in the rabbit and the cat
these nerves cause an inhibition of the bladder wall. In other animals
they may excite either contraction or relaxation (or both) of the detrusor.
They always contain motor fibres to the sphincter of the bladder as well as '
to the constrictor fibres surrounding the urethra. Where this effect is
tonic, micturition must be associated with a central inhibition of their tonic
activity. On the other hand, the retention of urine and the distension of
the bladder may be aided by a reflex dilatation of the bladder wall and a
reflex constriction of the sphincter, in each case excited through these nerves.
Normally therefore both sets of nerves are called into action. The hypo-
gastrics play an especially active part during the accumulation of mine
in the bladder, while the pelvic visceral nerves are necessary for the complete
evacuation of the bladder which occurs at micturition.
THE CENTRAL CONTROL OF THE BLADDER
The nerve centre which presides over the tonus and contraction of the
bladder is situated in the lumbo-sacral spinal cord. If this centre and its
connections be intact, micturition may be carried out normally even after
section of the cord in the dorsal region. The centre can be excited reflexly
by stimulation of almost any sensory nerve, such as the sciatic or the fifth
nerve. In many cases where, in consequence of obstruction to the passage
of impulses from the higher parts of the central nervous system, micturition
is delayed, this act may be excited by the application of^cold or hot
sponges to the perineum, and it is well known that almost any irritation
THE PHYSIOLOGY OF MICTURITION 1213
of the pelvic organs in children may give rise to reflex involuntary
micturition.
In the adult the processes of retention and evacuation of urine are
modified and controlled by voluntary effort. The normal action of the
sphincter mechanism may be aided by the contraction of the perineal
muscles which keep the urethra closed. The reflex process of evacuation
may be set in motion by voluntary contraction of the abdominal muscles,
by which the pressure in the bladder is increased and the normal sphincter
act lob overcome. It is probable too that the individual has a certain degree
of voluntary power over the unstriated muscles of the bladder, and that the
contraction of the muscular wall may be directly augmented by impulses
proceeding from the cortex to the upper part of the lumbar cord. This view
is favoured by the fact that stimulation of the crus cerebri has been observed
to cause contraction of the detrusor urinse. In this experiment the abdo-
im 11 was opened, so there could be no question of the contraction of the
abdominal muscles.
CHAPTER XVIII
THE SKIN AND THE SKIN GLANDS
In all classes of animals the skin performs two functions. In the first place,
it serves to protect the more delicate underlying parts from injury and
from penetration or invasion by foreign organisms. In the second place,
it serves as a sense organ, and is richly supplied with nerves, by means of
which the activities of the body as a whole may be brought into relation
with the changes going on in the environment and affecting the external
surface of the body. In warm-blooded animals the skin plays an important
part in the regulation of the body temperature, since the loss of heat from
the body must occur almost entirely through its surface. In the present
chapter we have to deal only with the first and third of these functions.
The development of the skin as an organ of protection shows wide modification in
various classes of animals. Thus it may become the seat of formation of horny plates,
as in the alligator ; of poisonous glands, as in the toad ; or of mucous glands, as in many
varieties of fishes. In warm-blooded animals the development of hair from the deeper
layers of the epidermis serves to diminish the loss of heat. Since the hair follicles are
richly supplied with nerve fibres, the hairs act also as organs of sensation. In man,
where the hairs are rudimentary except in certain localities, practically only this
tactile function is retained. The external layer of the skin in man consists of a tough
horny layer formed by the kcratinisation of the external layers of cells of the epidermis.
The skin is composed of two parts, the epidermis and the cutis (Fig. 555). The epidermis
is a stratified squamous epithelium. The deeper layers form the rete mucosum, being
soft and protoplasmic, while the superficial layers forming the cuticle are hard and horny.
The most superficial layer of the rete mucosum is formed of flattened cells filled with
granules of a material staining deeply with kaeraotoxylin and eosin, known as eleidin.
This layer is called the stratum granulosum. Immediately superficial to this layer is
another in which the cells are indistinct. The cells are clear in section and form what
is known as the stratum lucidum. These two layers evidently constitute the inter-
mediate stages in the transformation of the cells of the rete mucosum into the horny scales
which make up the superficial cuticle. The cutis or coriurn is composed of dense con-
nective tissue, which becomes more open in texture in its deeper part, where it merges
into the subcutaneous connective tissue. The most superficial layer of the corium is
prolonged into minute papilla; over which the epidermis is moulded. These papillae
contain for the most part capillary vessels; a few contain touch corpuscles, special
organs of tactile sensation. The blood vessels of the skin form a close capillary network
immediately at the surface of the cutis, sending up loops into the papillae. All parts
of the skin, except the palms of the hands and the soles of the feet, are beset with hair
follicles. The hair follicles are small pits which extend downwards into the deeper
part of the corium, being downgrowths of the rete mucosum. The hair grows from
a small papilla of cells at the bottom of the follicle, the part of the hah- lying within the
follicle being known as. the hah' root. The hair itself consists of long tapering, horny
cells, the nuclei of which are still visible, though the cell substance has been almost
entirely converted into keratin.
1214
THE ,SK1N AIN1) THE SKIN (i LANDS
1215
In order to keep the cuticle supple and preserve it from the drying
effects of the atmosphere, it is kept constantly impregnated with a fatty
material known as sebum. This material is formed by the sebaceous glands,
which are distributed all over the surface of the skin wherever hair follicles
are to be found, the mouths of the glands opening into the hair follicles. A
sebaceous gland is a pear-shaped body, consisting of a secreting part and a
short neck opening into the follicle. The gland proper is composed of a
solid mass of cells. The outermost cells are flattened and generally show
Stratum
corneum
Stratum
lucidum
Stratum
'j^anulosum
'• -Jss
*
Ecto
mucodum
i'lc;. 550. Vertical section through the skin of the palmar side of the linger, showing
two papilla (one of which contains a tactile corpuscle) and the deeper layer of
the epidermis. Magnified about 200 diameters. (Scuafee).
signs of proliferation. The cells lying internal to these are much larger,
and their protoplasm is transformed into a network, in the meshes of which
are granules which may show the reaction of fat. Further inwards the
protoplasmic network diminishes in amount, wliile the fatty granules increase
in size, so that, in the lumen adjoining the duct, we find only a mass of cell
debris and masses of fatty material. It has often been thought that the
secretion of sebum depended simply on a fatty degeneration of the cells.
The granules however, when they first appear, stain with acid fuchsin
rather than osmic acid, and one must regard the formation of sebum as an
act of true secretion , in which the secretory granules are gradually trans-
formed into the special constituents of the sebum. For it must be noted
that the sebum is not a true fat, nor does it correspond in composition with
1216 PHYSIOLOGY
the lai found in other parts of the body. It is true that it contains fatty
acids. Imi these are lor ihe most part in combination, not with glycerin bill
with higher alcohols, including cholesterol. A somewhat similar material,
known as wool-fat or lanoline, may be extracted from wool as well
as from the feather-glands of water birds, such as the goose and duck, ll
must be regarded rather as a wax than a fat. It presents many advantages
over ordinary fat as a protective salve for the surface of the body. In the
first place, it can take up a large amount, as much as 100 per cent., of water.
In the second place, it is not attacked by micro-organisms, so that it does
not tend to become rancid or to furnish a nidus for the growth of these
organisms on the surface of the body.
The secretion of sebum is a continuous process, though it is probably
quickened in conditions of increased vascularity of the skin. The extrusion
of the products of secretion is determined by the presence of unstriated
muscle fibres, the arrector pili, which pass from the surface of the cutis
obliquely over the outer surface of the sebaceous gland. When these muscle
fibres contract, the hair is erected and a certain amount of the sebum
squeezed out on to the root of the hair and the surrounding skin. This
contraction will occur whenever cold is suddenly applied to the skin. The
contracted condition of all the muscles of the hair follicles is shown by the
' goose-skin ' produced under such circumstances. There is no evidence
that the secretion of sebum is in any way under the control of the central
nervous system.
THE SWEAT GLANDS. Under normal circumstances in temperate
climates the greater part of the water taken in with the food in the course
of the day is excreted by the kidneys, a smaller proportion leaving by the
lungs and by the surface of the skin. On an average we may say that about
700 c.c. are got rid of through the skin. The excretion of water by the skin
is however mainly determined by the need for regulating the temperature
of the body, so that the amount leaving in this way depends on the heat
production of the body or on the external temperature, and is very little
affected by alterations in the quantity of fluid drank. A certain amount of
water is constantly evaporated from the surface of the body as the so-called
' insensible perspiration.' If a man's body be enclosed in a vessel through
which a current of air is parsed, and the temperature of the air gradually
raised, it will be noted that the amount of water given off rises slowly up
to a certain degree and then rises rapidly. The sudden kink in the curve
is due to the setting in of the activity of the sweat-glands, and we are
therefore justified in regarding the insensible perspiration as being de-
termined by evaporation of water from the surface of the cuticle itself, apart
altogether from the sweat glands. These are distributed over the whole
surface of the skin, and are especially abundant on the palm of the hand
and on the sole of the foot. They are composed of single imbranched
coiled tubes, which lie in the subcutaneous tissue and send their ducts up
through the cutis, to open on the surface by corkscrew-like channels which
pierce the epidermis. The secreting part of the tube consists of a basement
membrane fined by a double layer of cells; the innermost of these are
THE SKIN AND THE SKIN GLANDS 1217
cubical and represent the secreting cells proper. Between the secreting
cells and the basement membrane is a layer of unstriated muscle fibres.
The duct of the gland has an epithelium, consisting of two or three layers of
cells with a well-marked internal cuticular lining, but there, is no muscular
layer.
The sweat formed by these glands is the most dilute of all animal fluids.
As collected it generally contains epithelial scales and some admixture of
sebum. After filtration it forms a clear colourless fluid of a specific gravity
of about 1003. It contains over 99 per cent, of water. Among the solid
constituents sodium chloride is the most prominent — it may contain from
0-3 to 0-5 per cent, of this salt. It is generally hypotonic as compared with
the. blood plasma. It may also contain small traces of protein. This
constituent is especially marked in the horse. It generally contains also a
small quantity of urea, which may become a prominent constituent in cases
of renal disease. The quantity of sweat excreted in the day is very variable.
The secretion is under the control of the central nervous system and is
almost entirely adapted to the regulation of the body temperature. The
nervous mechanism can be set into activity either centrally or reffexly.
The most usual factor is a rise of the body temperature. If a man sit in a
warm room, e. y a
number of collections of chromaffine cells lying in close j uxtapcsition to the spinal nerves.
In some animals accessory suprarenals are not infrequent in which both cortex and
medulla may be represented. In all animals we find masses of tissue,' the so-called
paraganglia, in close association with the sympathetic system, which present the chro-
maffine reaction typical of the medulla. Since a watery extract or decoction of these
bodies has the same influence on injection into the blood stream as an infusion of the
medulla of the suprarenal body itself, we are probably justified in regarding these bodies
as equivalent to accessory medullary portions of the suprarenal. They have the same
origin, the same staining reactions, and the same physiological effect as the latter.
The functions of the suprarenal bodies were a matter of pure hypothesis
before Addison in 1850 drew attention to the coincidence of degenerative
destruction of these bodies witli a disease which has been known since that
time as Addison's disease. The three cardinal symptoms ol this disorder
are (1) bronzing of the skin, (2) vomiting, (3) excessive muscular weakness
and prostration. The disease is almost invariably fatal. Addison's observa-
tions have been amply confirmed since that time, but we are not yet in a
position to account for the occurrence of all these symptoms as a result of
interference with the cortex and medulla of the suprarenals. The experi-
mental destruction or extirpation of these bodies has naturally been
frequently carried out. The operation always leads to the death of the
animal within twelve to twenty-four hours. Even when the destruction is
carried out by degrees it has been impossible to reproduce the bronzing
which is so characteristic of Addison's disease. The one symptom which
is observed as a result of the experimental extirpation is the excessive pros-
tration, which is attended with muscular weakness and a lowered blood
pressure. In a few cases it has been found possible to keep rats alive after
total extirpation of these organs, but this result is probably due to the
frequent presence in these animals of accessory suprarenals.
Schafer and Oliver in 1894 found that a watery extract or decoction of
the suprarenal bodies, when injected into the circulation, caused a very great
rise of blood pressure, brought about chiefly by constriction of all the blood
vessels of the body. The active substance responsible for this rise was
limited entirely to the medulla, infusions of the cortex being without influence
on the blood pressure. Later on Takamine succeeded in isolating the active
substance, to which he gave the name of adrenaline, and since that time
physiological chemists have succeeded not only in determining the consti-
tution of adrenaline but also in preparing it synthetically. The constitution
of adrenaline is shown by the following formula :
HO_
HO<^ J>— CH(OH)— CH 2 NHCH 3
Since it possesses an asymmetric carbon atom, a substance of this formula
may be either lsevo- or dextrorotatory. Both forms, as well as the racemic
modification; have been prepared synthetically. The substance which
occurs in the suprarenal gland is the Isevorotatory modification, and Cushny
has shown that it is only this modification which is active, injection of the
THE DUCTLESS (I LANDS 1235
dextrorotatory compound having only one-twelfth, the effect of the lsevo-
rotatory. Adrenaline is active in excessively minute doses, injection of
one four-hundredth of a milligramme per kilo, body weight sufficing to evoke
a definite rise of blood pressure. On injecting it into the circulation there is
immediately a rise of blood pressure which, if the vagi are intact, is only
moderate in amount but is accompanied by a marked slowing of the heart.
This excitation of the vagus is however probably secondary to the rise
of blood pressure and is not due to direct action of the drag on the vagus
centre. If the vagi be divided, the injection of adrenaline evokes a huge
rise of pressure which may amount to 301) nun. Hg. It may indeed be so
great that the animal dies from heart failure or from pulmonary oedema.
The rise of pressure is observed even after destruction of the central nervous
system. The action is not limited to the blood vessels. It has been
shown by Langley and by Elliott that adrenaline injected into the circu-
lation arouses every activity which can be normally excited by stimulation
of the sympathetic system. A list of the actions of adrenaline is therefore
identical with a list of the chief functions of the sympathetic nervous
system. In the head it causes dilatation of the pupil, secretion of saliva,
and erection of the hairs. On the heart it has a strong augmentor and
accelerator influence, so that this organ beats more effectively as a rule
even against the enormously increased resistance offered by the constricted
arterioles. Whereas a rise of blood pressure generally causes increased
systolic volume of the heart, we may rind after an injection of adrenaline and
during the height of the rise of blood pressure that the heart empties itself
more effectively than it did before the injection. On the lung vessels
adrenaline has probably a slight constrictor influence. With regard to the.
vessels of the brain, we find the same divergence of opinion as in the case of
excitation of possible vaso-motor nerves to this organ. Some observers,
mi perfusing the brain with defibrinated blood, have obtained constriction
on adding adrenaline to the perfused blood, while others have been unable to
obtain any positive results in this direction. In the abdomen intravenous
injection of adrenaline causes complete relaxation of the musculature of
the stomach, small and large intestines, but~contraction of the ileocolic
sphincter. On the bladder its effect varies according to the animal studied,
but in every case is identical with that obtained by stimulating the hypo-
gastric nerves. It lias been shown by Dale that adrenaline may also excite
vaso-dilator fibres or produce vaso-dilator effects when such effects are also
obtained from stimulation of the sympathetic nerves. In order to evoke
these results it is necessary to paralyse the vaso-constrictors by the injection
i if ngotoxin, one of the active principles of ergot. This drug, when injected,
causes first active vaso-constriction and rise of blood pressure, followed by
paralysis of the vaso-constrictor mechanism. Excitation of the splanchnic
nerves or injection of adrenaline will now bring about a fall of blood pressure
due to dilatation of the vessels in the splanchnic area.
The point of attack of the adrenaline appears to be in the muscular
or glandular tissues themselves, since it may be obtained not only after
1236 PHYSIOLOGY
destruction of the cord and sympathetic plexuses but even after tune has been
allowed for the peripheral (post-ganglionic) fibres to degenerate as a result of
extirpation of the corresponding ganglia. Although the effect is not altered
under these circumstances, and it may still produce either relaxation or
contraction of muscles according to the original action of the sympathetic
on these fibres, we are not justified in regarding it as acting on the contractile
material of the cells themselves. Rather must we assume with Langley and
Elliott that the action of adrenaline is on some substance mediating between
the nerve and the responsive tissue. We may speak of this reactive material
as the receptor substance (Langley), or we may locate it in the situation
where the nerve joins the muscle or gland cell, and describe adrenaline as
acting on the myoneural junction.
Each suprarenal receives a number of filaments from the splanchnic
nerve on its own side. These pass to the medulla where they end apparently
without the interposition of any ganglion cells on their course (Elliott), the
cells of the medulla having themselves been developed by a modification of
sympathetic ganglion cells. Stimulation of the peripheral end of the
splanchnic nerve causes, as we have already seen, a discharge of adrenaline
into the blood stream. This discharge accoimts for the secondary rise,
often accompanied with quickening of the heart, observed on a blood-
pressure tracing as the result of stimulating the splanchnic nerve. Through
the splanchnic nerves a discharge of adrenaline can be excited by many
general conditions, such as pressure on the brain, puncture of the fourth
ventricle, administration of anaesthetics, mental disturbances such as excite-
ment or fright. Such a discharge is an important element in the adaptation
to environmental stress and enables the animal to react for the preservation
of its life either by offence or flight. If one splanchnic nerve be cut before the
administration of anaesthetics or the maintenance of a condition of irritation
or fright, the suprarenal gland on the corresponding side will be found to
contam two or three times as much adrenaline as the gland which has been
left in coimection with the central nervous system. It is interesting that
no such condition of exhaustion can be produced by electrical stimulation of
the peripheral end of the divided splanchnic. It has been suggested
therefore that the splanchnic nerve contains two sets of fibres, anabolic
and catabolic, that only the latter are stimulated by central irritation,
whereas electrical stimulation, exciting both sets of fibres, causes an increased
production of adrenaline in the gland, which exactly keeps pace with the
increased output.
When adrenaline is injected into the blood stream the effect is only
temporary. It is not excreted in the urine, but rapidly disappears from the
blood. Since it is easily oxidised and is extremely unstable in alkaline
solution, we may conclude that after performing its excitatory function it is
destroyed by oxidation in the fluids. Adrenaline is thus a typical hormone,
a body of comparatively low molecular weight, having a drug-like excitatory
action on specific tissues of the body, easily diffusible, and rapidly destroyed
after discharging its office.
THE DUCTLESS GLANDS 1237
Owing to the rapid destruction of adrenaline, relatively enormous doses have to be
given by the mouth in order to produce any effect on the blood pressure. There is
however a whole series of substances, more or less allied to adrenaline in chemical con-
stitution, which undergo less rapid destruction and can therefore be administered
as drugs in the usual way. Dale and Barger have recently described three such sub-
stances as occurring in infusions of putrid meat and as forming the most important of
the active principles of ergot. The constitution of these substances is shown in the
following formula? :
CH 3\
)CHCH,CH 2 NH, Isoamylamine
CH 3 /
HO<^ \— CH,CII 2 NH 2 p-hydroxyphenylethylaniine
/ \
_/
CH,CH 2 NH, phenylethylamine
N /
HO
HO' y— CH(OH)CH.,NHC'H 3 adrenaline
The formula of adrenaline is placed below in order to show the relation of these
substances to the natural hormone. These bodies are produced from the amino-acids
of proteins by a process of decarboxylation. Leucine would yield isoamylamine,
tyrosine, hydroxyphenylethylamine, and phenylalanine would give phenylethylamine.
Such substances may be formed in minute quantities dining the normal processes of
putrefaction which occur in the alimentary canal.
There seems little doubt that we must regard adrenaline as a true internal
secretion, and therefore must ascribe to the medulla of the suprarenal capsules
as well as to the other chromaffine tissue in the body, the function, of main-
taining the normal constriction of the arterioles and of facilitating hi some
way or other the functions of the sympathetic system generally. The
absence of this secretion in cases of destruction by disease of the suprarenals
would serve to account for the weakness, prostration, and lowered blood
pressure of Addison's disease. The two other symptoms of this disease,
namely, bronzing and vomiting, still remain to be accounted for. It is
possible that the latter may be due to some involvement by the. morbid
process of the numerous fibres of the solar plexus, which run in close
proximity to the suprarenals. We have no knowledge whatsoever of the
functions of the cortical portion of these organs. It is possible that future
work may show some connection between the cortex and the destruction of
pigment in the body. At present it is only by a process of exclusion that
we may guess at a causal relationship between the destruction of the cortex
and the bronzing which occurs in Addison's disease.
There seems little doubt that the rapidly fatal effects of extirpation of
both suprarenals is to be ascribed rather to the removal of the cortex than of
the medulla. The functions of the latter can be more or less effectively
maintained by the other chromaffine tissues found at the back of the
abdomen. Tn the few cases, where animals have survived double extirpation,
small masses of accessory cortical substance have been found embedded in
1238
PHYSIOLOGY
the kidney or elsewhere in the neighbourhood of the suprarenals. Hyper-
trophy or a tumour of the suprarenal bodies, involving the cortex, has been
found associated in children with premature sexual maturity.
Fig. 559.
Section of thyroid gland of dog.
(Swale Vincent.)
THE THYROID GLAND AND THE PARATHYROIDS
The thyroid gland consists of two oval bodies lying on either side of the trachea,
joined in many animals across the trachea by an isthmus. Surrounded by a capsule
of connective tissue, it is made up of
an aggregation of vesicles varying in
size from 15 to 150/4. The vesicles
are lined by a single layer of cubical
epithelial cells, and are tilled with a
translucent material known as colloid
(Fig. 559), Of the cells, some present
granules and resemble the cells of a
secreting gland, while others contain
masses of colloid, or have undergone
colloidal degeneration. Between the
vesicles may be seen, here and there,
solid masses of cells which by some
observers are regarded as destined to
replace vesicles the epithelium of which
has undergone complete degeneration.
The colloid matter can be traced be-
tween the cells into the lymphatics
lying between the vesicles. Since the
gland possesses no duct, it is supposed that the cells furnish an internal secretion,
which makes its way into the blood along the lymphatic efferents of the gland.
