i^ 0(3 CORNELL UNIVERSITY LIBRARY BOUGHT WITH THE INCOME OF THE SAGE ENDOWMENT FUND GIVEN IN 1891 BY HENRY WILLIAMS SAGE QP 34.H85"'l900"™™"' '-"'™^ V.I American,, text-book of physiolog 3 1924 024 543 153 'm Cornell University Library The original of tiiis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924024543153 Frontispiece. Plate 1. B C D 1. Solar spectrum with Fraunhofer lines. 2. Absorption spectruni of a concentrated solution of oxyhemo- globin; all the light is absorbed except in the red and orange. 3. Absorption spectrum of a less concentrated solution of oxyhaemoglobin. 4. Absorption spectrum of a dilute solution of oxyhfemoglobin, showing the two characteristic bands. 5. Absorption spectrum of a very dilute solution of oxyhsemoglobin, showing only the a-band. 6. Absorption spectrum of a dilute solution of reduced haemoglobin, showing the characteristic single band (to be compared with spectrum 4). 7. Absorption spectrum M a dilute solution of oarbon»monoxide- hsemoglobin (to be compared with spectrum 4). 8. Absorption spectrum of methtemoglobiu. 9. Absorption spectrum of acid hs&matin (alcoholic solution). 10. Absorption spectrum of alkaline hssmatin (alcoholic solu- tion) (modified from MacMunn, The Spectroscope in Medicine). AN AMERICAN TEXT-BOOK OF I PHYSIOLOGY BY HENRY P. BOWDITCH, M. D. WARREN P. LOMBARD, M.D. JOHN G. CURTIS, M.D. GRAHAM LUSK, Ph.D.,F.R.S. (Ed IN.) HENRY H. DONALDSON, Ph. D. W. T. PORTER, M.D. W. H. HOWELL, Ph.D., M.D. EDWARD T. REICHERT, M.D. FREDERIC S. LEE, Ph.D. HENRY SEWALL, Ph.D.,M.D. EDITED BY WILLIAM H. HOWELL, Ph.D., M.D. Professor of Physiology in the Johns Hopkins University, Baltimore, Aid. SECOND EDITION, REVISED Vol. I. BLOOD, LYMPH, AND CIRCULATION; SECRETION, DIGESTION, AND NUTRITION; RESPIRATION AND ANIMAL HEAT; CHEMISTRY OF THE BODY PHILADELPHIA W. B. SAUNDERS & COMPANY t900 K COPYKIGHT, 1900, By W. B. SAUNDERS & COMPANY. ELEOTBOTYPED BY PRESS OF WE9TC0TT It THOMSON. PKIl.ADft. W. 11 SAUNDERS Jt COMPANY CONTRIBUTORS TO VOL. I. JOHN G. CURTIS, M.D., Professor of Physiology in Columbia University (College of Physicians and Surgeons). W. H. HOWELL, Ph.D, M. D, Professor of Physiology in the Johns Hopkins University. GRAHAM LUSK, Ph.D., F.R.S. (Edin.), Professor of Physiology in the Yale Medical School. W. T. PORTER, M.D., Assistant Professor of Physiology in the Harvard Medical School. EDWARD T. REICHERT, M.D., Professor of Physiology in the University of Pennsylvania. PREFACE TO THE SECOND EDITION. Advantage has been taken of the necessity of issuing a second edition of the American Text-Book of Physiology to alter somewhat its general arrangement. The book has proved to be successful, and for the most part has met only with kindly and encouraging criticisms from those who have made use of it. ]Many teachers, however, have suggested that the size of the book, when issued in a single volume, has constituted to some extent an inconvenience when regarded from the standpoint of a student's text- book that may be needed daily for consultation in the lecture-room or the labora- tory. It has been thought best, therefore, to issue the present edition in two volumes, with the hope that the book may thereby be made more serviceable to those for whose aid it was especially written. This change in the appearance of the book has necessitated also some alteration in the arrangement of the sections, the part upon the Physiology of Nerve and ]Muscle being transferred to the second volume, so as to bring it into its natural relations with the Physiology of the Central Nervous System. The actual amount of material in the book remains substantially the same as in the first edition, although, naturally, very many changes have been made. Even in the short time that has elapsed since the appearance of the first edition there has been much progress in physiology, as the result of the constant activity of experimenters in this and the related sciences in all parts of the world, and an effort has been made by the various contributors to keep pace with this progress. Statements and theories that have been shown to be wrong or improbable have been eliminated, and the new facts discovered and the newer points of view have been incorporated so far as possible. Such changes are found scattered throughout the book. The only distinctly new matter that can be referred to specifically is found in the section upon the Central Nervous System, and in a short section upon the modern ideas and nomenclature of physical chemistry, with reference es])ocially to the processes of osmosis and diffusion. The section dealing with the Central Nervous System has been recast in large part, with the intention of making it more suitable to the actual needs of medical students ; while a brief presen- tation of some of the elementary conceptions of physical chemistry seems to be necessary at the present time, owing to the large part that these views are taking in current discussions in physiological and medical literature. The index has been revised thoroughly and considerably amplified, a table of contents has been added to each volume, and numerous new figures have been introduced. August, 1900. PREFACE. The collaboration of several teachers in the preparation of an elementary text-book of physiology is unusual, the almost invariable rule heretofore having been for a single author to write the entire book. It does not seem desirable to attempt a discussion of the relative merits and demerits of the two plans, since the metliod of collaboration is untried in the teaching of physi- ology, and there is therefore no basis for a satisfactory comparison. It is a fact, however, that many teachers of physiology in this country have not been altogether satisfied with the text-books at their disposal. Some of the more successful older books have not kept pace with the rapid changes in modern physiology, wliile few, if any, of the newer books have been uniformly satis- factory in their treatment of all parts of this many-sided science. Indeed, the literature of experimental physiology is so great that it would seem to be almost impossible for any one teacher to keep thoroughly informed on all topics. This fact undoubtedly accounts for some of the defects of our present text-books, and it is hoped that one of the advantages derived from the col- laboration method is that, owing to the less voluminous literature to be consulted, each author has been enabled to base his elementary account upon a comprehensive knowledge of the part of the subject assigned to him. Those wlio are acquainted with the difficulty of making a satisfactory elementary presentation of the complex and oftentimes unsettled questions of physiology must agree that authoritative statements and generalizations, such as are fre- quently necessary in text-books if they are to leave any impression at all upon the student, are usually trustworthy in proportion to the fulness of informa- tion possessed by the writer. Perhaps the most important advantage which may be expected to follow the use of the collaboration method is that the student gains thereby the point of view of a number of teachers. In a measure he reaps the same benefit as would be obtained by following courses of instruction under different teachers. The different standpoints assumed, and the differences in emphasis laid upon the various lines of procedure, chemical, physical, and anatomical, should give the student a better insight into the methods of the science as it exists. PREFACE. 7 to-day. A similar advantage may be expected to follow the inevitable over- lapping of the topics assigned to the various contributors, since this has led in many cases to a treatment of the same subject by several writers, who have approached the matter under discussion from slightly varying standpoints, and in a few instances have arrived at slightly different conclusions. In this last respect the book reflects more faithfully perhaps than if written by a single author the legitimate differences of opinion which are held by physi- ologists at present with regard to certain questions, and in so far it fulfils more perfectly its object of presenting in an unprejudiced way the existing state of our knowledge. It is hoped, therefore, that the diversity in method of treatment, which at first sight might seem to be disadvantageous, will prove to be the most attractive feature of the book. In the preparation of the book it has been assumed that the student has previously obtained some knowledge of gi'oss and microscopic anatomy, or is taking courses in these subjects concurrently with his physiology. For this reason no systematic attempt has been made to present details of histology or anatomy, but each author has been left free to avail himself of material of this kind according as he felt the necessity for it in developing the physiolog- ical side. In response to a general desire on the part of the contributors, references to literature have been given in the book. Some of the authors have used these freely, even to the point of giving a fairly complete bibliography of the subject, while others have preferred to employ them only occasionally, where the facts cited are recent or are noteworthy because of their importance or historical interest. References of this character are not usually found in ele- mentary text-books, so that a brief word of explanation seems desirable. It has not been supposed that the student will necessarily look up the references or commit to memory the names of the authorities quoted, although it is pos- sible, of course, that individual students may be led to refer occasionally to original sources, and thereby acquire a truer knowledge of the subject. The main result hoped for, however, is a healthful pedagogical influence. It is too often the case that the student of medicine, or indeed the graduate in medicine, regards his text-book as a final authority, losing sight of the fact that such books are mainly compilations from the works of various investigators, and that in all matters in dispute in physiology the final decision must be made, so far as possible, upon the evidence furnished by experimental work. To enforce this latter idea and to indicate the character and source of the great literature from which the material of the text-book is obtained have been the main reasons for the adoption of the reference system. It is hoped also that the » PREFACE. book will be found useful to many practitioners of medicine who may wish to keep themselves in touch with the development of modern physiology. For this class of readers references to literature are not only valuable, but frequently essential, since the limits of a text-book forbid an exhaustive discussion of many points of interest concerning which fuller information may be desired. The numerous additions which are constantly being made to the literature of physiology and the closely related sciences make it a matter of difficulty to escape errors of statement in any elementary treatment of the subject. It can- not be hoped that this book will be found entirely free from defects of this character, but an earnest effort has been made to render it a reliable repository of the important facts and principles of physiology, and, moi'eover, to embody in it, so far as possible, the recent discoveries and tendencies which have so characterized the history of this science within the last few years. CONTENTS OF VOLUME I. INTRODUCTION (By W. H. Howell) 17 Definitiou of physiology and protoplasm, 17 — Animal and plant physiology, 17 — Vital irritability, 18 — Nutrition, assimilation and disassimilation, anabolism, katabolism, metabolism, 19 — Eeproduction, 20,28 — Contractility and conductivity, 20 — Physiologi- cal division of labor, 22 — Pfliiger hypothesis of the structure of the living molecule, 23 — Loew's and Latham's hypothesis of the structure of the living molecule, 23 — The chemical structure of proteids, protamine, 24— Physical structure of living matter, 24 — Vital force, 25 — Secretion and absorption, 27 — Heredity and consciousness, 28 — Gen- eral and special .physiology, 29 — Methods of investigation used in the science of physiology, 30. BLOOD (By W. H. Howell) . . . 33 A. General Pkopekties — Physiology of the Coepuscles 33 Histological structure of blood, 33 — Definitiou of blood-plasma, blood-serum, and defibrinated blood, 33 — Reaction of blood, 34 — Speciiic gravity of blood, 34 — Histology of red corpuscles, 35 — Condition of the hjemoglobin in the red corpuscles, 35 — Laking of blood, 35 — Globulioidal and toxic action of blood-serum, 36 — Isotonic, hypertonic, hypotonic solutions, 36 — Nature and amount of haemoglobin, 37 — Compounds of haemo- globin with O, CO, NO, and CO2, 38 — The iron of the haemoglobin molecule, 39 — Haemo- globin crystals, 40 — Absorption spectra of haemoglobin, 40 — Derivative compounds of haemoglobin, 44 — Origin and fate of the red corpuscles, 45 — Variations in the number of red corpuscles, 46 — Morphology and physiology of the leucocytes, 47 — Physiology of the blood plates, 49. B. Chemical Composition of the Blood — Coagulation — Total Quantity of Blood — Eegeneeation after Hemorrhage 50 Composition of the plasma and corpuscles, 50 — Proteids of the blood plasma, 51 — Serum albumin, 52 — Paraglobulin, 53 — Fibrinogen, 53 — Coagulation of blood, super- ficial appearances, 54 — Time of clotting, 55 — Theories of coagulation, 55 — Nature and origin of fibrin ferment, 58 — Intravascular clotting, 60 — Means of hastening or retard- ing clotting, 61 — Total quantity of blood in the body, 63 — Eegeneration of the blood after hemorrhage, 63 — Transfusion of blood and salines, 64. C. Diffusion and Osmosis, and Their Importance in the Body . 65 Osmotic pressure, 65 — Calculation of, 67 — Electrolysis, 67 — Grammolecular solutions, 67 — Osmotic pressure of proteids, 69 — Diffusion of proteids, 70. LY3IPH (By W. H. Howell) . . . 70 Lymph-vascular system, 70 — Formation of lymph, theories of, 70 — The factors con- trolling the flow of lymph, 75, 145 — Pressure in lymph-vessels, 146 — Efiect of thoracic aspiration on lymph-flow, 147 — Effect of body movements and valves on lymph-flow, 147. CIRCULATION .... 76 PAET I. — The Mechanics of the Circulation of the Blood and of the Move- ment OF THE Lymph (By John G. Curtis) 76 A. General Considerations . . 76 General course of the blood-flow, 76 — Causes of the blood-flow, 77 — Working of the pumping mechanism, 78 — Pulmonary circuit, 78. B. Movement of the Blood in the Capillaries, Arteries, and Veins 79 Anatomical characteristics of the capillaries, 79 — The circulation as observed under the microscope, 80 — Behavior of the red corpuscles, 81 — Friction, axial stream, and inert layer, 81 — Behavior of the leucocytes, 82 — Emigration of the leucocytes, 83 — Velocity of the blood in the small vessels, 83 — Capillary blood-pressure, 84. C. The Pressure of the Blood in the Arteries, Capillaries, and Veins . 85 Method of studying blood-pressure, manometers, 85 — The mercurial manometer and graphic record of blood-pressure upon a kymograph, 88 — The mean pressure in arteries and veins, 90. 98 10 CONTENTS. PAGJr D. The Causes of the Pressuke in the Akteries, Capillaries, and Veins . 91 Balance of the factors producing arterial pressure, 92— The arterial pulse, 93— The capillary pressure and its cause, 93— Extinction of the arterial pulse in the capillaries, 94_ Venous pressure and its causes, 94— Subsidiary forces assisting the blood-How, 9o— Eespiratory pulse in the veins, 96— The dangerous region, entrance of air into veins, 97. E. The Velocity of the Blood in^ Arteries, Capillaries, and Veins Measurement of velocitv in large vessels. Stromuhr, 98— Measurement of rapid changes in velocity, 100— Velocity and pressure of blood compared, 101— Relation of velocity to the sectional area of the vascular bed, 102— Time spent by blood in capillary, 103. F. The Blood-flow through the Lungs . 103 G. The Pulse Volume and the Work Done by the Ventricles . . 104 The cardiac cycle, 104— The pulse volume, 105— The work of the ventricles, 106— Heart's contraction as a source of heat, 108. II. The Mechanism op the Valves of the Heart . . 108 Use of the valves, 108— The auriculoventricular valves, 108— Use of the tendinous cords, 109— The papillary muscles and their uses, 110— The semilunar valves, 110- Lunulae and corpora arantii. 111. I. The Changes in Form and Position of the Beating Heart, and the Cardiac Impulse 112 General changes in the heart and arteries, 112 — The heart and vessels in the open chest, 113 — Changes of size and form in the beating ventricles, 113 — Changes of posi- tion of the ventricle, 114 — Changes in the auricle, great veins, and great arteries, 115 — Effects of opening the chest, 115 — Probable changes in heart in the unopened chest, 116 — The cardiac impulse or apex beat, 117. J. The Sounds of the Heart 118 Relations and character of the heart-sounds, 118 — Cause of the second sound, 118 — Causes of the first sound, 119. K. The PREauENCv or the Cardiac Cycles . . . 121 L. The Relations in Time of the Main Events of the Cardiac Cycle . . 121 The auricular, ventricular, and cardiac cycles, 122 — Tlie variability of each cycle, 123 — Relative lengths of ventricular systole and diastole, 123 — Lengths of auricular systole and heart pause, 124. M. The Pressure Within the Ventricles . . 125 Range of pressure within ventricles, 125 — Methods of recording ventricular press- ures, 126 — General character of curve of intraventricular pressure, 128 — Effect of auricular systole on the curve of ventricular pressure, 130 — Tlie opening and closing of the heart valves in relation to the curve of ventricular pressure, 130 — Analysis of the curve of ventricular pressure, 133 — Negative pressure within the ventricles, 134. N. The Functions of the Auricles . ... 135 The auricle as a force pump, 135 — Time relations of auricular systole and diastole, 136 — Statement of functions of auricles, 136 — Negative pressure within the auricles, 137 — Is the auricle emptied by its systole? 138 — Question of regurgitation from auri- cles to veins, 138. O. The Arterial Pulse 139 Nature and importance of the arterial pulse, 139 — Rate of transmission of the pulse- wave, 140 — Frequency and regularity of the pulse, 141 — Arterial tension as indicated by the pulse, 141 — Size and celerity of pulse, 141 — The pulse-trace, or sphygmogram, 142 — Analysis of the sphygmogram, 143 — The dicrotic wave, 143 — The diagnostic use of the sphygmogram, 145. Part II. — The Innervation of the Heart (By W. T. Porter) 148 The cansi' of the rhythmic heart-beat, 148 — The intracardiac ganglion cells and nerves, 14H — The nerve theory of the heart-beat, 149 — The muscular theory of the heart-beat, 150 — The excitation wave and its passage over the heart, 152 — The passage of the excitation wave from auricle to ventricle, 154 — The refractory period and com- pensatory pause. 156. A. The Cardiac Nerves . . 159 Anatomical arrangement of the heart nerves, 1.59 — The inhibitory nerves, 161 — Effect of inhibition on the ventricles, 162— Effect of inhibition on the auricle and sinus, 164 — Effect of inhibition on the bulbus arteriosus, 165 — Effect of inhibition on the irritability of the heart, 16.5 — Relation of inhibition to rate and strength of stim- ulus, 16.5 — Arrest of the heart in systole, 165 — Comparative inhibitory power of the two vagi, 166 — Effect of the septal nerves on the inhibition, 166 — Theories of the nature of vagus inhibition, 166 — Relation of age, temperature, and intracardiac press- ure to inhibition, 167 — The augmentor or accelerator nerves of the heart, 167 — Effect of stimulating the augmentor nerves, 169 — Simultaneous stimulation of the accelerator and inhibitory fibres, 170 — Classification of the inhibitory and augmentor fibres, 171 — The centripetal nerves of the heart, 172 — ExihtL-nce of sensory nerves in the heart, CONTENTS. 11 PAGE. 172— The depressor nerve of the heart, 172— Analysis of the effect of stimulation of the depressor nerve, 173 — Ei^flex effect of sensory nerves on the heart, 175 — Eeflex effects through the sympathetic system on the heart, 175. B. The Centres op the Heakt-nerves . . 176 The inhibitory centre, 176— Tonus of the inhibitory centre, 176— Origin of the car- dio-iuhibitory fibres, 177 — Position of the augmentor centre, 177 — Action of higher parts of the brain on the cardiac centres, 178 — The existence of peripheral reflex centres, 178 — Ligatures of Stannius, 178. Part III. — The Nutrition of the Heart (By W. T. Porter) . 179 Spongy structure of frog's heart, 179 — The coronary arteries in the dog, 179 — The terminal nature of coronary arteries, 180 — The effect of closure of the coronary arte- ries, 181 — The cause of the arrest of the heart after closure of the coronary arteries, 183 — Fibrillary contractions aud recovery from, 183 — Olosure of the coronary veins, 184 — The volume of the coronary circulation, 184 — The effect of the heart-contractions on the coronary circulation, 1S5 — The vessels of Thebesius and the coronary veins, 186 — Blood-supply and heart-heat, 1H6 — Lymphatics of the heart, 186. C. Solutions which Maintain the Beat of the Heart 187 Methods of nourisliing the heart with solutions, 187 — The composition and action of nutrient solutions, 189 — The effect of CO2, organic substances, and physical character- istics of nutrient solutions, 191 — Nourishment of the isolated mammalian heart, 191. Part IV.— The Innervation of the Blood-vessels (By W. T. Porter) 192 Historical account of the discovery of vaso-motor nerves, 192 — Methods of demon- strating vaso-motor phenomena, 195 — Experimental distinctions betweeu vaso-constric- tor and vaso-dilator nerve-fibres, 196 — Anatomical course of vaso-motor fibres, 197 — Vaso-motor centre in the medulla, 198 — Vaso-motor centres in the spinal cord, 199 — Sympathetic vaso-motor centres — peripheral tone, 200 — Rhythmical chauges in vascular tone, 201 — \'iiso-motor reflexes, 201, 202 — Relation of cerebrum to vaso-motor centres, 202 — Pressor and depressor fibres, 202 — Vaso-motor fibres to the brain, 203— Vaso-motor fibres to the head, 204 —Vaso-motor fibres to the lungs, 203 — Vaso-motor fibres to the heart, 20fi — Vaso-motor fibres to the intestines, 206 — Vaso-motor fibres to the liver, 206 . — Vaso-motor nerves of the kidney, 207 — Vaso-motor nerves of the spleen, 207 — Vaso- motor nerves of the pancreas, 207 — Vaso-motor nerves of the external generative organs, 207 — Vaso-motor nerves of the internal generative organs, 208 — Vaso-motor nerves of the portal system, 209 — Vaso-motor nerves of the limbs, muscles, and tail, 209. SECRETION (By W. H. Howell) 211 A. General Considerations . . 211 Definition of gland and secretion, 211 — Types of glandular structure, 212 — Older views of secretion and excretion, 213 — General proofs that gland cells take an active part in secretion, 214 — Filtration through living and dead tissues, 215. B. MucoBS AND Albuminous Glands— Salivary Glands . . . 215 Distinction between mucous and albuminous glands, 215 — Goblet cells as unicellular mucous glands, 216 — Anatomical relations of salivary glands, 217 — Nerve-supply to salivary glands, 218 — Histology of salivary glands, 219 — Composition of the saliva, 220 — Significance of the potassium sulpliocyaiiide in saliva, 221 — Discovery of secre- tory nerve-fibres to the salivary glands, 221— Distinction between "chorda" and "sympathetic" saliva, 222 — Effect of varying the strength of the stimulus upon the composition of the saliva, 223 — Theory of trophic and secretory fibres, 224 — Vacuoles in gland cells during secretion, 226 — Histological changes in glands as a result of func- tional activity, 226 — Action of atropin, pilocarpin, and nicotin on secretory fibres, 229 — The normal mechanism of salivary secretion, 230 — Electrical changes in the salivary glands during secretion, 231. C. The Pancreas — Glands of the Stomach and Intestines . 231 Anatomical relations of the pancreas, 231 — Histological characters of the pancreas, 231 — Composition of the pancreatic secretion, 232 — Secretory nerves of the pancreas, 232 — Histological changes in pancreatic cells during secretion, 233 — Distinction between enzymes and zymogens, 2.35 — The normal mechanism of the pancreatic secre- tion, 235 — The histological characteristics of the gastric glands, 237 — Composition of the gastric secretion, 238 — Secretory nerves of the gastric glands, 239 — The normal mechanism of the gastric secretion, 240 — Histological changes in the gastric glands during secretion, 242 — The secretion of the intestinal glands, 243. D. Liver and Kidney . ... 244 Histology of liver in relation to the bile-ducts, 244 — Composition of the bile, 245 — The quantity of bile secreted, 246 — Relation of the blood-flow to the secretion of bile, 247 — Secretory nerve-fibres to the liver cells, 247 — Motor innervation of the bile-ducts and gall-bladder, 248 — The normal mechanism of the bile secretion, 248 — Effect of occlusion of the bile-ducts, 249 — Histological characteristics of the kidney, 249— Com- position of the urine, 250 — General theories of the secretion of urine, 251 — Secretion of urea and related nitrogenous bodies, 252 — Secretion of the water and salts, 253 — The blood-flow through the kidney and its relations to secretion, 255. 12 CONTENTS. PAGE E. Cutaneous Glands — Internal Secretion . . ■ ■ 257 Sebaceous secretion, 257— The sweat-glands and the quantity of their secretion, 258 —The composition of sweat, 258— Secretory fibres to the sweat-glands, 259— The posi- tion of the sweat-centres in the cord and medulla, 260— The structure and phylogeny of the mammary glands, 261— Composition of the milk, 261— Histological changes in the mammary glands during secretion, 262— Secretory nerve-fibres to the mammary glands, 263— Normal mechanism of the secretion of milk, 264— Internal secretions, general statements, 265— The internal secretions of the liver, 265— The internal secre- tion of the pancreas, 266 — The anatomical and histological relations of the thyroid body, 267— Accessory thyroids, 268— The anatomical relations of the parathyroids, 268— The functions of the thyroids and parathyroids, 268— Etfect of removal of the adrenal bodies, 271 — Action of adrenal extracts on the circulation, 271 — Secretory nerves to the adrenals, 272— The isolation of epinephrin, 272— Anatomical relations of the pituitary body, 272— Physiological eftects of extracts of the pituitary body, 272 —The internal secretions of the testis and the ovary, 273. CHEMISTRY OF DIGESTION AND NUTRITION (By W. H. Howell) 275 A. Definition and Composition of Foods — Characteristics of Enzymes . . 275 General statements regarding foods and food-stuUs, 275 — General nutritive sig- nificance of the food-stuti's, 276 — Analysis of foods, 278— Definition and classification of enzymes, 279 — General reactions of the enzymes, 281. B. Salivary Digestion 283 Properties and composition of the mixed saliva, 283 — Ptyalin and its action on starch, 284 — Conditions influencing the action of ptyalin, 286 — General functions of saliva, 287. C. Gastric Digestion . . .... . 287 General conditions in the stomach during digestion, 287 — Methods of obtaining gas- tric juice, 287 — The properties and composition of the gastric juice, 288 — The nature of the acid of the gastric juice, 289 — The theories as to the origin of the HCl, 289 — Nature • and properties of pepsin, 290 — The preparation of an artificial gastric juice, 291 — The digestive action of pepsin-hydrochloric acid, 292 — Definition of peptone, 294 — The preparation and properties of rennin, 29.5 — The action of gastric juice on fats and car- bohydrates, 296 — Action of gastric juice on albuminoids, 297 — Why does the stomach not digest itself? 297 — General summary of the functions of the stomach, 298. D. Intestinal Digestion . . . . . 299 The composition of pancreatic juice, 299 — The properties and methods of preparing trypsin, 301 — The products of tryptic digestion, 302 — Tryptic digestion of albumin- oids, 304 — Amylopsin, its occurrence and digestive action, 304 — Steapsin, its occur- rence and action on fats, 305 — Emulsification of fats, 306 — The intestinal secretion, 308 — The occurrence and action of the inverting enzymes, 308 — Digestion in the large intestine," 309 — Bacterial decompositions in the large intestine, 309. E. Absorption — Summary of Digestion and Ab.sorption of Food-stuffs— Feces. 