The thyroid is richly supplied with blood by the superior, middle, and inferior
thyroid arteries, and is surrounded with a plexus of veins lying immediately under
the capsule. In development the thyroid is formed by an outgrowth from the fore-
gut, but the connection with the gut disappears long before the end of foetal life.
In rare eases part of the duct may persist and, becoming gradually filled with fluid,
give rise to a hyoid cyst which lies below the tongue and may require excision by
the surgeon.
As in the case of the other ductless glands, clinical observations have
contributed materially to our knowledge of the functions of the thyroid.
Although the gland had been extirpated in animals by Astley Cooper and
by SchifEj the attention of physiologists and medical men was especially
directed to the importance of this organ by the observations of surgeons,
especially Kocher, on the untoward and even fatal effects following its
complete removal in man in operations for extirpation of goitre. In this
country attention had already been called to the connection of a disturbed
condition of metabolism known as mvxoedema with atrophy of the thyroid.
A patient affected with mvxoedema presents a gradually increasing blunting
of his or her mental activities; speech is slow, cerebration delayed. With
this nervous defect are associated changes in the connective tissues, the
subcutaneous connective tissue becoming thickened, so that the face and
hands appear swollen and puffy, looking at first sight as if oedema were
present. The swelling is however due to newly formed connective tissue
THE DUCTLESS GLANDS 1239
and not to the presence of an excess of interstitial fluid in the tissues. The
patient often has a yellow waxy appearance with a patch of colour on
the cheeks. The hair falls out, the pulse is slowed, and the temperature
tends to be subnormal owing to the diminution of the rate of metabolism in
the body. The intake of food and the excretion of urea are diminished.
If the atrophy of the thyroid occurs in early life during the period of growth,
e.g. in young children, the growth of the skeleton practically ceases. The
bones of the limbs may grow in thickness but not in length. There is
early synostosis of the bones of the skull and complete cessation of develop-
ment of mental powers. Children so affected may live for many years, but
when twenty-five or thirty present still a childish appearance (Fig. 560, c).
Stunted, pot-bellied, and ugly, they have the intelligence of a child of four
or five. They often present fatty tumours above each clavicle, and similar
subcutaneous tumours of fat or loose fibrous tissue are found in cases of
myxoedema in the adult.
When the thyroid is extirpated in man the result is often the production
of typical myxoedema. In some cases, especially in young individuals, the
results are more severe, a condition of tetany being set up in which there an 1
tunic spasms of the muscles of the body, especially of the extremities. When
the thyroid gland is extirpated in animals the results more closely resemble
these acute cases. In certain instances a chronic condition of malnutrition is
set up. but a tvpical myxoedema with thickening of the subcutaneous tissues
by new growth of connective tissue has been described by Horsley only in
monkeys. The effects are more pronounced in carnivora than in hcrbivora.
In the former a condition of tetany is produced, accompanied with
muscular tremors and clonic convulsions which come on at intervals and
may be accompanied with severe dyspnoea leading to death within fourteen
davs. In herbivora, wasting, diminution of respiratory exchange, and
disorders of nutrition are often the most prominent symptoms. These
results were ascribed by Munk to interference with the recurrent laryngeal
nerves during the operations, but the observations on man leave very
little doubt that they are due entirely to the removal of the chemical
influence of the thyroid gland. Many authorities were at first inclined to
ascribe these results in man and animals to the circulation in the blood of
toxic substances which would normally undergo destruction in the thyroid
gland. This theory is put out of court by the results of administration of
thyroid eland to patients with myxoedema or to animals deprived of their
thyroids. Schiff first showed that the effects of extirpation of the thyroid
might be prevented if, at the same time, the thyroid from another animal
were transplanted into the subcutaneous tissue to take the place of the one
removed. On removing the transplanted thyroid, the typical symptoms
of thyroid destruction at once ensued. It was later found that similar
good results could be obtained by subcutaneous injection of the expressed
juice of the thyroid, and later that even this was not necessary, and that it
was sufficient to administer the thyroid gland, either fresh, dried, or partially
cooked, by the mouth. The administration of the thyroid gland in this way
1240
PHYSIOLOGY
is indeed one of the therapeutic triumphs of the last twenty years. An ugly
and idiotic cretin can be converted by this means into a child of ordinary
intelligence with normal powers of growth (Fig. 560). Given to myxcedemic
patients, the thyroid gland reduces the swelling of the subcutaneous tissues,
causes a new growth of hair, and restores the patient to his or her former
state of mental health. Nor is the thyroid gland without influence on the
healthy individual. If given in large doses either to man or animals, it
quickens the pulse, even causing violent palpitation, and increases the meta-
bolic activities of the body, so that the appetite is increased, the nitrogenous
output rises above the intake, and the subcutaneous fat is diminished 01
Fig. 560. a, a cretin, 23 months old. E, the same child, 34 months old, after ad-
ministration of sheep's thyroids for 11 months, c, a cretin, untreated, 15 years
Old. (W. OSLBB.)
disappears. It is possible that a moderate degree of thyroid inadequacy is
not infrequent and that the beneficial effects on general health, in removing
excessive corpulence and in promoting the growth of hair, which are observed
on administering the drug to people of middle life, may be due to the
actual replacement of a function which is being insufficiently discharged.
The symptoms caused by excessive doses of thyroid gland are strikingly
similar to those occurring in the disease known as exophthalmic goitre,
where there is a true hypertrophy of the gland associated with cardiac
palpitation, proptosis (bulging of the eyes), wasting, and muscular weakness.
All these facts warrant us in including the thyroid body among the
glands with an internal secretion, the presence of which in the blood stream
is a necessary condition for the normal growth and functions of almost all
the tissues of the body. If this secretion is lacking we obtain the condition
known as mvxoedema in adults, as cretinism in young children. If it be
THE DUCTLESS GLANDS 1241
present in excess the symptoms of exophthalmic goitre are produced.
The exact character of the internal secretion cannot be regarded yet as
definitely established. It seems possible that it is identical with a substance
containing iodine in organic combination, which was isolated by Baumann
from the thyroid gland and is known as iodothyrin. Li certain experiments
the results of administration of iodothyrin were found to be identical with
those obtained by giving the whole gland. Doubt has been thrown on the
specific nature of this body on account of the fact that iodine may be
wanting in the thyroid gland in certain animals, though Reid Hunt has
end
'<■ \ ft * * ,'
Fro. 561. Section of parathyroid. (Koiin.)
i j>. secreting epithelium : pig, cells containing pigment; cap, sinus-like
capillaries; end, endothelial cells.
shown that the physiological effects of thyroid extract are proportional to
the amount of iodine contained therein.
SIGNIFICANCE OF THE PARATHYROIDS. The parathyroids are small
bodies, varying in number, situated on the border of the thyroid gland
or actually embedded in its substance. In histological appearance they
differ widely from the thyroid, and consist of solid masses or columns of
epithelial cells surrounded with connective tissue and richly supplied with
blood vessels (Fig. 561). Considerable divergence of opinion still exists as to
the significance of these bodies. In some animals e.g. in the dog, where
they are embedded in the gland,- they will be necessarily removed in any
operation for the extirpation of the thyroid. In others such as the rabbit,
where they lie outside the gland, it is easy to avoid them in the excision of
the thyroid. To this varying distribution of the parathyroids have been
ascribed the different results of extirpation of the thyroid in camivora and
Il'l-J
PHYSIOLOGY
herbivora respectively. Forsyth has shown that, in man, the situation of
tlic parathyroids corresponds almost exactly with the places in which arc
found occasionally accessory thyroids; and according to Edmunds, after
excision of the thyroid, the parathyroids undergo histological alteration and
are converted into thyroid tissue, the cells taking on an alveolar arrangement
and producing colloid material. According to this view the parathyroids
would represent simply immal ure t liyvoid i issue. ( )n 1 he oi her hand, il has
been suggested (Biedl) that the parathyroids have a function entirely dis-
tinct from that of the thyroid gland, removal of the thyroids producing
simply a condition of cachexia and the changes associated with myxoedema,
Fig. 562. Mesial sagittal section through the pituitary body of an adult monkey
(semi-diagrammatic). (After Herring.)
a, optic ehiasma; b, third ventricle; c, tongue-like process of pars intermedia;
d, epithelial investment of posterior lobe; r, anterior lobe; /, epithelial cleft;
■•.'■;■.-■■'.
Fig. 5r>4. Plethysuiu;jr.i|jlii<- tracing of spleen (upper curve) from a dog, showing the
spontaneous contractions of this organ. (Reduced from a tracing by Sciiafeu.)
and trabeculse has the property of rhythmic contraction. If the spleen be
enclosed in a plethysmograph or splenic oncometer, and its volume be
recorded by connecting this with an oncograph, it will be seen to be subject
to a series of large slow variations, each contraction and expansion lasting
about a minute and recurring with great regularity (Fig. 564). Superposed
on these large waves are smaller undulations due to the respiratory variations
of the blood pressure, and on these again the little excursions corresponding
to each heai"t beat. The contractile power of the spleen is under the
control of the nervous system, and a rapid contraction may be induced by
stimulation of the splanchnic nerves.
FUNCTIONS OF THE SPLEEN
The structure of this organ suggests that the splenic cells must exercise
a constant influence on the blood which surrounds them, and that this
influence is not purely of a chemical nature. In the liver and kidneys,
which exercise so powerful an effect on the composition of the blood passing
through them, the proper cells of the organs are separated from the blood
stream by the capillary wall. Microscopic examination of the cells of the
splenic pulp shows us that these are full of particles of brown pigment
or fragments of red corpuscles (Fig. 565). In many cases of infectious
THE DUCTLESS CLANKS
1247
disease, such as recurrent fever, the splenic cells are observed towards the
end of the attack to be full of the organism — spirillum — which is the cause of
the disease. In fact these cells are so arranged that they can take up solid
particles held in suspension in the blood plasma. We must indeed look
upon the spleen as the great blood filter, purifying the blood in its passage by
taking up particles of foreign matter and effete red corpuscles. The process
of phagocytosis, which was described under the cellular mechanisms of
defence (p. 1071). is in the spleen a normal occurrence.
.it.
*,
Fig. 565. Cells from ;i scraping of the spleen. (Kullikeu.)
a. splenic pulp cell containing red blood corpuscles, b (k - nucleus): b, leucocyte
with polymorphous nucleus; c, pulp cell containing disintegrated red corpuscles;
i). lymphocyte; E, giant- cell: F, nucleated red corpuscles; o, normal red corpuscle;
ji, multinuclear leucocyte; .>. eosinophils coll.
A function has also Keen assigned to the spleen in the formation of red
blood corpuscles, but the evidence is not sufficient to determine whether
such a process occurs normally.
Chemical analysis of the spleen n veals the presence of a large number of
what ate called extractives, such as succinic, formic, butyric, and lactic
acids, inosit, leucine, xanthine, hypoxanthine, and uric acid. There is also
a protein combined with iron, as well as several pigments probably derived
from the haemoglobin of the red corpuscles destroyed by the cells of the
splenic pulp. The fact that, in cases where the spleen is pathologically
enlarged as in leucocythaemia, the uric acid in the urine is largely increased
points to a connection between the spleen and the formation of uric acid
in the body. The numerous extractives which are found probably owe 1 beir
origin to the destructive changes effected on the effete constituents of the
blood by the agency of the splenic pulp cells.
BOOK IV
REPRODUCTION
79
CHAPTER XXI
THE PHYSIOLOGY OF REPRODUCTION
SECTION I
THE ESSENTIAL FEATURES OF THE SEXUAL PROCESS
TiiK. two fundamental characteristics of protoplasm, which distinguish it
above all others from unorganised matter, are growth and activity. Growth
occurs at the expense of surrounding non-living material, while activity is
in every case an adapted reaction to changes in the environment. The
.second characteristic would seem to involve a limitation of the first, and
docs in fact determine the conditions under which it may occur. In the
process of growth of a minute spherical mass of protoplasm, its bulk and
mass increase as the cube, while the surface increases only as the square, of
the radius. Thus the proportion of surface to mass diminishes with in-
creased size of the protoplasmic unit and, since activity is a function of the
surface, the larger the unit t lie smaller must be its activity. It follows that
there must be a limiting size bo the living protoplasmic unit, and it is on
this account that practically no unicellular animal or plant exceeds a fraction
of a millimetre in diameter. II' an organism is to attain any larger size, this
can only be by a multiplication of units, each presenting the same relative
amount of surface as a complete unicellular organism, though the surface
rnav be exposed to an internal and not to an external medium. Another
factor, limiting the size of the unicellular organism or of the unit of the
multicellular organism, is the necessity for maintaining a certain proportion
between the size of the nucleus and that of the cytoplasm composing the
body of the cell. Observations on artificial division of cells have shown
us that the functions of digestion, assimilation, and growth depend upon the
presence of a nucleus. Hence, when for any reason it is advantageous that
a cell should attain a large size, such a cell is almost always found to contain
main- nuclei. All the ' giant cells ' found in the body of man under normal
or pathological conditions are also multinuclear.
Thus the continuous display of the functions of assimilation and dis-
similation, of growth and activity, is possible only so long as cell division
keeps pace with growth. In unicellular organisms, under favourable con-
ditions, this growth and multiplication occur with prodigious rapidity. It
has been computed that a paramoecium, freely supplied with food material,
would, by growth and division, in the course of a year represent a mass of
protoplasm the size of the earth, assuming of course that no accidents or
1251
1252 PHYSIOLOGY
destructive agencies intervened to destroy the pararnoecia which were being
formed. This computation, which may seem a fanciful one, is useful as
indicating the enormous number of individuals brought under the action of
natural selection, which very few survive. In unicellular organisms such as
paramcecium or amoeba, death cannot be regarded as a natural process. They
may be eaten by higher organisms or serve as food to vegetable parasites,
but so long as conditions are favourable and food supply sufficient, they
will continue to grow and reproduce themselves eternally. In the course
of its existence each individual may be brought under many varieties of
conditions ; some of these may be so harmful that the individual is destroyed
and its race comes to an end. Other individuals, under circumstances of
less severity, may undergo modifications in their molecular structure which
will serve to neutralise the effect of the injurious environment. Any such
modification in structure, morphological or molecular, must be transmitted to
the next generation, so that with slowly varying external conditions there is
a possibility of a corresponding slow variation in type, which may finally
attain a form altogether different from that with which it set out. A new
species may in this way be formed by gradual alteration of environment.
It is not therefore difficult to understand in the case of such organisms either
the maintenance of type by heredity under constant conditions, or the
change of type with gradually varying conditions.
Reproduction by continuous growth and division is not however the
only means, even in the unicellular animals, by which new generations may
be produced. If protozoa such as pararnoecia be kept for a long time in
nutrient solutions, their rapidity of reproduction after a time falls off, while
many die, and others become the easy prey to infectious diseases. Under
these conditions a new phenomenon makes its appearance, viz. ' conjuga-
tion,' which is the analogue of the sexual reproduction of the higher animals.
Infusoria contain two kinds of nuclei, a large and a small, known as the
macro-nucleus and the micro-nucleus respectively. During conjugation the
macro-nucleus breaks up and disappears in two cells, which become closely
applied together, while in each the micro-nucleus divides twice to form four
spindle-shaped bodies. Three of these degenerate, (like the polar bodies of
trie ovum), while the fourth divides into two. This is followed by an
exchange of micro-nuclei, one micro-nucleus from a passing into b, while
one micro-nucleus from B passes into A. The two cells then separate, a single
micro-nucleus being formed in each by the amalgamation of the two. This
micro-nucleus then divides three times, so that eight nuclei are formed, while
the cell itself divides into four, two nuclei passing into each of the daughter
cells. Of these one enlarges to form the macro-nucleus, while the other
remains as the micro-nucleus. After conjugation has occurred, the colony of
infusoria takes on, so to speak, a new lease of life, and there is a rapid
production of new generations by simple division of the cells, in which both
macro-nucleus and micro-nucleus take part. Conjugation apparently occurs
only in the presence of adverse conditions, and may be prevented almost
indefinitely by maintaining the colonies in as favourable conditions as
ESSENTIAL FEATURES OF THE SEXUAL PROCESS 1253
possible. In certain organisms, especially in Algae, in which similar pheno-
mena take place, each organism after conjugation may surround itself with
a thickened wall and remain for a considerable length of time in a state of
suspended animation. It is very difficult to understand the advantage of
this interchange of nuclear material either to the individual or to the race.
It has been suggested that, as soon as each individual concerned in the pro-
eess receives the nuclear material from organisms which may have been
Second fission
First fission, after separation
Differentiation of micro- and
macro-nuclei
Separation of the gametes
Division of the cleavage-nucleus
Cleavage-nucleus
Exchange and fusion of the germ-
nuclei
Germ-nuclei
Formation of the polar bodies
Union of the gametes
Fio. 566. Diagram showing the history of the micro-nuclei during the
conjugation of paramcecium. (From Wilson after Matjpas.)
X and y represent the opposed macro- and micro-nuclei in the two gametes ;
circles represent degenerating and black dots persisting nuclei.
exposed to slightly different circumstances, cones ponding changes will be
int induced into the tendencies to growth of the product of the union. Some
of these tendencies may be more advantageous than before, while others may
be the reverse. Increased possibility of variation is however introduced
by this admixture of nuclear material, and this may be the advantage
of the process to the race. It should be noted that the half of the nucleus
lost by each conjugating organism is qualitatively different from that which
it retains and probably from that which it receives. A gamete in which
the nucleus can be represented by ab, and which by simple division will
produce similar organisms with nucleus ab. conjugates with an organism
of slightly different structure, and therefore with a nucleus which can be
represented as cd. After conjugation, the ab gamete will contain a nucleus
represented by ac, while the cd gamete will contain a nucleus represented
1254 PHYSIOLOGY
by bil; ac 01 bd may be better or worse combinations than ab or cd. If
either of them is better, that organism will survive under the less favourable
conditions, and the race will continue with a slight, and to us inappreciable,
change of type.
REPRODUCTION IN THE METAZOA
The numberless cells forming the bodies of the higher animals are all
produced by a scries of divisions from a single cell, the fertilised ovum.
This cell is the result of a process of conjugation between two cells derived
from different individuals. With the multiplication of cells forming a single
organism there is, of course, an increased size of the organism. It is doubtful
whether this of itself would be of any advantage, were it not that the
multiplication of cells goes hand in hand with differentiation, groups of
cells being modified structurally and set aside for one or other function of the
body. Differentiation of function implies higher functional capacity.
As a motor organ or as a means of locomotion, the differentiated muscle
cells, with their attached parts, must be more effective than the undif-
ferentiated protoplasm of the amoeba. Specialisation of function involves
changes of type in the cells resulting from the division of the primitive un-
differentiated ovum. In most cases this change of type is permanent. An
epithelial cell such as that forming the epidermis or the liver, when it divides,
produces another cell of the same kind. One might almost speak of the
evolution of a new species of cell, but that it takes place within the short
period of the development of the multicellular individual, instead of occupy-
ing a long space of time and involving the destruction of countless indi-
viduals, as is the case when a change of type gradually occurs in unicellular
organisms. Differentiation necessarily brings with it a limitation of the
powers of reproduction. Any one of the descendants of a unicellular
organism is in all respects equivalent to its ancestor, and can reproduce the
same type of individual. The specialised liver or muscle cell can produce
only a cell of the same type, one, that is to say, incapable of independent
existence or of forming the divergent series of types necessary for the pro-
duction of an individual. Differentiation of function therefore involves the
setting aside of certain cells, germ cells, which retain their primitive character
and are capable of indefinite division to form new generations each able
to develop into a complete individual. These germ cells can often be
recognised from the very earliest divisions of the fertilised ovum, which lead
to the production of the mature individual. Tims in Ascaris, the progenitor
of the germ cells differs from the somatic cells both by the greater size of
its nucleus and in its mode of division (Fig. 567). In the cells destined to
produce the somatic cells, a portion of the chromatin is cast out into the
cytoplasm, where it degenerates, so that only in the germ cells is the sum
total of the chromatin retained. Thus in the two-celled stage, in one cell
all the chromatin is preserved, while in the other cell the thickened ends of
the chromosomes are cast off into the cytoplasm and degenerate, only the
thinner central portions being preserved. When these divide again, the
ESSENTIAL FEATURES OF THE SEXUAL PROCESS 1255
same process is repeated in only one of the daughter cells derived from a
germ cell, and this recurs during five or six divisions, after which the
chromatin elimination ceases and the two primordial germ cells thence-
forward give rise only to other germ cells in which the entire chromatin is
preserved. Thus " the original nuclear constitution of the fertilised egg is
transmitted, as if by a law of primogeniture, only to one daughter cell, and
~* fJO' s
Fig. 567. Origin of the primordial gorni cells and casting out of chromatin in
the somatic cells of Ascaris. (Wilson and Boveri.)
a. two-cell stage dividing; 8, stem cell, from which arise the genu cells. B, the
same from the side, later in the second cleavage, showing the two types of mitosis
and tho casting out of chromatin (c) in the somatic cell. O, resulting four-cell
stage; the eliminated chromatin at c. D, the third cleavage, repeating the foregoing
process in the tw T o upper cells.
by this again to one. and so on, while in other daughter cells the chromatin
in part degenerates, in part is transformed, so that all of the descendants
of these side-branches receive small reduced nuclei" (Boveri, quoted by
Wilson).
The immortality, which was the property of all the unicellular ancestors
of the metazoa, has in the latter descended only to the germ cells. All the
other cells of the body, which form the nervous and muscular tissues,
glands, skin, etc., are mortal. They pass through a certain number of
divisions ; hut although this number is large, it is limited, and on the number
of divisions which are possible depends the normal duration of life of the
organism to which the cells belong. We may thus regard the egg (-ell as
dividing into two parts. From one part will be formed by differentiation
125G PHYSIOLOGY
all the complex somatic mechanisms of the adult animal; the other part
will divide, but will remain in an undifferentiated form, until its descendants
can conjugate with germ cells from other individuals and form fertilised
egg cells, destined to undergo the same series of changes.
The rnetazoan individual thus consists of a mortal host holding within itself the
immortal sexual cells or gonads. Gaskell has pointed out that the development of
the fertilised ovum involves two parallel processes — on the one hand, the elaboration
of the elements forming the host; on the other, of those derived from the tree-living
independent germ cells. From the very beginning the somatic part of the organism,
the host, is a reacting individual in which the nervous system acts as the integrator of
all the activities of the body and as the middleman between the internal and externa]
epithelial surfaces and the muscular system. The host may thus be regarded as a
neuro- epithelial syncytium, eveiy step in its evolution and differentiation being attended
by increased control of all the units by a central nervous system.
The gonads were placed at first within the interstices of this syncytium, and escaped
to form a new generation only after the death and disintegration of the host. But
differentiation and division of labour affect also the free-living gonads. Some of these
form a germ epithelium surrounding the body cavity, of which a few only of the elements
pass out of the host as perfect germ cells, while the others are subordinated to the
metabolic needs of these germ cells and are transformed into various elements, such as
nurse cells, wandering mesoderm cells or phagocytes, yolk cells, and so on. Gaskell
regards the greater part, if not the whole, of the connective-tissue framework of the
body, as well as the wandering corpuscles of the blood and tissue fluids, as derived from
these primitive germ cells. All these tissues, though useful to the host as well as to
the finally successful germ cells, present the common feature of an absolute independence
of the central nervous system. Thus the evolution of the animal kingdom means
essentially the evolution of the host, and must therefore be closely connected with the
evolution of the central nervous system, the ruling element in the neuro- muscular
syncytium. On. these grounds Gaskell has used the comparative morphology of the
central nervous system as a means of tracing the origin of the vertebrate from the in-
vertebrate type, and has come to the conclusion that the immediate ancestor of the
vertebrate must be sought in the invertebrate group presenting the most highly developed
central nervous system, namely, the Arthropoda.
All the complex mechanisms which are concerned in maintaining the
life of the individual have apparently been developed in order to give the
potentially immortal germ cells a better chance of survival in the struggle
for existence. From the broad biological standpoint, as Foster points out,
all the toil and turmoil of human existence may be regarded simply as the
by-play of an ovum-bearing organism. From the same standpoint one must
acknowledge that the mortality of the individual, resulting from the absence
of an indefinite power of multiplication among the somatic cells, must be
an advantage to the race. Throughout the living world the welfare of the
individual is subordinated to that of the species. With each new genera-
tion there are possibilities of variation and of the production of individuals
better or worse fitted for the maintenance of the race than those of the
previous generation. Immortality of the individual would handicap the
survival of the younger generations, and we should have the same retardation
of progress in a race that we see in many civilised communities, where the
power and the conduct of affairs are in the hands of the older members.
ESSENTIAL FEATURES OF THE SEXUAL PROCESS 1257
THE FORMATION OF GERM CELLS
In multicellular organisms the cells which conjugate to form a new cell,
capable of developing into an individual, are of two kinds. One, which
has generally a certain amount of reserve material stored up in its cytoplasm,
is the female element and is called the ovum. The other cell, which consists
of little more than nuclear material, is the male element and is called the
spermatozoon. Both kinds of cells are derived from a mass of undifferentiated
cells, the »cmi epithelium which, as we have seen, can often be traced directly
back to the first divisions of the, fertilised egg. The use of the reserve
material in the ovum is to serve as food for the developing individual. The
ovum and spermatozoon cannot be regarded as corresponding to complete
cells Before their union or conjugation both male and female germ, cells
undergo certain important changes which differentiate them from the.
ordinary somatic cells of the individual. The essential differences between
a genu cell and a somatic cell can be best seen by a study of the nuclear
changes w hich precede their formation. In division the nuclei of all somatic
cdls. whether of plants or animals, undergo a series of changes which, in
their broad outlines, are similar throughout both animal and vegetable
doms (Fig. 568), and result in the production of qualitatively identical
daughter nuclei.
The nucleus of the resting cell in its vegetative condition is generally separated
from the cytoplasm by a nuclear membrane, and contains irregular masses of a material
staining deeply with basic dyes, and known as chromatin. In the cytoplasm of most
animal cells mav be seen a small particle known as the centrosome. When division
is about to take place, the clumps of chromatin arrange themselves into a filament which
a continuous skein, the ' spireme stage.' This then breaks up into a number
of segments, often V-shaped, the chromatin filaments or chromosomes. Each of the
filaments, in large nuclei, may often be seen to be composed of rows of granules. While
this change has been occurring, the nuclear membrane in most cases disappears, and
the centrosome outside the nucleus divides into two parts, which travel to opposite
ends of the nucleus.' Round each centrosome the cytoplasm is modified and presents
iile appearance, the asler, while joining the two centrosomes is a spindle of fine
fibres, the achromatic spindle. The V-shaped segments of chromatin arrange themselves
in a circle at the equator of the spindle midway between the two centrosomes. Each
of the loops then splits longitudinally, and each half travels towards one or other of the
centrosomes, thus forming two daughter nuclei. The half-loops then join to form a
skein, and may return to the c. mditi< >n of a resting nucleus. These different phases in
division are presented by all somatic cells, and have received the following names :
(1) Prophase (the formation of the spireme and of the achromatic spindle, and the
breaking up of the spireme into chromatin loops or chromosomes).
(2) Metaphase (the splitting of the chromosomes).
(3) A naplui.se (the travelling of each half-chromosome to the extremity of the spindle).
(4) Telophase (the retrogressive changes, leading to the conversion of the chromatin
filaments into an ordinary resting nucleus, which are accompanied or preceded by a
division of the cytoplasm across the equatorial part of the spindle).
When the spireme has broken up into separate chromatin loops, it is possible to
count them, and it is found that the number present in any cell is constant f< 50% DR 25% It R
D 25% D 50% DR 25% R R
1268 PHYSIOLOGY
It has been suggested that a very large number, if not all, of the characters
of an individual might be brought under this law. This might be done
by indefinitely subdividing the characters, but the question would then
become beyond the limits of analysis or experimental investigation. There
is no doubt that many qualities are subject to Mendel's law, and that their
study will be of considerable assistance in guiding the efforts of our breeders
and horticulturists in the formation of new varieties desirable for their
value to man. In respect of many qualities the Mendelian law seems to
fail. Thus in man the progeny of a cross between a white and black race
are more or less intermediate between the two and vary according to the
amount of black and white blood introduced in succeeding generations.
Definite black and white individuals are not produced, but merelyindividuals
of various degrees of brownness.
SECTION III
REPRODUCTION IN MAN
THE DEVELOPMENT OF THE REPRODUCTIVE ORGANS
The most marked example of chemical correlation is found in the influence
exerted by the genital glands upon the other parts of the reproductive
apparatus and upon the body generally. Thus castration, i. e. removal of
the testes or ovaries, if carried out before the time of puberty, prevents the
development of the secondary sexual characters, which normally occurs
at this epoch in both sexes. Puberty denotes the period at which ripe
spermatozoa and ova are produced in the testis and ovary respectively. In
the human species this period is marked or preceded in the male by increased
growth of the skeleton, by growth of the larynx, leading to a lowering
in pitch of the voice, by the growth of hair on the face and pubes, and
by the development of sexual desire. In the female we find at puberty
enlargement of the breasts, attended by some growth of the mammary
glands and by a moulding of the whole form, making it more fit for the
bearing of children. The chief sign of puberty in the female consists in the
periodic changes in the uterus, which give rise to menstruation, i. e. a flow
of blood and mucus from the genital organs, lasting three to five days and
repeated every four weeks. Menstruation persists so long as the ovary is
functional, and is producing ripe ova. The activity of the ovary comes to
an end between the forty-fifth and fiftieth year (' the climacteric ' or
' change of life '). With the cessation of its activity menstruation also
stops, and the uterus undergoes a process of atrophy. These secondary
sexual characters must be ascribed to the influence of chemical substances
produced in the ovary and testis respectively. Castration after puberty,
though not causing any change in the skeleton, which has already assumed
its permanent form, brings about retrogressive changes in the other genital
organs, analogous to those occurring in the female at the climacteric. In
animals the phenomena of ' coming on heat ' or ' rat ' seem to be analogous
with menstruation in the human female, and like this depend on the normal
activity of the ovary. They are permanently abolished by extirpation of
the ovaries, but may be reinduced by implantation in the peritoneum of
an ovary from another animal of the same species. This fact shows that
the changes in the uterus responsible for rut, as well as for menstruation,
are independent of any nervous connections between the ovaries and the
rest of the body, and must therefore be brought about by the circulation in
the blood of specific chemical substances produced in the ovaries. According
L269
1270 PHYSIOLOGY
in some authors, the essential factors for the production of these genital
hormones are the 'interstitial cells' found both in the testes and ovaries
of various animals. These interstitial cells are not however universally
present. It has been shown that, by means of the Rontgen rays, it is
possible to destroy the germ cells in either testes or ovaries, so rendering
the animal sterile. The interstitial cells, when present, are not destroyed
by these rays, yet the effects on the accessory genital organs are stated to
be as marked as after complete extirpation of either ovaries or testes.
The chemical correlations between the ovaries and the other organs
concerned in reproduction are perhaps best marked in the changes which
attend pregnancy. In this case the fertilisation of the ovum by a sperma-
tozoon is followed by a great development, first of the mucous membrane
and later on of the muscular wall of the uterus. The mucous membrane
thickens, apparently in order to form a bed for the developing fertilised
ovum. With this growth of the uterus there is a corresponding growth
of the other parts of the genital tract, e. g. the vagina. At the same time
rapid changes take place in the mammarv glands. These changes may be
studied experimentally in the rabbit, in which gestation lasts only about
twenty-nine days. In a virgin rabbit of a year old it is difficult with the
naked eye to see any trace of the mammary gland in the tissue lying under
the nipples. Each gland is limited to an area not more than 1 cm. broad,
and consists entirely of ducts lined with a single layer of flattened epithelial
cells. With the occurrence of conception a marked change takes place.
Four or five days after fertilisation, when it is still impossible with the
naked eye to discover any embryos in the swollen uterine horns, on reflecting
the skin from the abdomen each mammary gland appears as a circular pink
area, about 3 cm. in diameter. On section the gland consists of ducts
which are in an active state of proliferation, their epithelial lining being
two or three cells thick and presenting numerous mitotic figures. By the
ninth day the whole abdomen is covered with a thin layer of glandular
tissue ; by the twenty-fifth day this tissue is \ cm. in thickness and consists
for the greater part of secreting alveoli, lined with cells containing numerous
fat globules. At full term the alveoli contain ready-formed milk.
This hypertrophy of the mammary glands occurs during pregnancy
after complete divisionof all possible nervous paths between the glands of
the ovaries or uterus. In the guinea-pig a mammary gland has been actually
transplanted to another part of the body, thus severing all its normal nervous
connections, and yet it enlarged as usual during a subsequent pregnancy.
Ancel and Bouin have brought forward evidence that the corpus luteum —
the tissue produced in the ovary as a result of the discharge of an ovum-
is intimately concerned with the growth of the mammary glands, and may
indeed cause a certain degree of hypertrophy of these glands in the entire
absence of any product of conception within the uterus. 1 The limited
1 According to Ancel and Bouin, in the rabbit discharge of an ovum and formation
of a corpus luteum occur only as a result of copulation. The same effect may be pro-
duced by artificial rupture of a ripe follicle, whereupon there is a development
of the mammary glands. If no impregnation has taken place (e. rj. if the buck has
REPRODUCTION IN MAN 1271
growth of the glands, which occurs at puberty, can certainly not be ascribed
to the presence of a foetus in the uterus, and must be connected with the
growth of ripe ova or, as suggested by the two French authors, with the
growth of the tissue of the corpus luteuni, resulting from the discharge
of ova.
There seem also to be obscure relationships between the activity of the
sexual organs and that of certain so-called ductless glands. Thus castra-
tion at an early age leads to persistence of the thymus gland, whereas
normally this gland atrophies just before the sexual organs commence their
functional activity. The existence of a connection between the thyroid
and the ovaries has been a popular belief for 2000 years. In many individuals
the thyroid is perceptibly enlarged at each menstrual period. On the other
hand, extirpation of the thyroid before puberty brings about, among the
other signs of cretinism, failure of development of the ovaries, so that
puberty is delayed partially or completely.
We must thus regard' the germ cells not only as representing the cells
from which the individuals of the new generation may be developed, but
also as concerned in the formation of chemical substances which, dis-
charged into their hosts, affect many or all of the functions of the latter,
with the object of finally subordinating the activities of the individual to
the preservation and perpetuation of the species.
THE MALE REPRODUCTIVE ORGANS
In all the. higher animals we may divide the reproductive organs into
the essential organs, which form the germ cells, the spermatozoa and ova
respectively, and the accessory organs, which have as their office the facilita-
tion of the access of the spermatozoa to the ova (fertilisation), and in the
female the nutrition of the product of fertilisation during the early period
of its development.
The essential sexual organ of the male is represented by the testis.
This is made up of a collection of convoluted tubules, the seminal tubules,
which are contained in a number of compartments separated by fibrous
septa. The tubules present few or no branches, each one being about
500 mm. long. The testis is formed in the first instance in the peritoneal
cavity from the germinal epithelium, but early in life leaves the abdominal
cavity by the abdominal ring to lie in a pouch of skin — the scrotum. Several
tubules unite to form a straight tubule, which leads by a series of com-
municating spaces, the rete testis, into the vasa efferentia (Fig. 573). These
join to form the duct of the epididymis, coiled into a mass lying at the
been sterilised by ligature of the vas deferens), the glands develop for fourteen days
and then begin to atrophy. This period corresponds to the period of active growth
of the corpus luteum. The continued growth during the latter half of pregnancy these
authors ascribe to the production of another hormone by a special glandular tissue
(' myoruetrial gland ') which makes its appearance about the fourteenth day in the wall
of the uterus, at the site of implantation of the placenta, and lasts until the end of
pregnancy.
1272
PHYSIOLOGY
back of the testis. The epididymis is composed of the convolutions of this
single duct, which is about 20 feet long. From the lower end of the epi-
didymis the vas deferens, a tube with thick muscular walls, leads by the
abdominal ring to the. base of the bladder, where it opens into the beginning
of the urethra in its prostatic part. Just before it joins the urethra each vas
deferens presents a diverticulum, the seminal vesicle, which lies along, and
is attached to, the base of the bladder. The prostate itself, which surrounds
the first part of the urethra, is composed of a matrix of unstriated muscular
fibres, enclosing numerous branched racemo-tubular glands. From the
point of entry of the vasa deferentia to its orifice, the urethra represents
Tunica vaginalis
Tunica albuginea
Septum
Seminal tubule?
Lobule
Fro. 573.
— Vas deferens
Vasa efferentu
_ Yas aberrans
mmatic representation of the course of the seminal tubules in the
testis and epididymis. (After Nagel.)
a common passage for the urine and for the sexual products-— the semen.
It passes therefore through tissues, forming the penis, which are especially
adapted for the purpose of intromission, i. e. the introduction of the semen
containing the spermatozoa into the female. In the urethra we distinguish
the prostatic, the membranous, and the penile portions. Into the beginning
of the penile portion, the bulb of the urethra, open the ducts of the two
glands of Cowper. In the penis itself the urethra is surrounded with
erectile tissue, forming the corpus spongiosum, and lies between the two
corpora cavernosa, which consist of the same kind of tissue. The erectile
tissue is a spongy meshwork of elastic and unstriated muscle fibres, enclosing
spaces in free communication with the efferent veins of the organ. The
arterioles also open into these spaces, but under normal circumstances both
the arterioles and the muscle tissues of the framework are contracted, so
that the blood trickles very slowly from the arterioles into the spaces,
whence it escapes readily by means of the veins. If the muscle fibres be
REPRODUCTION IN MAN 1273
relaxed, so that blood can pass rapidly into and distend the spaces, the
tissue swells and becomes harder, causing ' erection ' of the organ.
In the immature testis, i. e. from birth up to puberty, the seminal tubules
are filled with cells with large nuclei. Some of these are the spermatogonia,
the mother cells of the future spermatozoa, while the others form the cells
of Sertoli, whose function it is to act as nurse cells to the developing sper-
matozoa. The actual formation of spermatozoa begins at puberty, when
the spermatogonia divide many times to form the spermatocytes, which
in their turn undergo heterotype mitosis to form the spermatids, as already
described. By a modification of the latter the fully formed spermatozoa
are formed. These, when mature, pass by the tubules of the testis and of
the epididymis into the vas deferens, whence they make their way into the
seminal vesicles. Their movement is probably facilitated by the cells fining
the tubule of the epididymis as well as by the secretion of the fining mem-
brane of the seminal vesicles. It has been noted that the spermatozoa are
practically motionless while in the seminiferous tubules of the testis, but
become actively motile in the vas deferens, or when mixed with prostatic
secretion. It is difficult to understand how the spermatozoa are conveyed
through the resistance which must be offered by the huge length of the
tubule of the epididymis, unless their onward motion is facilitated by the
cilia-like structures attached to some of the cells lining this tubule. The
formation of the spermatozoa is continuous, though the rate at which this
occurs is variable and regulated by the sexual activity of the individual. In
the fully formed semen the spermatozoa originating in the testis are mixed,
not only with the fluid secreted by the fining membrane of the epididymis
and of the seminal vesicle, but also with the mucous secretions of the prostatic
glands and of Cowper's glands. Nevertheless it contains spermatozoa in
enormous numbers, the semen emitted at a single act of coitus containing
as many as 226,000,000 spermatozoa. Though the vast majority of these
are probably capable of fertilising an ovum, this act is carried out by only
one — a fact characteristic of the prodigality of nature when dealing with
the perpetuation of the type.
THE FEMALE REPRODUCTIVE ORGANS
The essential organ of reproduction in the female is the ovary, the seat
of production of the ova. The accessory organs include the oviducts or
Fallopian tubes, the uterus, in which the fertilised ovum is retained during
the first nine months of its development, and the vagina, which is especially
adapted for the reception of the male organ in the act of impregnation.
Among the accessory organs we may also reckon the mammary glands,
which undergo a special development during pregnancy, and serve for
the nourishment of the young individual during the first period of
extra -uterine life,
OVULATION. At birth the ovary consists of a stroma of spindle-shaped
cells, and is covered by a layer of cubical epithelium (the germ epithelium)
continuous with the endothelium lining the general peritoneal cavity.
1274
NIYSIOLOdY
Embedded in the stroma but especially numerous just underneath the epithe-
lium, are a vast number of ' primordial follicles.' These are formed during
foetal life by down growths of the germinal epithelium. Of the cells pro-
longed in this way from the germinal epithelium, some undergo enlargement
to form the primordial ova, while the others are arranged in a single layer
of flattened nucleated cells, the ' follicular epithelium,' as a sort of capsule
to the ovum. Of the primordial follicles, about 70,000 are to be found in
the ovary of the newborn child. During the first twelve to fourteen years of
Fig. 574. Graafian follicle of mammalian ovary. (Prenant and Bouin.)
ov, ovum; dip, discus proligerus; Iq.f, liquor folliculi; ch, theoa;
gr, membrana granulosa.
life they remain in a quiescent condition. With the onset of puberty one or
more of the primordial follicles begin to develop. Indeed, this development
may be regarded as the causative factor in the various phenomena which
are characteristic of puberty in the female (v. p. 1269). The first stage in
the growth of the follicle is a proliferation of the follicular epithelium, the
cells of which become cubical and are arranged in Iseveral layers round the
ovum. At one point in the mass of 'cells surrounding the ovum, a cavity
appears rilled with fluid, the liquor folliculi. The epithelium thus becomes
REPRODUCTION IN MAN - 1275
separated into two parts, i. e. the membrana granulosa, several layers thick,
lining the whole follicle, and the discus proldgerus, a mass of cells attached to
one side of the follicle, in which is embedded the ovum (Fig. 574). Round
the growing follicle the stroma assumes a concentric arrangement and forms
a capsule, of which the internal layer consists chiefly of spindle-shaped cells
richly supplied with blood vessels, while the outer layer — the theca externa
— is made up of a tough fibrous tissue. With the growth of the follicle
the ovum also becomes larger and surrounds itself with a distinct membrane,
known as the zona pellvcida. This membrane presents a fine radial striatum,
which is supposed to indicate the existence of canals through which the
ovum can obtain sustenance from the surrounding cells of the follicular
epithelium. The nucleus also becomes larger, and forms the germinal
vesicle containing one or two well-marked nucleoli — the germinal spot. The
mature Graafian follicle projects from the surface of the ovary as a trans-
parent vesicle about the size of a pea. (Its diameter is about 15 mm.) In
the process of growth the ovum has increased from a diameter of 25/x to
200jW.. Before the ovum can undergo fertilisation, the double division of
the nucleus or germinal vesicle has to take place, which leads to the forma-
tion and extrusion of the two polar bodies. This process probably occurs
just before or just after the discharge of the ovum from the ovary.
With increasing size of the Graafian follicle the membrane covering it
becomes progressively thinner. At certain periods, or under certain con-
ditions, the membrane ruptures, and the ovum is discharged in the liquor
fbllicidi, still surrounded by an adherent mass of the cells of the discus
proligerus. Li some animals this process of ovulation occurs at definite
periods of the year. In others such as the rabbit, the occurrence, of ovula-
tion depends upon coitus taking place during the period of sexual activity.
We shall have later to discuss the relation of ovulation in the human female
to the periodic changes occurring in the other parts of the reproductive
apparatus.
After the discharge of the ovum the remaining portions of the follicle
undergo a characteristic series of changes, svhich result in the production
of the corpus luteum. Immediately after the rupture the follicle becomes
filled with blood, apparently resulting from the sudden release of the pressure
on the capillaries in the walls of the follicle. The cells of the membrana
granulosa rapidly increase in size, a few of them undergoing mitotic division,
so that a dense mass of cells is formed, nearly filling the original follicle. At
the same time the cells of the internal theca proliferate, with the formation
of connective tissue, which grows in among the cells filling the Graafian
follicle. These cells finally attain a size four or five times that of the cells
of the membrana granulosa in the mature follicle. Blood vessels grow from
the external theca tow T ards the centre of the follicle. The cells within the
follicle then undergo fatty degeneration and present a yellow colour due
to a fatty pigment known as lutein. The corpus luteum, as the body so
formed is called, attains its greatest size about a week after ovulation, and
then gradually undergoes regressive changes. If however the ovum,
1270
PHYSIOLOGY
which has been discharged, undergoes fertilisation, and pregnancy results,
the corpus luteum continues to grow for a considerable time and attains its
largest size at about the third month of pregnancy. It does not entirely
disappear until after the end of pregnancy. The big corpus luteum found
in pregnancy is often spoken of as the ' true ' corpus luteum, and is
distinguished from the corpus luteum spurntm of menstruation or of
ovulation without fertilisation. There is no essential difference other than
that of size between these two kinds of corpus luteum. It must not be
imagined that all the 70,000 primordial follicles found in the ovary of a
newborn child undergoes this series of changes ; it is probable that in the
human female ovulation occurs, as a rule, once every four weeks during the
Fig. 575. Fully developed corpus luteum o£ the mouse. (Sobotta.)
thirty-five years of sexual life. A vast number of the Graafian follicles,
after developing to a certain extent, undergo regressive changes, both during
childhood and during adult life. The cellular elements degenerate, leuco-
cytes wander into the follicle and attack the degenerating ovum, so that
finally the follicle is replaced by connective tissue, without the formation
of any corpus luteum.