311 General statement of the conditions and products of absorption, 311 — Absorption in the stomach, 312 — Absorption in the stomach of water, salts, sugars, peptones, and fats, 313 — Absorption in the small intestine, 313 — Absorption in the large intestine, 314 — Absorption of proteids, 315 — Absorption of sugars, 317 — Absorption of fats, 317 — Absorption of water and salts, 318 — Composition of the feces, 319. F. Physiology of the Liver and the Spleen . . 320 Histological arrangement of the liver lobule, 320 — The composition of bile, 321 — The bile-pigments, 322— The bile-acids, 323— Cholesterin, 324— Lecithin, fats, and nuclco-albumin in bile, 325 — General physiological importance of bile, 325 — Glycogen in the liver, 326 — The origin of glycogen with reference to the food-stufls, 327 — The effect of proteids on glycogen-fomiation, 328 — The effect of fats on glycogen-formation, 329 — The function of glycogen, and the glycogenic theory, 329 — Glycogen in the mus- cles and other tissues, 330 — Conditions affecting the supply of glycogen in the body, 331 — Formation of urea in the liver, 331 — Physiology of the spleen, 332. G. The Kidney and Skin as Excretory Organs ... ... 334 General composition of the urine, 334 — The properties and origin of urea, 334 — The physiological history of uri« acid and the xanthin bodies, 338 — The physiological his- tory of creatinin, 339— The physiological history of hippuric acid, 339— The conju- gated sulphates in the urine, 340— The physiological history of the water and salts' of the urine, 341— The functions of the skin, 341— Sweat as an excretion, 342— The seba- ceous secretion, 3 12— The excretion of the C'Q.i through the skin, 342. H. BoDY-METAEOLiSM— Nutritive Value op the Food-stuffs 343 Determination of the total metabolism of tlie body, 343— Definition of nitrogen- equilibrium, .344 — Definition of carbon- and general body-equilibrium, 345 — The nutri- tive importance of the proteids, 345— The luxus-consum'ption idea, 348— The nutritive value of albuminoids, 349— The nutritive value of fats, 3.50— The formation of fat in the body, 3.51— The nutritive value of carbohydrates, 353— The nutritive value of water and salts, 354. CONTENTS. 13 PAGE I. Accessory Articles of Diet — Variations of Body-metabolism under Dif- ferent Conditions — Potential Energy of Food — Dietetics . . . 357 Accessory articles of diet, 357 — Stimulants, 357 — Condiments, flavors, and meat extracts, 359 — Conditions influencing body-metabolism, 359 — The effect of muscular work on metabolism, 359 — Metabolism during sleep, 361 — The effect of variations in temperature on body-metabolism, 362 — The effect of starvation on body-metabolism, 362 — The potential energy of food, 364 — The principles of dietetics, 366. MOVEMENTS OF THE ALIMENTARY CANAL, BLADDER, AND URETER (By W. H. Howet.l) . . 36» The physiology of plain muscle tissue, 369 — Mastication, 372 — Deglutition, 372 — The Kvonecker-Meltzer theory of deglutition, 375 — The nervous control of degluti- tion, 376 — Movements of the stomach, 377 — The extrinsic nerves controlling the move- ments of the stomach, 381 — Movements of the intestines, 382 — The peristaltic move- ments, 382 — Mechanism of the peristaltic movement, 384 — Pendular movements of the intestines, 384 — Extrinsic nerves of the intestines, 384 — Elfect of various conditions on the intestinal movements, 385 — The mechanism of defecation, 386 — The act of vomiting, 387 — The nervous mechanism of vomiting, 388 — Micturition, 389 — Move- ments of the ureters, 389 — Movements of the bladder, 390 — Nervous control of the bladder movements, 392. RESPIRATION (By Edward T. Reichert) 395 General statements, internal and external respiration, 395. A. The Respiratory Mechanism in M.an ... . . 395 Physiological anatomy of the lungs and thorax, 395 — Conditions of pressure within the thorax. 396 — Definition of respiration, inspiration, and expiration, 398 — Movements of the diaphragm, 398 — Movements of other muscles assisting the diaphragm, 399 — Movements of the ribs, 400 — The function of the intercostal muscles, 402 — Summary of the action of the inspiratory muscles, 405— Movements of expiration, 406— Summary of the action of the expiratory muscles, 407 — Associated respiratory movements, 408 — Intrapulmonary and intrathoracic pressure, 408 — Respiratory sounds and nasal breathing, 409. B. The Gases in the Lungs, Blood, and Tissues . . . 409 Alterations in the gases in the lungs, 409 — Alterations in the gases in the blood, 411 — The forces concerned in the diff'usion of O and CO2 in the lungs, 412 — The interchange of and CO2 between the alveoli and the blood, 414 — The tension of O in the blood and tissues, 415 — The tension of CO2 in the blood and tissues, 416 — The tension of N, 417 — The forces producing the interchange of and COa in the lungs, 417 — The forces producing the interchange of O and CO2 in the tissues, 419 — The extraction of gases from the blood, 420 — Cutaneous respiration, 422 — Internal or tissue respira- tion, 422. C. The Rhythm, Frequency, and Depth of the Respiratory Movements 423 The rhythm of the respiratory movements, 423 — The frequency and depth of the respiratory movements, 425. D. The Volumes of Air, Oxygen, and Carbon Dioxide Respired 426 Normal volumes of air respired and capacity of lungs and bronchi, 426 — Tlie volumes of O and CO2 respired, 428 — Conditions influencing the volumes of and C02 respired, 429 — The respiratory quotient, 436 — Conditions influencing the respiratory quotient, 437. E. Principles of Ventilation : 439 r. The Effects of the Respiration of Various Gases . 440 G. The Effects of the Gaseous Composition of the Blood on the Respi- ratory Movements . 440 Eupnoea, dyspncea, apncea, and polypnoea, 440— The causes of apncea, 441 — The effect of muscular activity on the respiratory movements, 442— Tiie conditions producing polypncea, 443 — The conditions producing dyspnoea, 443 — Asphyxia, 445. H. Artificial Respiration 446 I. The Effects of the Respiratory Movements on the Circulation 447 The effects of respiration on blood-pressure, 447 — The effects of respiration on blood- flow, 450 — The effects of respiration on the pulse, 451 — The effects of obstruction of the air-passages and of the respiration of rarefied and compressed air on the circula- tion, 451. J. Special Respiratory Movements . 454 The movements in coughing, hawking, sneezing, laughing, crying, sobbing, sighing, etc., 454. K. The Nervous Mechanism of the Respiratory Movements . 455 The respiratory centres, 455 — The rhythmic activity of the respiratory centre, 458 — The aflferent respiratory nerves, 460 — Effects of section and stimulation of the pneumo- 14 CONTENTS. PAGE gastric nerves, 460— Effects of stimulation of the superior laryngeal nerve, 462— Effects of stimulation of the glosso-pharyngeal nerve, 462— Effects of stimulation oi the tri- geminal nerve, 463— Effects of stimulation of the cutaneous nerves, 463— The etterent respiratory nerves, 463. L. The Condition of the Eespikatoby Centre in the Fetus . 464 The reasons for the absence of respiratory movements in the fetus, 464. M. The Innervation op the Lungs . _ ■ ■ 465 Broncho-constrictor and broncho-dilator fibres, 465— Vaso-motor fibres to the lungs, 466— Summary of the pulmonary fibres found in the vagus, 466. ANIMAL HEAT (By Edwaed T. Beichert) 467 A. Body-tempeeature . . ■ • 467 Homothermous and poikilothermous animals, 467 — Temperatures of different spe- cies of animals, 467 — The 'temperature of the different regions of the body, 468 — The conditions affecting body-temperature, 469 — Temperature regulation, 473. B. Income and Expenditure of He.^t ... • 474 The potential energy as furnished by the food-stuffs, 474 — The income of heat and methods of measuring, 475 — The expenditure of heat, 476. C. Heat-production and Heat-dissipation 477 Calorimetry, 477 — The construction and use of calorimeters, 478 — Conditions affect- ing heat-production, 482 — Conditions affecting heat-dissipation, 48.5. D. The Heat-mechanism . . . 489 The mechanism concerned in thermogenesis, 489 — The thermogenic tissues, 490 — The thermogenic nerves and centres, 490 — The mechanism concerned in thermolysis, 494 — Thermotaxis, 495 — Abnormal thermotaxis, 496 — Post-mortem rise of tempera- ture, 497. THE CHEMISTRY OF THE ANIMAL BODY (By Graham Lusk) 499 A. The Non-metallic Elements . . 499 The preparation, occurrence, and properties of hydrogen, 499 — The preparation, occurrence, and properties of oxygen, 500 — Ozone, 502 — Traube's theory of oxidations in the body, 502 — Occurrence, properties, and functions of water, 503 — Peroxide of hydrogen, 505 — The preparation, occurrence, and properties of sulphur, sulphuretted hydrogen, sulphurous and sulphuric acids, 505 — Preparation and properties of chlorine, 508^Bromine and its compounds in the body, 508 — Iodine and its compounds in the body, 509 — Fluorine and its compounds in the body, 510 — Occurrence and properties of nitrogen and its compounds, 510 — Occurrence of phosphorus, 513 — Phosphorus-pois- oning, 513 — Compounds of phosphorus, 514 — Phosphorus in the body, 515 — Occurrence of carbon, 516 — Compounds of carbon, 517 — Metabolism of carbon in the body, 518 — Properties and compounds of silicon, 519 — Occurrence and properties of potassium compounds, 519 — Potassium in the body, 520 — Occurrence and properties of sodium and its compounds, 521 — Occurrence of ammonium carbonate and its fate in the body, 523 — Occurrence and properties of calcium' and its compounds, 523 — The history of cal- cium in the body, 525— Occurrence of strontium in thebody,526 — Occurrence and prop- erties of magnesium compounds, 527 — The compounds of iron and its history in the metabolism of the body, 528. B. The Compounds of Carbon . . 531 The derivatives of methane, 531 — General formula and reactions of the monatomic alcohols, 531 — General formula and reactions of the fatty acids, 532 — The properties and occurrence of methane, 532 — Properties of trichlormethane (chloroform), 533 — The properties of methyl aldehyde and general properties of aldehydes, 533— Other methyl compounds and their action in the body, 534 — Properties and occurrence of formic acid, 534— The properties of ethyl alcohol, 535— The fate of alcohol in the body, 535— The properties of ethyl ether and chloral hydrate, 53.5— The properties of acetic acid, 536— The properties of aceto-acetic acid, 537 — The properties of glycocoll (amido-acetic acid), 5.37— The properties of sarcosin, 537— Propyl compounds and their occurrence in the body, 538— Butyl compounds and their occurrence in the body, 539 — Pentyl compounds and their occurrence in the body, 539— Acids containing more than five carbon atoms (leucin, palmitin, etc.), 540— ,\mines, their structure and occurrence, 541— The cyanogen compounds, .541— The amines of the defines {ptoma,ines, toxines, etc.), 542— Occurrence and structure of taurin, 543— Occurrence and properties of the biliary salts, 543— The properties and occurrence of lactic acid, .545— The properties and occurrence of cystein and cystin, 546— The amido-derivatives of carbonic acid (urea, carbamic acid), 51«— The properties and occurrence of urea, 548— Crcatin creatinin, histidin, arginin, 5.-,0— The purin or alloxuric bodies and bases, .552— Oxalic! succinic, and aspartic acids, 557— The properties and occurrence of glycerin and its compounds, 558— The properties and occurrence of lecithin, 5.59— The "history of fats m the body, 559— The properties of oleic acid, 560. CONTENTS. 15 PAGE 'Cakbohydeates . .... . . 561 The structure and classification of carboliydrates, 561— Tlie glycoses, 562 — Tlie di- saccliarides, 564 — The cellulose group (starch), 565. -Benzol Deeivatives, oe Aromatic Compounds . . . 568 The benzol ring, 568— Phenol, its structure and occurrence, 569— Benzoic acid, its structure and occurrence, 569 — Tyrosiu, its structure aud occurrence, 570 — Indol, its structure and occurrence, 571 — Epiuephrin, its structure aud occurrence, 572 — The history of the aromatic bodies in the urine, 572 — The structure aud history of inosit, 573. :SUBSTANCES OF UNKNOWN COMPOSITION . 573 The properties and occurrence of hsemoglobin and its compounds, 573— The bile-pig- ments and the melanins, 574— The properties and occurrence of cholesterin, 575— The general structure and reactions of proteids, 575— The classification of the proteids, 576 — The protamins and remarks upon the theoretical composition of the proteid molecule, 580. Index . . 583 CONTENTS OF VOLUME 11. THE GENERAL PHYSIOLOGY OF MUSCLE AND NERVE (By Wareen p. Lombard). THE CENTRAL NERVOUS SYSTEM (By Heney H. Donaldson). THE SPECIAL SENSES— VISION (By Henry P. Bowditch). HEARING, CUTANEOUS AND MUSCULAR SENSIBILITY, EQUI- LIBRIUM, SMELL, AND TASTE (By Henry Sewall). THE PHYSIOLOGY OF SPECIAL MUSCULAR MECHANISMS. THE ACTION OF LOCOMOTOR MECHANISMS (By War- ren P. Lombard). VOICE AND SPEECH (By Henry Sewall). REPRODUCTION (By Feedeeic S. Lee). AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. I. INTRODUCTION The term " physiology " is, in au etymological sense, synonymous with " natural philosophy," and occasionally the word is used with this significance even at the present day.^ By common usage, however, the term is restricted to the living side of nature, and is meant to include the sum of our know- ledge concerning the properties of living matter. The active substance of which living things are composed is supposed to be fundamentally alike in structure in all cases, and is commonly designated as protoplasm {npajvo:;, first, and TtXda/xa, anything formed). It is usually stated that this word was first introduced into biological literature by the botanist Von Mohl to designate the granular semi-liquid contents of the plant-cell. It seems, however, that priority in the use of the word belongs to the physiologist Purkinje (1840), who employed it to describe the material from which the young animal embryo is constructed.^ In recent years the term has been applied indif- ferently to the soft material constituting the substance of either animal or plant-cells. The word must not be understood to mean a substance of a definite chemical nature or of an invariable morphological structure ; it is applied to any part of a cell that shows the properties of life, and is therefore only a convenient abbreviation for the phrase " mass of living matter." Living things fall into two great groups, animals and plants, and corre- sponding to this there is a natural separation of physiology into two sciences, one dealing with the phenomena of animal life, the other with plant life. In what follows in this introductory section the former of these two divisions is chiefly considered, for although the most fundamental laws of physiology are, without doubt, equally applicable to animal and vegetable protoplasm, nevertheless the structure as well as the properties of the two forms of matter are in some respects noticeably different, particularly in the higher types of organisms in each group. The most striking contrast, perhaps, is found in the fact that plants exhibit a lesser degree of specialization in form and function and 1 See Mineral Physiology and Physiography, T. Sterry Huut, 1886. ^ O. Hertwig : Die Zelle und die Gewebe, 1893. Vol. I.— 2 17 18 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. a muor Rh greater power of assimilation. Owing to this latter property the plant-cell is able, with the aid of solar energy, to construct its protoplasm from very simple forms of inorganic matter, such as water, carbon dioxide, and inorganic salts. In this way energy is stored within the vegetable cell in the substance of complex organic compounds. Animal protoplasm, on the con- trary, has comparatively feeble synthetic properties ; it is characterized chiefly by its destructive power. In the long run, animals obtain their food from the plant kingdom, and the animal cell is able to dissociate or oxidize the complex material of vegetable protoplasm and thus liberate the potential energy con- tained therein, the energy taking the form mainly of heat and muscular work. "We must suppose that there is a general resemblance in the ultimate structure of animal and vegetable living matter to which the fundamental similarity in properties is due, but at the same time there must be also some common dif- ference in internal structure between the two, and it is fair to assume that the divergent properties exhibited by the two great groups of living things are a direct outcome of this structural dissimilarity ; to make use of a figure of speech employed by Bichat, plants and animals are cast in different moulds. It is difficult, if not impossible, to settle upon any one property that absolutely shall distinguish living from dead matter. Nutrition, that is, the power of converting dead food material into living substance, and repro- duction, that is, the power of each organism to perpetuate its kind by the formation of new individuals, are probably the most fundamental charac- teristics of living things ; but in some of the specialized tissues of higher animals the power of reproduction, so far as this means mere multiplication by cell-division, seems to be lost, as, for example, in the case of the nerve-cells in the central nervous system or of the matured ovum itself before it is fertil- ized by the spermatozoon. Nevertheless these cellular units are indisputably living matter, and continue to exhibit the power of nutrition as well as other properties characteristic of the living state. It is possible also that the power of nutrition may, under certain conditions, be held in abeyance, tempo- rarily at least, although it is certain that a permanent loss of this property is incompatible with the retention of the living condition. It is frequently said that the most general property of living matter is its irritability. The precise meaning of the term vital irritability is hard to define. The \vord implies the capability of reacting to a stimulus and usually also the assumption that in the reaction some of the inner potential energy of the living material is liberated, so that the energy of the response is many times greater, it may be, than the energy of the stimulus. This last idea is illustrated by the case of a contracting muscle, in wiiich the stimulus acts as a liberating force causing chemical decompositions of the substance of the muscle with the liberation of a comparatively large amount of energy, chiefly in the form of heat or of heat and work. It may be remarked in passing, however that we are not justified at present in assuming that a similar liberation of stored energy takes place in all irritable tissues. In the case of nerve-fibres for instance, we have a typically irritable tissue which responds readily to INTB OD UC'TION. 1 9 external stimuli, but as yet it has not been possible to show that the forma- tion or conduction of a nerve impulse is accompanied by or dependent upon a liberation of so-called potential chemical energy. The nature of the response of irritable living matter is found to vary with the character of the tissue or organism on the one hand, and, so far as intensity goes at least, with the nature of the stimulus on the other. Response of a definite character to appropriate external stimulatiou may be observed frequently enough in dead matter, and in some cases the nature of the reaction simulates closely some of those displayed by living things. For instance, a dead catgut string may be made to shorten after the manner of a muscular contraction by the appropriate application of heat, or a mass of gunpo\\der may be exploded by the action of a small spark and give rise to a great liberation of energy that had previously existed in potential form within its molecules. As regards any piece of matter we can only say that it exhibits vital irritability when the reaction or response it gives upon stimulation is one characteristic of living matter in general or of the particular kind of living matter under observation ; thus, a muscle-fibre contracts, a nerve-fibre conducts, a gland-cell secretes, an entire organism moves or in some way adjusts itself more perfectly to its environment. Considered from this standpoint, irritability means only the exhibition of one or more of the peculiar properties of living matter and can- not be used to designate a property in itself distinctive of living structure ; the term, in fact, comprises nothing more specific or characteristic than is implied in the more general phrase vitality. When an amoeba dies it is no longer irritable, that is, its substance no longer assimilates when stimulated by the presence of appropriate food, its conductivity and contractility disappear so that mechanical irritation no longer causes the protrusion or retraction of pseudopodia — no form of stimulation, in fact, is capable of calling forth any of the recognized properties of living matter. To ascertain, therefore, whether or not a given piece of matter possesses vital irritability we must first become acquainted with the fundamental properties of living matter in order to recog- nize the response, if any, to the form of stimulation used. Nutrition or assimilation, in a wide sense of the word, has already been referred to as probably the most universal and characteristic of these prop- erties. By this term we designate that series of changes through which dead matter is received into the structure of living substance. The term in its broadest sense may be used to cover the subsidiary processes of digestion, respiration, absorption, and excretion through which food material and oxygen are pi'epared for the activity of the living molecules, and the waste products of activity are removed from the organism, as well as the actual conversion of dead material into living protoplasm. This last act, which is presumably a synthetic process effected under the influence of living matter, is especially designated as anabolism or as assimilation in a narrower sense of the word as opposed to disassimilation. By disassimilation or katabolism M'e mean those changes leading to the destruction of the complex substance of the living molecules, or of the food material in contact with these molecules. 20 A^^ AMERICAN TEXT-BOOK OF PHYSIOLOGY. As was said before, animal protoplasm is pre-eminently katabolic, and the evidence of its katabolism is found in the waste products, such as COj, HP, and urea, which are given off from animal organisms. Assimilation and disassimilation, or anabolism and katabolism, go hand in hand, and togethei" constitute an ever-recurring cycle of activity that persists as long as the material retains its living structure, and is designated under the name metabolism. In most forms of living matter metabolism is in some way self-limited, so that gradually it becomes less perfect, old age comes on, and finally death ensues. It hus been asserted that originally the metabolic activity of protoplasm was self-perpetuating — that, barring accident, the cycle of changes would go on forever. Resting upon this assumption it has been suggested by Weissmann that the protoplasm of the reproductive elements still retains this primitive and perfect metabolism and thus provides for the continuity of life. The speculations bearing upon this point will be discussed in more detail in the section on Reproduction. Reproduction in some form is also practically a universal property of living matter. The unit of structure among living organisms is the cell. Under proper conditions of nourishment the cell may undergo separation into two daughter cells. In some cases the separation takes place by a simple act of fission, in other cases the division is indirect and involves a number of interesting changes in the structure of the nucleus and the protoplasm of the body of the cell. In the latter case the process is spoken of as karyokinesis or mitosis. This act of division was supposed formerly to be under the con- trol of the nucleus of the cell, but modern histology has shown that in kary- okinetic division the process, in many cases at least, is initiated by a special structure to which the name centrosome has been given. The manj'-celled animals arise by successive divisions of a primitive cell, the ovum, and in the higher forms of life the ovum requires to be fertilized by union with a sper- matozoon before cell-division becomes possible. The sperm-cell acts as a stimulus to the egg-cell (see section on Reproduction), and rapid cell-division is the result of their union. It must be noted also that the term reproduc- tion includes the power of hereditary transmission. The daughter-cells are similar in form to the parent-cell, and the organism produced from a fertilized ovum is substantially a facsimile of the parent forms. Living matter, there- fore, not only exhibits the power of separating off other units of living matter, but of transmitting to its progeny its own peculiar internal structure and properties. Contractility and conductivity are properties exhibited in one form or another in all animal organisms, and we must concede that they are to be counted among the primitive properties of protoplasm. The power of con- tracting or shortening is, in fact, one of the commonly recognized features of a living thing. It is generally present in the simplest forms of animal as well as vegetable life, although in the more specialized forms it is found most highly developed in animal organisms. The opinion seems to be general among physiologists that wherever this property is exhibited, whether in the INTBOD UCTION. 21 formation of the pseudopodia of an amoeba or white blood-corpuscle, or in the vibratile movements of ciliary structures, or iu the powerful contractions of voluntary muscle, the underlying mechanism by which the shortening is produced is essentially the same throughout. However general the property may be, it cannot be considered as absolutely characteristic of living struc- ture. As was mentioned before, Engelmanu ' has been able to show that a dead catgut string when surrounded by water of a certain temperature and exposed to a sudden additional rise of temperature will contract or shorten in a man- ner closely analogous to the contraction of ordinary muscular tissue, and it is not at all impossible that the molecular processes involved in the shortening of the catgut string and the muscle-fibre may be essentially the same. That conductivity is also a fundamental property of primitive protoplasmic structure seems to be assured by the reactions which the simple motile forms of life exhibit when exposed to external stimulation. An irritation applied to one point of a protoplasmic mass may produce a reaction involving other parts, or indeed the whole extent of the organism. The phenomenon is most clearly exhibited in the more specialized animals possessing a distinct nervous system. In these forms a stimulus applied to one organ, as for instance light acting upon the eye, may be followed by a reaction involving quite distant organs, such as the muscles of the extremities, and we know that in these cases the irritation has been conducted from one organ to the other by means of the nervous tissues. But here also we have a property that is widely exhibited in inanimate nature. The conduction of heat, electricity, and other forms of energy is familiar to every one. While it is quite possible that con- duction through the substance of living protoplasm is something sui generis, and does not find a strict parallel iu dead structures, yet it must be admitted that it is conceivable that the molecular processes involved in nerve conduction may be essentially the same as prevail in the conduction of heat through a solid body, or in the conduction of a wave of pressure through a liquid mass. At present we know nothing definite as to the exact nature of vital conduction, and can therefore affirm nothing. ' The four great properties enumer?