MENSTRUATION. Puberty in the girl is marked by the onset of
menstruation. Under this term is understood a flow of blood and mucus
from the uterus, which recurs every four weeks and lasts each time from four
to five days. Before the first menstrual period, other signs of puberty, i. e.
of approaching sexual maturity, are usually observed. These include
rapid growth, with changes in the skeleton, leading to the typically feminine
type of pelvis, a development of the mammary glands, and the growth of
hair on the pubes. At the same time there is increased development of the
mental characteristics which are typical of the sex. The amount of blood
REPRODUCTION IN MAN 1277
lust at each menstrual period varies between luo and 300 grm. During the
' period ' there are often disturbances of other functions of the body, which
are so common that to be ' unwell ' is the recognised polite description of
the menstrual period. Thus it is often attended with pains in the abdomen,
a feeling of weight and fulness, disturbance of digestion, headache, and
neuralgias of various distribution. At the same time there is a general
disinclination for exertion.
Menstruation is due to periodic changes in the uterine mucous membrane.
During the few days previous to the period the mucous membrane undergoes
a rapid hypertrophy, increasing in thickness from 2 mm. to 6 mm. At the
same time there is increased vascularity of the membrane in consequence of
dilatation of its blood vessels. At the commencement of the menstrual
period there is an escape of the red blood corpuscles, chiefly by diapedesis,
but partly by actual rupture of the blood capillaries into the spaces between
the uterine glands. At this period sections of the uterine mucous mem-
brane show numerous collections of red blood corpuscles, lying immediately
under the superficial epithelium. In some cases this stage is followed by
an almost complete desquamation of the superficial epithelium. Generally
the desquamation is only partial, but in either case the blood escapes into
the cavity of the uterus, where it becomes mixed with the increased secre-
tion from the uterine glands and, is discharged into and from the vagina as
t lie menstrual fluid. With the occurrence of the menstrual flow the mucous
membrane begins to diminish in thickness. The vascularity decreases, and
much of the blood in the deeper parts of the mucosa becomes reabsorbed.
The desquamated epithelium is replaced by proliferation of the cells which
remain intact, so that finally the mucosa is completely regenerated and
brought back to its original condition. This period of regeneration lasts
about fourteen days. During the next few days the condition of the mem-
brane is stationary, but this period of rest lasts but a short time, since signs
of the pre-menstrual swelling can be detected as early as three days before
the onset of the next menstrual period.
THE RELATION OF OVULATION TO MENSTRUATION
There is no doubt that menstruation depends on the functional activity
of the ovary. Its onset coincides with the first production of ripe ova in the
ovary, and it ceases with the cessation of ovulation at the climacteric or
menopause. In cases where the ovaries have been removed before puberty
menstruation never occurs. Removal of both ovaries during adult life
generally brings about a premature menopause. It seerns probable that
the ripening of the ova in the human ovary occurs at periods corresponding
to those of menstruation. But there has been much division of opinion as to
the exact relation between the two processes. Fairly definite clinical and
■post-mortem evidence has 1 n brought forward for the theory that ovula-
tion precedes the menstrual flow. On this theory the degeneration of
the uterine mucous membrane, which occurs at each period, represents, so
1278 PHYSIOLOGY
to speak, the undoing of a preparation for the reception of a fertilised ovum.
The ovum has been discharged, the mucous membrane has been prepared
for its reception, but fertilisation not having taken place, ovum and mucous
membrane are cast out together in the menstrual flow. Unfortunately
almost equally definite cluneal evidence has been adduced for the view that
ovulation occurs during or after the menstrual period. Light is thrown
upon the question by the study of the phenomena of ' rut ' or ' heat ' in the
lower animals. In most mammals impregnation and conception can only
occur at certain definite periods of the year. At these seasons the female
presents a swelling of the mucous membrane of the external genitals, and
often a flow of blood or mucus. As a rule it is only when in this condition
that it will permit the approach of the male. Thus the bitch ' comes on
heat ' as a rule twice in the year ; the cat three or four times ; most car-
nivora only once a year. At these periods the uterus shows well-marked
histological changes, which may be divided into the following periods :
(1) The period of rest. During this time, which extends over the greater
part of the year, the mucous membrane is thin and pale. The period of
heat being known as the oestrus, this first period is denoted by Heape the
anoBstrum.
(2) The period of growth or congestion. This corresponds to the pre-
menstrual thickening of the mucous membrane of the human female.
(3) Period of destruction, associated with haemorrhages into the mucous
membrane, desquamation of the superficial epithelial cells, and occasionally
discharge of blood and mucus from the vagina. These two periods are
grouped together as the pro-oeslrum.
(4) Period of recuperation corresponding to the post-menstrual regenera-
tion of the mucous membrane. It is during the first part of this period or at
the very end of the last period that ovulation occurs in those animals where
ovulation is independent of coitus. It is at this time too that the animal
exhibits sexual desire and permits the approaches of the male. If fertilisa-
tion occurs, the mucous membrane undergoes rapid hypertrophy, much
more marked than that occurring during the pro-oestrum. In the absence
of impregnation the mucous membrane returns to the condition of rest, the
stage of return being known as the metcestram.
These results have been found by Heape and Marshall to apply to a
large number of different mammals. We are therefore justified in con-
cluding that menstruation is the physiological homologue of the pro-oestrum
in the lower mammals, and that ovulation occurs, or at any rate that the
ova attains maturity, after or at the very end of the menstrual flow. If we
consider that the ovum may take some days to pass down the Fallopian
tube to the uterus, and that the spermatozoa may retain their vitality for
ten days or more in the Fallopian tubes or uterus, it is evident that in man
impregnation may take place at any time between two menstrual periods.
Sexual desire is thus not limited to certain seasons, as is the case with most
of the lower animals.
REPRODUCTION IN MAN 1279
FERTILISATION
The act of impregnation consists in the introduction of spermatozoa
into the female genital tract, where they may come in contact with and
fertilise the ovum, which is discharged from the ovary by bursting of a
Graafian follicle. This is effected in the act of coitus or sexual congress by
the insertion of the penis into the vagina of the female. Before this can
occur erection of the male organ must take place. The mechanism of
erection is twofold. The most important factor, as was shown by Eckhard
and Loven. is an active dilatation of the vessels of the penis, especially of the
medium-sized and smaller arteries. If the penis be cut across while in the
flaccid condition, venous blood merely trickles away from the cut surface,
whereas, if erection be excited, the flow of blood from the cut surface is
increased eight to ten times, and the blood becomes bright arterial in colour.
It is thus possible to excite erection in an animal, in whom the second factor
has been abolished by paralysing the muscles by means of curare. This
second factor is the contraction of the ischio-ca/oe/rnosus or erector penis
muscle, certain fibres of which pass over the dorsal vein of the penis and
compress this vessel when they contract. Since ligature of the veins
coming from the penis does not produce erection, the contraction of this
muscle must be regarded as simply aiding the effects of the arterial
dilatation.
Before or at the beginning of coitus analogous changes occur in the
female organs, leading to erection of the clitoris and of the erectile structures
of the vulva. The glands of the vulva, especially the glands of Bartholini,
secrete a mucous fluid, thus lubricating the passage into the vagina. The
friction between the clans penis and the wall of the vagina causes a reflex
discharge of motor impulses in both male and female (the ' orgasm '). hi
the former the muscular walls of the vasa deferentia and seminal vesicles
enter into rhythmic contractions, thus forcing the spermatozoa they contain
into the urethra. The spermatozoa, mixed with the secretions of the
epididymis, the seminal vesicles, the prostatic glands, and the glands of
Cowper, form the semen, which is pressed along the urethra by rhythmical
contractions, from behind forwards, of the bulbo- and ischio-cavernosi
muscles. It has been stated that movements take place coincidently in the
uterus, so that its axis more nearly corresponds to that of the vagina. The
movement of the semen along the uterus and Fallopian tubes is ascribed by
certain observers to an antiperistaltic contraction of these organs. A more
important factor is probably the movement of the spermatozoa themselves.
As we have already seen, these are introduced into the female passage in
countless numbers. They will be chemiotactically attracted by the alkaline
mucus, secreted by and filling the cervix of the uterus. When they have
entered this organ they will meei the downward stream of mucus impelled
by the action of the cilia lining tin' uterus and Fallopian tubes. It seems
probable that their reaction to tins carrenl is to swim 1 against it (positi/ve
1 Spermatozoa move in a straight line, at (lie rate of 2 to 3 mm. per minute. Thus
1280 PHYSIOLOGY
•rheotaxis), so that they reach the upper part of the Fallopian tubes or the
surface, of the ovary itself. Fertilisation of the ovum occurs in most cases
in the Fallopian tube, and the fertilised ovum is then earned slowly down
the tube into the uterus.
NERVOUS MECHANISM OF IMPREGNATION. Although, in both sexes,
coitus is attended by a high degree of psychical excitement, yet it is
essentially a spinal reflex, and can be carried out when all impulses from the
higher centres are cut off by section of the cord in the dorsal region. The
centre presiding over the act is situated in the lumbar spinal cord. The
external generative organs, like the bladder, are supplied from two sets of
nerve fibres — from the lumbar nerves through the sympathetic, and from
the sacral nerves. The fibres from the lumbar nerves arise in the cat from
the second, third, and fourth, or the third, fourth, and fifth lumbar nerve
roots, and in the dog from the thirteenth thoracic, and the first to the fourth
lumbar roots. They run in the white rami conimunicantes to the sympathetic
chain, whence they may take two paths.
(a) The great majority of the fibres rim down the sympathetic chain to
the sacral ganglia, whence fibres are given off in the grey rami conimunicantes
to the sacral nerves ; their further course is by the pudic nerves, none
running in the nervi erigentes.
(b) A few fibres go by the hypogastric nerves to the pelvic plexus.
Excitation of these fibres causes contraction of the arteries- of the penis,
and of the unstriated muscles of the tunica dartos of the scrotum. In animals
which possess a retractor penis muscle, excitation of the lumbar nerves
causes strong contraction of the muscle.
The fibres from the sacral nerves can be divided into two classes —
visceral and somatic. The visceral branches run in the pelvic nerves, or
nervi erigentes. Stimulation of these fibres produces active dilatation of the
arteries of the penis or vulva, and also inhibition of the unstriated muscle of
the penis, of the retractor muscle of the penis, when present, and of the vulva
muscles. The somatic branches supply motor nerves to the ischio- and
bulbo-cavernosi, as well as to the constrictor urethrse. In the female they
supply the analogous muscles, namely, the erector clitoridis (ischio-caver-
nosus) and the sphincter vaginae (bulbo-cavernosus). Both these sets of
fibres are therefore involved in the erection of the generative organs which
accompanies coitus.
The internal organs, i. e. the uterus and vagina in the female, and vasa
deferentia, seminal vesicles, and uterus mascuhnus in the male, differ from
the external organs in receiving no efferent nerve fibres from the sacral nerves,
as has been pointed out by Langley and Anderson. They are supplied with
fibres, which pass out through the anterior roots of the third, fourth, and
fifth lumbar nerves (in the rabbit and cat), and run through the sympathetic
they might traverse the distance of 16 to 20 cm. between the os uteri and the trumpet-
shaped orifice of the Fallopian tubes in three-quarters of an hour. In animals sper-
matozoa have been found at the peritoneal end of the Fallopian tubes within an hour
or two after coitus.
REPRODUCTION IN MAN 1281
to the inferior mesenteric ganglia, whence they proceed by the hypogastric
nerves. On stimulating these fibres, two effects are produced on the uterus
and vagina, namely, a contraction of the small arteries leading to palior
of the organs, and a strong contraction of the muscular coats. 1 In the
vagina the contraction can usually be seen to start from one end and spread
to the other. The whole then remains for a time in a state of powerful
tonic contraction, which affects both longitudinal as well as circular muscles.
In the male stimulation of these nerves excites contraction of the whole
musculature of the vasa deferentia and seminal vesicles, which may be
strong enough to cause emission of semen from the penis. These effects on
the utems and seminal vesicles are not abolished by injection of atropine.
The course of the sensory fibres from the generative organs to the
lumbosacral cord has not yet been fully made out, but it seems probable
that it corresponds to the course taken by the efferent fibres.
An accessory genital muscle, the retractor penis, which is found in the dog, cat, horse,
donkey, hedgehog (not in the rabbit or man), presents considerable physiological
interest. It was first described by Eckhard as the Afterruthenband, and consists of a
thin band of longitudinally arranged unstriated muscle (15 to 20 cm. long in a spaniel
weighing about 15 kilos.), which is inserted at the attachment of the prepuce, and is
continued backwards in a sheath of connective tissue to the bulb, when it divides into
two slips which pass on either side of the anus. A few striated fibres are found in the
back part of this muscle, derived from the external sphincter of the anus and the bulbo-
cavernosus muscles. This muscle is extremely sensitive to changes of temperature,
and is at the same time very tenacious of life. Thus it may be cut out of the body and
kept in serum or blood in a cool place for two days. At the end of this time it will,
on warming, relax and enter into spontaneous rhythmic contractions. At about 40° C.
the muscle is quite flaccid. On cooling slightly (to 35°) it will shorten, and at the same
time may enter into slow rhythmic contractions. If cooled to 15° C. the muscle will
contract to about a quarter of its previous length. The same shortening may be
produced on exciting the muscle with strong interrupted currents.
The muscle is innervated from two sources, the two nerves having antagonistic
actions (cp. p. 247). The motor fibres to the muscle are derived from the lumbar sympa-
thetic (i. e. the upper set of nerve roots), and run to the muscle in the internal pudic
nerve. The pelvic nerves, on the other hand, carry inhibitory impulses to the muscle,
thus enabling the concomitant vascular dilatation to take effect in producing erection
of the penis.
1 Under some circumstances stimulation of the sympathetic nerves may cause
ition of the uterus.
SI
SECTION IV
PREGNANCY AND PARTURITION
PREGNANCY
Fertilisation of the ovum takes place, as a rule, in the Fallopian tube.
Directly one spermatozoon has penetrated into the ovum, a membrane is
formed round the yolk, which prevents the entrance of any other sperma-
tozoa. The fusion of the male and female pronuclei is followed immediately
by division of the fertilised ovum, so that, by the time it arrives in the uterus
(about eight days after fertilisation), it consists of a mass of cells known as
the morula. At this time the ovum has a diameter of about 0-2 mm.
Pregnancy in the human being lasts about nine months, birth generally
taking place 280 days, i. e. ten periods after the last menstrual period.
During pregnancy menstruation is absent.
With the arrival of the fertilised ovum in the uterus, extensive changes
begin in this and the neighbouring organs of generation. The virgin uterus
is pear-shaped, and its cavity amounts to about 2-5 c.c. Just before birth
the volume of the uterus is about 5000-7000 c.c, and the walls of the organ
are thickened in proportion. In the hypertrophy of the uterine wall all
its elements are involved, but especially the muscle cells. It is doubtful
whether there is an actual new formation of muscle fibres, but each fibre
glows in length and thickness, becoming finally between seven and eleven
times as long and three to five times as thick as in the unimpregnated
uterus (Fig. 576). There is at the same time a great growth of the blood
vessels, which have to supply not only the growing wall of the uterus but
also by means of a special organ — the placenta — the nutritional needs of
the developing foetus.
CHANGES IN THE UTERINE MUCOUS MEMBRANE. At the moment
of conception the uterine mucous membrane begins to undergo hyper-
trophy. Within fourteen days it has attained a thickness of \ cm., and
by the end of the second month f cm. On section it shows a compact
layer, lining the cavity of the uterus, and beneath this, abutting on the
muscular tissue, is a spongy layer three times as thick as the compact
layer. The superficial epithelium becomes flattened, loses its cilia, and de-
generates. In the spongy layer the uterine glands" proliferate, the stroma
cells are enlarged, and the blood capillaries are widely dilated. The stroma
cells become converted into the large decidual cells. By the time the
fertilised ovum arrives in the uterus, the process of Ivypertrophy of the
1282
PREGNANCY AND PARTURITION
1283
layers of the mucous membrane has already made some progress. As it
lies on the mucous membrane, the outermost cells of the developing ovum
exercise a destructive influence on the adjacent cells of the mucous mem-
brane, apparently through some sort of digestion, so
that the ovum sinks in the membrane and reaches the
sub-epithelial connective tissue. Round the margins
of the depression which the ovum has made for itself,
the mucous membrane grows over the protruding
part of the ovum (Fig. 577). When this has taken
place, the different parts of the mucous membrane
receive different names. Since (in man) they are all
to be cast off with the foetus at birth, each part is
spoken of as the decidua, that lining the main body
of the uterus being known as the decidua vera, that
covering the protruding part of the egg as the decidua
rejlexa,, while that to which the egg is immediately
attached is the decidua serotina or basalis. It is from
the latter that the placenta is formed. By the end
of the second week the blood vessels in this situa-
tion are considerably enlarged. This enlargement
proceeds, affecting especially the capillaries and
veins, until these form venous sinuses at the junc-
tion between the mucous membrane and the muscular
coat. Changes take place at the same time in the
embryo. When it sinks into the mucous membrane
it has a diameter of 1 mm. The blastoderm is fully
formed with its three layers; the yolk sac, the
body cavity, and the amnion are present. The
outermost layer of the epiblast becomes specially
modified to serve for the nutrition of the embryo,
and gives rise to the production of numerous villi, the
chorionic villi, so that the whole ovum has a shaggy
appearance. Since this tissue takes no part in the
further development of the embryo, but serves simply
for its nutrition, it is often spoken of as the tropho-
blast. With the formation of festal blood vessels,
these penetrate into the villi, together with mesoblast.
The villi grow into the venous spaces, especially in
the basal part of the decidua, so that at this period the foetal villi are
immersed in maternal blood, the foetal blood vessels being separated from
the maternal blood by a double layer of epithelium, one layer of which is
maternal and the other festal in origin. Later these cells become reduced
to a single layer.
NUTRITION OF THE EMBRYO. At the earliest period of its develop-
ment the fertilised ovum is dependent for its nourishment on the remains
of the cells of the discus proligerus adhering to it, or on the thud of the
Fjg. 576. Isolated mus-
cle cells from the
uterus, showing the
hypertrophy during
pregnanc3'.
a, fibre from uterus
in ninth month of preg-
nancy ; b, fibre from a
non-gravid uterus.
(After Bumm.)
1284
LMIYSlOLOCY
Fallopian tube in which it is immersed. The first blood vessels which are
formed serve to take up nourishment from the yolk sac. In man this
source of supply is insignificant, and from the second week onwards blood-
vessels traversing the chorionic villi come into close relation with the
maternal blood, from which henceforth the whole growth of the foetus is to
be maintained by a special development of these connections in the placenta.
In the fully formed foetus blood passes from the foetus to the placenta
by the umbilical artery, and is returned by the umbilical veins. There is
no communication between foetal and maternal circulations. The placenta
represents the foetal organ for respiration, nutrition, and excretion. Thus
^e^B
Fig. 577. Diagram to illustrate the imbedding of the ovum in the deeidua, and the
first formation of the foetal villi in the form of a syncytial trophoblast (derived
from the outer layer of the ovum) which is invading sinus-like blood spaces in the
deeidua. ( After T. H. Bryce. )
the umbilical artery carries to the placenta a dark venous blood, which in
this organ loses carbonic acid and takes up oxygen, so that the blood of the
umbilical vein is arterial in colour. The oxygen requirements of the foetus
are however but small. It is protected from all loss of heat, movements are
sluggish or for the most part absent, and the only oxidative processes are
those required in the building up of the developing tissues. On the other
hand, the foetus has need of a rich supply of foodstuffs, which it must
obtain through the placental circulation. It is imagined that the epithelium
covering the villi serves as an organ for passing on the necessary foodstuffs
from the maternal to the foetal blood in the form best adapted for the
requirements of the fcetus. We know however practically nothing as to
the changes or mechanism involved in this transference. Although most of
the organs of the fcetus are fully formed some time before birth, they are
for the most part in a state of suspended activity. The nitrogenous excreta
are turned out by the placenta, so that the foetal secretion of urine is minimal
PREGNANCY AND PARTURITION 1285
or absent. The alimentary apparatus is for the most part ready. Thus
pepsin can be extracted from the foStal gastric mucous membrane. The
pancreas contains tripsinogen and the intestinal mucous membrane pro-
secretin. Amy lo lytic ferments seem however to be absent both from
the salivary glands and the pancreas. The liver stores up glycogen and
secretes bile, -which accumulates in the small intestine, forming the meco-
nium. This is generally voided by the child shortly after birth.
THE FCETAL CIRCULATION. In the foetus, from the middle of intra-
uterine life, we find certain arrangements of the circulation which are
directed to providing the forepart of the body, especially the rapidly growing
brain, with oxygenated blood, while the less important tissues of the limbs
and trunk receive venous blood (Fig. 578). The arterial blood coming from
the placenta along the umbilical vein can pass directly into the liver. The
greater part of it however traverses the ductus venosus to enter the inferior
vena cava, by which it is carried to the right auricle. Here it impinges on
the Eustachian valve, and is directed thereby through the foramen ovale into
the left auricle, whence it passes into the left ventricle to be driven into the
aorta. As this arterial blood passes into the inferior cava, it is of course
mixed with the venous blood, returning from the lower limbs and lower part
of the trunk. By the aorta this mixture, containing chiefly arterial blood,
is carried to the head and fore limbs. The venous blood from these parts is
carried by the superior vena cava to the right auricle, and thence to the
right ventricle, by which it is driven into the pulmonary artery. Only a
small part of the blood passes through the lungs, the greater part
traversing the patent ductus arteriosus to be discharged into the aorta
below the arch, whence it flows partly to the lower limbs and trunk, but
chiefly to the placenta by the umbilical arteries. In the foetus therefore
the work of the circulation is largely carried out by the right ventricle. The
greater thickness of the left ventricular walls, which is so characteristic of
the adult, does not become evident until shortly before birth.
With the first breath taken by the newborn child all the mechanical
conditions of the circulation are modified. The resistance to the blood flow
through the lungs being diminished, the blood passes from the pulmonary
arteries through the lungs into the left auricle. The pressure in the left
auricle is thus raised, while that in the right auricle falls, so that the foramen
ovale is maintained closed. Even before birth proliferation of the lining
membrane may be seen both in the ductus arteriosus and in the ductus
venosus ; and with the mechanical relief of the vessels afforded by respira-
tion and the changed conditions of the foetus, this proliferation goes on to
complete obliteration of the vessels.
PARTURITION
As the uterus increases in size and becomes more distended, its irritability
becomes greater, so that it is easily excited to contract. The stimulus may
be supplied from adjacent abdominal organs, from the brain, as by emotions,
or by direct excitation of the internal surface of the litems, in consequence
286
PHYSIOLOGY
of movements of the foetus. Tn many cases no antecedent stimulus can be
discovered, and the automatic contraction of the uterus seems to be analo-
FlQ. 578. Diagrammatic outline of the organs of circulation in the
foetus of six months. (After Allen Thomson.)
ha, right auricle of the heart; rv, right ventricle; la, left auricle; ev, Eustachian
valve ; LV, left ventricle ; L, liver ; E, left kidney ; I, portion of small intestine ; a, arch
of the aorta ; a', its dorsal part ; a", lower end ; vcs, superior vena cava ; vci, inferior
vena where it joins the right auricle; vci', its lower end; s, subclavian vessels;
j, right jugular vein ; c, common carotid arteries ; four curved dotted arrow-lines are
carried through the aortic and pulmonary opening and the auriculo-ventricular ori-
fices ; da, opposite to the one passing through tho pulmonary artery marks the place
of the ductus arteriosus ; a similar arrow-line is shown passing from the inferior vena
cava through the fossa ovalis of the right auricle and the foramen ovale into the left •
auricle ; hv, the hepatic veins ; vp, vena portse ; x to vci, the ductus venosus ; uv,
the umbilical vein; va, umbilical arteries; vc, umbilical cord cut short; %%', iliac
vessels.
gous to that which occurs in the distended bladder. These contractions
ordinarily give rise to no sensations, and are felt only when they are aug-
mented in consequence of reflex stimulation. During the greater part of
PREGNANCY AND PARTURITION 1287
pregnancy they have little or no effect on the contents of the uterus. During
the last weeks or days of pregnancy however, these contractions, which have
now become more marked, have a distinct physiological effect. Not only
do they, by pressing on the foetus, cause it in most instances to assume a
suitable position for its subsequent expulsion but, affecting the whole body
of the uterus including the longitudinal muscular fibres surrounding its
neck, they assist the general enlargement of the organ in dilating the
internal os uteri, so that the upper part of the cervix is obliterated and
drawn up into the body of the uterus some little time before labour has
commenced.
With these changes hi the uterus are associated changes in the round
ligaments and in the vagina and vulva. The muscular fibres of the round
ligaments become much hypertrophied and lengthened, and these structures
can therefore aid appreciably the uterine contractions in the subsequent
expulsion of the foetus. The vaginal walls become thickened and of looser
texture, so as to afford less resistance to distension during the passage of
the foetal head.
Considerable discussion has taken place as to the cause for the onset of
the processes comprised under the heading of labour or parturition at a nearly
constant period of two hundred and seventy -two days after conception.
Most of the explanations which have been suggested, such as the great irrita-
bility of the uterus at the termination of pregnancy, the loosening of the
foetal membranes, the return of the menstrual congestion after ten months,
thrombosis of the placental sinuses, simply replace one question by another.
According to Spiegelberg the phenomena accompanying the birth of twins,
which are often bom at a considerable interval from each other, the onset of
contractions of the uterus at the right time in extra-uterine as well as in
normal fcetation, the fact that the extra-uterine foetus dies when it has
become mature, all go to show that the reason why labour occurs at a
definite time must be sought for in foetal rather than in uterine changes.
This author suggests that some substances which had previously been used
up by the foetus gradually accumulate in the maternal blood as the foetus
becomes mature, and provoke, by their direct action on the uterus or spinal
cord, the uterine contractions which give rise to labour.
Actual parturition in the woman is generally divided into two stages.
In the first stage the contractions are confined to the uterus, and chiefly act
in dilating the os uteri. In this dilatation two factors are involved, namely,
the active dilatation brought about by the contraction of the longitudinal
muscular fibres which form the chief constituent of the lower part of the
uterine wall ; and in the second place, a passive dilatation by the pressure
of the foetal bag of membranes, which is filled with amniotic fluid, and forced
down as a fluid wedge into the os by the contractions of the uterine fundus.
The uterine contractions are essentially rhythmical, being feeble at first, and
increasing gradually in intensity to a maximum which endure; a certain
time, and then gradually subsides. The frequency and duration of the
contractions increase as labour advances.
1238 PHYSIOLOGY
As soon as the os uteri is fully dilated and the foetal head has entered
the pelvis, the contractions change in character, being much more prolonged
and frequent, and attended by more or less voluntary contractions of the
abdominal muscles. This action of the abdominal muscles is associated
with fixation of the diaphragm and closure of the glottis, so that pressure is
brought to bear on the whole contents of the abdomen, including the uterus.
No expelling force can be ascribed to the vagina, since it is too greatly
stretched by the advancing foetus. In this way the foetus is gradually
thrust through the pelvic canal, dilating the soft parts which impede its
progress, and is finally expelled through the vulva, the head being bom
first. The membranes generally rupture towards the end of the first stage
of parturition.
A third stage of labour is generally described. . This consists in a re-
newal of uterine contractions about twenty to thirty minutes after the
birth of the child, and results in the expulsion of the placenta and decidual
membranes.
NERVOUS MECHANISM. We possess little experimental knowledge of
the nervous mechanism of parturition. The most important observation
on this point is the already quoted experiment by Goltz, in which this
physiologist observed the normal performance of menstruation (heat),
impregnation, and parturition in a bitch whose spinal cord had been com-
pletely divided in the dorsal region during the previous year. On the other
hand, destruction of the lumbo-sacral cord completely abolishes the normal
uterine contractions of parturition, so that this act must be regarded as
essentially reflex, presided over by a controlling ' centre ' in the grey matter
of the cord. The activity of the centre can be inhibited or augmented by
impulses arriving at it from the peripheral parts of the body, as by the
stimulation of sensory nerves, or from the brain, as under the influence of
emotions. The nerve paths from the centre to the uterus have been already
described.
SECTION V
THE SECRETION AND PROPERTIES OF MILK
LACTATION
During pregnancy the foetus obtains the whole of its nourishment from the
mother by means of the placenta. After birth the quality of the nutriment
supplied to the young child depends on the activity of the cells of the
mammary glands. Now however nutrition involves further activity on
the part of the young animal, the alimentary canal being concerned in the
digestion of the milk supplied by the mother, and the excretory organs,
especially the kidneys, being made use of for getting rid of waste material.
The preparation of the mammary glands for the subsequent nourishment
of the newborn child begins in the first month of pregnancy, and is marked
by swelling of the glands, rapid proliferation of the duct epithelium, and
production of many new secreting alveoli. The development of these
glands in the rabbit has been already described, and there is no doubt
that in the human species the process follows very much the same course,
being however spread over nine months instead of four weeks, as is the
case with the rabbit. During the latter half of pregnancy a watery fluid
can generally be expressed from the nipple. In certain mammals this
watery secretion gives place to a secretion of true milk at the end of gesta-
tion or during the process of parturition itself. In the woman the secretion
does not begin as a rule until the second or third day after birth, though
the formation of milk may be anticipated if a child has been put to the
breasts during the latter part of pregnancy. Secretion begins on the
second or third day, even if the child has been born dead and no attempt
at suckling has taken place. For the maintenance of the secretion the
process of suckling is absolutely necessary. If the woman does not nurse
her child, the swelling of the breasts gradually passes off, the milk disappears,
and the glands undergo a process of involution. Under normal conditions
the secretion of milk lasts for six to nine months and may in rare cases
extend over more than a year. The amount secreted increases at first with
the growth and size of the child. The Table on p. 1290 represents the
average amount of milk secreted during the thirtyrseven weeks after birth.
It will of course be greater with strong big children, and smaller with
weakly children.
COLOSTRUM. Refore the secretion of true milk begins, the fluid which
1289
1290
PHYSIOLOGY
is obtained from the breast is known as colostrum. It may be expressed
from the breasts immediately after birth and is ingested by the child during
the first two days after birth. The colostrum is formed only in slight
quantities. It is an opalescent fluid, often somewhat yellowish, containing
fat globules which, if the fluid be allowed to stand, form a yellowish layer
on the top. Under the microscope, in addition to the fat globules, may be
seen the so-called colostrum corpuscles, which consist of multinucleated cells
loaded with particles of fat. They are probably leucocytes or phagocytes
which have wandered into the alveoli and have taken up fat globules. Some
of the corpuscles may be desquamated secretory cells. Colostrum is distin-
guished from true milk by containing little or no caseinogen. It contains
about 3 per cent, of proteins, namely, lactalbumen and lactoglobulin, which
coagulate on boiling. Lactose and salts are present in the same proportions
as in ordinary milk. It is popularly supposed to have a laxative effect
on the child.
Table Showinq Amount of Milk Secreted by a Nursing Woman.
increase
Time
1st day
2nd.,'
3rd ..
4th ,.
5th „
6th „
7th „
2nd week
3rd— 4th week
5th-8th ..
9th-12th .,
13th-16th ..
17th-20th „
21st-24th „
25th-28th ,..
Milk secreted
20 grm.
97
211
326
364
4(12
478
502
572
736
797
836
867
944
963
l'i:cl;i;\s[.:
29th-32nd week
33rd-36th .,
37 th week ,.
'.illi 'Jim.
909 „
885 „
PROPERTIES OF MILK
Fully formed milk presents certain features which are common to all
mammals. These have been chiefly studied in the case of cows' milk. We
may therefore deal with the composition of cows' milk and point out later
in what respects human milk differs therefrom. Milk is an opaque white
fluid with characteristic odour and sweetish taste. Its specific gravity
varies between 1028 and 1034. Its reaction to litmus is neutral, to lacmoid
THE SECRETION AND PROPERTIES OF MILK 1291
it reacts alkaline, and to phenolphthalein, acid. One hundred cubic centi-
metres of fresh milk, when treated with lacmoid, require 41 c.c. w/10 acid
for neutralisation. When treated with phenolphthalein the same amount
requires 19-5 »/l0 alkali for neutralisation. When exposed to the air. milk
rapidly undergoes changes in consequence of infection by micro-organisms.
The most common of these changes is the formation of lactic acid bv the
bacillus lacticus. In some cases the milk may undergo a species of alcoholic
fermentation, as in the formation of kephir, which is made by the fermenta-
tion of mares' milk.
The opaque appearance of milk is due chiefly to the presence of multi-
tudes of fine fatty particles. On allowing the milk to stand, the particles rise
to the surface, forming cream, and by mechanical agitation, especially if the
milk is slightly sour, they may be caused to run together with the formation
of butter. Much discussion has arisen as to the reason why the fat globules
do not run together naturally. By many authors it has been imagined that
they are clothed with a special protein membrane (liaptogen membrane)
originating from the protoplasm of the cell in which the fat globules were
originally formed. It must be remembered that in any protein solution,
such as that in which the globules are suspended, the protein tends to aggre-
gate, with the formation of a pellicle, at the surface, so that an emulfion
once produced in such a fluid will tend to be more or less permanent. There
seems no reason to assume the presence of a distinct membrane differing
in composition from the proteins present in the surrounding fluid. The
fats of milk consist for the greater part of the neutral glycerjdes, tripal-
initin, tristearin, and triolein. In smaller quantities it contains the tri-
glycerides of myristic acid, butyric acid (?), and capronic acid, with traces
of caprylic, capric, and lauric acids.
The milk plasma, the fluid in which the fat globules are suspended,
contains various proteins, a carbohydrate (lactose), and inorganic salts,
with a small amount of lecithin and nitrogenous extractives.
THE PROTEINS OF MILK. The chief protein of milk is cmeinogen,
belonging to the class of phosphoproteins. Like other bodies of this class
it presents distinct acid characteristics, being precipitated by acids and
soluble in dilute alkalies. It may be prepared from separated milk by the
addition of weak acids. A convenient method is to dilute one litre of milk
with ten litres of distilled water and add to the mixture 10 c.c. of glacial
acetic acid. The precipitate which is formed rapidly sinks to the bottom
and may be washed two or three times by decantation. It may be purified
by solution in dilute ammonia and precipitation by acetic acid two or three
times. The precipitate finally obtained is extracted with alcohol and
ether, and the dried caseinogen prepared in this way forms a snow-white
powder which is practically insoluble in water and dilute salt solutions. It
is easily dissolved on the addition of a little alkali, when it yields solutions
which are acid to litmus. When rubbed up with chalk it dissolves, displacing
the carbonic acid and forming a calcium caseinogenate. A solution of case-
inogen in soda or potash is transparent and passes easily through a clay cell.
1292 PHYSIOLOGY
The calcium caseinogenate forms only opalescent solutions. Apparently
the compound is dissociated by water with the formation of caseinogen acid
which is in a state of partial solution as swollen-up aggregates. It is
impossible therefore to filter calcium caseinogenate through a clay cell. It
is mainly in this form that caseinogen is contained in milk, hence the
opalescent appearance of the milk plasma. When calcium caseinogenate
solution is boiled, it forms a pellicle on the surface in the same way as milk
does. On treating the caseinogen with rennet ferment it is converted into a
modification known as paracasein, which in the presence of lime salts is
thrown out as insoluble casein. To this process is due the clotting of whole
milk by rennet, which is made use of in the preparation of cheese, the curd
consisting of a network of casein enclosing fat globules in its meshes. On
allowing the clot to stand it shrinks, pressing out a milk serum.
From the milk serum or whey may be obtained two other proteins,
known as lactalbumen and lactoglobulin. These resemble very nearly the
albumen and globulin of blood serum. They are coagulated on heating.
According to some authors a third protein is present in the whey, to which
the name whey protein has been given, and which is supposed to be split off
from the caseinogen under the action of the rennet ferment.
•Milk can be boiled without undergoing any coagulation. If it be
allowed to stand and become sour by the formation of lactic acid, at a certain
degree of acidity boiling the milk causes its complete coagulation. Later on
the acid produced is sufficient in itself to precipitate the caseinogen. Both
these processes, namely, coagulation of half-sour milk by heating, and
spontaneous clotting of milk by the production of acid, are made use of in
different countries for the manufacture of cheese.
MILK SUGAR. The sugar of milk, or lactose, is most easily obtained
from whey which, after separation of the clot, is boiled to precipitate the
remaining proteins. On filtering and evaporating slowly, the milk sugar
crystallises out.. Lactose is a disaccharide and has the formula C 12 H 22 1:l .
It is only known to occur in milk. It may be found in the urine of nursing
women when the breasts are not kept empty, so that there is reabsorption
of the lactose formed in the mammary glands. It is unaltered by ordinary
yeast, so that the yeast test is the best means of distinguishing lactose from
dextrose in the urine. It gives the ordinary tests for reducing sugar. The
salts of milk include insoluble salts, soluble calcium salts, sodium and
potassium, phosphates and chlorides.
Mere enumeration of the constituents of milk presents but little interest
unless we realise how closely the composition of this fluid is adapted to the
needs of the growing animal. Li the first place, we find a proportionality
between the total solids of the milk and the rate at which the young animal
grows. It must be remembered that the milk taken by the animal serves
only in part for the production of energy in its body, a great proportion of
it being required for the building up of new tissue. Li no respect is this
correspondence seen better than in the comparative analyses of the ash of
milk and of the young animal of the same species which were made by
THE SECRETION AND PROPERTIES OF MILK
1293
Bunge. The following Table shows the composition of the ash of a rabbit
fourteen days old, of the milk which it was receiving from its mother, of
the ash of rabbit's blood and blood serum. Nothing could be more striking
than the marvellous way in which the cells of the mammary gland have
picked out from the salts of the circulating plasma exactly those salts which
are needed for the growing animal and in the same proportion :
Rabbit
Rabbit's
Babbit's
Rabbit's
1 i days old
milk
blood
blood serum
Potash .... . 10-8
101
23-8
3-2
Soda
6-0
7-9
31-4
54-7
Lime
350
35-7
0-8
1-4
Magnesia
2-2
2-2
0-6
0-6
Iron oxide
0-2.'!
0-08
<;•'.)
Phosphoric acid
41-9
39-9
hi
30
Chlorine
4-9
5-4
32-7
47-8
This close correspondence is necessary only where growth is very rapid,
so that the greater part of the constituents of the milk have to be utilised
in the building up of the animal tissues. As Bunge has shown, the slower
the growth of the animal the greater the divergence between the composition
of the milk and that of the new-born animal . We may compare for instance
the rabbit, which doubles its weight in six days, with the dog, which doubles
its weight in ninety -six days, and the human infant, which takes one hundred
and eighty days to double its weight at birth.
The last column of the following Table represents the composition of the
ash of cow's milk, and shows how very inefficiently this milk can be regarded
as replacing human milk, the natural food of the infant.
Rabbit 14
days old
Rabbit's
milk
•
Puppy few-
hours old
Bitch's
milk
Infant
some
minutes
alter birth
Human
milk
35-2
Cow's
milk
Potash
10-8
101
11-4
150
8-9
221
Soda .
60
7-9
10-6
8-8
100
10-4
13-9
Lime
350
35 T
29-5
27-2
33-5
14-8
20-0
Magnesia
2-2
2-2
1-8
1-5
1-3
2-9
2-6
Iron oxide .
0-23
0-08
0-72
012
1-0
0-18
0-04
Phosphoric acid
41!»
39-9
39-4
34-2
37-7
21-3
24-8
Chlorine
4-9
5-4
8-4
16-9
8-8
19-7
21-3
Thr relation between rate of growth and protein content of fond is well
illustrated by a comparison of the composition of the milk in different
animals. In the following Table (Proscher) it will be seen that the more
rapidly an animal urows the greater is the protein content of the milk with
which it is supplied :
L294
I'llYSIOLOGY
Time in which
100 parts of Milk contain
the body weight
of the newborn
animal was
doubled.
1 lays
Protein
Ash
Lime
Phosphoric
acid
Man
ISO
10
0-2
0-328
0-473
Horse
60
20
0-4
1-240
1-310
Cow
47
3-5
0-7
1-600
1-970
Goat
19
4-3
0-8
2100
3-220
Pig.
18
5-9
—
—
—
Sheep
10
6-5
0-9
2-720
4-120
Dog.
8
71
1-3 4-530
4-930
Cat .
7
9-5
— —
—
We should expect that the milk, which is the sole food of the growing infant,
should contain a relatively greater proportion of protein than is necessary in the case
of the adult. In an experiment by E. Feer, quoted by Bunge, a child weighing 8226 grm.
at the thirtieth week took 951 grm. of milk. Human milk contains :
Protein
Pat .
1-6 per cent.
3-4 „
61 „
0-2 „
The child was therefore receiving daily :
Protein
Fat .
Sugar ....
Ash .
15-2 grm.
32-3 „
58-0 „
1-9 „
According to the same proportions a man of 70 kilos, would take in :
Protein
Fat .
Sugar .
Ash .
129 grm.
275 „
494 „
16 „
It is interesting to note that the protein of this diet differs but little from that in
the. diets ordinarily accepted as standard, but there is a large excess in the fat and in
the total caloric value, as would be expected from the more rapid metabolism and the
relatively larger body surface of the young child.
The fitness of caseinogen for building up the tissues of the body is evident
when we compare, as in the Table on page 89, the products of its hydrolysis
with those of all the proteins in other foodstuffs. It will be seen that
practically every ammo-acid and : allied substance employed in the building
up of the various proteins is represented in caseinogen. The only exception
is glycine, which can be easily formed from other amino-acids.
In another point we find an adaptation of the milk to the growth of the
young animal, and that is in its lecithin content. Lecithin is probably
employed to the largest extent in the building up of the central nervous
system, where it forms the most important constituent of the medullary
THE SECRETION AND PROPERTIES OF MILK
1295
sheaths of the nerve fibres. There is a corresponding proportionality between
the lecithin content of milk and the relative brain weight of the young
Chemical Constitution of Different Proteins
3
1
3
a
5
B
t
1
JJ
|
I
ft
W
a
3
05
a
3
03
S
1
3
•3
.2
3
J3
.a
3
a
o
Glycine
3-5
0-4
0-1
1-0
16-5
360
20
Alanine
4-19
2-1
2-2
0-9
20
2-0
2-5
0-8
21-0
3-7
Valine .
4-3
+
10
0-3
1-0
1-0
0-9
Leucine
29-04
20-0
18-7
105
8-0
5-6
15-0
2-1
1-5
111
Isoleucine
Phenylalanine
4-24
31
3-8
3-2
3-7
2-4
3-2
04
1-5
3-1
Tyrosine
1-33
2-1
2-5
4-5
1-5
1-2
1-5
10-5
2-2
Serine .
7-8
0-56
0-6
0-2
0-5
0-2
0-4
1-6
Cystine
0-31
2-5
0-7
0-6
0-5
Proline
110
2-34
1-0
2-8
31
3-2
7-0
5-4
5-2
+
5-1
Oxyprolrne .
1-04
0-2
3-0
Aapartic acid
4-43
31
2-5
1-2
5-3
0-6
4-0
0-6
+
41
Glutamic acid
1-73
7-7
8-5
11-0
13-8
37-4
18-4
o-!i
151
Tryptophane
+
+
+
1-5
+
+
+
Arginine
87-4
5-42
4-8
101
3-2
7-6
10
7-1
Lysine .