<^3, namely, nutrition or assimilation (including digestion, secretion, absorptia(jBf€xci;etion, anabolism, and katabolism), reproduction, conduction, and contr^ility,form the important features which we may recognize in all living things and wjjidi we make use of in distin- guishing between dead and living niatt^ii^^^^^fffth property perhaps should be added, that of sensibility or sensation*, mit concerning this property as a general accompaniment of living structure our knowledge is extremely im- perfect ; something more as to the difficulties connected with this subject will be said presently. The four fundamental properties mentioned are all ex- hibited in some degree in the simplest forms of life, such as the protozoa. In the more highly organized animals, however, we find that specialization of function prevails. Hand in hand with the differentiation in form that is displayed in the structure of the constituent tissues there goes a specialization ' Veber den Vrsprung der Mv^kelkraft, Leipzig, 1893. 22 AX A2IERICAX TEXT-BOOK OF PHYSIOLOGY. in certain properties with a concomitant suppression of other properties, the outcome of which is that muscular tissue exhibits pre-eminently the power of contractility, the nerve tissues are characterized by a highly developed power of conductivity, and so on. While in the simple unicellular forms of animal life the fundamental properties are all somewhat equally exhibited within the compass of a single unit or cell, in the higher animals we have to deal with a vast community of cells segregated into tissues each of which possesses some distinctive property. This specialization of function is known technically as the physiological division of labor. The beginning of this process may be recognized in the cell itself. The typical cell is already au organism of some complexity as compared with a simple mass of undifferentiated protoplasm. The protoplasm of the nucleus, particularly of that material in the nucleus which is designated as chromatin, is differentiated, both histologically and physiologically, from the protoplasm of the rest of the cell, the so-called cyto- plasm. The chromatin material in the resting cell is arranged usually in a network, but during the act of division (karyokinesis) it is segmented into a number of rods or iilaments known as chromosomes. In the ovum there are good reasons for believing that the power of transmitting hereditary charac- teristics is dependent upon the structure of these chromosomes. The nucleus, moreover, controls in some way the metabolism of the entire cell, for it has been shown, in some cells at least, that a non-nucleated piece of the cytoplasm is not only deprived of the power of reproduction, but has also such limited powers of nutrition that it quickly undergoes disintegration. On the other hand contractility and conductivity, and some of the functions connected with nutrition, such as digestion and excretion, seem often to be specialized in the cytoplasm. As a further example of differentiation in the cell itself the ex- istence of the centrosome may be referred to. The centrosome is a body of very minute size that has been discovered in numerous kinds of cells. It is considered by many observers to be a jirrmanent structure of the cell, lying either in the cytoplasm, or possibly in some cases within the boundaries of the nucleus. When present it seems to have some special function in connection with the movements of the chromosomes during the act of cell-division. In the many-celled animals the primitive properties of protoplasm become highly developed, in consequence of this subdivision of function among the various tissues, and in many ways the most complex animals are, from a physiological standpoint, the simplest for purposes of study, since in them the various prop- erties of living matter are not only exhibited more distinctly, but each is, as it were, isolated from the others and can therefore be investigated more directly. 'SA'e are at liberty to suppose that the various properties so clearly recognizable in the differentiated tissues of higher animals are all actually or potentially contained in the comparatively undifferentiated protoplasm of the simplest uni- cellular forms. That the lines of variation, or in other words the direction of specialization in form and function, are not iniinite, but on the contrary comparatively limited, seems evident when we reflect that in spite of the numerous branches of the phylogenetic stem the properties as well as the INTR OD UCTIOX. 23' forms of the differentiated tissues throughout the animal kingdom are strikingly- alike. Striated muscle, with the characteristic property of sharp and powerful contraction, is everywhere found ; the central nervous system in the inver- tebrates is built upon the same type as in the highest mammals, and the variations met with in different animals are probably but varying degrees of perfection in the development of the innate possibility contained in primitive protoplasm. It is not too much to say, perhaps, that were we acquainted with the structure and chemistry of the ultimate units of living substance, the key to the possibilities of the evolution of form and function would be in our possession. Most interesting suggestions have been made in recent years as to the essential molecular structure of living matter. These views are necessarily very incomplete and of a highly speculative character, and their correctness or incorrectness is at present beyond the range of experimental proof; never- theless they are sufficiently interesting to warrant a brief statement of some of them, as they seem to show at least the trend of physiological thought. Pfliiger,^ in a highly intefresting paper upon the nature of the vital pro- cesses, calls attention to the great instability of living matter. He supposes that living substance consists of very complex and very unstable molecules of a proteid nature which, because of the active intra-molecular movement pre- sent, are continually dissociating or falling to pieces with the formation of simpler and more stable bodies such as water, carbon dioxide and urea, the act of dissociation giving rise to a liberation of energy. " The intra-molecular heat (movement) of the cell is its life." He suggests that iu this living mole- cule the nitrogen is contained in the form of a cyanogen compound, and that the instability of the molecule depends chiefly upon this particular grouping. Moreover the power of the molecule to assimilate dead proteid and convert it to living proteid like itself he attributes to the existence of the cyanogen group. It is known that cyanogen compounds possess the property of polymerization, that is, of combining with similar molecules to form more complex mole- cules, and we may suppose that the molecules of dead proteid when brought into contact with the living molecules are combined with the latter by a pro- cess analogous to polymerization or condensation. By this means the stable structure of dead proteid is converted to the labile structure of living proteid, and the molecules of the latter increase in size and instability. When living substance dies its molecules undergo alteration and become incapable of ex- hibiting the usual properties of life. Pfliiger suggests that the change may consist essentially iu an absorption of water whereby the cyanogen grouping passes over into an ammonia grouping. Loew^ assumes also that the dif- ference between dead and living or active proteid lies chiefly in the fact that iu the latter we have a very unstable or labile molecule in which the atoms are in active motion. The instability of the molecules he likewise attributes to ' ArchivfUr die gesammte Phymlogie, 1875, Bd. 10, S. 251. ' Ihid., 1880, Bd. 22 ; Loew and Bokorny : Die chemuche Kraftquelle in lebendeii Proioplasma, Miinchen, 1882; Imperial Institute of Tokyo (College of Agriculture), 1894. 24 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the existence of certain groupings of the atoms. Influenced in part by the power of living material to reduce alkaline silver solutions, he supposes that the specially important labile group in the molecule is the aldehyde radical - C i^ ^ . The jiitrogen exists also in a labile amido- combination, -NH,, and the active or living form of these two groups may be expressed by the - CH - NH^ formula I = q . If this grouping by chemical change became con- verted to the grouping I! ^ -CHOH ' ^*^ ^^^"^^ f"^™^ ^ comparatively inert compoimd such as we have in dead proteid. Latham ' proposes a theory wliicli combines the ideas of Pfluger and of Loew. He suggests that the living molecule may be composed of a chain ot cyan-alcohols united to a ben- zene nucleus. The cyan -alcohols are obtained by the union of an aldehyde with hydrocyanic acid ; they contain, therefore, the labile-aldehyde grouping as well as the cyanogen nucleus to which Pfliiger attributes such importance. Actual investigation of the chemical structure of living matter can hardly be said to have made a beginning. The first step in this direction has been made in the study of the chemical structure of the group of proteids which have usually been considered as forming the most characteristic constituent of protoplasm. Proteids as we obtain theni from the dead tissues and liquids of the body have proved to be very varied in properties and structure, so much so in fact that it is impossible to give a satisfactory definition of the group. Many of them can be obtained in a pure, even in a crystalline form, and their percentage composition can therefore be determined with ease. But the fundamental chemical structure that may be supposed to characterize the proteid group, and the changes in tliis structure producing the diil'ereiit varieties of proteids are matters as yet undetermined. Several promising efforts have been made to construct proteids synthetically, but the results obtained are at present incomplete. On the other hand, Kossel ^ has isolated from the spermatozoa of certain fishes a comparatively simple nitrogenous body of basic properties (protamine), which he regards as the simplest form of proteid and the essential core or nucleus characterizing the structure of the \vhole group. It is an interesting thought that in the heads of the sperma- tozoa with their complex possibilities of development and hereditary trans- mission, dependent as these properties must be upon the chemical structure of the germ protoplasm, there may be found the simplest form of proteid. Kossel's work, it may be noted, has not gone so far as to indicate the possible molecular structure of the protamines. It has been assumed by many observers that the properties of living matter, as we recognize them, are not solely an outcome of the inner structure of the hypothetical living molecules. They believe tliat these latter units are ' British Medical Journal, 1886, p. 629. ' Zeitschrift fur physiol. Chem., 1898; xxv. 1899, xxvi. INTRODUCTION. 25 fashioned into larger secoudary units each of which -is a definite aggregate of chemical molecules and possesses certain properties or reactions that depend upon the mode of arrangement. The idea is similar to that advanced by mineralogists to explain the structure of crystals. They suppose that the chemical molecules are arranged in larger or smaller groups to which the name " physical molecules " has been given. So in living protoplasm it may be that the smallest particles capable of exhibiting the essential properties of life are groups of ultimate molecules, in the chemical sense, having a definite arrangement and definite physical properties. These secondary units of structure have been designated by various names such as " physiological molecules,'" " somacules," ^ micellae,^ etc. Many facts, especially from the side of plant physiology, teach us that the physical constitution of protoplasm is probably of great importance in understanding its reaetion to its environ- ment. Microscopic analysis is insufficient to reveal the existence or character of these " physiological molecules," but it has abundantly shown that proto- plasm has always a certain physical construction and is not merely a struc- tureless fluid or semi-fluid mass. What has been said above may serve at least to indicate the prevalent physiological belief that the phenomena shown by living matter are in the main the result of the action of the known forms of energy through a substance ■of a complex and unstable structure which possesses, moreover, a physical organization responsible for some of the peculiarities exhibited. In other words, the phenomena of life are referred to the physical and chemical struc- ture of protoplasm and may be explained under the general physical and chemical laws which control the processes of inanimate nature. Just as iu the case of dead organic or inorganic substances we attempt to explain the dififereuces in properties between two substances by reference to the difference in chemical and physical structure between the two, so with regard to living matter the peculiar differences in properties that separate them from dead matter, or for that matter the differences that distinguish one form of living matter from another, must eventually depend upon the nature of the under- lying physical and chemical structure. In the early part of this century many prominent physiologists were still so overwhelmed with the mysteriousuess of life that they took refuge in the hypothesis of a vital force or principle of life. By this term was meant a something of an unknown nature that controlled all the phenomena ex- hibited by living things. Even ordinary chemical compounds of a so-called organic nature were supposed to be formed under the influence of this force, and it was thought could not be produced otherwise. The error of this latter view has been demonstrated conclusively within recent years : many of the substances formed by the processes of plant and animal life are now easily produced within the laboratory by comparatively simple synthetic methods. ' Meltzer : " Ueber die fundamentale Bedeutung der Erschiitterung fiir die lebende Ma- Tterie," Zeitschriftfiir Biologic, Bd. xxx., 1894. ^Foster: P%sio%i/ (Introduction). ^Nageli: Theorie der GaAj-jtmj', Munchen, 1879. 26 AN AMERICAN TENT-BOOK OF PHYSIOLOGY. Bv the distinguished labors of Emil Fischer ' even the structure of carbohy- drate bodies has been determined, and bodies belonging to this group have been synthetically constructed in the laboratory. Moreover, the work of Scliiitzenberger, Grimaux, and Pickering gives promise that before long pro- teid bodies may be produced by similar methods. Physiologists have shown, furthermore, that the digestion that takes place in the stomach or intestine may be effected also in test-tubes, and at the present day probably no one doubts that in the act of digestion we have to deal only with a series of chemical reactions which in time will be understood as clearly as it is possible to comprehend any form of chemical activity. Indeed, the whole history of food in the body follows strictly the great physical la^\s of the conservation of matter and of energy which prevail outside the body. No one disputes the proposition that the material of growth and of excretion comes entirely from the food. It has been demonstrated that the measureable energy given off from the body is all contained potentially within the food that is eaten.'' Living things, so far as can be determined, can only transform matter and en- ergy ; they cannot create or destroy them, and in this respect they are like inan- imate objects. But, in spite of the triumphs that have followed the use of the experimental method in physiology, every one recognizes that our knowledge is as yet very incomplete. Many important manifestations of life cannot be explained by reference to any of the known facts or laws of physics and chemistry, aud in some cases these phenomena are seemingly removed from the field of experimental investigations. As long as there is this residuum of mystery connected with any of the processes of life, it is but natural that there should be two points of view. Most physiologists believe that as our knowledge and skill increase these mysteries will be explained, or rather will be referred to the same great final mysteries of the action of matter and energy under definite laws, under which we now classify the phenomena of lifeless matter. Others, however, find the difficulties too great, — they perceive that the laws of physics and chemistry are not comj)letely adequate at present to explain all the phenomena of life, and assume that they never will be. They suppose that there is something in activity in living matter which is not present in dead matter, and which for want of a better term may be desig- nated as vital force or vital energy. However this may be, it seems evident that a doctrine of this kind stifles inquiry. Nothing is more certain than the fact that the great advances made in physiology during the last four decades are mainly owing to the abandonment of this idea of an unknown vital force and the determination on the part of experimenters to make the greatest pos- sible use of the known laws of nature in explaining the phenomena of life. There is no reason to-day to suppose that we have exhausted the results to be obtained by the application of the methods of physics and chemistry to the study of living things, and as a matter of fact the great bulk of physiological research is proceeding along these lines. It is interesting, however, to stop ' hie Chemie der Kohlenhydrate, Berlin, 1894. ^Eubner : Zcilschrift fiir Biologic, Bd. xxx. S. 73, 1894. INTRODUCTION. 27 for a moment to examine briefly some of the problems whicii as yet have escaped satisfactory solution by these methods. The phenomena of secretion and absorption form important parts of the digestive processes in higher animals, and without doubt are exhibited in a minor degree in the unicellular types. In the higher animals the secretions may be collected and analyzed, and their composition may be compared with that of the lymph or blood from which they are derived. It has been found that secretions may contain entirely new substances not found at all in the blood, as for example the mucin of saliva or the ferments and HCl of gastric juice ; or, on the other hand, that they may contain substances which, although pres- ent in the blood, are found in much greater percentage amounts in the secre- tion — as, for instance, is the case with the urea eliminated in the urine. In the latter case we have an instance of the peculiar, almost purposeful, elective action of gland-cells of which many other examples might be given. With regard to the new material present in the secretions, it finds a sufficient general explanation in the theory that it arises from a metabolism of the protoplasmic material of the gland-cell. It offers, therefore, a purely chemical problem which may and probably will be worked out satisfactorily for each secretion. The selective power of gland-cells for particular constituents of the blood is a more difficult question. We find no exact parallel for this kind of action in chemical literature, but there can be no reasonable doubt that the phe- nomenon is essentially a chemical or physical reaction involving the activity of some of the forms of energy with which the study of inanimate objects has already made us partially familiar. We may indulge the hope that the details of the reaction will be discovered by more complete chemical and micro- scopical study of the structure of these cells. If in the meantime the act of selection is spoken of as a vital phenomenon, it is not meant thereby that it is referred to the action of an unknown vital force, but only that it is a kind of action dependent upon the living structure of the cell-substance. The act of absorption of digested products from the alimentary canal was for a time supposed to be explained completely by the laws of imbibition, diffusion, and osmosis. The epithelial lining and its basement membrane form a septum dividing the blood and lymph on the one side from the contents of the alimentary canal on the other. Inasmuch as the two liquids in question are of unequal composition with regard to certain constituents, a diffusion stream should be set up whereby the peptones, sugar, salts, etc. would pass from the liquid in the alimentary canal, where they exist in greater concen- tration, into the blood, where the concentration is less. Careful work of recent years has shown that the laws of diffusion and osmosis are not adequate to explain fully the absorption that actually occurs ; a more detailed account of the difficulties met with may be found in the section on Digestion and Nutrition. It has become customary to speak of absorption as caused in part by the physical laws of diffusion and osmosis, and in part by the vital activity of the epithelial cells. It will be noticed that the vital property in this case is again an elective affinity for certain constituents similar to that which has been 28 AX AMERICAN TEXT-BOOK OF PHYSIOLOGY. referred to in discussing the act of secretion. The mere fact that the physical theory has proved so far to be insnificient is in itself no reason for abandoning all hope of a satisfactory explanation. Most physiologists probably believe that further experimental work will bring this phenomenon out of its obscurity and show that it is explicable in terms of known physical and chemical forces exerted through the peculiar substance of the absorptive cell. The facts of heredity and consciousness offer difficulties of a much graver character. The function of reproduction is two-sided. In the first place there is an active multiplication of cells, beginning with the segmentation of the ovum into two blastomeres, and continuing in the larger animals to the formation of an innumerable multitude of cellular units. In the second place there is present in the ovum a form-building power of such a character that the great complex of cells arising from it produces not a heterogeneous mass, but a definite organism of the same structure, organ for organ and tissue for tissue, as the parent form. The ovum of a starfish develops into a starfish, the ovum of a dog into a dog, and the ovum of man into a human being. Herein lies the great problem of heredity. The mere multiplication of cells by direct or indirect division is not beyond the range of a conceivable me- chanical explanation. Given the properties of assimilation and contractility it is possible that the act of cell-division may be traced to purely physical and chemical causes, and already cytological work is opening the way to credible hypotheses of this character. But the phenomena of heredity, on the other hand, are too complex and mysterious to justify any immediate expectation that they can be explained in terms of the known properties of matter. The crude theories of earlier times have not stood the test of investigation by modern methods, the microscopic anatomy of both ovum and sperm showing that they are to all appearances simjile cells that exhibit no visible signs of the wonderful potentialities contained within them. Histological and experi- mental investigation has, however, cleared away some of the difficulties for- merly surrounding the subject, for it has shown with a high degree of prob- ability that the power of hereditary transmission resides in a particular sub- stance in the nucleus, namely in the so-called chromatin materal that forms the chromosomes. The fascinating observations ' that have led to this con- clusion promise to open up a new field of experimentation and speculation. It seems to be possible to study heredity by accepted scientific methods, and we may therefore hoj)e that in time more light will be thrown upon the con- ditions of its existence and possibly upon the nature of the forces concerned in its production. In the facts of consciousness, lastly, we are confronted with a problem seemingly more difficult than heredity. In ourselves we recognize different states of consciousness following upon the physiological activity of certain parts of the central nervous system. "We know, or think we know, that these so-called psychical states are correlated with changes in the protoplasmic material of the cortical cells of the cerebral hemispheres. When these cells ' AVilson : The Cell in Development and Inheritance, 1896. INTRODUCTION. 29 are stimulated, psychical states result; when they are injured or removed, psychical activity is depressed or destroyed altogether according to the extent of the injury. From the physiological standpoint it would seem to be as justifiable to assert that consciousness is a property of the cortical nerve-cells as it is to define contractility as a property of muscle-tissue. But the short- ening of a muscle is a physical phenomenon that can be observed with the senses — be measured aud theoretically explained in terms of the known prop- erties of matter. Psychical states are, however, removed from such methods of study ; they are subjective, and cannot be measured or weighed or otherwise esti- mated with sufficient accuracy and completeness in terms of our units of energy or matter. There must be a causative connection between the objective changes in the brain-cells and the corresponding states of consciousness, but the nature of this connection remains hidden from us ; and so hopeless does the problem seem that some of our profouudest thinkers have not hesitated to assert that it can never be solved. Whether or not consciousness is possessed by all animals it is impossible to say. In ourselves we know that it exists, and we have convincing evidence, from their actions, that it is possessed by many of the higher animals. But as we descend in the scale of animal forms the evidence becomes less impressive. It is true that even the simplest forms of animal life exhibit reactions of an apparently purposeful character which some have explained upon the simple assumption that these animals are endowed with consciousness or a psychical power of some sort. All such reactions, however, may be explained, as in the case of reflex actions from the spinal cord, upon purely mechanical principles, as the necessary response of a definite physical or chemical mechanism to a definite stimulus. To assume that in all cases of this kind conscious processes are involved amounts to making psychical activity one of the universal and primitive properties of protoplasm whether animal or vegetable, and indeed by the same kind of reasoning there would seem to be no logical objection to extending the property to all matter whether living or dead. All such views are of course purely speculative. As a matter of fact we have no means of proving or disproving, in a scientific sense, the exist- ence of consciousness in lower forms of life. To quote an appropriate remark of Huxley's made in discussing this same point with reference to the crayfish, " Nothing short of being a crayfish would give us positive assurance that such an animal possesses consciousness." The study of psychical states in our- selves, for reasons ^\hich have been suggested above, does not usually form a part of the science of physiology. The matter has been referred to here simply because consciousness is a fact that our science cannot as yet explain. So far, some of the broad principles of physiology have been considered — principles which are applicable with more or less modification to all forms of animal life and which make the basis of what is known as general physiology. It must be borne in mind, however, that each particular organism possesses a special physiology of its own, which consists in part in a study of the properties exhibited by the particular kinds or variations of protoplasm in each individual, and in large part also in a study of the various mechan- 30 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. isms existing in each animal. In the higher animals, particularly, the com- binations of various tissues and organs into complex mechanisms such as those of respiration, circulation, digestion, or vision, differ more or less in each group and to a minor extent in each individual of any one species. It follows, therefore, that each animal has a special physiology of its own, and in this sense we may speak of a special human physiology. It need scarcely be said that the special physiology of man is very imperfectly known. Books like the present one, which profess to treat of human physiology, con- tain in reality a large amount of general and special physiology that has been derived from the study of lower animal forms upon which exact experi- mentation is possible. Most of our fundamental knowledge of the physiology of the heart and of muscles and nerves has been derived from experiments upon frogs and similar animals, and much of our information concerning the mechanisms of circulation, digestion, etc. has been obtained from a study of other mammalian forms. We transfer this knowledge to the human being, and in general without serious error, since the connection between man and related mammalia is as close on the physiological as it is on the morphological side, and the fundamental or general physiology of the tissues seems to be every- where the same. Gradually, however, the material for a genuine special human physiology is being acquired. In many directions special investigation upon man is possible ; for instance, in the study of the localization of function in the cerebral cortex, or the details of body metabolism as obtained by exam- ination of the excreta, or the peculiarities of vaso-motor regulation as revealed by the use of plethysmographic methods, or the physiological optics of the human eye. This special information, as rapidly as it is obtained, is incorpo- rated into the text-books of human physiology, but the fact remains that the greater part of our so-called human physiology is founded upon experiments upon the lower aninals. Physiology as a science is confessedly very imperfect; it cannot compare in exactness with the sciences of physics and chemistry. This condition of affairs need excite no surprise when we remember the very wide field that physiology attempts to cover, a field co-ordinate in extent with the physics as well as the chemistry of dead matter, and the enormous complexity and instability of the form of matter that it seeks to investigate. The progress of physiology is therefore comparatively slow. The present era seems to be one mainly of accumulation of reliable data derived from laborious experiments and observa- tions. The synthesis of these facts into great laws or generalizations is a task for the future. Corresponding with the diversity of the problems to be solved we find that the methods employed in physiological research are mani- fold in character. Inasmuch as animal organisms are composed either of single cells or aggregates of cells, it follows that every anatomical detail with regard to the organization of the cell itself or the connection between dif- ferent cells, and every advance in our knowledge of the arrangement of the tissues and organs that form the more complicated mechanisms, is of imme- diate value to physiology. The microscopic anatomy of the cell (a branch of INTR OD UCTION. 3 1 histology that is frequently designated by the specific name of cytology), general histology, and gross anatomical dissection are therefore frequently employed in physiological investigations, and form what may be called the observational side of the science. On the other hand, we have the experimental methods, that seek to discover the properties and functional relationships of the tissues and organs by the use of direct experiments. These experiments may be of a surgical character, involving the extirpation or destruction or alteration of known parts by operations upon the living animal, or they may consist in the application of the accepted methods of physics and ■chemistry to the living organism. The physical methods include the study of the physical properties of living matter and the interpretation of its activity in terms of known physical laws, and also the use of various kinds of physical apparatus such as manometers, galvanometers, etc. for recording with accuracy the phenomena exhibited by living tissues. The chemical methods imply the application of the synthetic and analytic operations of chemistry to the study of the composition and structure of living matter and the products of its activity. The study of the subjective phenomena of conscious life — in fact, the whole question of the psychic aspects or properties of living matter — for reasons that have been mentioned is not usually included in the science of physiol- ogy, although strictly speaking it forms an integral part of the subject. This province of physiology has, however, been organized into a separate science, psychology, although the boundary line between psychology as it exists at present and the scientific physiology of the nervous system cannot always be sharply drawn. It follows clearly enough from what has been said of the methods used in animal physiology that even an elementary acquaintance with the subject as a science requires some knowledge of general histology and anatomy, human as well as comparative, of physics, and of chemistry. When this preliminary training is lacking, physiology cannot be taught as a science ; it becomes simply a heterogeneous mass of facts, and fails to accomplish its function as a preparation for the scientific study of medicine. The mere facts of physiology are valuable, indeed itidispensable, as a basis for the study of the succeeding branches of the medical curriculum, but in addition the subject, properly taught, should impart a scientific discipline and an acquaintance with the possible methods of experimental medicine ; for among the so-called experi- mental branches of medicine physiology is the most developed and the most ■exact, and serves as a type, so far as methods are concerned, to which the 'Others must conform. II. BLOOD AI(D LYMPH. BLOOD. A. General Pbopeetibs : Physiology op the Oobpusclbs. The blood of the body is contained in a practically closed system of tubes, the blood-vessels, within which it is kept circulating by the force of the heart- beat. The blood is usually spoken of as the nutritive liquid of the body, but its functions may be stated more explicitly, although still in quite general terms, by saying that it carries to the tissues food-stuffs after they have been properly prepared by the digestive organs ; that it transports to the tissues oxygen absorbed from the air in the lungs ; that it carries off from the tissues various waste products formed in the processes of disassimilation ; that it is the medium for the transmission of the internal secretion of certain glands ; and that it aids in equalizing the temperature and water contents of the body. It is quite obvious, from these statements, that a complete consideration of the physiological relations of the blood would involve substantially a treat- ment of the whole subject of physiology. It is proposed, therefore, in this section to treat the blood in a restricted way — to consider it, in fact, as a tissue in itself, and to study its composition and properties without special reference to its nutritive relationship to other parts of the body. Histological Structure. — The blood is composed of a liquid part, the plasma, in which float a vast number of microscopic bodies, the blood-corpus- dfs. There are at least three different kinds of corpuscles, known respectively as the red corpuscles ; the white corpuscles or leucocytes, of which in turn there are a number of different kinds ; and the blood-plates. As the details of structure, size, and number of these corpuscles belong properly to text- books on histology, they will be mentioned only incidentally in this section when treating of the physiological properties of the corpuscles. Blood-plasma, when obtained free from corpuscles, is perfectly colorless in thin layers — for example, in microscopic preparations ; when seen in large quantities it shows a slightly yellowish tint, the depth of color varying with different animals. This color is due to the presence in small quantities of a special pigment, the nature of which is not definitely known. The red color of blood is not due, there- fore, to coloration of the blood-plasma, but is caused by the mass of red cor- puscles held in suspension in this liquid. The proportion by bulk of plasma to corpuscles is usually given, roughly, as two to one. Blood-serum and Defibrinated Blood. — In connection with the explanation of the term " blood-plasma" just given, it will be convenient to define briefly the terms " l)lood-serum " and "defibrinated blood." Blood, after it escapes from the vessels, usually clots or coagulates ; the nature of this process is Vol. I.— 3 33 84 .l.V AMEBICAK TEXT-BOOK OF PHYSIOLOGY. discussed in detail on p. 54. The clot, as it forms, gradually shrinks and squeezes out a clear liquid to which the name blood-serum is given. Serum resembles the plasma of normal blood in general appearance, but differs from it in composition, as will be explained later. At present we may say, by way of a preliminary definition, that blood-serum is the liquid part of blood after coagulation has taken place, as blood-plasma is the liquid part of blood before coagulation has taken place. If shed blood is whipped vigorously with a rod or some similar object while it is clotting, the essential part of the clot — namely, the fibrin — forms differently from what it does when the blood is allowed to coagulate quietly ; it is deposited in shreds on the whipper. Blood that has been treated in this way is known as defibrinated blood. It consists of blood-serum plus the red and white corpuscles, and as far as appearances go it resembles exactly normal blood ; it has lost, however, the power of clot- ting. A more complete definition of these terms will be given after the sub- ject of coagulation has been treated. Reaction. — The reaction of blood is alkaline, owing mainly to the alka- line salts, especially the carbonates of soda, dissolved in the plasma. The degree of alkalinity varies with different animals: reckoned as Na^COj, the alkalinity of dog's blood corresponds to 0.2 per cent, of this salt; of human blood, 0.35 per cent. The alkaline reaction of blood is very easily demon- strated upon clear plasma free from corpuscles, but with normal blood the red color prevents the direct application of the litmus test. \ number of simple devices liave been suggested to overcome this difficulty. For example, the method employed by Zuntz is to soak a strip of litmus-paper in a concentrated solution of XaCI, to place on this paper a drop of blood, and, after a few seconds, to remove the drop with a stream of water or with a piece of filter- paper. The alkaline reaction becomes rapidly less marked after the blood has been shed ; it varies also slightly under different conditions of normal life and in certain pathological conditions. After meals, for instance, during the act of digestion, it is said to be increased, while, on the contrary, exercise causes a diminution. In no case, however, does the reaction become acid. For details of the methods used for quantitative determinations of the alka- linity of human blood, reference must be made to original sources.' Specific Gravity. — The specific gravity of human blood in the adult male may vary from 1041 to 1067, the average being about 1055. Jones ^ made a careful study of the variations in specific gravity of human blood under different conditions of health and disease, making use of a simple method which requires only a few drops of blood for each determination. He found that the specific gravity varies with age and sex, that it is diminished after eating and is increased by exercise, that it falls slowly during the day and rises gradually during the night, and that it varies greatly in individuals, "so mucli so that a specific gravity which is normal for one may be a sign of dis- ease in another." The specific gravity of the corpuscles is slightlv greater 'Wright: The Lancet, 1897, p. 8; Winternitz: Zeiischrift fur physiol. Chemie, 1891, Bd. 15 S. 505. 'Journal of Physiology, 1891, vol. xii., p. 299. BLOOD. 35 than that of the plasma. For this reason the coi'puscles in shed blood, when its coagulation is prevented or retarded, tend to settle to the bottom of the containing utensil, leaving a more or less clear layer of supernatant plasma. Among themselves, also, the corpuscles differ slightly in specific gravity, the red corpuscles being heaviest and the blood-plates being lightest. Red Corpuscles. — The red corpuscles in man and in all the mammalia, with the exception of the camel and other members of the group Camelidse, are biconcave circular disks without nuclei ; in the Camelidse they have an elliptical form. Their average diameter in man is given as 7.7/i (l/i = 0.001 of a mm.) ; their number, which is usually reckoned as so many in a cubic millimeter, varies greatly under different conditions of health and disease. The average number is given as 5,000,000 per cubic mm. for males and 4,500,000 for females. The red color of the corpuscles is due to the presence in them of a pigment known as " hsemoglobin." Owing to the minute size of the corpuscles, their color when seen singly under the microscope is a faint yellowish-red, but when seen in mass they exhibit the well-known blood-red color, which varies from scarlet in arterial blood to purplish-red in venous blood, this variation in color being dependent upon the amount of oxygen contained in the blood in combination with the hsemoglobin. Speaking generally, the function of the red corpuscles is to carry oxygen from the lungs to the tissues. This function is entirely dependent upon the presence of hsemoglobin, which has the power of combining easily with oxygen gas. The physiology of the red corpuscles, therefore, is largely contained in a description of the properties of hsemoglobin. Condition of the Hsemoglobin in the Corpuscle. — The finer structure of the red corpuscle is not completely known. It is commonly believed that the corpuscle consists of two substances — a delicate, extensible, colorless pro- toplasmic material, which gives to the corpuscle its shape and which is known as the stroma, and the hsemoglobin. The latter constitutes the bulk of the cor- puscle, forming as much as 95 per cent, of the solid matter. It was formerly thought that hsemoglobin is disseminated as such in the interstices of the porous spongy stroma, Ijut there seem to be reasons now for believing that it is present in the corpuscles in some combination the nature of which is not fully known. This belief is based upon the fact that Hoppe-Seyler ' has shown that hsemoglobin while in the corpuscles exhibits certain minor differ- ences in properties as compared with hsemoglobin outside the corpuscles. In various ways the compound of hsemoglobin in the corpuscles may be destroyed, the hsemoglobin being set free and passing into solution in the plasma. Blood in which this change has occurred is altered in color and is known as " laky blood." In thin layers it is transparent, whereas normal blood with the hsemoglobin still in the corpuscles is quite opaque even in very thin strata. Blood may be made laky by the addition of ether, of chloroform, of bile or the bile acids, of the serum of other animals, by an excess of water, by alternately freezing and thawing, and by a number of other methods. In connection with two of these methods of discharging hsemoglobin from the ' Zeitschrift fiir physiologisehe Ghemie, Bd. xiii., 1889, S. 477. 36 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. corpuscles there have come into use in current medical and physiological literature two technical terms which it may be well to attempt to define. Glohulicidal Action of Serum.— It was shown first by Landois that the serum of one animal may have the property of destroying the red corpuscles in the blood of another animal, thus making the blood laky. This fact, which has since been investigated more fully, is now designated under the term of " glohulicidal " action of the serum. It has been found that different kinds of serum show different degrees of glohulicidal activity, and that white as well as red corpuscles may be destroyed. Dog's serum or human serum is strongly glohulicidal to rabbit's blood. It would seem that this a-ction is not due to^ mere variations in the amounts of inorganic salts in the different kinds of serum, since the remarkable fact has been discovered that heating serum to 65° or 60° C. for a few minutes destroys its glohulicidal action, although such treatment causes no coagulation of the proteids nor any visible change in the liquid. Moreover, it is known that foreign serum injected into the veins of a living animal may exert a marked toxic effect that cannot be explained solely by its glohulicidal action— for instance, 7 to 14 c.c. of fresh dog's serum will suffice to kill a rabbit — and lastly, serum is known to exert a similar- destructive effect on bacteria, its so-called bactericidal action. These three effects of serum, glohulicidal, bactericidal and toxic, seem all to be destroyed by heating to 50°-60° C, and it is possible that they are all traceable to the. existence in the blood of some proteid substance, an alexine, which is present in small quantity aud is different for each species of animal, the material in the blood of one species being more or less glohulicidal and toxic, as a rule, to the tissues of another species.' Isotonic So/idions. — \\^hen blood or defibrinated blood is diluted with water, a point is soon reached at which hfemoglobin begins to pass out of the corpuscles into the plasma or the serum, and the blood begins to appear laky. It appears that the liquid surrounding the corpuscles must have a certain concentration as regards salts or other soluble substances, such as sugar, in order to prevent the entrance of water into the substance of the corpuscle- Normally the substance of the red corpuscle possesses a certain osmotic pressure which may be supposed to be equal to that of the plasma by which it is surrounded, so that the interchange of water between them is at an equilibrium. If the concentration of the outside liquid is diminished, this equilibrium is destroyed aud water passes into the corpuscle ; if the dilution has been sufficient, enough water passes into the corpuscle to make it swell and eventually to force out the hsemoglobin. Liquids containing inorganic salts, or other soluble substances that possess an osmotic pressure sufficient to pre- vent the imbibition of water Ijy the corpuscles, are said to be " isotonic to the corpuscles." Red corpuscles suspended in such liquids do not change in shape nor lose their hsemoglobin. When solutions of different substances are com- pared from this standpoint, it is found that the concentration necessary varies with the substance used. Thus, a solution of XaCl of 0.64 per cent, is isotonic • For a recent paper and the literature see Friedenthal and Lewandowsky, Archiv fur Phys- iologic, 1899, S. 531. BLOOD. 37 with a solution of sugar of 5.5 per cent, or a solution of KXO3 of 1.09 per cent. When placed in any of these three solutions red corpuscles do not take up water — at least not in quantities sufficient to discharge the haemo- globin. For a more complete account of these relations the reader is referred to original sources (Hamburger'). A solution whose osmotic pressure is loNver than that of blood-plasma is said to be hypo-isotonic or hypotonic to blood. Such solutions may cause the blood to lake. Solutions of a higher osmotic pressure than that of the plasma are spoken of as hyper-isotonic or hypertonic. AVhenever it is necessary to dilute shed blood or to inject any quantity of a neutral liquid into the circulation care must be taken to have the solution isotonic with the blood. (See p. 65 for an explanation of the term osmotic pressure.) Nature and Amount of Hsemoglobin. — Hismoglobin is a very complex substance belonging to the group of combined proteids. (For the definition and classification of proteids, as well as for the purely chemical properties of hfemoglobin and its derivatives, reference must be made to the section on "The Chemistry of the Body.") When decomposed in various ways hsemoglobin bi'eaks up into a proteid (globin, 86 to 96 per cent.), a simpler pigment (hsema- tin, 4 per cent.), and an unknown residue.^ When the decomposition takes place in the absence of oxygen, the products formed are globin and heemo- chromogen, instead of globin and hsematin. Hsemochromogen in the presence of oxygen quickly undergoes oxidation to the more stable haematin. Hoppe- Seyler has shown that hsemochromogen possesses the chemical grouping which gives to hsemoglobin its power of combining readily with oxygen and its distinctive absorption spectrum. On the basis of facts such as these, hsemo- globin may be defined as a compound of a proteid body with hsemochromogen. It seems, then, that although the hsemochromogen portion is the essential thing, giving to the molecule of hsemoglobin its valuable physiological prop- erties as a resj)iratory pigment, yet in the blood-corpuscles this substance is incorporated into the much larger and more unstable molecule of hsemoglobin, whose behavior toward oxygen is different from that of the hsemochromogen itself, the difference being mainly in the fact that the hsemoglobin as it exists in the corpuscles forms with oxygen a comparatively feeble combination that may be broken up readily with liberation of the gas. Hsemoglobin is widely distributed throughout the animal kingdom, being found in the blood-corpuscles of mammalia, birds, reptiles, amphibia, and fishes, and in the blood or blood-corpuscles of many of the invertebrates. The composition of its molecule is found to vary somewhat in different animals, so that, strictly speaking, there are probably a number of different forms of hsemoglobin — all, however, closely related in chemical and physiological properties. Elementary analysis of dog's hsemoglobin shows the following percentage composition (Jaquet) : C 53.91, H 6.62, N 15.98, S 0.542, Fe 0.333, O 22.62. Its molecular formula is given as CysgHijosNigsSjFeOju, which would make the molecular weight 16,669. Other estimates are given of > Du Bois-Eeymond's Archivfiir Physiologie, 1886, S. 476; 1887, S. 31. ^ See Schulz, ZeitschriftfUr physiol. Chemie, Bd. 24; also Lauraw, ibid., Bd. 26. 38 A^^ AMERICAN TEXT-BOOK OF PHYSIOLOGY. the molecular formula, but they agree at least in showing that the molecule is of enormous size. The molecular formula for hajmochromogen is much sim- pler ; one estimate makes it Cj.H^eN^FeOs. The exact amount of hsemoglobin in human blood varies naturally with the individual and with different condi- tions of life. According to Preyer/ the average amount for the adult male is 14 grams of haemoglobin to each 100 grams of blood. It is estimated that in the blood of a man weighing 68 kilos, there are contained about 750 grams of hsemoglobin, which is distributed among some twenty-five trillions of corpuscles, giving a total superficial area of about 3200 square meters. Practically all of this large surface of hsemoglobin is available for the absorption of oxygen from the air in the lungs, for, owing to the great number and the minute size of the capillaries, the blood, in passing through a capillary area, becomes subdivided to such an extent that the red corpuscles stream through the capil- laries, one may say, in single file. In circulating through the lungs, therefore, each corpuscle becomes exposed moi'e or less completely to the action of the air, and the utilization of the entire quantity of hemoglobin must be nearly perfect. It may be worth while to call attention to the fact that the biconcave form of the red corpuscle increases the superficies of the corpuscle and tends to make the surface exposure of the hsemoglobin more complete. Compounds -with Oxygen and other Gases. — Hsemoglobin has the property of uniting with oxygen gas in certain definite proportions, forming a true chemical compound. This compound is known as oxylicemoglobin ; it is formed whenever blood or hsemoglobin solutions are exposed to air or otherwise brought into contact with oxygen. Each molecule of heemoglobin is supposed to combine with one molecule of oxygen, and it is usually estimated that 1 gram of dried hsemoglobin (dog) can take up 1.59 c.c. of oxygen measured at 0° C. aud 760 mm. of barometric pressure, although according to a later determination by Hiifner,^ the O-capacity of the Hb of ox's blood is only 1.34 c.c. O to each gram of Hb. Oxyhemoglobin is not a very firm compound. If placed in an atmosphere containing no oxygen, it will be dissociated, giving off free oxygen and leaving behind hsemoglobin, or, as it is often called by way of distinction, "reduced hcemor/loljiit." This power of combining with oxygen to form a loose chemical compound, which in turn can be dissociated easily when the oxygen-pressure is lowered, makes possible the function of hsemoglobin in the blood as the carrier of oxygen from the lungs to the tissues. The details of this process are described in the section on Respiration. Hsemoglobin forms with carbon- monoxide gas (CO) a compound, similar to oxy hsemoglobin, which is known as carbon-vionoxide haemoglobin. In this compound also the union takes place in the proportion of one molecule of hemoglobin to one molecule of the gas. The compound formed differs, however, from oxy- hemoglobin in being much more stable, and it is for this reason that the breathing of carbon monoxide gas is liable to prove fatal. The CO unites with the hemoglobin, forming a firm compound; the tissues of the body are ^ Die Blutkrystalk, Jena, 1871. ^ Anhivfur Physiologic, 1894, S. 130. BLOOD. 39 thereby prevented from obtaining their necessary oxygen, and death results from suffocation or asphyxia. Carbon monoxide forms one of the constituents of coal-gas. The well-known fatal effect of breathing coal-gas for some time, as in the case of individuals sleeping in a room where gas is escaping, is trace- able directly to the carbon monoxide. Nitric oxide (NO) forms also with hsemoglobin a definite compound that is even more stable than the CO- hsemoglobin ; if, therefore, this gas were brought into contact with the blood, it would cause death in the same way as the CO. Oxy haemoglobin, carbon-monoxide hsemoglobin, and nitric-oxide hemoglo- bin are similar compounds. Each is formed, apparently, by a definite combina- tion of the gas with the hsemochromogen portion of the hsemoglobin molecule, and a given weight of hsemoglobin unites presumably with an equal volume of each gas. In marked contrast to these facts, Bohr ^ has shown that hsemoglobin forms a compound with carbon-dioxide gas, cai-bo-hcenioglobin, in which the quantitative relationship of the gas to the hsemoglobin differs from that shown by oxygen. In a mixture of O and CO2 each gas is absorbed by hsemoglobin solutions independently of the other, so that a solution of haemoglobin nearly saturated with oxygen can unite with as much CO2 as though it held no oxygen in combination. Bohr suggests, therefore, that the O and the CO2 must unite with different portions of the hsemoglobin — the oxygen with the pigment portion, the hsemochromogen, and the CO2 possibly with the proteid portion. It seems probable that hsemoglobin plays a part in the transportion of the carbon dioxide as well as the oxygen of the blood, but its exact value in this respect as compared with the blood-plasma, which also acts as a carrier of CO3, has not been definitely determined (see Respiration). Presence of Iron in the Molecule. — It is probable that iron is quite generally present in the animal tissues in connection with nuclein compounds, but its existence in hsemoglobin is noteworthy because it has long been known and because the important property of combining with oxygen seems to be connected with the presence of this element. According to the analyses made, the proportion of iron in hsemoglobin varies somewhat in different animals : the figures given are from 0.335 to 0.47 per cent. The amount of hsemoglobin in blood may be determined, therefore, by making a quantitative determination of the iron. The amount of oxygen with ■which hsemoglobin will combine may be expi'essed by saying that one molecule of oxygen will be fixed for each atom of iron in the hsemoglobin molecule. In the decom- position of hsemoglobin into globulin and hsematin, which has been spoken of above, the iron is retained in the hsematin. Crystals. — Hsemoglobin may be obtained readily in the form of crystals (Fig. 1). As usually prepared, these crystals are really oxyhsemoglobin, but it has been shown that reduced hsemoglobin also crystallizes, although with more difficulty. Hsemoglobin from the blood of different animals vai'ies to a marked degree in respect to the power of crystallization. From the blood of the rat, dog, cat, guinea-pig, and horse, crystals are readily obtained, while hsemoglobin from the blood of man and of most of the vertebrates crystallizes ' Skandivamsches Archiv/ur Physiologie, 1892, Bd. 3, S. 47. 