4-28
5-8
4-3
0-0
2-8
+
7-1
Histidine
10-96
2-5
25
1-0
0-4
+
1-1
Ammonia
1-6
2-0
51
0-4
10
animal. Thus in the calf the brain is only vAi> of the whole animal. In
cow's milk lecithin is present in the proportion of 1-4 per cent, of the total
protein. In the puppy the brain is - :i \ of the whole body and the proportion
of lecithin to protein in the milk is 2-11 per cent. In the infant the brain
forms \ of the body weight, while the lecithin is 3-05 per cent, of the protein
of human milk.
Calf
Puppy
Infant
Kelative brain weight .....
Lecithin content of milk in percentage of protein
1:370
1-40
1: 30
2-lL
1 : 7
3-05
We thus see that under normal conditions the young animal is supplied
through its natural food with all the foodstuffs in the proportions which it
requires for its normal nourishment and growth. It is impossible therefore
satisfactorily to replace the natural milk of an animal by that of another
species. In civilised communities it is becoming more and more the custom
to endeavour to feed the child with cow's milk, more or less modified, in the
vain endeavour to reproduce the properties of human milk. Among all
classes this involves the administering of a milk differing in its qualities
and in the relative proportions of its proteins, fats, carbohydrates, and
salts, from human milk. So-called ' humanised ' milk is only a rough imita-
tion of the natural mother's milk. Among the poorer classes this artificial
feeding means the replacement of a natural sterile food, throwing very little
1296 PHYSIOLOGY
work on the digestive organs of the child, by a foreign milk, very difficult
to digest and often teeming with micro-organisms. There is no doubt that
of the children dying during the first year of life four-fifths are murdered by
this unnatural method of feeding. In some cases it is necessary to adopt
artificial feeding because the mother is abnormal, and there is an insufficient
secretion of milk. It is therefore important to lcnow what are the main
differences in composition between human and cow's milk. In human milk
the caseinogen is not only absolutely but also relatively less than in cow's
milk, while the latter is relatively poorer in milk sugar. Human milk is
poorer in salts, especially in lime, containing only one-sixth of the amount
present in cow's milk. Human milk is also said to be poorer in citric acid.
The main differences may be summarised as follows :
Water
Proteins
Fat
Milk sugar
Salts
0-2
0-7
Caseinogen
Albumin
Human milk .
Cow's milk
88-5
87-1
1-2
302
0-5
0-53
3-3
3-7
60
4-8
The caseinogen of human milk presents several points of difference from
the caseinogen of cow's milk. It is less easily precipitated by acids. When
coagulated by rennet it does not form a firm clot, but is thrown out in a
flocculent form. It is thus much more susceptible to the action of gastric
juice. Whereas the caseinogen of cow's milk generally gives a precipitate
of ' pseudonuclein ' on digestion with pepsin and hydrochloric acid, a smaller
or no precipitate is formed with human caseinogen.
Another important advantage of human milk for the infant lies in the
presence of antitoxins. It has been shown by Ehrlicb that, when a female
animal has been immunised against any toxin and has produced in conse-
quence antitoxins in its blood, these antitoxins will, if it has young, pass over
into the milk. The same passage of anti-bodies into the milk has been
proved in the case of various infective disorders. The ingestion of human
milk will therefore not only nourish the infant, but will provide it with a
certain measure of passive immunity against possible infection by diseases
to which its species is liable.
THE SECRETION OF MILK. When fully formed, each mammary gland
consists of fifteen to twenty lobes embedded in connective tissue. Each lobe
is made up of a mass of secreting alveoli which lead by narrow ducts into one
large lactiferous duct. These lactiferous ducts, one from each lobe, open on
the nipple, undergoing in the nipple itself an oval enlargement. Before secre-
tion begins, the alveoli as well as the ducts are lined with a cubical epithe-
lium. When secretion commences a marked difference develops between the
epithelium of the alveoli and that of the ducts. While that of the latter
retains its previous character, the cells of the secreting epithelium grow in
length and project into the lumen of the gland. In the innermost part of the
THE SECRETION AND PROPERTIES OF MILK 1297
protoplasm numerous fat globules make their appearance. If sections be
made of the gland during the various stages of its activity and stained
bv Altmann's method (acid fuchsia and picric acid), it will be seen that the
commencement of activity is marked by the growth of the innermost part of
the cells and the development in these of a number of granules (Fig. 579).
These granules finally lengthen into shapes like spirilla, while others of them
form fat and become metamorphosed into fat granules. The nuclei of the
cells also divide, apparently in preparation for the replacement of some cells
which undergo complete degeneration and are cast off into the secretion.
We know verv little about the mechanism of milk secretion. It seems
Fig. 579. Sections of mammary gland of guinea-pig (fat granules
stained black with osmic acid).
A, during rest. r.. during active secretion. It will be noticed that in this case
the active formation of products of cell metabolism (granules, etc.) begins with
the commencement of secretion, and does not occur almost exclusively during rest,
as in the salivary glands. In the mammary gland, the active growth of protoplasm,
the formation of granules from the protoplasm, and the discharge of these granules
in the socretion appear to go on at one and the same time.
impossible at present to explain the very close adaptation between the
activity of the secretory cells and the needs of the infant or young animal.
Two at least of the constituents of milk, caseinogen and lactose, are peculiar
to this secretion. It has been assumed that the caseinogen is produced by
some sort of alteration in the nucleo-proteinsof the gland cells, and that the
lactose is derived in the same way from some sort of gluco-protein or gluco-
nucleoprotein ; but the evidence for either of these assumptions is very scanty.
The growth of the mammary glands during pregnancy is largely determined
by some form of chemical stimulation, the specific hormone being produced in
the corpus luteum of the ovary and possibly also in the growing foetus. It
has been suggested by Hildebrandt that this stimulus is inhibitory in character
— inhibitory, that is to say, of secretion- — and therefore tending to the con-
tinuous growth of the gland cells. With the expulsion of the fcetus at birth
82
1298 PHYSIOLOGY
the source of the inhibitory stimulus is removed and the overgrown gland
cells enter into a condition of spontaneous activity. However this may be,
there is no doubt that the secretion of the gland, once formed, is continued
independently of the foetus or indeed of any of the pelvic organs. The
onset of a new pregnancy brings the secretion to a close. Removal of
the ovaries in a cow is sometimes employed as a means of prolonging the
secretion of milk. The only condition in the human being, which is
necessary for secretion to continue during six to nine months after birth,
is the repeated emptying of the gland, i. e. the removal of the secreted
milk. The process of suckling not only removes the milk already secreted
but' excites the secretion of more milk. The secretion is certainly subject
to nervous influences, but physiologists have not succeeded in either pro-
ducing secretion by stimulation of the nerves going to the glands, or in
stopping secretion by section of these nerves. Moreover the food of the
animal may be varied within very wide limits without altering the composi-
tion or amount of the milk secreted, provided that the food is sufficient
in amount. The only constituent of the milk for which we have direct
evidence of alteration by changes in the food supply of the mother is the fat.
It is well known that the composition of butter may be affected according to
the food supplied to the cow. A large supply of oilcake, for instance, may
result in the production of a butter which is deficient in the higher fatty acids
and is therefore oily at ordinary temperatures. Abnormal fats and fatty
acids such as iodised fats or erucic acid, when administered to an animal in
lactation, may appear among the fats of the milk. Not only can the secretion
and composition of the milk be affected reflexly through the nervous system,
as e. g. under the influence of emotions, but the influence may be reciprocal.
This is especially marked in the case of the pelvic organs. The act of
suckling excites tonic contractions of the uterus. Putting the child to the
breast shortly after birth is therefore an important means of causing
contraction of the uterus and stopping any tendency to haemorrhage from
the veiious sinuses opened by the separation of the placenta and fcetal
membranes. The nursing of the child is thus an important means of
procuring a proper involution of the uterus after labour. Many uterine
troubles among women may be ascribed to the previous neglect of this
elementary duty.
INDEX
Absobftiox of fats, 784
of foodstuffs, 779
intestinal, 779
through membranes, 131
from tissues, 1068
Acapnia, 1151
Accelerator nerves, 470
Accessory food substances, 693
Accommodation, amplitude of, 527
effect of drugs on, 52 8
of old age on, 528
of eye, 496, 524
in birds, 504
innervation of, 527
in man, 504
mechanism of, 526
spasm of, 538
theories of, 524
Acetone in uriDe, 1173
Acid albumin, 96
intoxication, S10
Acidosis, 810
A aids, organic, 48
Acroodextrine, 68
Acrose, 62
Acrylic acid scries, .",4
Activity associated with disintegration, 4
Adaptation, r>. 177
dark, 556
sensory. 4 s:>
visual, 608, 570
Addison's disease. 1234
Adenine, 100
Adrenaline, 51
action of, 1234
on heart, 1020
on nerve endings, 278
on pupil, 509
influence of, 1046
in muscular exercise, 1055
production of glycosuria by, 840
Adsorption, 145
by protein. 72
^rotonometer, 1107
Afferent impulses, 345
After image, 567
cause of, 574
fate of, 570
utility of, 574
Alanine, 80
Albumin, crystallisation of, 73
in plants, 1 1
Albuminoids, 104
Albumins, 95
Alcaptonuria, 814
Alcohol as food, 702
Alcohols, 46
Aldehydes, 17
Aldol condensation, 118
Aldoses, 60
Aleurone crystals, 72
Alexia, 456
Allantoin, 822
' All or none ' law, 205
Alveolar air, analysis of, 1101
Amboceptor, 1085
Amines, 49
formation from amino-acids, 76, 154
Amino-aeetic acid, 80
Amino-acids, 48, 75-95
action of bacteria on, 76
aromatic, 83
containing sulphur, 85
conversion into sugar, 845
into urea, 803
distribution in albumoids, 106
in proteins, 89
energy value of, 805
fate after absorption, 795
formation of, 154
in plants, 37
heterocyclic, 84
intestinal absorption of, 793
linkage of, 87
optical activity of, 78
pancreatic digestion of, 7- r >0
properties of, 77
separation of, 79
synthesis of, 808
in plant, 112
transformation of, 116
value as food, 690
Amino-propionic acid, 80
Ammonia, effects on muscle, 186
estimation in urine, 1177
excretion of, 809
formation of purines from, 11«>
of urea from, 803
Amoeba, removal of nucleus in, 28
structure of, 14
Amoeboid movements, 248
Amphoteric nature of amino-acids, 7!)
of colloids, 147
Amylodextrin, 68
Anacrotic pulse, 971
Anaesthesia, 454
Anaesthetics, influence on peripheral nerves,
260
Anelectrotonus, 265
Anisometropia, 539
Anode, 187
excitation at, 263
Antidromic impulses, 323, 1041
Antigens, 1085
1300
INDEX
\ni illirornbin, 889
Antitoxins, 1080
of milk, L296
\ [ 1 1 1 . i ia. 454
Apncea, 1145
Appetite, influence on gastric secretion, 7:S'>
Aqueous humour. 516
Arabinose, (>1
Archipallium, 41<>
Arcuate fibres, 366
Arginine, fate of, 810
Aromatic compounds. 49
groups, metabolism of, 81 I
sulphates, 813
in urine, 1170
Arteries, blood flow through, 962
pressure in, 916
structure of, 915
Asparagine, 81
in seedlings, 112
Aspartic acid, 81
Asphyxia, 1129
influence on circulation, 1027
Assimilation, 2, 25
by cells, mechanism of, 24
relation of nucleus to, 31
Associated fibres of brain, 424
Association processes in brain. 451
Asthma, 1099
Astigmatism, 538
radial, 532
Ataxia, 346
Auditory ossicles, 602
sensations, 611
Auricles, pressure in, 945
Auriculo-vcntricular bundle, 9:iii, 993
Axis cylinder, electrolytes in, 172
Axon, 295, 301, 309
-reflexes, 323, 475
' Bahntog,' 305
Basal metabolism, 675
Batteries, electrical, 186
Beats (sound), 613
Benzene derivatives, 49
Bidwdl's experiment. 572
Bile, 759-763
composition of, 760
digestive functions of, 762
secretion of, 762
Binocular vision, 588-594
Biogen molecule, 20
Biophore, 20
Biuret reaction, 92 •
Bladder, functions of, 1206
in spinal animal, 332
innervation of, 1211
in man, after transection of cord, 337
Blindness, 577
Blindspot, 549
Blood, 853-912
characters of, 854
circulation of, 913-1060
coagulation of, 882
conductivity of, 906
-corpuscles, 854
destruction of, 1085
enumeration of, 901
hemolysis of, 23
red, 861
Blood eorpuscles, red, life history of, 874
white, 856
functions of, 34
gases of, 1103
general composition of, 907
osmotic pressure of, 906
oxygen capacity of, 901
-pigment of cephalopoda, 44
-plasina, absorption of, 891
collection of, 882
composition of, 909
properties of, 885
protein of, 909
relative amount of, 900
-platelets, 879
in coagulation, 887
-pressure, 916
dependence on heart output,
929
diastolic, 919
in different vessels, 922
distribution of, 919
effect of asphyxia on, 1027
of spinal centres on,
1032
influence on heart, 1023
of capacity on, 927
measurement of, 916
in man, 920
in spinal shock, 331
systolic, 919
venous, 922
quantity of, 897
reaction of, 904
regeneration of, 874
serum, composition of, 910
proteins of, 910
specific gravity of, 903
tension of gases in, 1 107
velocity of, 931
methods of measuring, 932
-vessels, chemical control of, 1045
nervous control of, 1025
tone of, 1033
-volume, estimation of, 897
Body, material basis of, 36-120
Bone, composition of, 105
Brain. See Cerebral hemispheres,
chemical composition of, 58
development of, 360
nerve cells of, 426
path of motor impulses in, 389, 422
-pressure, 464
-stem, conduction in, 381
descending tracts of, 389
functions of, 390-394
structure of, 360-394
tracts of, 384
structure of, 416
vertebrate, comparative structure of,
363
Broca's convolution, 454
Bronchi, innervation of, 1096
Brown-Seqnard paralysis, 359
Bulbo-spinal animal, 391
Burch's experiment, 573
Butyric fermentation, 119
Caffeine, 101
Calcium, 43
INDEX
1301
Calcium, importance for blood clotting, 884
Calorie value of normal diet, 695
Calorimeter, construction of, 668
Cane Bugar, 67
ies, blood flow through, 1048
circulation through, 973
in muscles, 1054
inflammatory changes in, 1074
measurement of pressure in, 974
Capillary electrometer, 173, 227
Capsule, internal, 375, 423
Carbamino-acids. 7ii
Carbohydrates, 45
absorption of, 789
chemistry of, 59-70
as constituent of protein, 86
of nueleins,
102
conversion into fat, 830
digestion of, 767
influence on metabolism, 081
metabolism of, 839
lor, in proteins, 93
Carbon, assimilation of, 107—111
by plants, 37
as a constituent of protoplasm, 3ti
dioxide, a ssimilation by green plants,
108
in atmosphere, 38
condition in blood, 1015
effect on circulation, 1047
elimination in lungs, 1121
influence on nervous con-
duction, 261
production in isolated mus-
cle, 216
reduction in plants, 37
of respiration,
1137
! monoxide, influence oa blood, 1153
Cardiac cycle, 93$
1 points, 522
i ardiograph, 948
( '.milometer, 957
Cartilage, chemical composition of, 104
n, 9s, 73o. 752, 1291
■ n. influence of, 1269
Catacrotic pulse, 971
Catalysis, 158
mechanism of, 159
. specificity of, 159
i latelectrotonus, 265
Cathode, 187
excitation at, 263
Cell organs, 32
as structural unit, 13
structure of, 10
-wall. 22
Cells, chemical reactions in, 153
division of, 31, 35
histological differentiation of, 31
galvanic, 186
osmotic phenomena in, 22
of plants. 1.'!
surface layer of, 21
vital phenomena of, 25
i '• llulose, 22
properties of, 69
use in food, BOO
Central nervous system, 2SS-311
Central nervous system, continuity in, 309
Centres, cortical, arrangement of, 431 '
motor, 439
sensory, 443
Cereals, proteins of, 96
Cerebellar functions in man, 403
tracts of cord, 354
Cerebellum, 370
functions of, 395-404, 451
influence on muscular tone, 336,
398
removal of, 4(12
stimulation of. 401
structure of, 398
tracts of, 387, 400
Cerebral cortex, connection with cord, 35(1
functions of, 394
influence on equilibrium, 654
localisation of functions in,
433
stimulation of, 435
structure of, 41(i, 42(1
hemispheres, 415-460
afferent tracts of, 421
association fibres in.
424
commissural fibres in,
425
effects of removal of,
439
efferent tracts of, 422
evolution of, 419
functions of, 433
general character of
functions of, 449
higher associative func-
tions of, 451
localisation in, 434
minute structure of,
426
motor functions of, 435
projection fibres of, 42!
sensory functions of,
443
stimulation of, 435
structure of, 415
time relations of, 457
tracts of, 420
Cerebral vesicles, 361
Ccrebrin, 58
Cerebro-spinal fluid, 4(52
Cetyl alcohol, 47
Charpentier' s bands, 566
Chemical energy of dissohed substances,
128
sense, 639
Chemiotaxis, 27, 639, 1075
Cheyne-Stokes' breathing, 111 1 '
Chitin, composition of, 65
Chlorides of urine, 1162
Chlorine, 43
Chloroform, influence on nervous conduction,
261
Chlorophyll, function of. 6, 37, 107
necessity of iron in formation
of, 43
Chloroplasts, 17, 107
'in, 47
i i in i it ui'iit of surface layer,
23
1302
INDEX
Cholesterol, significance of, 56
esters, 56
Choline, composition of, 57
Chondroitin, 104
-sulphuric acid, 104
Chorda tympani nerve, 412
effect on secretion, 710
Choroid, 500
structure of, 506
Chromatic aberration, 530
Chromatin, 17
Chromoproteins, 99
Chromosomes, 31, 33
Cilia, 33
Ciliary body, structure of, 506
movement, 248
muscle, action of, 526
nerves, functions of, 511.
Circulation, physiology of the, 913-1000 —
action of heart on, 935
through arteries, 919, 962
capacity of, 925
through capillaries. 973
capillary, regulation of, 1048
cerebral, 464
chemical relation of, 1045
coronary, 1010
influence of anaemia on, 1060
on lymph, 1066
of nervous system
on, 1025
of plethora on, 1058
in invertebrates, 913
during muscular exercise, 1051
pulmonary, 979
through veins, 976
Circulatory system, evolution of, 34
Clark's column, 325
Clonus, 241, 336
Clotting of blood. See Coagulation.
Coagulation of blood, 855, 882-896
of colloids, 148
heat, 93, 148
history of, 892
intravascular, 889
mechanism of, 149
of muscle plasma, 212
of protein, 72, 93
theory of, 891
of transudations, 892
Cochlea, 606
Cochlear nerve, 411
central connections of, 379
Ccelenterata, differentiation in, 33
nervous system of, 289
Ccelomata, 33
Coelum, 34
Coil, induction, 188
Coitus, physiology of, 1279
Collagen, digestion in stomach, 732
Colloidal compounds, influence on diffusion,
135
properties of protoplasm, '20
solution of metal, 138
Colloids, 72, 137-151
adsorption by, 145
amphoteric nature of, 147
classification of, 137
coagulation of, 148
combination between, 148
Colloids, definition of, 137
electrical charges on, 147
properties of, 144
imbibition by, 149
molecular weight of, 138
optical properties of, 143
osmotic pressure of, 140
precipitation of, 145
properties of, 137-151
surface phenomena in, 145
Colostrum, 1289
Colour blindness, 578
mixing, 562
triangle, 486
vision, effect of intensity on, 5SI
peripheral, 581
theories of, 583
Colours, complementary, 487
mixture of, 487
Combination tones, 616
Comma tract, 353
Commissural fibres in brain, 425
Complement, 1085
Complemental air, 1095
Complementary colours, 571
Concentration battery, 170
Conchiolin, 106
Condenser, 191
Conditioned reflexes, 453
Conduction in brain stem, 381
irreciprocal, in synapse, 275
in spinal cord, 351
Cones, function of, 583
Conjugated proteins, 98
sulphates, 813
Conjugation in metazoa, 1254
in protozoa, 1252
Consciousness, 9, 451, 481
Conservation of energy in living beings, 2
of mass in living beings, 2
Consonance, 614
Consonants, 625
Contractile stress of voluntary muscle, 200
tissues, 177-249
Contractility of muscle, 179
Contraction of muscle, 194-204, 234-238
arrested, 200
isometric, 197
isotonic, 197
osmotic theory of,
235
surface tension, theorv
of, 235
energy of, 236
in relation to surface tension, 24
secondary, 233
-wave in muscle, 228
Contrast, effect on sensation, 483
simultaneous, 571
successive, 571
Co-ordination of eye movements, 495
of movement in spinal animal,
331
muscular, 395
influence of eyes
on, 406
part played by afferent im-
. pulses in, 345
Copper as necessary constituent of certain
plants and animals, 44
INDEX
1303
Cornea, 500
structure of, 504
Coronary circulation, 1010
Corpora quadrigemina, 373, 392, 405
Corpus luteum, 1275
striatum, functions of, 442
Cortex, cerebral. See Brain.