40 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. much less easily. Methods for preparing and purifying these crystals will be found in works on Physiological Chemistry. To obtain specimens quickly for examination under the microscope, one of the most certain methods is to take some blood from one of the animals whose haemoglobin crystallizes easily, place it in a test-tube, add to it a few drops of ether, shake the tube thoroughly until the blood becomes laky — that is, until the haemoglobin is discharged into the plasma — and then place the tube on ice until the crystals are deposited. Small portions of the crystalline sedi- ment may then be removed to a glass slide for examination. Hemoglobin from different animals varies not only as to the ease witli which it crystal- lizes, but in some cases also as to the form that the crystals take. In man and in most of the mammalia hsemoglo- bin is deposited in the form of rhom- bic prisms; in the guinea-pig it crys- tallizes in tetrahedra (d, Fig. 1), and in the squirrel in hexagonal plates. The crystals are readily soluble in water, and by repeated crystallizations the haemo- globin may be obtained perfectly pure. As in the case of other soluble proteid- like bodies, solutions of haemoglobin are precipitated by alcohol, by mineral acids, by salts of the heavy metals, by boiling, etc. Notwithstanding the fact that haemoglobin crystallizes so readily, it is not easily dialyzable, behaving in this respect like proteids and other colloidal bodies. The compounds which haemoglobin forms with carbon monoxide (CO) and nitric oxide (XO) are also crystallizable, the crystals being isomor- phous with those of oxyhaemoglobin. Absorption Spectra. — Solutions of haemoglobin and its derivative com- pounds, when examined with a spectroscope, give distinctive absorption bands. A brief account of the principle and arrangement of the spectroscope, although unnecessary for those familiar with the elements of Physics, is given by way of introduction to the description of these absorption bands. Light, when made to pass through a glass prism, is broken up into its constituent rays, giving the play of rainbow colors known as the spectrum. A spectroscope is an apparatus for producing and observing a spectrum. A simple form, which illus- trates sufficiently well the construction of the apparatus, is shown in Figure 2, P being the glass prism giving the spectrum. Light falls upon this prism through the tube (a) to the left, known as the " collimator tube." A slit at the end of this tube (s) admits a narrow slice of light — lamplight or sunlight — which then, by means of a convex lens at the other end of the tube, is made to fall upon the prism Fig. l.-CrystallizedhEemoglobin (after Frey) : o, b, crystals from venous blood of man ; c, from the Wood of a cat ; d, from the blood of a guinea-pig ; e, from the blood of a hamster ; /, from the blood of a squirrel. BLOOD. 41 (p) with its rays parallel. In passing through the prism the rays are dispersed hy unequal refraction, giving a spectrum. The spectrum thus produced is examined by the observer with the aid of the telescope (b). When the telescope is properly focussed for the rays entering it from the prism (p), a clear picture of the spectrum is seen. The length of the spectrum will depend upon the nature and the number of prisms through which the light is made to pass. For ordinary purposes a short spectrum is preferable for haemoglobin bands, and a spectroscope with one prism is generally used. If the source of light is a lamp-flame of some kind, the spectrum is continuous, the colors gradually merging one into another from red to violet. If sunlight is used, the spectrum will be crossed by a number of narrow dark lines known as the " P>aunhofer lines " Fig. 2.— Spectroscope : p, the glass prism ; A, the collimator tube, showing the slit (s) through which the light is admitted ; B, the telescope for observing the spectrum. {see PI. I., Frontispiece, for an illustration in colors of the solar spectrum). The position of these lines in the solar spectrum is fixed, and the more distinct ones are designated by letters of the alphabet. A, b, c, d, e, etc., as shown in the charts below. If while using solar light or an artificial light a solution of any substance which gives absorption bands is so placed in front of the slit that the light is obliged to traverse it, the spectrum as observed through the telescope will show one or more narrow or broad black bands, "that are characteristic of the substance used and constitute its absorption spectrum. The positions of these bands may be designated by describing their relations to the Fraun- hofer lines, or more directly by stating the wave-lengths of the portions of the spectrum between which absorption takes place. Some spectroscopes are provided with a scale of wave-lengths superposed on the spectrum, and when properly adjusted this scale enables one to read off directly the wave-lengths of any part of the spectrum. When very dilute solutions of oxyhsemoglobin are examined with the spectroscope, tvi^o absorption bands appear, both occurring in the portion of the spectrum included between the Fraunhofer lines D and E. The band nearer the red end of the spectrum is known as the " a-band ;" it is narrower, darker, and more clearly defined than the other, the "/9-band" (Fig. 3, and also PI. I. spectrum 4). With a solution containing 0.09 per cent, of oxy- hsemoglobin, and examined in layers one centimeter thick, the a-band extends over the part of the spectrum included between tlie wave-lengths ^ 583 42 ^.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. (583 raillionths of a millimeter) and I 571, and the /3-band between X 550 and X 532 (Gamgee). The width and distinctness of the bands vary naturally with the concentration of the solution used (see PI. I. spectra 2, 3, 4, and 5), 70 6S 60 55 4-5 B E b G Fig. 3.— Diagrammatic representatiou of the absorption spectrum of oxylisemoglobin (after Eollett). Tlie numerals give tlie wave-Iengtlis in liundred-tliousandths of a millimeter ; the letters show the positions of the more prominent Praunhofer lines of the solar spectrum. The red end of the spectrum is to the left. The a-baud is to the right of d, the p-band to the left of E. or, if the concentration remains the same, with the width of the stratum of liquid through which the light passes. With a certain minimal percentage of oxyhsemoglobiu (less than 0.01 per cent.) the /3-band is lost and the «- band is very faint in layers one cen- timeter thick. With stronger solu- tions the bands become darker and wider and finally fuse, while some of the extreme red end and a great deal of the violet end of the spec- trum is also absorbed. The varia- tions in theabsorption spectrum with differences in concentration are clear- ly shown in the accompanying illus- tration from Eollett ' (Fig. 4) ; the thickness of the layer of liquid is supposed to be one centimeter. The numbers on the right indicate the percentage strength of the oxy- hsemoglobiu solutions. It will be noticed that the absorption which takes place as the concentration of the solution increases aifects the red- orange end of the spectrum last of all. Solutions of reduced haemo- globin examined with the spectro- scope show only one absorption band, known sometimes as the "y-band." This band lies also in the portion of the spectrum included between the lines D and E; its relations to these lines and the bands of oxyhsemoglobin are shown in Figure 5 and in PI. I. spectrum 6. The ' Hermann's Handbuch der Physiologic, Bd. iv., 1880. oBC Fig. 4.— Diagram to show the variations in the ab- sorption spectrum of oxyhasmoglobin with varying concentrations of the solution (after Eollett). The numbers to the right give the strength of the oxy- hEemoglobin solution in percentages ; the letters give the positions of the Fraunhofer lines. To ascertain the amount of absorption for any given concentration up to 1 per cent., draw a horizontal line across the diagram at the level corresponding to the concentra- tion. Where this line passes through the shaded part of the diagram absorption takes place, and the width of the absorption bands is seen at once. The diagram shows clearly that the amount of absorption increases as the solutions become more concentrated, especially the absorption of the blue end of the spectrum. It will be noticed that with concentrations between 0.6 and 0.7 per cent, the two bands between d and e fuse into one. BLOOD. y-band is much more diffuse than the oxyhsemoglobin bands, and its limits therefore, especially in weak solutions, are not well defined; in solutions of blood diluted 100 times with water, which would give a haemoglobin solution of about 0.14 per cent., the absorption band lies in the part of the spectrum included between the wave-lengths I 572 and X 542. The width F G Fig. 5.— Diagrammatic representation of the absorption spectrum of lisemoglobin (reduced haemoglo- bin) (after Rollett). The numerals give the wave-lengths In hundred-thousandths of a millimeter ; the letters show the positions of the more promiuent Fraunhofer lines of the solar spectrum. The red end of the spectrum is to the left. The single diffuse absorption band lies between D and e. and distinctness of this band vary also with the concentration of the solution. This variation is sufficiently well shown in the accompanying illustration (Fig. 6), which is a companion figure to the one just given for oxyhsemoglobin (Fig. 4). It will be noticed that the last light to be absorbed in this case is partly in the red end and partly in the blue, thus explaining the purplish color of haemoglobin solutions and of venous blood. Oxyhaemoglobin so- lutions can be converted to haemo- globin solutions, with a correspond- ing change in the spectrum bands, by placing the former in a vacuum or, more conveniently, by adding reducing solutions. The solutions most commonly used for this pur- pose are ammonium sulphide and Stokes's reagent.' If a solution of reduced haemoglobin is shaken with air, it quickly changes to oxyhsemo- globin and gives two bands instead of one when examined through the spectroscope. Any given solution may be changed in this way from oxyhaemoglobin to haemoglobin, and the reverse, a great number of times, thus demonstrating the facility with which haemoglobin takes up and surrenders oxygen. ' Stokes's reagent is an ammoniacal solution of a ferrous salt. It is made by dissolving 2 parts (by weight) of ferrous sulphate, adding 3 parts of tartaric acid, and then ammonia to dis- tinct alkaline reaction. A permanent precipitate should not be obtained. oBC Fig. 6.— Diagram to show the variations in the ab- sorption spectrum of reduced haemoglobin with vary- ing concentrations of the solution (after Rollett). The numbers to the right give the strength of the h£emo- globin solution in percentages ; the letters give the posi- tions of the Fraunhofer lines. For further directions as to the use of the diagram, see the description of Figure 4. 44 AJY AMERICAN TEXT-BOOK OF PHYSIOLOGY. Solutions of carbon-monoxide haemoglobin also give a spectrum with two absorption bands closely resembling in position and appearance those of oxy- hffimoglobin (see PI. I. spectrum 7). They are distinguished from the oxy- hismoglobin bands by being slightly nearer the blue end of the spectrum, as may be demonstrated by observing the wave-lengths or, more conveniently, by superposing the two spectra. Moreover, solutions of carbon-monoxide hsemoglobin are not reduced to haemoglobin by adding Stokes's liquid, two bands being still seen after such treatment. A solution of carbon-monoxide haemoglobin suitable for spectroscopic examination may be prepared easily by passing ordinary coal-gas through a dilute oxyhfemoglobin solution for a few minutes and then filtering. Derivative Compounds of Hsemoglobin. — A number of compounds directly related to hsemoglobin have been described, some of them being found normally in the body. Brief mention is made of the best known of these substances, but for the details of their preparation and chemical proper- ties reference must be made to the section on " The Chemistry of the Body." Mdhcrnioglobin is a compound obtained by the action of oxidizing agents on hsemoglobin ; it is frequently found, therefore, in blood stains or patho- logical liquids containing blood that have been exposed to the air for some time. It is now supposed to be identical in composition with oxyhsemoglobin, with the exception that the oxygen is held in more stable combination. Methsemoglobin crystallizes in the same form as oxyhsemoglobin, and has a characteristic spectrum (PI. I. spectrum 8). HwmocJu-omogen is the substance obtained when hsemoglobin is decomposed by acids or by alkalies in the absence of oxygen. It crystallizes and has a characteristic spectrum. Hoematin (C32H3o^jFe03) is obtained when oxyhsemoglobin is decomposed by acids or by alkalies in the presence of oxygen. It is amorphous and has a characteristic spectrum (PI. I. spectra 9 and 10). Hcemin (CjjHjjN^FeOjHCl) is a compound of hsematin and PICl, and is readily obtained in crystalline form. It is much used in the detection of blood in medico-legal cases, as the crystals are very characteristic and are easily obtained from blood-clots or blood-stains, no matter how old these may be. Hmnatoporphyrin (CigHigNjOj) is a compound characterized by the absence of iron. It is frequently spoken of as " iron-free hsematin." It is obtained by the action of strong sulphuric acid on hsematin. Hcematoidin (CijHigNjOj) is the name given to a crystalline substance found in old blood-clots, and formed undoubtedly from the hsemoglobin of the clotted blood. It has been shown to be identical with one of the bile- pigments, bilirubin. Its occurrence is interesting in that it demonstrates the relationship between hsemoglobin and the bile-pigments. Histohcematins are a group of pigments said to be present in many of the tissues — for example, the muscles. They are supposed to be respiratory pig- ments, and are related physiologically, and possibly chemically, to hsemoglobin. They have not been isolated, but their spectra have been described. BLOOD. 45 Bile-pigments and Urinary Pigments — Haemoglobin is regarded as the parent-substance of the bile-pigments and the urinary pigments. Orig-in and Pate of the Red Corpuscles. — The mammalian red corpuscle is a cell that has lost its nucleus. It is not probable, therefore, that any given corpuscle lives for a great while in the circulation. This is made more certain by the fact that hasmoglobin is the mother-substance from which the bile- pigments are made, and, as these pigments are being excreted continually, it is fair to suppose that red corpuscles are as steadily undergoing disintegration in the blood-stream. Just how long the average life of the corpuscles is has not been determined, nor is it certain where and how they go to pieces. It has been suggested that their destruction takes place in the spleen, but the observa- tions advanced in support of this hypothesis are not very numerous or con- clusive. Among the reasons given for assuming that the spleen is especially concerned in the destruction of red corpuscles, the most weighty is the histo- logical fact that one can sometimes find in teased preparations of spleen-tissue certain large cells which contain red corpuscles in their cell-substance in various stages of disintegration. It has been supposed that the large cells actually ingest the red corpuscles, selecting those, presumably, that are in a state of physiological decline. Against this idea a number of objections may be raised. Large leucocytes with red corpuscles in their interior are not found so frequently nor so constantly in the spleen as we would expect should be the case if the act of ingestion were constantly going on. There is some reason for believing, indeed, that the whole act of ingestion may be a post- mortem phenomenon ; that is, after the cessation of the blood-stream the amoeboid movements of the large leucocytes continue, while the red corpuscles lie at rest — conditions that are favorable to the act of ingestion. It may be added also that the blood of the splenic vein contains no haemoglobin in solu- tion, indicating that no considei'able dissolution of red corpuscles is taking- place in the spleen. Moreover, complete extirpation of the spleen does not seem to lessen materially the normal destruction of red corpuscles, if we may measure the extent of that normal destruction by the quantity of bile-pigment formed in the liver, remembering that haemoglobin is the mother-substance from which the bile-pigments are derived. It is more probable that there is no special organ or tissue charged with the function of destroying red corpus- cles, and that they undergo disintegration and dissolution while in the blood- stream and in any part of the circulation, the liberated hsemoglobin being carried to the liver and excreted in part as bile-pigment. The continual destruction of red corpuscles implies, of course, a continual formation of new ones. It has been shown satisfactorily that in the adult the organ for the reproduction of red corpuscles is the red marrow of bones. In this tissue hcematopoiesis, as the process of formation of red corpuscles is termed, goes on continually, the process being much increased after hemorrhages and in certain pathological conditions. The details of the histological changes will be found in the text-books of histology. It is sufficient here to state simply that a group of nucleated colorless cells, erythroblasts, is found in the red marrow. 46 AN AJTEBICAK TEXT-BOOK OF PHYSIOLOGY. These cells multiply by karyokinesis, and the daughter-cells eventually pro- duce hemoglobin in their cytoplasm, thus forming nucleated red corpuscles. The nuclei are subsequently lost, either by disintegration or, more likely, by extrusion, and the newly-formed non-nucleated red corpuscles are forced into the blood-stream, owing to a gradual change in their position during develop- ment caused by the growing haematopoietic tissue. When the process has been greatly accelerated, as after severe hemorrhages or in certain pathological conditions, red corpuscles still retaining their nuclei may be found in the circu- lating blood, having been forced out prematurely as it were. Such corpuscles may subsequently lose their nuclei while in the blood-stream. In the em- bryo, hsematopoietic tissue is found in parts of the body other than the mar- row, notably in the liver and spleen, which at that time serve as organs for the production of new red corpuscles. In the blood of the young embryo nucleated red corpuscles are at first abundant, but they become less numerous as the fetus grows older.' Variations in the Number of Red Corpuscles. — The average number of red corpuscles for the adult male, as has been stated already, is usually given as 5,000,000 per cubic mm. The number is found to vary greatly, however. Outside of pathological conditions, in which the diminution in number may be extreme, differences have been observed in human beings under such conditions as the following: The number is less in females (4,500,000); it varies in individuals with the constitution, nutrition, and manner of life ; it varies with age, being greatest in the fetus and in the new- born child ; it varies with the time of the day, showing a distinct diminution after meals ; in the female it varies somewhat in menstruation and in preg- nancy, being slightly increased in the former and diminished in the latter condition. Perhaps the most interesting example of variation in the number of red corpuscles is that which occurs with changes in altitude. Residence in high altitudes is quickly followed by a marked increase in the number of red corpuscles. Yiault^ has shown that living in the mountains for two weeks at an altitude of 4392 meters caused an increase in the corpuscles from 5,000,000 to over 7,000,000 per cubic mm., and in the third week the number reached 8,000,000. The accuracy of this observation has been demonstrated since by many investigators. Some very careful work done under the direction of Miescher^ has shown that a comparatively small increase in altitude, 700 meters, causes a marked increase in the number of red corpuscles and in the amount of haemoglobin, while return to a lower altitude quickly brings the blood back to its normal condition. From these observations it would seem that a diminished pressure of oxygen in the atmosphere stimulates the hsema- topoietic organs to greater activity, and it is interesting to compare this result with the effect of an actual loss of blood. In the latter case the production of red corpuscles in the red marrow is increased, because, apparently, the anaemic condition causes a diminution in the oxygen-supply to the haamatopoietic tissue, ' Howell : " Life History of the Blood-corpuscles,'' etc., Journal of Morphology, 1890, vol. iv. ' La Semaine medicate, 1890, p. 464. ' Archivfiir exp. Pathol, u. Pharmakol, 1897, Bd. 39, S. 426-464. BLOOD. 47 and thereby stimulates the erythroblastic cells to more rapid multiplication. In the case of a diminution in oxygen-pressure, as happens when the altitude is markedly increased, we may suppose that one result is again a slight dimi- nution in the oxygen-supply to the tissues, including the red marrow, and in consequence the erythroblasts are again stimulated to greater activity. This variation in haemoglobin with the altitude is an interesting adaptation which ensures always a normal oxygen-capacity for the blood. Physiology of the Blood-leucocytes. — The function of the blood-leuco- cytes has been the subject of numerous investigations, particularly in connection with the pathology of blood diseases. Although many hypotheses have been made as the result of this work, it cannot be said that we possess any positive information as to the normal function of these cells in the body. Tt must be borne in mind in the first place that the blood-leucocytes are not all the same histologically, and it may be that their functions are as diverse as is their mor- phology. Various classifications have been made, based upon one or another difference in microscopic structure and reaction. Thus, Ehrlich groups the leuco- A n o b Fig. 7.— Blood stained with Elirlich's "triple stain" of acid-fuehsin, methyl-green, and orange G. (drawn with the camera lucida from normal blood) (after Osier) : a, red corpuscles ; b, lymphocytes ; c, large mononuclear leucocytes; d, transitional forms; e, neutrophilic leucocytes with polymorphous nuclei (polynuclear neutrophiles) ; /, eosinophilic leucocytes. cytes according to the size, the solubility, and the staining of the granules contained in the cytoplasm, making in the latter respect three main groups ; oxyphiles or eosinophiles, those whose granules stain only with acid aniline dyes — that is, with dyes in which the acid part of the dye acts as the stain j basophiles, those which stain only with basic 'dyes ; and neutrophiles, those which stain only with neutral dyes* (Fig. 7). This classification is fre- quently used, especially in pathological literature, but it is not altogether satisfactory, since no definite functional relationship of the granules has been established ; and, moreover, it is undecided whether or not the granules are permanent or temporary structures in the cells. A simpler classification ' Ehrlich : Die Anomiie, Vienna, 1898 ; Kanthack and Hardy, Journal of Physiology, vol., xvii., 1894, p. 81. 48 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. based on morphological characteristics is the following: 1. Lymphocytes, which are small corpuscles with a round vesicular nucleus and very scanty cytoplasm ; they are not capable of amoeboid movements. These corpuscles are so called because they resemble the leucocytes found in the lymph-glands, and are supposed in fact to be brought into the blood through the lymph. According to Ehrlich, they form from 22 to 25 per cent, of the total number of leucocytes. 2. Mononuclear leucocytes, which are large corpuscles with a vesicular nucleus and abundant cytoplasm : they have the power of making amoeboid movements and are present in only small numbers, 1 per cent. 3. Pobfiiinrphou.^ or polymicleated leucocytes, which are large corpuscles with the nucleus divided into lobes that are either entirely separated or are con- nected by fine protoplasmic threads. This form shows active amoeboid move- ments and constitutes the largest proportion of the blood leucocytes, 70 to 72 per cent. 4. The eosinophUe cells, similar in general to the last, except that the cytoplasm contains numerous coarse granules that take acid stains (eosin) readily. They are present in small numbers, 2 to 4 per cent. It is impossible to say whether these varieties of blood-leucocytes are distinct histological units that have independent origins and more or less dissimilar functions, or whether, as seems more probable to the writer, they represent different stages in the development of a single type of cell, the lymphocytes forming the youngest and the polymorphic or polynucleated leucocytes the oldest stage. Perhaps the most striking property of the leuco- cytes as a class is their power of making amoeboid movements — a charac- teristic which has gained for them the sobriquet of " wandering " cells. By virtue of this property some of them are able to migrate through the walls of blood-capillaries into the surrounding tissues. This process of migration takes place normally, but is vastly accelerated under pathological conditions. As to the function or functions fulfilled , by the leucocytes, numerous sugges- tions have been made, some of which may be stated in brief form as follows: (1) They protect the body from pathogenic bacteria. In explanation of this action it has been suggested that they may either ingest the bacteria, and thus destroy them directly, or they may form certain substances, defensive proteids, that destroy the bacteria. Leucocytes that act by ingesting the bacteria are spoken of as "phagocytes" (\xt the ready diffusi- bility of most of these salts through animal membranes limits very materially their influ- ence upon the flow of water in the body. Thus if we should inject a strong solution of common salt directly into the blood-vessels, the first effect would be the setting up of an osmotic stream from the tissues to the blood and the production of a condition of hydrtemic plethora within the blood-vessels. The salt, however, would soon diffuse out into the tis- sues, and to the degree that this occurred its effect in diluting the blood would tend to dimin- ish because the part of the salt that got into the extra-vascular lymph-spaces would now exert an osmotic pressure in the opposite direction, drawing water from the blood. This fact, together with the further fact that an excess of salts in the body is soon removed by the excreting organs, gives to such substances a smaller influence in directing the water stream than would at first be supposed when the intensity of their osmotic action is con- sidered. In addition to the crystalloids the liquids of our bodies contain also a certain amount of proteid, the blood, especially, containing over 6 per cent, of this substance. It has been generally assumed that proteids in solution exert little or no osmotic pressure, but Starling ' and others have claimed, on the contrary, that proteids in solution exert a distinct although small osmotic pressure, and it is probable that this fact is of special importance in absorption because the proteids do not diffuse or diffuse with great difllculty, and their effect remains therefore, so to speak, as a permanent factor. Accord- ing to Starling, the osmotic pressure exerted by the proteids of serum is equal to about 30 mm. of mercury. That the osmotic pressure of the serum proteids is so small is not surprising if we remember the very high molecular weight of this substance. In serum the proteids are present in a concentration of about 7 per cent., but owing to their large molecular weight con)paratively few proteid molecules are present in a solution of this concentration ; and assuming that the dissolved proteid follows the laws discovered for crystalloids its osmotic pressure would depend upon the number of molecules in solu- tion. By means of this weak but constant osmotic pressure of the indiffusible proteid it is possible to explain the fact that an isotonic or even a hypertonic solution of diffus- ible crystalloid may be completely absorbed by the blood from the peritoneal cavity. Isotonic, Hypertonic, and Hypotonic Solutions. — In physiology the osmotic pressures exerted by various solutions are compared usually with that of the blood-serum. In this sense an isotonic or isosmotic solution is one having an osmotic pressure equal to that of serum, a hypertonic or hyperosmotic solution is one whose osmotic pressure exceeds that of serum, and a hypotonic or hyposmotic solution is one whose osmotic pressure is less than that of serum. Diffusion, or Dialysis, of Soluble CoMtituents. — If two liquids of unequal concentration in a given constituent are separated by a membrane entirely permeable to the dissolved molecules of the substance, a greater number of these molecules will pass over from the more concentrated to the less concentrated side, and in time the composition will be the same on the two sides of the membrane. Diffusion of soluble constituents continually takes place, therefore, from the points of greater concentration to those of less, and this may hap- pen quite independently of the direction of the osmotic stream of water. If, for instance, a 0.9 per cent, solution of sodium chloride is injected into the peritoneal cavity, it will enter into diffusion relations with the blood in the blood-vessels ; its concentration in sodium chloride being greater than that of the blood, the excess will tend to pass into the blood, while sodium carbonate, urea, sugar, and other soluble crystalloidal substances will pass from the blood into the salt solution in the peritoneal cavity. Through the action of this process of diffusion we can understand how certain constituents of the blood may pass ' Journal of Physiology, 1899, vol. 24, p. 317. 70 .l.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. to the tissues of various glands in amounts greater than could be explained if we sup- posed that the lymph of these tissues was derived solely by filtration from the blood- plasma. (See p. 72 for an illustration.) Another important conception in this con- nection is the possibility that the capillary walls may be permeable in different degrees to the various soluble constituents of the blood, and furthermore the possibility that the permeability of the capillary walls may vary in different organs. With regard to the first possibility it has been shown by Roth ' that the blood-capillaries are more per- meable to the urea molecules than to sugar or NaCl. With the aid of these facts it is possible to explain in large measure the transportation of material from the blood to the tissues, and vice versa. For example, to follow a line of reasoning used by Eoth, we may suppose that the functional activity of the tissue-elements is attended by a con- sumption of material which in turn is made good by the dissolved molecules in the tissue-lymph. The concentration of the latter is thereby lowered, and in consequence a diffusion stream of these substances is set up with the more concentrated blood. In this way, by diffusion, a constant supply of dissolved material is kept in motion from the blood to the tissue-elements. On the other hand, the functional activity of the tissue- elements is accompanied by a breaking down of the complex proteid molecule with the formation of simpler, more stable molecules of crystalloid character, such as the sul- phates, phosphates, and urea or some precursor of urea. As these bodies pass into the tissue-lymph they tend to increase its molecular concentration, and thus by the greater osmotic pressure which they exert serve to attract water from the blood to the lymph, forming one efficient factor in the production of lymph. On the other hand, as these substances accumulate in the lymph to a concentration greater than that possessed by the same substances in the blood, they will diffuse toward the blood. By this means the waste-products of activity are drawn off to the blood, from which in turn they are removed by the action of the excretory organs. Diffusion of Proteids. — This simple explanation on purely physical grounds of the flow of material between the blood and the tissues can only be applied, however, at present to the diffusible crystalloids, such as the salts, urea, and sugar. The proteids of the blood, which are supposed to be so important for the nutrition of the tissues, are prac- tically indiffusible, so far as we know. It is difficult to explain their passage from the blood through the capillary walls into the lymph. Provisionally it may be assumed that this passage is due to filtration. The blood-plasma in the capillaries is under a slightly higher pressure than the lymph of the tissues, and this higher pressure tends to squeeze the blood-constituents, including the proteid, through the capillary walls. This explanation, however, cannot be said to be satisfactory, and in this respect the purely physical theory of lymph-formation waits upon a clearer knowledge of the nature of the nutritive proteids and their relations to the capillary walla. LYMPH. Ly.mph is a colorless liquid found in the lymph-vessels as well as in the oxtrava.scular .spaces of tlie body. A 11 the tissue-elements, in fact, may be regarded as being bathed in lymph. To understand its occurrence in the body one has only to bear in mind its method of origin from the blood. Throughout the entire body there is a rich supply of blood-vessels penetrating cverv tissiie with the exception of the epidermis and some epidermal structures, as the nails and the hair. The plasma of the blood, by the action of physical or chemical processes, the details of which are not yet entirely under.stood, makes its wav through the thin walls of the capillaries, and is thus brought into immediate ' Areiiivfiir PJiysiologie, 1899, S. 416. L YMPH. 71 contact with the tissues, to which it brings the nourishment and oxygen of the blood and from which it removes the waste-products of metabolism. This extravascular lymph is collected into small capillary spaces that in turn open into definite lymphatic vessels. These vessels unite to larger and larger trunks, forming eventually one main trunk, the thoracic or left lymphatic duct, and a second smaller right lymphatic duct, which open into the blood- vessels, each on its own side, at the junction of the subcla\'iau and internal jugular veins, ^\'hile the supply of lymph in the lymph-vessels may be consid- ered as being derived ultimately entirely from the blood-plasma, it is well to bear in mind that at any given moment this supply may be altered by direct inter- change with the plasma on one side and the extravascular lymph permeating the tissue-elements on the other. The intravascular lymph may be augmented, for example, by a flow of water from the plasma into the lymph-spaces, or by a flow from the tissue-elements into the lymph-spaces that surround them. The lymph movement is from the tissues to the veins, and the flow is main- tained chiefly by the difference in pressure between the lymph at its origin in the tissues and in the large lymphatic vessels. The continual formation of lymph in the tissues leads to the development of a relatively high pressure in the lymph capillaries, and as a result of this the lymph is forced toward the point of lowest pressure — namely, the points of junction of the large lymph- ducts with the venous system. A fuller discussion of the factors concerned in the movement of lymph will be found in the section on Circulation. As would be inferred from its origin, the composition of lymph is essentially the same as that of blood-plasma. Lymph contains the three blood-proteids, the extractives (urea, fat, lecithin, cholesterin, sugar), and inorganic salts. The salts are found in the same proportions as in the plasma ; the proteids are less in amount, espe- cially the fibrinogen. Lymph coagulates, but does so more slowly and less firmly than the blood. Histologically, lymph consists of a colorless liquid con- taining a number of leucocytes, and after meals a number of minute fat-drop- lets ; red blood-corpuscles occur only accidentally, and blood-plates, according to most accounts, are likewise normally absent. f'ormation of Lymph. — The careful researches of Ludwig and his pupils were formerly believed to prove that the lymph is derived directly from the plasma of the blood mainly by filtration through the capillary walls. Emphasis was laid on the undoubted fact that the blood within the capillaries is under a pressure higher than that prevailing in the tissues outside, and it was sup- posed that this excess of pressure is sufficient to squeeze the plasma of the blood through the very thin capillary walls, ^"arious conditions that alter the pressure of the blood were shown to influence the amount of lymph formed in accordance with the demands of a theory of filtration. ^Nlore- over, the composition of lymph as usually given seems to support such a theory, inasmuch as the inorganic salts contained in it are in the same concen- tration, approximately, as in blood-plasma, while the proteids are in less con- centration, following the well-known law that in the filtration of colloids through animal membranes the filtrate is more dilute than the original solution. 72 ^;\" AMERICAN TEXT-BOOK OE PHYSIOLOGY. This simple and apparently satisfactory theory has been subjected to critical examination within recent years, and it has been shown that filtration alone does not suffice to explain the composition of the lymph under all circum- stances. At present two divergent views are held upon the subject. Accord- ing to some physiologists, all the facts known with regard to the composition of lymph may be satisfactorily explained if we suppose that this liquid is formed from blood-plasma liy the combined action of the physical processes of filtration, diffusion, and osmosis. According to others, it is believed that, in addition to filtration and diffusion, it is necessary to assume an active secretory process on the part of the endothelial cells composing the capillary walls. A discussion upon these points is in progress in current physiological literature, and it is impossible to foresee definitely what the outcome will be, since a final conclusion can be reached only by repeated experimental investigations. The actual condition of our knowledge of the subject can be presented most easily )iy briefly stating some of the objections that have been raised by Heiden- hain ' to a pure filtration-and-diffusion theory, and indicating how these objec- tions have been met. 1 . Heidenhain shows by simple calculations that an impossible formation of lymph \vould be required, upon the filtration theory, to supply the chemical needs of the organs in various organic and inorganic constituents. Thus, to take an illustration that has been much discussed, one kilogram of cows' milk contains 1.7 grams CaO, and the entire milk of twenty-four hours would contain in round numbers 42.5 grams C'aO. Since the lymph contains nor- mally about 0.18 parts of CaO per thousand, it would require 236 liters of lymph per day to supply the necessary CaO to the mammary glands. Heiden- hain himself suggests that the difficulty in this case may be met by assuming active diffusion processes in connection with filtration. If, for instance, in the case cited, we suppose that the CaO of the lymph is quickly combined by the tissues of the mammary gland, then the tension of calcium salts in the lymph will be kejjt at zero, and an active diffusion of calcium into the lymph will occur so long as the gland is secreting. In other words, the gland will receive its calcium by much the same process 'as it receives its oxygen, and will get its daily supply from a comparatively small bulk of lymph. .Strictly speaking, therefore, the difficulty we are dealing with here shows only the insufficiencv of a pure filtration theory. It seems possible that filtration and diffusion together would suflBce to supply the organs, so far at least as the diffusible substances are concerned. 2. Heidenhain found that occlusion of the inferior vena cava causes not only an increase in the flow of lymph — as might be expected, on the filtration theory, from the consequent rise of pressure in the capillary regions — but also an increased concentration in the percentage of proteid in the lymph. This latter fact has been satisfactorily explained by the experiments of Starling.^ According to this observer, the lymph formed in the liver is normally more ' Archie fiir die gesammte Physiologic, 18'Jl, Bd. xlix. !S. 209. ^ Journal of Physiology, 1894, vol. xvi. p. 234. L YMPH. 73 ■concentrated than that of the rest of the body. The occlusion of the vena cava causes a marked rise in the capillary pressure in the liver, and most of the increased Jymph-flow under these circumstances comes from the liver, hence the greater concenti-ation. The results of this experiment, therefore, do not antagonize the filtration-and-diifusion theory. 3. Heidenhein discovered that extracts of various substances which he designated as " lymphagogues of the first class " cause a marked increase in the flow of lymph from the thoracic duct, the lymph being more concentrated than normal, and the increased flow continuing for a long period. Nevertheless, these substances cause little, if any, increase in general arterial pressure; in fact, if injected in sufficient quantity they produce usually a fall of arterial pressure. The substances belonging to this class comprise such things as pep- tone, egg-albumin, extracts of liver and intestine, and especially extracts of the muscles of crabs, crayfish, mussels, and leeches. Heidenhain supposed that these extracts contain an organic substance which acts as a specific stimulus to the endothelial cells of the capillaries and increases their secretory action. The results of the action of these substances has been differently explained by those who are unwilling to believe in the secretion theory. Starling ^ finds experi- mentally that the increased flow of lymph in this case, as after obstruction of the vena cava, comes mainly from the liver. There is at the same time in the portal area an increased pressure that may account in part for the greater flow of lymph ; but, since this effect upon the portal pressure lasts but a short time, while the greater flow of lymph may continue for one or two hours, it is obvious that this factor alone does not suffice to explain the result of the injec- tions. Starling suggests, therefore, that these extracts act pathologically upon the blood-capillaries, particularly those of the liver, and reuder them more- permeable, so that a greater quantity of concentrated lymph filters through them. Starling's explanation is supported by the experiments of Popoff'.^ According to this observer, if the lymph is collected simulta- neously from the lower portion of the thoracic duct, which conveys the lymph from the abdominal organs, and from the upper part, which contains the lymph from the head, neck, etc., it will be found that injection of peptone increases the flow from only the abdominal organs. PopofP finds also that the peptone causes a dilatation in the intestinal circulation and a marked rise in the portal pressure. At the same time there is some evidence of injury to the walls of the blood-vessels from the occurrence of extravasations in the intestine. As far, therefore, as the action of the lymphagogues of the first class is concerned, it may be said that the advocates of the filtration-and-difFu- sion theory have suggested a plausible explanation in accord with their theory. The facts emphasized by Heidenhain with regard to this class of substances do not compel us to assume a secretory function for the endothelial cells. 4. Injection of certain crystalline substances, such as sugar, NaCl, and other neutral salts, causes a marked increase in the flow of lymph from the thoracic duct. The lymph in these cases is more dilute than normal, and the 1 Jmirmd of Physiology, 1894, vol. xvii. p. 30. ^ Centralblait fiir Phymlogie, 1895, Bd. ix. No. 2. 74 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. blood-plasma also becomes more watery, thus indicating that the increase in water comes from the tissues themselves. Heidenhain designated these bodies as " lymphagogues of the second class." His explanation of their action is that the crystalloid materials introduced into the blood are eliminated by the secretory activity of the endothelial cells, and that they then attract water from the tissue-elements, thus augmenting the flow of lymph. These sub- stances cause but little change in arterial blood-pressure, hence Heidenhain thought that the greater flow of lymph could not be explained by an increased filtration. Starling^ has shown, however, that, although these bodies may not seriously alter general arterial pressure, they may greatly augment intracapil- lary pressure, particularly in the abdominal organs. His explanation of the greater flow of lymph in these cases is as follows : " On their injection into the blood the osmotic pressure of the circulating fluid is largely increased. In consequence of this increase water is attracted from lymph and tissues into the blood by a process of osmosis, until the osmotic pressure of the circulating fluid is restored to normal. A condition of hydrasmic plethora is thereby pro- duced, attended with a rise of pressure in the capillaries generally, especially in those of the abdominal viscera. This rise of pressure will be proportional to the increase in the volume of the blood, and therefore to the osmotic pres- sure of the solutions injected. The rise of capillary pressure causes great increase in the transudation of fluid from the capillaries, and therefore in the lymph-flow from the thoracic duct." This explanation is well supported by experiments, and seems to obviate the necessity of assuming a secretory action on the part of the capillary walls. 5. One of the most interesting facts developed by the experiments of Hei- denhain and his pupils is that after the injection of sugar or neutral salts in the blood the percentage of these substances in the lymph of the thoracic duct may be greater than in the blood itself. It is obviously difficult to explain how this can occur by filtration or diflxision, since it seems to involve the pas- sage of crystalloid bodies from a less concentrated to a more concentrated solu- tion. Cohnstein ^ has endeavored to show a fallacy in these results. Pie con- tends that since it requires some time (several minutes) for the lymph to form and pass into the thoracic duct, it is not justifiable to compare the quantitative composition of specimens of blood and lymph taken at the same time. If one compares, in any given experiment, the maximal percentage in the blood of the substance injected with its maximal percentage in the lymph, the latter will be found to be lower. This, however, does not seem to be the case in all the experiments reported. The work of Mendel ^ with sodium iodide seems to establish the fact that when this salt is injected slowly its maximal percentage in the lymph may exceed that in the blood ; and in the experiments made by Cohnstein, as well as those by Mendel, it is shown that the percentage of the substance in the lymph remains above that in the blood throughout most of the experiment. In this point, therefore, there seems to be a real difficulty in ' Op. cit. ^Archil' fur die gesammie Physiologic, 1894-95, Bde. lix., Ix. and Ixii. ^Journal of Physiology, 1896, vol. xix. p. 227. L YMPH. 75 the direct application of the laws of filtration and diffusion to the explanation of the composition of lymph, but it is a point upon 'ivhich more information is necessary before it alone can be accepted as a basis for a secretion theory, ^leanwhile it seems evident that in spite of the very valuable work of Heidenhain, which has added so much to our knowledge of the conditions influencing the formation of lymph, the existence of a definite secretory activity of the endothelial cells of tlie capillaries has not been proved. Summary of the Factors Controlling- the Flow of Lymph. — "VVe may, therefore, adopt, provisionally at least, the so-called mechanical theory of the origin of lymph. Upon this theory the forces in activity are, first, the intra- capillary pressure tending to filter the plasma through the endothelial cells composing the walls of the capillaries ; second, the force of diffusion depend- ing upon the inequality in chemical composition of the blood-plasma and the liquid outside the capillaries, or, on the other side, between this liquid and the contents of the tissue-elements ; third, the force of osmotic pressure. These three forces acting everywhere control primarily the amount and com- position of the lymph, bnt still another factor must be considered. For when we come to examine the flow of lymph in different parts of the body striking differences are found. ' It hag been shown, for instance, that in the limbs, under normal conditions, the flow is extremely scanty, while from the liver and the intestinal area it is relatively abundant. In fact, the lymph of the thoracic duct may be considered as being derived almost entirely from the latter two regions. Moreover, the lymph from the liver is cliaracterized by a greater percentage of proteids. To account for these difi*erences Starling suggests the plausible explanation of a variation in permeability in the capil- lary walls. The capillaries seem to have a similar structure all over the body so far as this is revealed to us by the microscope, but the fact that the lymph-flow varies so much in quantity and composition indicates that the similarity is only superficial, and that in different organs the capillary -walls may have different internal structures, and therefore different permeabilities. This factor is evidently one of great importance. From the foregoing con- siderations it is evident that changes in capillary pressure, however produced, may alter the flow of lymph from the blood-vessels to the tissues, by increas- ing or decreasing, as the case may be, the amount of filtration ; changes in the composition of the blood, such as follow periods of digestion, will cause diffusion and osmotic streams tending to equalize the composition of blood and lymph ; and changes in the tissues themselves following upon physio- logical or pathological activity will also disturb the equilibrium of composi- tion, and, therefore, set up diffusion and osmotic currents. In this way a continual interchange is taking place by means of which the nutrition of the tissues is effected, each according to its needs. The details of this interchange must of necessity be very complex when we consider the possibilities of local effects in different parts of the body. The total effects of general changes, such as may be produced experimentally, are simpler, and, as we have seen, are explained satisfactorily by the physical and chemical factors enumerated. III. CIRCULATION. PART I.— THE aiECHANICS OF THE CIRCULATION' OF THE BLOOD AND OF THE MOVEMENT OF THE LYMPH. A. Gbneeal Oonsidbbations. The metaphorical phrase " circulation of the blood " means that every par- ticle of blood, so long as it remains within the vessels, moves along a path which, no matter how tortuous, finally returns into itself; that, therefore, the particles which pass a given point of that path may be the same which have passed it many times already ; and that the blood moves in its path always in a definite direction, and never in the reverse. The discoverer of these weighty facts was " William Harvey, physician, of London," as he styled himself. In the lecture notes of the year 1616, mostly in Latin, which contain the earliest record of his discovery, he declares that a "perpetual movement of the blood in a circle is caused by the beat of the heart" ("perpetuum sanguinis motum in circulo fieri pulsu cordis").' For a long time afterward the name of the discoverer was coupled with the expression which he himself had introduced, and the true movement of the blood was known as the "Harveian circulation."^ Course of the Blood. — The metaphorical circle of the blood-path may be shown by such a diagram as Figure 8. If, in the body of a warm-blooded animal, we trace the course of a given particle, beginning at the point where it leaves the right ventricle of the heart, we find that course to be as follows : From the trunk of the pulmonary artery (PA) through a succession of arterial branches derived therefrom into a capil- lary of the lungs (PC) ; out of that, through a succession of pulmonary veins, to one of the main pulmonary veins (PF) and the left auricle of the heart (L^) ; thence to the left ventricle (LV); to the trunk of the aorta (A); through a succession of arterial branches derived therefrom into any capillary (C) not supplied by the pulmonary artery; out of that, through a succession of veins (F) to one of the veuse cavse or to a vein of the heart itself; thence to the right auricle (PA), to the right ventricle (PV), and to the trunk of the pul- monary artery, where the tracing of the circuit began. ' William Harvey: Prelectiones Anatomice Universalis, edited, with an autotype reproduction of the original, by a committee of the Royal College of Physicians of London, 1886, p. 80. ^ Harvey's discovery of the circulation was first published in the modern sense in liis work Exerdtaiio anatomica de motu cordis el sanguinis in animalibus, Francofurti, 1628. This great classic can be read in English in the following : On the Motion of the Heart and' Blood in Animals. By William Harvey, M. D. ; Willis's translation, revised and edited by Alex. Bowie, 1889. 76 CIRCULATION. 77 It must be noted here that a particle of blood which traverses a capillary of the spleen, of the pancreas, of the stomach, or of the intestines, and enters the portal vein, must next traverse a series of venous branches of diminishing size, and a capillary of the liver, before entering the succession of veins which will conduct the particle to the ascending vena cava (compare Figs. 8 and 9). Most of the blood, therefore, which leaves the liver has traversed two sets of capillaries, connected with one another by tlie portal vein, since quit- ting the arterial system. , This ar- FiG. 8.