Cramptori 8 muscle, 504
Cranial nerves, connections and functions of,
414
Creatine metabolism, 811
Creatinine, origin of, si 1
in urine, 1106, 1178
Cretinism, 1239
Crusta, 373
Crystallin, 95
Cuorin, 58
Curare, effect of, 1S5, 259
on nerve endings, 277
Currents, galvanic, 186
induced, 188
Cutaneous sensations, Head's classification
of, 635
Cystine, 74, 85
Cytase, 70
Cytolysins, 1085
Cytoplasm contrasted with nucleus, 30
Cytosine, 102
Dark adaptation, .".."id
Deaminisation, 153, 803
of amino-acids, 798
Death,
Decarboxylation, 154
of amino-acids, T t ;
brate rigidity, 392
Defalcation, 777
Defence, cellular mechanisms of, 1070-1078
chemical mechanisms of, 1079-
1087
Degeneration of nerve fibres in cord, 320
retrograde, 320
Deglutition, 721-727
nervous mechanism of, 720
Delirium cordis, 1011
Demarcation current, 225, 233
Dendrites, 301
Depressor impulses, 1044
nerves, 1022
Depth perception, hypothesis of, 593
Development of egg, 1264
Dextrorotatory compounds, 52
Dextrose, 63
Diabetes, 838, 843, 831
glycogen in. Sis
Diabetic puncture, S43
Dialysis, 134
Diamino-acids, 82
in histones, 95
Diamino-trioxydodecoic acid, 83
Diapedesis, 1073
Diaphragm, 1090
Dicrotic notch, 969
Diet, distribution of foodstuffs in, 698
influence on urinary composition, 802
of man. 695
Diffusibility in relation to electrical potential,
171
Diffusion, 122. 129-136
Digestion, 25, 703-800
Digestion, course in dog, 797
intestinal, 74S-75S. 707
loss of food in, 698
in mouth, 706-720
of protein, 76
in stomach, 728-741
Dilemma, 460
Diphasic variation, 229
Disaceharides, 61, 67
Discrimination, tactile, 631
Dissimilation, located in cytoplasm, 31
Dissociation of colloidal salts, 135
Dissonance, 613
Diuretics, action of, 1201
Diving, respiration in. 1153
Ductless glands, 1230-1247
interaction between, 849
Ear, internal, 600, 606
middle, 601
structure of, 600
Eck's fistula, 804
Edestin, 74
Edridge Green's theory of colour vision
566
Efficiency, mechanical, of body, 684
Egg albumin, 95
molecular weight of, 74
Elastin, 106
Electrical changes, in voluntary contraction,
241
in living tissues, 169-173
in muscle, 169, 224-233
in retina, 545
Electrodes, 187
Electrotonic current, 280
Electrotonus, 264, 280
Elements essential to life. 36
Embryo, nutrition of, 1283
Emulsions, formation of, 56
Emulsoids, 139
Endocardiac pressure, 942
Endplate, 275
fatigue situated in, 276
Energetic basis of body, 121-173
Energy balance sheets, 666
chemical, of dissolved substances,
128
evolved in fermentative changes, 155
income and output, 3
of muscular contraction. 201
muscular, effects of, 169
source of, 686
origin in cells, 25
from fat, 830
value of amino-acids, 805
Enterokinase, 751
Epiblast, 33
Epicritic sensibility, 636
Epilepsy, 437
analysis of spasms in, 24 1
Equilibration, 397
Equilibrium, maintenance of, 654
Erepsin, 766
Erythroblasts, 876
Erythrocytes. See Blood corpuscles, red.
Erythrodextrin, 68
Ether, influence on nervous conduction, 261
Eustachian tube, 604
Excitability, 26
1304
INDEX
Excitation, propagation in invertebrate ner-
vous system, 296
•in involuntary mus-
cle, 24(1
Excitatory process, nature of, 284
Eye, abnormal refraction of, 534
accommodation of, 524-528
anatomy of, 500
central connections of, 405
chromatic aberration of, 530
comparative anatomy of, 502
diffraction in, 529
development of, 501
malnutrition of, 518
minute anatomy of, 504
movements, 409, 493^199
muscles, nuclei of, 406, 409
nourishment and protection of, 514-
518
optical constants of, 521
defects of, 533
system of, 519-528
peripheral aberrations of, 532
reduced, 524
refraction in, 522, 529-539
refractive indices of, 522
spherical aberration of, 531
Eyeball, muscles of, 494
nerve supply to, 505
structure of, 500-513
EyeUds, anatomy of, 514
closure of, 514
Eyes, conjugate deviation of, 496
fixation of, 589
Facial herve, 412
Facilitation, 305
Fajces, 799
False image, produced by squint. 498
Faraday -Tyndall phenomenon, 143
Fasting, influence on metabolism, 666
Fatigue of muscle, 208
of nerves, 259, 285
of reflex arc, 304
of sense organs, 4sj
situated in endplates, 276
in synapse, 343
Fats, 45
absorption of, 784
chemistry of, 53—58
formation of, 155, 828
in plants, 37
sugar from, 837
history in body, 826-838
identification of, 56
influence of bile on digestion "1, 7i>:i
on metabolism, 681
metaboUsm of, 826, 838
of milk, 55
origin of, 827
oxidation of, 155, 835
properties of, 55
significance in diet, 699
synthesis of, 117-120, 168
Fatty acids, 48
formation of, 118
list of, 54
Fatty degeneration, 832
Fechner's law, 485
Ferment action, 152-168
Ferment action, influence of concentration
on, 162-165
mechanism of, 160
methods of investigation,
163
reversibility of, 166
Ferments, action of, 148
as catalysts, 158
chemical character of changes
effected by, 153
colloidal character of, 157, 167
definition of, 156
list of, 157
as synthetic agents, 167
Fertilisation in man, 1279
nature of, 1262
nervous mechanism of, 1280
Fibrin, 884
-ferment, 885
Fibrinogen, 95, 884
tissue-, 99
Fibroin, 106
Fillet, 367
Filtration-angle of eye, 516
Fischer's methods of separating amino-acids,
79
Flicker, 568
-method, 565
Fluorine, 44
Focus, depth of, 530
Foetus, circulation in, 1285
Food, changes during digestion, 704
effect on metabolism, 677
fsecal residue from, 800
in normal diet, 695
passage from mouth to stomach, 712
requirements of man, 696
of woman, 696
Foodstuffs, absorption of, 779
distribution in normal diet, 698
fate in body, 3
heat value of, 667
history in body, 801-852
inorganic, 692
significance of, 688
as source of energy, 2
Foramen of Monro, 375
Fore brain, 373
connection with cord, 356
structure of, 373
Formaldehyde, formation of amino-acids
from, 114
from carbon dioxide, 109
as stage in carbon assimila-
tion, 109
Fornix, 375
Fovea, 543
vision by, 548
Fructose, 63
formation in plant, 111
Galactose, 64
as constituent of phospholipids,
58
structure of, 66
Galactosides, 58
Ganglia, 293
functions of, 474
inhibition in peripheral, 475
root development of, 298
INDEX
1305
Gastric digestion, 728-741
juice, 728
acidity of, 730
action on albuminoids, 7;{2
on carbohydrates, 734
on food, 730
on milk, 733
effect of vagus on, 737
secretin, 740
secretion of, 734
chemical mechan-
isms in, 73S
Gauss' theorem, 522
Gelatin, 105
diffusion through, 140
as food, 081
Gels, 137
properties of, 139
Gemmules, 20
Geniculate bodies, 373, 375, 386
Geotaxis, 27
Germ-cells, formation of, 1257
Glands, ductless, 1230-1247
mammary. 333, 1270, 1289
Glaui oma, 509, 517
Gliadins, 96
Globin, 868
Globulin, 74
precipitation of, 95
Glomeruli, functions of, 1192
Glossopharyngeal nerve, 413
Glucosamine, 65
from proteins, 86
Glucose, 67
conversion into lactic acid, 113
formation from ammo-acids,
808
in plants. II I
tests for, 62
Glucosides, formation of, 65
hydrolysis of, 10(1
methyl-, 66
i Uutamic acid, 81
Glutelins, 96
Glycerides, 53, 59
Glycerin, effects on muscle, 186
origin of, 119, 831
Glycerol, 53
Glycine, 80, 114
Glycocoll. Si)
Glycogen in diabetes, 84S
formation of, 840
in muscle. 218
preparation of, 839
properties of, 69
Glj coproteins, 103
Glycosuria, 843
Glycuronic acid, 65
in urine. I 173
Glyoxilic acid in plants, 114
Golgi method, 300
network, 309
Gout, nature of, 824
Gracilis experiment (Kiihnc , 254
nucleus, 365
Grape sugar, 63
Growth, 4
relation of nucleus to, 31
of tissues, 681
Guanine, 100
H.KMATIX, S68
chemical relations of, 870
Hrernatoblasts, 854
Hematocrit, 900
Haematocytes (blood platelets), 879
Haematoporphyrin, 870
Hseniin, 868
Haemochromogen, 870
Haemocyanin, 44
Haemoglobin, 99. 8113
crystallisation of. 73
derivatives of, 868
dissociation curve of, 1109
fate of, 877
molecular weight of, '.III
osmotic pressure of, 75
properties of, 864
Haemolymph glands, 1245
Haemolysis, 23, 1085
osmotic pressure of electrolites,
126
Haemopyrroles, 872
Haemorrhage, effects of, 1060
Halogen-proteins, 96
Hausmann's method of protein analysis, 90
Hearing, physiology of, 595-617
central paths of, 411
cortical localisation of, 448
Heart, 933-961
apex beat of, 947
arrangement of muscle fibres in, '.135
-beat, causation of, 982
-block, 988
blood pressure in. 04(1
changes in form of, 946
compensation in. lout
contraction wave in, 990
effects of potassium on, 1018
of salts on muscle of, 1005
of sympathetic on, 1018
electrical changes in, 230, 990 996
-failure in asphyxia, 1027
filling of, 953 _
frog's, anatomy of, 982
influence of length of muscle fibre on
contraction. 1001
of reaction of blood on. Ions
of temperature on, 1005
of tension of, 1001
of vagus on, 1013
inhibition of, 1017
law of, 1003
of Limulus, 988
mammalian, contraction of, 992
origin of rhythm in, 994
mechanical measurement of, 935
methods of determining output, 955
-murmurs, 950
-muscle, excitation time of. 272
-nerves, circulation of, 1012
nutrition of, 1009
output of, 954
during exercise, 1052
physiological properties of mil
-pressure curves, '.112
propagation in, 986
reflexes from, L02I
refractory period in, 999
rhythm of, 983
sequence of contraction in. 935
1306
INDEX
Heart sounds, 949
'staircase phenomena ' in, 999
tone of, 1004
valves of, 938
work of, 959
during exercise, 1054
Heat-formation in muscle, 219-223, 237
-loss, regulation of, 1226
in isolated muscle, 291
in nerve, 285
-production in body, 3, 668, 1223
-value of foods, 607
Hdler's test, 94
Hiimholtz, theory of hearing, 611
Helweg's tract, 353
Hemiansesthesia, 445
Heminanopia, 553, 577
Hemiplegia, 445
Heredity, 1264-1268
Bering's theory of colour vision, 583
Herpes zoster, 349
Hexonc bases, 82
Hexoses, 61
derivatives of, 64
in nucleins, 102
Hibernation, 837
Hind brain, connection with cord, 354
Hippuric acid in urine, 1169
Hippus, 512
His, bundle of, 936, 993
Histidine, 85
metabolism of, 816
Histological differentiation, 7
Histones, 95
Hojmanris test, 83
Homogentisic acid, 51, 814
Homoiothermic animals, 1221
Hopkins' reactions for tryptophane, 92
Hormones, 1230-1247
food-, 693
Horopter, 590
Hunger, influence of gastric movements on, 746
Hyaloplasm, 18
Hydenia, 1058
Hydrocarbons, 45
Hydrogels, 138
Hydrogen, sources of, 39
peroxide, production in green
plant, 110
effect of platinum on,
158
Hydrolysis of protein, 97
Hydrosols, 137
properties of, 140
Hypernietropia, 534, 536
Hypoblast, 33
Hypoglossal nerve, 414
Hypoxanthine, 100
Imbibition by colloids, 149
Iminazol, 84, 101
synthesis of, 115
Immunity, 1079
Ehrlich's theory of, 1083
Incisure, 969
Indol, 813
Inflammation, 1073
Inhibition, 26
in central nervous system, 306
of cord, effect of strychnine on, 347
Inhibition of heart, 1017
nature of, 1017
in peripheral ganglia, 475
of reflexes, 306
of voluntary muscles, 339
Inhibitory functions of cortex, 450
nerves, 248
Innervation, reciprocal. See Reciprocal inner-
vation.
Inogen, 237
Inosite, 116
Insanity, 457
Intellectual processes in brain, 457
Intercostal muscles, 1092
Internal capsule, 375, 423
secretion, 1230-1247
Intestinal juice, 764
villi, functions of, 780
Intestines, large, functions of, 768
movements of, 775
law of, 773
small, movements of, 771
peripheral nervous system
of, 469
secretion by, 704
Intraocular fluid, 516
pressure, 517, 526
Introduction, 1—9
Inulin, 69
Involuntary muscle, 243-248. See Muscle,
influence of temperature
on, 247
propagation of excita-
bility in, 246
Iodine, in living mechanisms, 44
in thyroid gland, 1241
Iris, functions of, 507
innervation of, 510
structure of, 505
Iron, excretion of, 43
in haemoglobin, 74
oxidative functions of, 43
sources of, 42
Irradiation in cord, 339
Irreciprocal conduction in nervous system,302
in synapse, 275
Irritability of muscle, 184
of nerves, 265
Isoleucine, 81
Isomerism in amino-acids, 77
Isometric method, 197
Isotonic method, 197
Kerasin, 58
Keratin, 105
' Kernleiter,' 281
Keto-acids, 49
Ketonic acids, formation of amino-acids
from, 115
Ketose, 60
Keys, electrical, 178
Kidneys, function of, 1160-1213
structure of, 1181
Kjeldahl's method, 90, 1175
Knee jerk, 333, 451
Labyrinth, anatomy of, 652
auditory, 606
functions of, 396
Lactation, 1289
INDEX
1307
Lacteal, 780
Lactic acid, 804
formation in muscle, 215. 237
of amino-acids from,
113
as stage in fat synthesis, 117
tests for, 215
Lactose hydrolysis, 104
time relations of, 104
Lsevorotatory compounds, 51
Lsevulose, 64
Langerhans' islets, 850
Lanoline, 50
Lardaceous tissue, 104
Larynx, anatomy of, 618
Latent period of muse 1<, 198
Lateral nucleus, 369
Law of contraction in human nerves. 269
Pjliiger's, 267
of the minimum, 30
Lecithin, composition of, 57
formation of, 43
in surface layer, 23
Lens, crystalline, 519
composition of, 95
influence on refraction of eye, 533
refraction by, 520
Leucine, 81
Leucinide, 87
Leucocytes, 858
action in inflammation, 1073
classification of, 1076
formation of, 858
functions of, 859
Lcucocytosis after ingestion of nucleins, 824
Leucoplasts, 109
Liebermanri s reactions for proteins, 92
Life, conditions of, 6
definition of, 4
fundamental phenomena of, 2
evolution of, 5
without oxygen, 26
Light, absorption of, 488
chemical changes due to, 490
diffraction of. 489
physical properties of, 486
-reflexes, 512
refraction of, 490
white, composition of, 486
Liminal stimulus. 1!»3. 482
Limulus, heart of, 988
Linoleic series, 54
Lipsemia in diabetes, 849
Lipase, 168
Lipoid character of protoplasm surface, 23
Liver, formation of urea in, 803
secretory functions of, 759
Localisation, cerebral, 433
tactile, 032
Lock's fluid, 1006
Locomotion in spinal animal, -•'>!
Lungs, circulation through, 979
exchangoofoxygenin.lll 1,1 120,1 1- I
movements of, 1089
Lymph and tissue fluids, 1061-1069
absorption of, 1068
movement of, 1066
Lymphagogues, 1065
Lymphatics of brain, 464
Lysine, 82
McDoUOALLS THEORY OB COLOUK VISION,
587
Magnesium, 43
Maltase, influence on glucosides, I 66
Maltose, structure of, 66
Mammary glands, development of, 1270
growth in spinal animal,
333
secretion by, 1289
Mannose, 64
Marey's law, 1023
Marginal bodies, 291
Marie, tract of, 353
Meat, value of, 701
Mechanical efficiency of body, 084
Mechanism, 8
Medulla oblongata. 364
centres in, 414
functions of, 390
respiratory functions of,
1127
Medusa, nervous system of, 290
Membrana tympani, 601
Membranes, electrical differences at surface
of, 171
passage of dissolved substances
through, 129-136
Mendel's law, 1267
Menstruation, 1269, 127.~>
Metabolism, 659
of aromatic groups, 814
basal, 675
of carbohvdrates, 839-852
of fat, 826-838
influence of fats and carbo-
hydrates on, 681
of food on, 677
of muscular work on,
683
of proteins on, 677
methods employed in investi-
gating, 660
of nuclein, 818-825
of protein, 801-817
of purine, 818-825
during starvation, 670-676
of sulphur, 813
tissue-, 801
Methyl glucosides, 66
Micella;, 20
Micturition, 1205-1213
Mid brain, connection with cord, 350
structure of, 364, 372
Milk, action of gastric juice on; 733
composition of, 1290
fats of, 55
secretion of, 1289, 1290
in spinal animal, 333
sugar of, 67
Milton's reaction. S3, 92
I/--/..,/,',' test, 63, 93
Monosaccharides, 61
Moore's test, 63
Motor cent res, 43!)
end plate of muscle, 182
functions of nervous system, 434
impulses, path in brain, 3S'j, 422
nerve roots, 322
es, 1149
Movement, ciliary, 248
1308
INDEX
Movement, dependent on differences of sur-
face tension, 2-1
mechanisms of, 177-287
of co-ordinated, 338-
348
sense of, 648
Movements of eye, 409, 493^99 -
Mucins, 86, 103
Mucoids, 104
Mailer's law, 255, 481
Muscle, action of salts on, 210
of drugs on. 2] 1
afferent, impulses from, :!:!4
arrangement in frog's leg, 189
break-excitation of, 192
chemical changes in, 212-218
ciliary, action of, 526
conditions affecting mechanical re-
sponse of, 205-211
contraction, 194-204
arrested, 200
isometric. 197
isotonic, 197
osmotic theory of, 235
surface tension, theory
of, 235
effects of ammonia on, 186
of constant current on, 192
of glycerin on, 186
of length on contraction of,
201
of load on, 200-203
on polarised light, 182
of temperature on, 207
electrical changes in, 169, 224—233
energy of contraction of, 236
excitation of , 185-193
time of, 271
extensibility of, 203
fatigue in, 208
heart-, 178, 272
of insects, 1S2
intimate nature of contraction of,
234-238
involuntary, 178, 243-248
' all or none ' law in,
205
double innervation of,
247
influence of tempera-
ture on, 247
inhibition of, 248
propagation of excita-
bility in, 246
rhythmic contraction
in, 244
stimulation of, 244
structure of, 243
summation in, 245
irritability of, 184
latent period of, 198
make excitation of, 192
mechanical changes during contrac-
tion, 194-204
methods of stimulating, 186-192
motor end-plate of, 182
oxidative changes in, 237
oxygen supply to, 1013
-plasma, 212
production of heat in, 219-223
Muscle, production of lactic acid in, 215, 237
of tension in, 202, 222
propagation of contraction in, 203
relation of energy of response to
energy of stimulus, 27
of tension to length, 202
rigor of, 20s. 214
sartorius, Is'.i
-sound, 241
-spindles, 334, 648
summation in. 21 Hi
' threshold ' or liminal stimulus, 193
tone of, 654
-twitch, 194-201
methods of recording, 194-198
mxstriated. See involuntary.
varieties of, 178
voluntary, chemical composition of,
212
contraction of, 239-242
propagation in, 204
refractory period of, 206
structure of, 177-184
Muscular energy, source of, 686
exercise, effect on circulation, 1051
sense, 647
sensibility, 346
tone, 333
effect of cerebellum on, 336,
398
work, effect on metabolism, 683
on respiratory quotient,
686
Musical scale, 615
Myelin, 58, 251
Myelination in central nervous system, 319
Myogen, 213
Myographs, 194
Myopia, 534, 537
Myosin, 96, 212
Myosinogen, 212
Myxoedema, 1239
Naoeli's theory op protoplasm struc-
ture, 20
Negative variation, 226
Neopallium, 416
Nerve, physiology of, 250-287
characteristics of, 271
chemical changes in, 256
conduction in, 253
degeneration in, 274
effect of temperature on, 258, 262, 273
electrical changes in, 172, 256
stimulation of, 270-274
electrotonic changes in, 264
-endings, delay in, 27ii
effect of curare on, 277
function of, 276
excitability of, 261
excitation of, 262-269
influence of Lutrapolar
length, 268
-time of, 271
fatigue in, 285
-fibre, degeneration in cord, 320
regeneration of, 30
human, electric stimulation of, 268
-impulse, 253
influence of anesthetics on, 260
INDEX
1309
Nerve, influence of constant current on, 263
of curare on, 185. 259
of drugs on, 260
of fatigue on, 259
of injury on. 274
-junction with muscle fibres, 27S
law of excitation in, 266
medullated, 251
methods of stimulating, 1S<> r.'2
nature of excitatory process in, 284-
287
non-rnedullated, 252
oxygen consumption by, 256
polarisation of, 260, 280-283
ttion in, 253-255, 281
rate of conduction in, 258
refractory period of. 273
-roots, distribution in cord, 3.">ii
functions of, 255
motor, 322
structure of, 250-252
summation of stimuli in, 272
Telocity of conduction in, 253
-Wives, ciliary, functions of, 511
grafting of, 255
inhibitory, 248
irritability of, 265
V i \ e cells, automaticity of, 314
of brain, 426
effects of section of axon on,
321
functions of, 310, 312-314
liberation of energy in, 313
structure of, 300
Nervous impulse, 256
conditions affecting, 258-
261
processes, energy of, 464
system, blood supply of, 462
central, 288-477
of Ccelenterata. 289
conduction in, 296, 301-389
connection with periphery,
299
control of co-ordinated
movements by, 33S-34S
of cra3'fish, 294
development of, 297
of control in,
293
evolution of, 33, 2ss 296
function of cells in, 312—314
higher reflex functions of,
340-408
invertebrate, 288-296
irreciprocal conduction in,
302
law of forward direction in,
302
motor functions of, 434
of medusa, 290
nutrition of, 461
paths in. 299
psychical functions of, 433,
451
reflex action in, 303-311
:i iory functions of, 443
-tincture of, 360-389, 415-
432
trophic functions of, 349
Nervous system, vascular arrangements of,
461
of vertebrates, 297-302
Nervus erigens, 473
Neural groove, 297
Neurilemma, 251
Neurine, composition of, 57
Neuro-blasts, development of, 298
Neuro-epithelial cells, 295
Neuro-fibrils, 251, 296, 307
of vertebrates, 301
Neuro-keratin, 105
Neuro-muscular function, 275
Neurons, definition of, 295
nature of connection between, 307-
311
Neuro-pilem, 296
Neutral salts, action on protein, 94
Nicotine, action on nerve cells, 472
on nerve endings, 277
Nictitating membrane, 515
Night blindness, 578
Nissl bodies, 301
Nitrates, fate in plants, 114
Nitrification, 40
Nitrogen, assimilation of, 40
in cells, 40
distribution in protein molecule, 90
digestion in urine, 802
-fixing bacteria, 40
source of, 39
Nucleic acid, 99
I. . i i "
Nuclei of cranial nerves, 376-380
Nuclein, 99
decomposition of, 102
fate of, 821
formation of, 43
metabolism of, 818
phosphoproteins converted into, 116
Nucleoplasm, 17
Nucleoprotems, 98, 99
fate in stomach, 733
Nucleotides, 103
Nucleus, 14, 33
of Bechlerew, 379
chemical composition of, 27
cuneatus, 365
of Deiiers, 379. 389, 410
functions of, 27
gracilis, 365
red, 376
structure of, 16
Nutrition, influence of nervous system on,
349
mechanism of, 657 1217
Nystagmus, 656
OCUXO-MOTOR NEEVE, 409. 196
(Esophagus, action of, 724
Ohm's law (sound analysis), lilt;
Old age, effect on accommodation, :,i's
Olfactometer, 645
Olfactory apparatus, 420
bulb, connection of, 387
lobe, structure of, 420
Olivary body, 366. 381
I llivo spinal tract, 363, 389
Ophthalmoscope, 553
Opsonins, 1086
1310
INDEX
Optic chiasina, 3SI>. 405
cup, 502
disc, 554
radiations, 422
thalamus, 373
functions of, :{'.):(
tracts, 386, 405, 551
i >p1 Leal activity, 51
in sugars, 00
Orbit, anatomy of, 493
Organ of Corti, 609
Organic compounds, chief, of body, 45
Organs, evolution of, 34
Ornithine, 82
Osazones, 62
Osmometer, 140
Osmosis, 129-136
Osmotic machine, 123.
phenomena in colls, 22
pressure, 121
of blood, 906
of colloids, 14
of protein, 75
effects of, 134
measurements of, 123
by blood corpuscle
method, 125
by depression of
freezing point,
127
by plasmolysis, 125
by vapour tension,
127
relation to electrical
changes, 171
Otolith organ, 397
Otoliths, functions of, 656
Ova, development of, 1273
Ovary, changes in, 1275
Ovulation, 1275
Oxidation in cells, 25
of fats, 155, 835
of fatty acids, 805
mechanism of, 156
relation to muscular contraction,
237
in tissues, 1155-1159
Oxyacids, 49
formation in plants, 1 11
Oxygen capacity of blood, 898
consumption by nerve, 256
functions of, 25
influence on muscular contraction,
217
lack of, 1138
life without, 26
source of, 39
supply to muscle, 1013
Oxyhemoglobin, 99
molecular weight of, 74
Oxyproline, 84
Pacchionian bodies, 463
Pain, cause of, 634
referred, 476
in spinal animal, 331
Pancreas, effects of extirpation, 847
histological changes in, 757
Pancreatic juice, 748-758
activation of, 750
l'ancrea tic juice, action on carbohydrates. 7">:J
on fats, 753
on intestinal secre-
tion, 765
on milk, 752
on proteins, 749
conditions of activity, 751 >
secretion of, 753
Pangene, 20
Paradoxical contraction, 282
Paraglobulin, 95
Paralysis, cortical, 439
Paramucin, 104
Paramyogen, 213
Paramyosinogen, 95
Paraplegia, spastic, 336
Parathyroids, functions of, 1241
Parturition, 1285-1288
nervous mechanism of, 1288
Pelvic visceral nerves, 471
action on bladder, 1212
Pentose, 61
in nucleic acid, 102
tests for, 61
Pepsin, action of, 97
Peptones in gastric digest, 730
Perimeter, 549
Peripheral aberration of eye,. 532
nervous system, 469
Permeability of membranes, 134
of surface layer of cells, 22
Peroxides, function in carbon assimilation,
110
Pfluger's law, 266
Phagocytosis, 859, 1071
Phenyl alanine, 77, 83
Phenyl hydrazine tests for sugars, 62
Phloridzin diabetes, 844
Phosphates of urine, 1163
estimation of, 1179
Phosphatides, 57
Phospholipines, 57, 58
Phosphoproteins, 98
conversion into nuclein, 110
digestion in stomach, 733
Phosphoric acid in nucleic acid, 100
Phosphorus, sources of, 43
Phototaxis, 27
Phrenosin, 58
Physiology, scope of, 1, 7, 35
Pilomotor nerves, 469
Pineal gland, 504, 1245
Pituitary body, 1242-1245
Placenta, formation of, 1284
Plants, assimilation of nitrogen by, 11
chemical process in, 38
Plasma, blood-, 854, 882
muscle-, 212
Plasmolysis, 22, 30, 125
Plasome, 20
Plastids, 17, 33
permanence of. 20
Plethora, 1058
Poikilothermic animals, 1221
Polarimeter, 51
Polypeptides, 88
isomerism in, 88
Polysaccharides, 62, 67
Pons Varolii, 368
functions of, 392
INDEX
1311
Posterior longitudinal bundle, 380, 389,
407
Postural tone, 450
Potassium, 43
Pregnancy, 1282
in spinal animal, 333
Pressor impulses, 1044
Pressure, intrathoracic, 1094
Principal point of eye, 522
Projection, tactile, 633
Proline, 84
Proprioceptive system, 395
Propriospinal fibres, 354
Protamines, 94, 99
Proteid, 98 (footnote)
Proteins, 45, 71-106
absorption of, 790
action of bacteria on, 76
of intestinal juice on. 766
of neutral salts on, 94
of pancreatic juice on, 749
alkaloidal reaction of, 93
amino-acids of, 80
aromatic constituents of. S3
behaviour with acids and alkalies,
147
biological value of, 691
of blood plasma, 909
building up of, 86
carbohydrates contained in, 80
chemical analysis of. ~'.i
chemistry of, 7! L06
coagulation of, 93
colour reaction of, 92
compounds with salts, 93
conjugated, 98
crystallisation of, 72
derivatives of, 96
digestion of, 76, 730, 749, 766
disintegration products of, 80
distribution of nitrogen in. 90
elementary composition of, 71
empirical formuli of, 74
formation of fat from, 831
gastric digestion of, 730
hydrolysis of, 75, 96
isomerism in, 88
metabolism of, 801-817
influence of carbo-
hydrates, S46
molecular structure of, 75
weight of, 73, 90
origin of aromatic constituents, 111'
osmotic pressure of, 75
physical structure of, 72
precipitation of, 94
putrefaction of, 76
significance of, 888
surface phenomena in, 21
specific dynamic action of. 681,
688, 804
sulphur in, 85
synthesis of, 87
in plant, 111-117
tests for, 92
transport in plant, 1 12
varyins constitution of, B9
vegetable. 96
Proteoses, fractional separation of, 7:;o
Protopathic sensibility, 635
Protoplasm, 14
Altmann s granules in, 17
definition of, 15
elementary constituents of,
36-44
fibrillar theory of, 18
granular theory of, 17
physical structure of, 17
proximate constituents of,
45-106
ultramicroscopic structure of, 20
Pseudo-ions, 147
Pseudomucins, 104
Pseudopodia, 33
Pulse, arterial, 962
causation of secondary elevations in,
967
-curves, 970
abnormalities in, 972
effect of exercise on, 1056
-rate, influence of altitude on, 1151
in man, 1024
velocity of transmission of, 967
Pupil, Argyll Robertson, 512
contraction of, 507
dilatation of, 509
effect of drugs on, 509, 513
movement of, 507
reflex paths of, 553
Purine bases, 100
origin in plants, 115
metabolism of, 818
synthesis of, 1 16
Purlcinje's fibres of heart, 994
figures, 554
Putrefaction of protein, 76
Pyramidal tracts, 352, 422
decussation, 365
Pyrimidine, 101
Pyrrol, 84
metabolism of, 816
origin in plants, 1 15
Pyruvic acid, 804
as stage in fat formation, 119
Quotient, respiratory. See Respiratory.
Racemic compoxtnds, 52
Rami communicantes, 468
Reaction of blood, 904
chemical, velocity of, 159
of urine, 1161
estimation of, 1175
based on consciousness, 4S2
cerebral, time relations of, 4.">7
-time. 4.">7
Receptor cells, 295
substance. :277
excitation time of. -77
Reciprocal innervation, 339
of eye mo\ i
497
in iris, 511
of voluntary muscles,
335
Recurrent sensibility, 32:;
Red marrow, 875
nucleus. 37n
Reduced eye, 52 1
Reduct ion, mechanism of, !■"><'
1312
INDEX
Referred pain, 476
Reflex action, 177
characteristics of, 303-306,
344
in nervous system, 303-311
peripheral, 474
' stepping,' 332
structural basis of, 299
arc, 177
of brain stem, 382
evolution of, 289
fatigue of, 304
irreciprocal conduction in. 202
of muscle, 335
axon-, 323
functions of brain stem, 393
mass, 337
Reflexes from heart, 1021
inhibition of, 306
light-, 512
segmental, 321
spinal, 328
structural basis of, 341
visual, 405
Refractory period of heart, muscle, 999
of muscle, 206
of nerves, 273
Regeneration, influence of nucleus on, 29
Renal excretion, 1 160-1213
Rennin, action of, 733
Reproduction, 4
physiology of, 1251-1298
in man, 1264-1281
Residual air, 1095
Resonance in ear, (ill
Resonators (sound), 597
Respiration, 2, 108S-1159
action of vagi on, 1139
air movements in, 1095
blood changes in, 1104
changes in lungs, 1119
chemical regulation of. 1129
chemistry of, 1100-1125
Cheyne-Stokes ', 1146
effect of altitude on, 1150
of changes in air breathed
on. 1148
in diving, 1153
lung changes in, 1089
mechanics of, 1088
medulla oblongata in, 1127
-murmurs, 1094
of muscles, 1113
muscular mechanism of, 1090
nervous regulation of, 1129
underpressure, 1153
rib movements in, 1092
secretory processes in, 1124
by skin,' 1218
-tissue, 1112, 1155-1159
Respiratory centre, functions of, 1127
exchanges, measurement of, 662
during starvation,
675
during work, 683
movements, influence on circu-
lation, 980
quotient, 685, 830, 1100
effect of diet on, 834
Restiform body, 367
Retieulin, 105
Retina, abnormalities of, 577
development of, 543
central connections of, 551
connections with brain, 445
effect of light on, 544
of periodical stimuli on, 569
electrical changes in, 545
fatigue of, 570
histology of, 540
pigments of, 545
Retinoscopy, 535
Retractor penis, 1281
Reverser, 188
Rheocord, 192
Rheonome, 270
Rheoseopic frou'. --'*
Rhythm of bladder, 1209
of cortex, 241
of heart, 983
of intestinal muscle, 771
of medusa, 292
of nerve impulse. 241
respiratory. 1128
of voluntary muscle, 240
of ureters, 1205
Ribose, 61, 103
Rigidity, decerebrate. 392
' Rigor Mortis,' 208, 214
Ringer's fluid, 1006
Ritter- Valli law, 274
Rods, function of, 583
Roof nucleii of cerebellum, 381
Rotation, optical, 51
Riibncr on heat production in body, 3
Rubro-spinal tract. 353, 389
Hut. nature of, 1269
Rutherford's theory of bearing, 613
Saccharose, 67
Saccule, 397
Saliva, different forms of, 708
digestion of starch, 707
secretion of, 708
uses of, 707
Salivary glands, 708
nerve supply to, 711
significance of double nerve
"supply, 718
Salmon, formation of generative glands in,
116
Salts, absorption of, 7S1
action on muscle, 210
electrical changes in, 169
precipitation of colloids by, 144
in urine, 1165
value in food , 692
Saponification, 46, 55
Sarcolemma, 179
Sarcomeres, 179
Sarcoplasma, 179
Sarcosine, 83
Sarcostyles, 179
Sarcous elements, 1 80
Sartorius muscle, 189
Sclera, 500
structure of, 506
Scleroproteins, 104
' Scratch ' reflexes, 331
Sebaceous glands, secretion of, 56
INDEX
1313
Sebum, 1216
Secretin, gastric, 740
pancreatic, 755
Secretion, electrical changes accompany ing,
169, 717
energy involved in, 719
histological changes during, 715
internal, 1230-1247
mechanism of. 713
of milk. 333, 1289, 1296
relation of nucleus to, 31
Seedlings, occurrence of asparagine in, s2
Semicircular canal, 652
Semipermeable, definition of, 123
Sensation bodies in brain. 42 1
cortical apprecial Loo of, 146
disturbances of, 441
localisation of, 443
cutaneous, 626-638
gustatory. 640
histological elements involved, 637
in invertebrata, 293
labyrinthine, 651
localisation of, 303
measurements of, 479
of movement, 646
Jffiflcr'slaw of, 4S1
olfactory. 642
pain-, 634
paths of, 324
in central nervous system,
440
in cord, 357
projection of. 48]
relation to stimulus, 478, 482
in eve, 555-568
spatial. 65]
static, 646
tactile. 629
temperature
Weber's law of, 483
Sense organs, plvysiology of, 47
classification of, 479
fatigue of, 482
projieient, 293
of skin, 637
Sensibility, recurrent, 323
Sensoparalysis, 345
Sensory functions of cortex. 44:'.
nerve roots, 322
tracts in brain stem, 384
Septo-marginal bundle, 353
Serine, 80
Serum albumin, 74, 95
colloids, molecular weight of, 142
globulin, 95
Sexual process, essential functions of, 12.~>l
reproduction, 1254
Shock, nervous, 330
in man. 3!7
Silicon, significance of, 44
Skatol, 813
Skin, functions of, 1214-1218
innervation of, 326
structure of. 121 1
Sleep, state of pupils in, 508
Smedley, theory of fat synthesis, 119
Smell, cortical localisation of, 4 19
Soaps, formation of, 55
Sodium, 43
Sols, 137
Solutions, energy of, 121
Sound analysis, 596
in ear. theories of, 609
appreciation of, 61 I
conduction of, 600
localisation of, 616
muscle-, 241
properties of, 595
Spastic paraplegia, 336
Specific dynamic action of protein, 681,688,804
irritability, law of, 255, 480
rotatory power, 52
Spei I ra luminosity, curves of, 556
Spectrum. 486
energy of, 489
Speech, central mechanism of, 453-457
mechanism of, 623-625
Spermatozoa, composition of, 95, 99
development of. 1271
formation of, 1259
Spherical aberration of eye, 531
Sphingosine, 58
Sphygmograph, 965
Spinal animal, 329
conduction, 344
cord, 315-359
anatomy of, 351
classification of nerve cells in, 318
as conductor, 351-359
course of fibres in, 319
development of, 297
effect of poisons on, :U7
of transection, 330
in man, 330
grey matter of, 324
hemisection of, 359
methods of studying tracts in.
319
motor functions of, 327
paths in, 324
of impulses in, 356
reflex functions of, 322, 329
structure of, 315-321
tracts of, 352
trophic functions of, 349
visceral functions of, 327
nerve roots, central connection of, 324
dilator functions of. 323
functions of, 323-337
reflex, nervous paths of, 328
reflexes, structural basis of, 324
shock, 330
Spindles, muscle-, 334, 648
Spino-tectal tract, 354
Spinothalamic tract, 354
Spleen, functions of, 1245-1247
Spongin, 106
Spongioblasts, 298
Spongioplasm. 18
Squint, 497
treatment of, 499
Stapedius muscle, 603
Starch, digestion by saliva, 707
formation in plant-, 6, 17. .'>7. 107
moleoula c I net ure of, 69
proper) Les of, 68
Slarval i. i lit during, 071
metabolism during. 670
nil rogeiioiis excretion during, 074
1314
INDEX
Stenopeic aperture, 536
' Stepping ' reflex, 332
Stereoisomerism in the sugars, 60
Stimulation of muscle, 186-192
of nerve, 262-269
of sense organs, 47 f)
Stimulus, definition of, 26
energy of, 262
influence of strength on, 205
of stress on, 205
inhibitory, 26
liminal, 193, 482
relation of response to, 26
summation of, 245, 272. 304
Stomach, digestion in, 728-741
influence of vagus on, 737
movements of, 742-747
Strabismus, 497
from myopia, 53S
String galvanometer, 227
Stroma of red corpuscles, 863
Structural basis of the body, 13-35
Strychnine, effects of, 347
Substrate, 163
Suckling, importance to mothers, 1298
Sugar in blood, 839
conversion into fats, 117
into lactic acid, 113
formation from amino-acids, 845
from fat, 837
of milk, 67
in urine, 843, 1172
synthesis of, 62
utilisation of, 842
value of, 701
Sugars, assimilable, 61
chemistry of, 59-67
reaction of, 62
Sulphates of urine, 1103
Sulphur in amino-acids, 85
in keratin, 105
metabolism, 813
in protein, 74
sources of, 42
test for in protein, 92
Summation in muscle, 206, 245
of stimuli, 245, 272
in reflex action,
304
Supplemental air, 1095
Suprarenal bodies, 1233-1238
Surface action in emulsions,
layer, properties of, 21
phenomena in soap solution, 56
tension in cells, 20
effect of electrical changes
on, 172
in protoplasm, 19
Surfaces, electrical changes on, 172
Suspensoids, 139
Swallowing, 721-727
Sweat, secretion of, 1216-1218
Sympathetic action on heart, 1018
ganglia, 465
nerve, effect on blood vessels,
1037
on salivary glands,
712
-supply to eye-ball, 511
system, 465
Synapse, fatigue in, 343
functions of, 310
between nerve and muscle, 275
structure of, 298, 308
Tactile discrimination, 631
sensibility, 629
Taste, cortical localisation of, 449
nerves of, 411
sense of, 640
Tears, secretion of, 515
Tecto-spinal tract, 389
Tegmentum, 373
Teleology, justification of, 5
Temperature changes in muscle, 219
effei I on excitability, 273
on ferment action, 159
on heart, 1005
on muscle, 207, 247
nervous mechanism of, 1228
regulation of, 443, 1219-1229
-sense, 626
Tendon phenomena, 333
reflex, 333
Tension of muscle, 202
relation to heat produc-
tion, 222
Tensor tympani, 603
Tetanus, closing, 264
involuntary movement, 241)
in muscle, 206
-toxin, 347
Thalamo-spinal tract, 353, 389
Thalamus, optic, structure of, 373
functions of, 393
Theobromide, 101
Thermopile, 219
Thigmotaxis, 27
Thorax movements in respiration, 1091
' Threshold value ' of sensation, 482
Thrombin, 885
Thrombogen, 887
Thrombokinase, 887
Thrombosis, 880, 888
Thymine, 102
Thyroid gland, 123S-1241
Tidal air, 1095
Timbre, 597
Tissue fibrinogen, 99, S89
metabolism, 811
Tissues, electrical changes in living, 169-173
Tone of muscle, 333, 654
Tonus cerebella, 398
Touch, sense of, 629
Toxins, 148
influence of, 1080
Tracts of brain stem, 384
of eord, 352
optic, 386, 405, 551
Training, influence of, 1055
Traube curves, 1031
Triglycerides, 54
Trammer's test, 63
Trophic functions of 5th nerve, 411
of spinal cord, 349
Trypsin, 749
action of, 97
action of polypeptides on, 88
velocity of reaction, 165
Trypsinogen, 751
INDEX
1315
Tryptophane, 84
metabolism of, 815
Twilight vision, 547, 583
Twitch, muscle-, 194-201
methods of recording,
194-198
Tympanum, functions of, 604
Tvrosin, 50. 83
action of bacteria on, 76
metabolism of, 814
Uracil, 101
Urates. 1168
Urea, estimation of, 1176
origin of, 802
production from arginine, 810
from creatine, 83
in urine, 1165
Uric acid, 100, S19
excretion of, S22
formation in birds, 804
origin of, 821
in urine, 1 167
Urinary deposits. 1174
Urine, abnormal constituents of, 1171
in blood plasma, 1181
composition of, 1160-1180
inorganic constituents of, 1162
phosphates in. 1163
pigments of, 1170
organic constituents of, 1155
quantitative estimation of chief con-
stituents of, 1175-1180
salts in, 1165
secretion of. 1181-1204
sugar in, 843, 1172
Urobilin. 871
Uterus, changes during birth. 1287
during menstruation, 1275
Utricule, 397
Vagus, action ox heakt, 1013
on intestines, 775
on oesophagus, 726
on respij ition, 1139
on stom.ich, 746
function- of, J. 3
respiratory til res of, 413
Valves of heart, 93 S
370
Vaso-dilatation in ralivary glands, 712
Vaso-dilator nerve? . 1039
Vaso-motor inipul es, path in cord, 359
nerve •, 469
course ot, 1033
reflexes, UM3
I em, 1025--1050
Wins, blood flow in, 976
pulse in, 977
Ventricles. j.'ee Heart.
1 1 essure in, 940
Veratrin, action on muscles, 211
Vertigo, 651
\ esicular murmur, 1094
Vestibular nerve, 379, 412
functions of, 396
Vestibulo-spinal tract, 353, 389
Viscera, sensibility of, 476
Visceral nervous system, 465—477
afferent functions
of, 476
Vision, physiology of, 486-594
binocular, r,88-594
colour threshold for, 557
cortical localisation of, 447
different thresholds for, 561
types of. 502
field of, 549
intensity threshold, 555
mechanism of, 490
monocular, 590
paths in brain. 386, 405
peripheral, 551
colour-, 581
psychic cortex, 430
sensation curve of, 566
sensory cortex. 430
size threshold for, 558
stereoscopic, 591
subjective phenomena of, 566-576
theories of colour-, 583
Visual acuity, 558
determination of, 535
colour threshold for, 561
add, 549 •
impulses, path of, 406
impressions, I IT
persistence, 568
purple, 545, 5S3
Vital force, 8
Vitalism, 8
Vitamines, 693
Vocal cords, 620
Voice, mechanism of. 618
production of, 621
Volition, 451
Voluntary contraction, 239-242
electrical changes in,
241
movement, effect of hemisection
of cord on, 359
muscle. See Muscle.
Vomiting, 746
\ owi I ound . 624
Walleeij-S method, 320
Waller's theory of hearing. 613
\\ ater, as oi i. ition to life, 6
Weber's law, 483
for touch, 031
Work of heart, 959
during exercise, 1054
of isolated muscle, 202
Xanthine, 100
Xylose, 61
Yquso'S theory of colour vision, 583
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