— General diagram of the circulation; the arrows indicate the course of the blood : P A, pulmonary artery ; P C, pulmonary capillaries ; P V, pulmonary veins ; L A, left auricle ; L V, left ventricle : A, systemic arteries ; C, systemic capil- laries ; V, systemic veins ; B A, right auricle ; S V, right ventricle. Fig. 9. — Diagram of the portal system ; the ar- rows indicate the course of the blood: A, arterial system ; V, venous system : C, capillaries of the spleen, pancreas, and alimentary canal; P V, portal vein ; C", capillaries of the liver ; C, the rest of the systemic capillaries. The hepatic artery is not represented. rangement is of extreme importance for the physiology of nutrition. An arrangement of the same order, though less conspicuous, exists in the kidney. Causes of the Blood-flow. — The force by which the blood is driven from the right to the left side of the heart through the capillaries which are related to the respiratory surface of the lungs, is nearly all derived from the contrac- tion of the muscular wall of the right ventricle, which narrows the cavity thereof and ejects the blood contained in it ; the force by which the blood is driven from the left to the right side of the heart through all the other capil- laries of the body, often called the "systemic" capillaries, is derived nearly all from the contraction of the muscular wall of the left ventricle, which nar- rows its cavity and ejects its contents. The contractions of the two ventricles are simultaneous. The force derived from each contraction is generated by the conversion of potential energy, present in the chemical constituents of the muscular tissue, into energy of visible motion ; a part also of the potential energy at the same time becoming manifest as heat. In the maintenance of the circulation the force generated by the heart is to a very subordinate degree supplemented by the forces which produce the aspiration of the chest and by 78 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the force generated by the contractions of the skeletal muscles throughout the body (see p. 95). Mode of "Working' of the Pumping Mechanism. — During each contrac- tion or " systole " of the ventricles the blood is ejected into the arteries only, because at that time the auriculo- ventricular openings are each closed by a valve. During the immediately succeeding " diastole " of the ventricles, which con- sists in the relaxation of their muscular walls and the dilatation of their cavities, blood enters the ventricles by way of the auricles only, because at that time the arterial openings are closed each by a valve which was open during the ventricular systole ; and because the auriculo-ventricular valves which were closed during the systole of the ventricles are open during their diastole. During the first and longer part of the diastole of the ventricles the auricles, too, are in diastole ; the whole heart is in repose ; and blood is not only enter- ing the auricles, but passing directly through them into the ventricles. Near the end of the ventricular diastole a brief simultaneous systole of both auricles takes place, during which they, too, narrow their cavities by the muscular contraction of their walls, and eject into the ventricles blood which had entered the auricles from the " systemic " and pulmonary veins respec- tively. The systole of the auricles ends immediately before that of the ventri- cles begins. The brief systole of the auricles is succeeded by their long dias- tole, which corresponds in time with the whole of the ventricular systole and with the greater part of the succeeding ventricular diastole. During the dias- tole of the auricles blood is entering them out of the veins. Thus it is seen that the direction in which the blood is forced is essentially determined by the mechanism of the valves at the apertures of the ventricles ; and that it is due to these valves that the blood moves only in the definite direction before alluded to. In the words, again, of Harvey's note-book, at this point M'ritten in English, the blood is perpetually transferred through the lungs into the aorta " as by two clacks of a water bellows to rayse water."' Pulmonary Blood-path. — In the birds and mammals the entire breadth of the blood-path, at one part of the physiological circle, consists in the capillaries spread out beneath the respiratory surface of the lungs. The right side of the heart exists only to force the blood into and past this portion of its circuit, where, as in the systemic capillaries, the friction due to the fineness of the tubes causes much resistance to the flow. This great comparative development of the pulmonary portion of the blood-path in the warm-blooded vertebrates is related to the activity, in them, of the respiration of the tissues, which calls for a cor- responding activity of function at the respiratory surface of the lungs, and for a rapid renewal in every systemic capillary of the internal respiratory medium, the blood. This rapid renewal implies a rapid circulation ; and that the speed is great with which the circuit of the heart and vessels is completed has been proven by experiment, the method being too complicated for description here.^ ' Prelecliones, etc., p. 80. ^ Karl Vierordt : Die Erscheinungen und Gesetze der Stromgeschwindigkeilen des Blules. 2te Ausgabe, 1882. CIRCULATION. 79 Rapidity of the Circulation. — By experiment the shortest time has been measured which is taken by a particle of blood in passing from a point in the •external jugular vein of a dog to and through the right cavities of the heart, the pulmonary vessels, the left cavities of the heart, the commencement of the aorta, and the arteries, capillaries, and veins of the head, to the starting- point, or to the same point of the vein of the other side. This time has been found to be from fifteen to eighteen seconds. Naturally, the time would be different in different kinds of animals and in the different circuits in the «ame individual. Order of Study of the Mechanics of the Circulation. — The significance and the fundamental facts of the circulation have now been indicated. Its phenomena must next be studied in detail.' As the blood moves in a circle, we may, in order to study the movement, strike into the circle at any point. It will, however be found both logical and instructive to study first the move- ment of the blood in the capillarie.s, whether systemic or pulmonary. It is ■only in passing through these and the minute arteries and veins adjoining that the blood fulfils its essential functions ; elsewhere it is in transit merely. Moreover, it is only in the minute vessels that the blood and the nature of its movement are actually visible. After the capillary flow shall have become familiar, it will be found that the other phenomena of the circulation will fall naturally into place as indi- cating how that flow is caused, is varied, and is regulated. B. The Movement of the Blood in the Capillabies and in the Minute Abtebies and Veins. Characters of the Capillaries, — Each of the vessels which compose the '-mmensely multiplied capillary network of the body is a tube, commonly of less than one millimeter in length, and of a few one-thousandths only of a millimeter in calibre, the wall of which is so thin as to elude accurate measure- FiG. 10.— A capUlary from the mesentery of the frog (Ranvier). ment. The calibre of each capillary may vary from time to time. These facts indicate the minute subdivision of the blood-stream in the lungs, and among the tissues — that is, at the two points of its course where the essential functions of the blood are fulfilled. These facts also show the shortness of ' The following is a very valuable book of reference : Eobert Tigerstedt : Lehrbuch der Physiologie des Kreislaufes, 1893. 80 ^l.Y AMERICAN TEXT-BOOK OF PHYSIOLOGY. the distance to be traversed by the blood while fulfilliDg these fuuctions;; and explain the importance of the comparatively slow rate at which it will be found to move through that short distance. The histological study of a typ- ical capillary (see Fig. 10) shows that its thin wall is composed of a single layer only of living flat endothelial cells set edge to edge in close contact ; and that the edges of the cells are united by a small quantity of the so-called cement-substance. If the capillary be traced in either anatomical direction, the wall of the vessel is seen to become less thin and more complex, till it merges into that of a typical arteriole or venule, the walls of which are still delicate, though less so than that of a capillary. That the capillary walls are so thin and soft, and are made of living cells, are very important facts as regards the relations between blood and tissue. It is of great importance for the variation of the blood-supply to a part that they are also distensible, elastic, and possibly contractile. Direct Observation of the Plow in the Small Vessels. — The capillary flow is visible under the compound microscope, best by transmitted light, in the transparent parts of both warm-blooded and cold-blooded animals. It is important that the jihenomena observed in the latter should be compared with observations upon the higher animals ; but the fundamental facts can be most fruitfully studied in the frog, tadpole, or fish, inasmuch as no special arrange- ments are needed to maintain the temperature of the exposed parts of these animals. Moreover, their large oval and nucleated red blood-corpuscles are well fitted to indicate the forces to which they are subjected. The capillary movement, therefore, will be described as seen in the frog ; it being under- stood that the phenomena are similar in the other vertebrates. In the frog the movement may be studied in the lung, the mesentery, the urinary bladder, the tongue, or the web between the toes. During such study the proper wall of the living capillary is hardly to be seen, but only the line on each side which marks the profile of its cavity. Even the proper walls of the transparent arterioles and venules are but vaguely indicated. The plasma of the blood, too, has so nearly the same index of refraction as the tissues, that it remains invisible. It is only the red corpuscles and leucocytes that are conspicuous ; and when one speaks of seeing the blood in motion, he means, strictly speaking, that he sees the moving corpuscles, and can make out the calibre of the vessels in which they move. The observer uses as low a power of the microscope as will suffice, and takes first a general survey of the minute arteries, veins, and capillaries of the part he is studying, noting their form, size, and connections. In the arteries and veins he sees that the size of the vessels is ample in comparison with that of the corpuscles ; that, in the veins, the movement of the blood is steady, but. in the arteries accelerated and retarded, with a rhythm corresponding to that of the heart's beat. In some parts, if the circumstances of the observation have somewhat retarded the circulation, the individual red corpuscles can be distinguished in the veins, while in the arteries they cannot, as at all times they shoot past the eye too swift))'. The fundamental observation now is verified that the blood is incessantly moving out of the arteries, through the capillaries, into the veins.. CIRCULATION. 81 Behavior of the Red Corpuscles. — Capillaries will readily be found iu which the red corpuscles move two or three abreast, or only in single file. They generally go with their long diameters parallel to, or moderately oblique to, the current. In no case will any blockade of corpuscles occur, so long as the parts are normal. The numerous red corpuscles are seen to be well fitted by their softness and elasticity, as well as by their form and size, for moving through the narrow channels. They bend easily upon themselves as they turn sharp corners, but instantly regain their form when free to do so (see Fig. 11). A very common occurrence is for a corpuscle to catch upon the edge which parts two capillaries at a bifurcation of the network. For some time the corpuscle may remain doubled over the projection like a sack thrown acro.ss a horse's back ; but, after oscillating for a while, it will be disengaged, at once return to its own shape, and disappear in one of the two branches Fig. 11.— To illustrate the behavior of red cor- puscles in the capillaries : the arrows mark the course of the blood: a, a "saddle-bag" corpus- cle; 6, a corpuscle bending upon itself as it enters a side branch. Fig. 12.— To illustrate the deformity pro- duced in red corpuscles in passing through a capillary of a less diameter than them- selves. (see Fig. 11). It is instructive to watch red corpuscles passing in single file through a capillary the calibre of which, at the time, is actually less than the shorter diameter of the corpuscles. Through such a capillary each corpuscle is squeezed, with lengthening and narrowing of its soft mass, but on emerging into a larger vessel its elasticity at once corrects even this deformity ; it regains its form, and passes on (Fig. 1 2). Evidences of Friction. — In the minute vessels, capillary and other, cer- tain appearances should carefully be observed which are the direct ocular evidence of that friction which we shall find to be one of the prime forces concerned in the blood-movement, to which it constitutes a strong resistance. If, in a channel which admits three red corpuscles beside one another, three be observed when just abreast, it will be found that very soon the middle one forges ahead, indicating that the stream is swiftest at its core. This is because the friction within the vessel is least in the middle, and progressively greater outward to the wall (Fig. 13). In the small veins the signs of friction are Vol. I.— 6 82 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. strikingly seen, as the outer layers among the numerous corpuscles lag con- spicuously. In the arterioles similar phenomena are seen if the normal swift- ness of movement become sufficiently retarded for the individual corpuscles to be visible. Fig. 13.— To iUustrate the forging ahead of a Fig. 14.— The inert layer of plasma in the corpuscle at the centre of the blood-stream. small vessels. The arrow marks the direction of the blood. An appearance which also tells of friction is that of the so-called " inert layer " of plasma.' In vessels, of whatever kind, which are wide enough for several corpuscles to pass abreast, it is seen that all the red corpuscles are always separated from the profile of their channel by a narrow clear and colorless interval — occupied, of course, by plasma. This is caused by the excess of the friction in tlie layers nearest to the vascular wall (see Fig. 14). The friction thus indicated, other things being equal, is less in a dilated than in a con- tracted tube ; and less in a sluggish than in a rapid stream. It probably varies also with changes of an unknown kind in the condition of the cells of the vascular wall. Behavior of the Leucocytes. — If the behavior of the leucocytes be watched, it will be seen to differ markedly from that of the red corpuscles, at least when the blood-stream is somewhat retarded, as it so commonly is under the microscope. Whereas the friction within the vessels causes the throng of red corpuscles to occupy the core of the stream, the scantier leucocytes may move mainly in contact with the wall, and thus be present freely in the inert layer of plasma. Naturally their progression is then much slower and more irregular than that of the red disks. Indeed, the leucocytes often adhere to the wall for a while, in spite of shocks from the red cells which pass them. Moreover, the spheroidal leucocyte rolls over and over as it moves along the wall in a way very different from the progression of the red di.sk, which only occasionally may revolve about one of its diameters. A leucocyte entangled among the red cells near the middle of the stream is seen generally not only to move onward but also to move outward toward the wall, and, before long, to join the other leucocytes which are bathed by the inert layer of plasma. It is due solely to the lighter specific gravity of the leucocytes that, under the forces at work within the smaller vessels, they go to the wall, while the denser disks go to the core of the current. This has been proved experimen- tally by driving through artificial capillaries a fluid having in suspension par- ticles of two kinds. Those of the lighter kind go to the wall, of the heavier ' Poiseuille: "Kecherches sur les causes dii mouvement du sang dans les vaisseaux capil- laires," Academie des Sciences — Savans etrangers, 1835. CIRCULATION. 83 kind to the core, even when the nature and form of the particles employed are varied.' Emigration of Leucocytes. — It has been said that a leucocyte may often adhere for a time to the wall of the capillary, or of the arteriole or venule, in which it is. Sometimes the leucocyte not only adheres to the wall, but passes through it into the tissue without by a process which has received the name of "emigration."^ A minute projection from the protoplasm of the leucocyte is thrust into the wall, usually where this consists of the soft cement- substance between the endothelial cells. The delicate pseudopod is seen pres- ently to have pierced the wall, to have grown at the expense of the main body of the cell, and to have become knobbed at the free end which is in the tissue. Later, the flowing of the protoplasm will have caused the leucocyte to assume something of a dumb-bell form, with one end within the blood-vessel and the other without. Then, by converse changes, the flowing protoplasm comes to lie mainly within the lymph-space, with a small knob only within the vessel ; and, lastly, this knob too flows out ; what had been the neck of the dumb-bell shrinks and is withdrawn into the cell-body, and the leucocyte now lies wholly without the blood-vessel, while the minute breach in the soft wall has closed behind the retiring pseudopod. This phenomenon has been seen in capillaries, venules, and arterioles, but mainly in the two former. It seems to be due to the amoeboid properties of the leucocytes as well as to purely physical causes. Emigration, although it may probably occur in normal vessels, is strikingly seen in inflammation, in which there seems to be an increased adhesiveness between the vascular wall and the various corpuscles of the blood. Speed of the Blood in the Minute Vessels. — As a measui-e of the speed of the blood in a vessel, we may fairly take the speed of the red corpuscles. It must, however, be remembered that as the friction increases toward the wall, the speed of the red corpuscles is least in the outer layers of blood, and in- creases rapidly toward the long axis of the tube. At the core of the stream the speed may be twice as great as near the wall. As we have seen, the stream of red corpuscles in an arteriole is rapid and pulsating. In the corresponding venule, which is commonly a wider vessel, the stream is less swift, and its pulse has dis- appeared. In the capillary network between the two vessels the speed of the red corpuscles is evidently slower than in either arteriole or venule ; and here, as in the veins, no pulse is to be seen ; the pulse comes to an end with the artery which exhibits it. In one capillary of the network under observation the movement may be more active than in another ; and even in a given capillary irregular variations of speed at different moments may be observed. Where two capillaries in which the pressure is nearly the same are connected by a cross-branch, the red corpuscles in this last may sometimes even be seen to 'A. Schklarewsky : "Ueber das Blut und die Suspensionsfliissigkeiten," Pfiilger's Archivfiir die gesammte Physioloyie, 1868, Bd. i. S. 603. ^ For the literature of emigration see E. Tlioma : Text-book of General Pathology and Patho- logical Anatomy, translated by A. Bruce, 1896, vol. i. p. 344. 84 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. oscillate, come to a standstill, and then reverse the dii-eetion of their move- ment, and return to the capillary whence they had started. Naturally, no such reversal will ever be seen in a capillary which springs directly from an artery or which directly joins a vein. It will be remembered, however, that any apparent speed of a corpuscle is much magnified by the microscope, and that therefore the variations referred to are comparatively unimportant. We may, in fact, without material error, treat the speed of the blood in the capil- laries which intervene between the arteries and veins of a region as approxi- mately uniform for an ordinary period of observation, as the minute varia- tions will tend to compensate for one another. This speed is sluggish, as already noted. In the capillaries of the web of the frog's foot it has been found to be about 0.5 millimeter per second. The causes of this sluggishness will be set forth later. That the very short distance between artery and vein is traversed slowly, deserves to be insisted on, as thus time is afforded for the uses of the blood to be fulfilled. Capillary Blood-pressure. — The pressure of the blood against the capil- lary wall is low, though higher than that of the lymph without. This pres- sure is subject to changes, and is readily yielded to by the elastic and deli- cate wall. From these changes of pressure changes of calibre result. The microscope tells us less about the capillary blood-pressure than about the other phenomena of the flow ; but the microscope may sometimes show one striking fact. In a capillary district under observation, a capillary not noted before may suddenly start into view as if newly formed under the eye. This is because its calibre lias been too small for red corpuscles and leucocytes to enter, until some slight increase of pressure has dilated the transparent tube, hitherto filled with transparent plasma only. This dilatation has admitted corpuscles, and has caused the vessel to appear. That the capillary pressure is low is shown, moreover, by the fact that when one's finger is firicked or slightly cut, the blood simply drips away ; that it does not spring in a jet, as when an artery of any size has been divided. That the capillary pressure is low may also be shown, and more accurately, by the careful scientific application of a familiar fact: If one press with a blunt lead-pencil upon the skin between the base of a finger-nail and the neigh- boring joint, the ruddy surface becomes pale, because the blood is expelled from the capillaries and they are flattened. If delicate weights be used, instead of the pencil, the force can be measured which just suffices to whiten the surface somewhat, that is, to counterbalance the pressure of the distend- ing blood, which pressure thus can be measured approximately. It has been found to be very much lower than the pressure in the large arteries, con- siderably higher than that in the large veins, and thus intermediate between the two; whereas the blood-speed in the capillaries is less than the speed in either the arteries or the veins. The pressure in the capillaries, meas- ured by the method just described, has been found to be equal to that required to sustain against gravity a column of mercury from 24 to 54 milli- CIB C ULA TION. 8 5 meters high ; or, in the parlance of the laboratory, has been found equal to from 24 to 54 millimeters of mercury.' Summary of the Capillary Flow. — Whether in the lungs or in the rest of the body, the general characters of the capillary flow, as learned from direct iuspection and from experiment, may be summed up as follows : The blood moves through the capillaries toward the veins with much friction, contin- uously, slowly, without pulse, and under low pressure. To account for these facts is to deal systematically with the mechanics of the circulation ; and to that task we must now address ourselves. C. The Pressure of the Blood in the Arteries, Capillaries, and Veins. Why does the blood move continuously out of the arteries through the capillaries into the veins ? Because there is continuously a high pressure of blood in the arteries and a low pressure in the veins, and from the seat of high to that of low pressure the blood must continuously flow through the capillaries, where pressure is intermediate, as already stated. Method of Stud3dng Arterial and Venous Pressure, and General Results. — Before stating quantitatively the differences of pressure, we must see how they are ascertained for the arteries and veins. The method of obtain- ing the capillary pressure has been referred to already. If, in the neck of a mammal, the left common carotid artery be clamped in two places, it can, without loss of blood, be divided between the clamps, and a long straight glass tube, open at both ends, and of small calibre, can be tied into that stump of the artery which is still connected with the aorta, and which is called the "proximal" stump. If now the glass tube be held upright, and the clamp be taken off which has hitherto closed the artery between the tube and the aorta, the blood will mount in the tube, which is open at the top, to a consid- erable height, and will remain there. The external jugular vein of the other side should have been treated in the same way, but its tube should have been inserted into the " distal " stump — that is, the stump connected with the veins of the head, and not with the subclavian veins. If the clamp between the tube and the head have been removed at nearly the same time with that upon the artery, the blood may have mounted in the upright venous tube also, but only to a small distance. To cite an actual case in illustration, in a small etherized dog the arterial blood-column has been seen to stand at a height of about 155 centimeters above the level of the aorta, the height of the venous column about 18 centimeters above the same level. The heights of the arterial and venous columns of blood measure the pressures obtaining within the aorta and the veins of the head respectively, while at the same time the circulation con- tinues to be free through both the aorta and the venous network. Therefore, in the dog above referred to, the aortic pressure was between eight and nine ' N. V. Kries : " Ueber den Druck in den Bliitcapillaren der menschlichen Haut," Berichte Uber die Verhandlungen der k. sachsischen Oesellschafl der Wissemehaften zu Leipzig, math.-physische Classe, 1875, S. 149. 86 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. times as great as that in the smaller veins of the head. As, during such an experiment, the blood is free to pass from the aorta through one carotid and both vertebral arteries to the head, and to return through all the veins of that part, except one external jugular, to the vena cava, it is demonstrated that there must be a continuous flow from the aorta, through the capillaries of the head, into the veins, because the pressure in the aorta is many times as great as the pressure in the veins. Obviously, such an experiment, although very instructive, gives only roughly qualitative results. Two things will be noted, moreover, in such an experiment. One is that the venous column is steady ; the other is that the arterial column is perpetu- ally fluctuating in a rhythmic manner. The top of the arterial column shows a regular rise and fall of perhaps a iew centimeters, the rhythm of which is the same as that of the breathing of the animal ; and, while the surface is thus rising and falling, it is also the seat of frequent flickering fluctuations of smaller extent, the rhythm of which is regular, and agrees with that of the heart's beat. At no time, however, do the respiratory fluctuations of the arte- rial column amount to more than a fraction of its mean height ; compared to which last, again, the cardiac fluctuations are still smaller. It is clear, then, that the aortic pressure changes with the movements of the chest, and with the systoles and diastoles of the left ventricle. But stress is laid at present upon the fact that the aortic pressure at its lowest is several times as high as the pressure in the smaller veins of the head. Therefore, the occurrence of incessant fluctuations in the aortic pressure cannot prevent the continuous movement of the blood out of the arteries, through the capillaries, into the veins. The upright tubes employed in the foregoing experiment are called " man- ometers." ^ They were first applied to the measurement of the arterial and venous blood-pressures by a clergyman of the Church of England, Stephen Hales, rector of Farringdou in Hampshire, who experimented with them upon the horse first, and afterward upon other mammals. He published his method and results in 1733.^ The height of the manometric column is a true measure of the pressure which sustains it ; for the force derived from gravity with which the blood in the tube presses downward at its lower open- ing is exactly equal to the force with which the blood in the artery or vein is pressed upward at the same opening. The downward force exerted by the column of blood varies directly with the height of the column, but, by the laws of fluid pressure, does not vary with the calibre of the manometer, which cali- bre may therefore be settled on other grounds. It follows also that the arterial and venous manometers need not be of the same calibre. Were, however another fluid than the blood itself used in the manometer to measure a given intravascular pressure, as is easily possible, the height of the column would differ from that of the column of blood. For a given pressure the height 1 From liavdg, rare. The name was given from such tubes being used to measure the tension of gases. ^ Stephen Hales : Statical Essays: containing Hcemastaticks, etc., London, 1733, vol. ii. p. 1. CIRCULATION. 87 of the column is inverse to the density of the manometric fluid. For example, a given pressure will sustain a far taller column of blood than of mercury. The Mercurial Manometer. — The method of Hales, in its orig- inal simplicity, is valuable from that very simplicity for demonstra- tion, but not for research. The clotting of the blood soon ends the experiment, and, while it continues, the tallness of the tube required for the artery, and the height of the column of blood, are very incon- venient. It is essential to under- stand next the principles of the more exact instruments employed in the modern laboratory. In 1828 the French physician and physiologist J. L. M. Poiseuille devised means both of keeping the blood from clotting in the tubes, and of using as a measuring fluid the heavy mercury instead of the much lighter blood. He thereby secured a long observation, a low column, and a manageable man- ometer.^ The "mercurial man- ometer " of to-day is that of Poi- ^"'- IS-magram of the recording mercurial man- •' _ _ ometer and the kymograph ; the mercury is indicated in Seuille, though modified (see Fig. deepWacktl/, the manometer, connected by the leaden 1 K\ T_ „ * J ^ 'i. pipe, L, with a glass cannula tied into the proximal 15). In an improved form it con- ^^^ •, ^^^ ieft%ommon carotid artery of a dog ; A, sistS of a glass tube open at both the aorta; C, the stop-cock, by opening which the man- ometer may he made to communicate through BT, the rubber tube, with a pressure-bottle of solution of sodium carbonate ; i?, the float of ivory and hard rubber ; S, the light steel rod, kept perpendicular by B, the steel bear- ing ; P, the glass capillary pen charged with quickly dry- ing ink ; T, a thread which is caused, by the weight of a light ring of metal suspended from It, to press the pen the U, it will fill both branches to obliquely and gently against the paper with which is an eonal heiVht Tf fluid be dri vpn ""^''^'^ -^' ^^^ ^™ss ■' drum " of the kymograph, which an equal neignt. ir nuia oe ariven ^^^^ reyoiyes m the direction of the arrow. The sup- down upon the mercury in one P^^s of the manometer and the body and clock-work 1 1 iiy uv f fU f u "x of the kymograph are omitted for the sake of simplicity. Orancn or limO OI tne tube, it The aorta and its branches are drawn disproportionately will drive some of the mercury out '"k^ ^°^ *h® ^^^^ °f clearness. of that limb into the other, and the two surfaces of the mercury may come to rest at very unequal levels. The difference of level, expressed in millimeters, ' J. L. M. Poiseuille: Becherches mr la force du cceut- aoriique, Paris, 1828. ends, and bent upon itself to the shape of the letter U. This is held upright by an iron frame. If mer- cury be poured into one branch of 88 AJV AMERICAN TEXT-BOOK OF PHYSIOLOGY. measures the height of the mauometric column of mercury the downward pres- sure of which in one limb of the tube is just equal to the downward pressure of the fluid in the other. In order to adapt this " U-tube " to the study of the blood-pressure, that limb of the tube which is to communicate with the artery or vein is capped with a cock which can be closed. Into this same limb, a little way below the cock, opens at right angles a short straight glass tube, which is to communicate with the blood-vessel through a long flexible tube of lead, sup- ported by the iron frame, and a short glass cannula tied into the blood-vessel itself. Two short pieces of india-i-ubber tube join the lead tube to the manometer and the cannula. Before the blood-vessel is connected with the manometer, the latter is filled with fluid between the surface of the mercury next the blood- vessel and the outer end of the lead tube, which fluid is such that when mixed with blood it prevents or greatly retards coagulation. With this same fluid the glass cannula in the blood-vessel is also filled, and then this cannula and the lead tube are connected. The cock at the upper end of the " proximal limb " of the manometer is to facilitate this filling, being connected by a rub- ber tube with a " pressure bottle," and is closed when the filling has been accomplished. The fluid introduced by Poiseuille and still generally used is a strong watery solution of sodium carbonate. A solution of magnesium sul- phate is also good. If, in injecting this fluid, the column of mercury in the "distal limb" is brought to about the height which is expected to indicate the blood-pressure, but little blood will escape from the blood-vessel when the clamp is taken from it, and coagulation may not set in for a long time. The Recording Mercurial Manometer and the Graphic Method. — When the arterial pressure is under observation, the combined respiratory and cardiac fluctuations of the mercurial column are so complex and fre- quent that it is very hard to read oif their course accurately even with the help of a millimeter-scale placed beside the tube. In 1847 this difficulty led the German physiologist Carl Ludwig to convert the mercurial manometer into a self-registering instrument. This invention marked an epoch not merely in the investigation of the circulation, but in the whole science of physiology, by beginning the present "graphic method" of physiological work, which has led to an immense advance of knowledge in many depart- ments. Ludwig devised the " recording manometer " by placing upon the mercury in the distal air-containing limb of Poiseuille's instrument an ivory float, bearing a light, stiff", vertical rod (see Fig. 15). Any fluctuation of the mercurial column caused float and rod to rise and fall like a piston. The rod projected well above the manometer, at the mouth of which a delicate bear- ing was provided to keep the motion of the rod vertical. A very delicate pen placed horizontally was fastened at right angles to the upper end of the rod. If a firm vertical surface, covered with paper, were now placed lightly in contact with the pen, a rise of the mercury would cause a corresponding vertical line to be marked upon the paper, and a succeeding fall would cause the descending pen to inscribe a second line covering the first. If now the vertical surface were made to move past the pen at a uniform rate, CIRCULATION. .s9 the successive up-and-down movements of the mercury would no longer be marked over and over again in the same place so as to produce a single ver- tical line. The space and time taken up by each fluctuation would be graph- ically recorded in the form of a curve, itself a portion of a continuous trace marked by the successive fluctuations ; thus both the respiratory and cardiac fluctuations could be registered throughout an observation by a single complex curving line. Ludwig stretched his paper around a vertical hollow cylinder of brass, made to revolve at a regular known rate by means of clock-work, and the conditions above indicated were satisfied ^ (see Fig. 15). Upon the surface of such a cylinder vertical distance represents space, and a vertical line ■of measurement is called, by an application of the language of mathematics, an " ordinate ; " horizontal distance represents time, and a horizontal line of measurement is called an " abscissa." The curve marked by the events re- corded is always a mixed record of space and time. The instrument itself, the essential part of which is the regularly revolving cylinder, is called the "kymograph."^ It has undergone many changes, and many varieties of it are in use. Any motor may be used to drive the cylinder, provided that the speed of the latter be uniform and suitable. The curve written by the manometer or other recording instrument may either be marked upon paper with ink, as in Ludwig's earliest work ; or may be marked with a needle or some other fine pointed thing upon paper black- p B L T Fig. 16.— The trace of arterial blood-pressure from a dog anaesthetized with morphia and ether. The cannula was in the proximal stump of the common carotid artery. The curve is to be read from left to right. P, the pressure-trace written by the recording mercurial manometer ; B L, the base-line or abscissa, representing the pressure of the atmosphere. The distance between the base-line and the pressure-curve varies, in the original trace, between 62 and 77 millimeters, there- fore the pressure varies between 124 and 154 millimeters of mercury, less a small correction for the weight of the sodium-carbonate solution ; T, the time-trace, made up of intervals of two seconds each, and written by an electro-mag- netic chronograph. ened with soot over a flame. The trace written upon smoked paper is the more delicate. After the trace has been written, the smoked paper is removed from the kymograph and passed through a pan of shellac varnish. This ' C. Ludwig: "Beitrage zur Kenntniss des Einflusses der Eespirationsbewegungen auf den Blutlauf im Aortensysteme," Mailer's Archiv fur Anatomie, Physiologie, und wissenschaftliche Medicin, etc., 1847, S. 242. ' From Kv/ia, a wave. 90 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. when dry fixes the trace, which thereafter will not be spoiled by handling. In Figure 16 the uppermost line shows a trace which fairly represents the successive fluctuations of the aortic pressure of the dog. The longer and ampler fluctuations are respiratory, the briefer and slighter are cardiac. In each respiratory curve the lowest point and the succeeding ascent coincide with inspiration; the highest point and the succeeding descent with expiration. The horizontal middle line is the base line, representing the pressure of the atmosphere. The base-line has been shifted upward in the figure simply m order to save room on the page. In the lowermost line the successive spaces from left to right of the reader represent successive intervals of time of two seconds each, written by an electro-magnetic chronograph. The pressure-trace taken from a vein may in certaiu regions near the chest show respiratory fluc- tuations, but nowhere cardiac ones, as the pulse is not transmitted to the veins. The venous pressure is so small, that for the practical study of it a recording manometer must be used in which some lighter flaid replaces the mercury,, which would give a column of insufficient height for working purposes. The values obtained are then reduced by calculation to millimeters of mercury, for comparison with the arterial pressure. The intravascular pressure at a given moment can be measured by measuring a vertical line or " ordinate " drawn from the curve written by the manometer to the horizontal base-line. The- latter represents the height of the manometric column when just disconnected from the blood-vessel ; that is, when acted ujion only by the weight of the atmosphere and of the solution of sodium carbonate. To ascertain the blood- pressure, the length of the line thus measured must be doubled ; because the mercury in the proximal limb of the manometer sinks under the blood-pres- sure exactly as much as the float rises in the distal limb. A small correction, must also be made for the weight of the solution of sodium carbonate. The Mean Pressure. — The " mean pressure " is the average pressure dur- ing whatever length of time the observer chooses. The mean pressure for the given time is ascertained from the manometric trace by measurements too. complicated to be explained here. As the weight and consequent inertia of the mercury cause it to fluctuate according to circumstances more or less than the pressure, the mean pressure is much more accurately obtained from the mercurial manometer than is the true height of each fluctuation, which is very commonly written too small. Therefore, it is especially the mean pressure that is studied by means of the mercurial manometer. The true extent and finer characters of the single fluctuations caused by the heart's beat are better studied with other instruments, as we shall see in dealing with the pulse. It has been seen that the blood flows continuously through the capillaries because the pressure is continually high in the arteries and low in the veins. The reader is now in position to understand statements of the blood-pressure- expressed in millimeters of mercury. The mean aortic pressure in the dog is far from being always the same even in the same animal. AVe have found it, in the case referred to on page 85, to be equivaleut to about 121 millimeters of mercury. It will very commonly be found higher than this, and may range CIRCULATION. 91 up to, or above, 200 millimeters. lo man it is probably higher than in the dog. The pressure in the other arteries derived from the aorta which have been studied manometrically is not very greatly lower than in that vessel. In the pulmonary arteries the pressure is probably much lower than in the aortic system. The pressure in the small veins of the head of the dog, the cannula being in the distal stump of the external jugular vein, we have found already in one case to equal about 14 millimeters of mercury. In such a case the presence of valves in the veins and other elements of difficulty make the mean pressure hard to obtain as opposed to the maximum pressure during the period of observation. If a cannula be so inserted as to transmit the pressure obtaining within the great veins of the neck just at the entrance of the chest, without interfer- ing with the movement of the blood through them, and if a manometer be connected with this cannula, the fluid will fall below the zero-point in the distal limb, indicating a slight suction from within the vein, and thus a slightly " negative " pressure.* This negative pressure may sometimes become more pronounced during inspiration and regain its former value during ex- piration. Sometimes, again, the pressure during expiration may become posi- tive. The continuous flow from the great arteries through the capillaries to the veins, and through these to the auricle, is therefore shown by careful quantitative methods, no less than by the tube of Hales, to be simply a case of movement of a fluid from seats of high to seats of lower pressure. The Symptoms of Bleeding- in Relation to Blood-pressure. — The dif- ferences of pressure revealed scientifically by the manometer exhibit them- selves in a very important practical way when blood-vessels are wounded and bleeding occurs. If an artery be cleanly cut, the high pressure within /drives out the blood in a long jet, the length of which varies rhythmically with the cardiac pulse, but varies only to a moderate degree. From wounded capil- laries, or from a wounded vein, owing to the low pressure, the blood does not spring in a jet, but simply flows out over the surface and drips away without pulsation. At the root of the neck, where the venous pressure may rhythmi- cally fall below and rise above the atmospheric pressure, the bleeding from a wounded vein may be intermittent. D. The Causes op the Pressure in the Arteries, Capillaries, AND Veins. The causes of the continuous high pressure in the arteries must first engage our attention. Resistance. — The great ramification of the arterial system at a distance from the heart culminates in the formation of the countless arterioles on the confines of the capillary system. We have already seen direct evidence of the friction in the minute vessels which results from this enormous subdivision of the blood-path. The force resulting from this friction is propagated back- ' H. Jacobson : " Ueber die Blutbewegnng in den Venen," Meicherfs und du Bois-Rey- mond's Archiv fiir Anatomic, Physiologie, etc., 1867, S. 224. 92 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ward according to the laws of fluid pressure, and constitutes a strong resist- ance to the onward movement of the blood out of the heart itself. Friction is everywhere present in the vessels, but is greatest in the very small ones collectively. Power.— Where the aorta springs from the heart, the rhythmic contrac- tions of the left ventricle force open the arterial valve, and force intermittent charges of blood into the arterial system, overcoming thus the opposing force derived from friction. The wall of the arterial system is very elastic every- where. Thus the high pressure in the arteries results from the interaction of the power derived from the heart's beat and the resistance derived from fric- tion. That the high pi-essure is continuous depends upon the capacity for distention possessed by the elastic arterial wall. Balance of the Pactors of the Arterial Pressure. — In order to study the causation of the arterial pressure, let us imagine that it has for some reason sunk very low ; but that, at the moment of observation, a normally beating heart is injecting a normal blood-charge into the aorta. The first injection would find the resistance of friction present, and the elastic arterial wall but little distended. For this injection some room would be made by the displacement of blood into the capillaries. But it would be easier for the arterial wall to yield than for the friction to be overcome, so the injected blood would largely be stored within the arterial system and thus raise the pressure. Succeeding injections would have similar results ; it would continue to be easier for the injected blood to distend the arteries than to escape from them ; and the arterial pressure would rise rapidly toward its normal height. Presently, however, a limit would be reached ; a time would come when the elastic wall, already well stretched, would have become tenser and stiffer and would yield less readily before the entering blood ; and now a larger part than before of each successive charge of blood would be accommodated by the displacement of an equivalent quantity into the capillaries, and a smaller part by the yielding of the arterial wall. Normal conditions of pressure would be reached and maintained when the blood accommodated, during each systole of the ventricle, by the yielding of the arterial wall should exactly equal in amount the blood discharged from the arteries into the capillaries during each ventricular diastole ; for then the quantity of blood parted with by the arteries during both the systole and the diastole of the heart would be exactly the same as that received during its systole alone. We see that, at each cardiac systole, the cardiac muscle does work in main- taining the capillary flow against friction, and also does work upon the arte- rial wall in expanding it. A portion of the manifest energy of the heart's beat thus becomes potential in the stretched elastic fibres of the artery. The moment that the work of expansion ceases, the stretched elastic fibres recoil ; their potential energy, just received from the heart, becomes manifest, and work is done in maintaining the capillary flow against friction during the repose of the cardiac muscle. At the beginning of this repose the arterial valves have been closed by the arterial recoil. When, at each cardiac systole, CIBCULATION. 93 the arterial wall expands before the entering blood, the pressure rises, for more blood is entering the arterial system than is leaving it ; when, at each cardiac diastole, the arterial wall recoils, the pressure falls, for blood is leaving the arterial system, and none is entering it. But before the fall has had time to become pronounced, while the arterial pressure is still high, the cardiac sys- tole recurs, and the pressure rises again, as at the preceding fluctuation. The Arterial Pulse. — The increased arterial pressure and amplitude at the cardiac systole, followed by diminished pressure and amplitude at the cardiac diastole, constitute the main phenomena of the arterial pulse. They are marked in the manometric trace by those lesser rhythmic fluctuations of the mercury which correspond with the heart-beats. The causes of the arte- rial pulse have just been indicated in dealing with the causes of the arterial pressure. The pulse, in some of its details, will be studied further for itself in a later chapter. For the sake of simplicity, the respiratory fluctuations of the arterial pressure have not been dealt with in the discussion just con- cluded. The causes of these important fluctuations are very complex and are treated of under the head of Respiration. The arterial pressure, then, results from the volume and frequency of the injections of blood made by the heart's contraction ; from the friction in the vessels ; and from the elasticity of the arterial wall. The Capillary Pressure and its Causes. — When we studied the move- ment of the blood in the capillaries, we found the pressure in them to be low and free from rhythmic fluctuations. In both of these qualities the capillary pressure is in sharp contrast with the arterial. What is the reason of the differ- ence ? The work of driving the blood through as well as into the capillaries is done during the contraction of the heart's wall by its kinetic energy. During the repose of the heart's wall and the arterial recoil this work is continued by kinetic energy derived, as we have seen, from the preceding cardiac contraction. The work of producing the capillary flow is done in overcoming the resistance of friction. The capillary walls are elastic. The same three factors, then — the power of the heart, the resistance of friction, the elasticity of the wall — which produce the arterial pressure produce the capillary pressure also. Why is the capillary pressure normally low and pulseless? The answer is not difficult. The friction which must be overcome in order to propel the blood out of the capillaries into the wider venous branches is only a part of the total friction which opposes the admission of the blood to the minuter vessels. The resistance is therefore diminished which the blood has yet to encounter after it has actually entered the capillaries. The force which propels the blood through the capillaries, although amply sufficient, is greatly less than the force which propels it into and through the larger arteries. In both cases alike the force is that of the heart's beat. But, in overcoming the friction which resists the entrance of the blood into the capillaries, a large amount of the kinetic energy derived from the heart has become converted into heat. The power is therefore diminished. As, in producing the high arterial pressure, much power is met by much resistance, and the elastic wall 94 Ay AMERICAN TEXT-BOOK OF PHYSIOLOGY. is, therefore, distended with accumulated blood ; so, in producing the low capil- lary pressure, diminished power is met by diminished resistance, outflow is relatively easy, accumulation is slight, and the elasticity of the delicate wall is but little called upon. The Extinction of the Arterial Pulse. — But why is the capillary pres- sure pulseless, as the microscope shows ? To explain this, no new factors need discussion, but only the adjustment of the arterial elasticity to the intermittent injections from the heart and to the total friction which opposes the admission of blood to the capillaries. This adjustment is such that the recoil of the arteries displaces blood into the capillaries during the ventricular diastole at exactly the same rate as that produced by the ventricular contraction during the ventricular systole. Thus, through the elasticity of the arteries, the car- diac pulse undergoes extinction ; and this becomes complete at the confines of the capillaries. The respiratory fluctuations become extinguished also, and the movement of the blood in the capillaries exhibits no rhythmic changes. This conversion of an intermittent flow into one not merely continuous but approximately constant affords a constant blood-supply to the tissues, at the same time that the cardiac muscle can have its diastolic repose, and the ven- tricular cavities the necessary opportunities to receive from the veins the blood which is to be transferred to the arteries. A simple experiment will illustrate the foregoing. Let a long india-rubber tube be taken, the wall of which is thin and very elastic. Tie into one end of the tube a short bit of glass tubing ending in a fine nozzle, the friction at which will cause great resistance to any outflow through it. Tie into the other end of the rubber tube an ordinary syringe-bulb of india-rubber, with valves. Expel the air, and inject water into the tube from the valved bulb by alternately squeezing the latter and allowing it to expand and be filled from a basin. The rubber tube will swell and pulsate, but if its elasticity have the right relation to the size of the fine glass nozzle and to the amplitude and frequency of the strokes of the syringe, a continuous and uniform jet will be delivered from the nozzle, while the injections of water will, of course, be intermittent. The Venous Pressure and its Causes.— The pressure in the peripheral veins is less than in the capillaries and declines as the blood reaches the larger veins. Very close to the chest the pressure is below the pressure of the atmosphere, and may sometimes vary from negative to positive, following the rhythm of the breathing. These respiratory fluctuations will be considered later. The low and declining pressures under which the blood moves through the venules and the larger veins are due to the same causes as those which account for the capillary pressure. It is still the force generated by the heart's con- tractions, and made uniform by the elastic arteries, which drives the blood into and through the veins back to the very heart itself. As the blood moves through the veins, what resistance it encounters is still that of the friction ahead. But the friction ahead is progressively less ; the conversion of kinetic energy into heat is progressively greater. The venous wall possesses elas- CIBCULA TION. 95 ticity, but this is even less called upon than that of the capillaries ; and, pres- ently, in the larger veins, the moving blood is found to press no harder from within than the atmosphere from without. Subsidiary Forces which Assist the Plow in the Veins. — There are certain forces which, occasionally or regularly, assist the heart to return the venous blood into itself. Too much stress is often laid upon these ; for it is easy to see by experiment that the heart can maintain the circulation wholly without help. The origins of these subsidiary forces are, first, the contraction of the skeletal muscles in general ; second, the continuous traction of the lungs; third, the contraction of the muscles of inspiration. The Skeletal Muscles and the Venous Valves. — A vein may lie in such relation to a muscle that when the latter contracts the vein is pressed . upon, its feeble blood-pressure is overborne, the vein is narrowed, and blood is squeezed out of it. The veins in many parts are rich in valves, competent to prevent regurgitation of the blood while permitting its flow in the physio- logical direction. The pressure of a contracting muscle, therefore, can only squeeze blood out of a vein toward the heart, never in the reverse direction. Muscular contraction, then, may, and often does, assist in the return of the venous blood with a force not even indirectly derived from the heart. But such assistance, although it may be vigorous and at times important, is tran- sient and irregular. Indeed, were a given muscle to remain long in contrac- tion, the continued squeezing of the vein would be an obstruction to the flow through it. The Continuous Pull of the Elastic Lungs. — The influence of thoracic aspiration upon the movement of the blood in the veins deserves a fuller dis- cussion. The root of the neck is the region where this influence shows itself most clearly, but it may also be verified in the ascending vena cava of an animal in which the abdomen has been opened. The physiology of respira- tion shows that not only in inspiration, but also in expiration, the elastic fibres of the lungs are upon the stretch, and are pulling upon the ribs and intercostal spaces, upon the diaphragm, and upon the heart and the great vessels. This dilating force at all times exerted upon the heart by the lungs is of assistance, as we shall see, in the diastolic expansion of its ventricles. In the same way the elastic pull of the lungs acts upon the vense cavse within the chest, and generates within them, as well as within the right auricle, a force of suction. The effects upon the venous flow of this continuous aspiration are best known in the system of the descending vena cava. This suction from within the chest extends to the great veins just without it in the neck. In these, close to the chest, as we have seen, manometric observation reveals a continuous slightly negative pressure. A little farther from the chest, however, but still within the lower portions of the neck, the intravenous pressure is slightly positive. The elastic pull of the lung, therefore, continuously assists in unloading the terminal part of the venous system, and thus differs markedly from the irreg- ular contractions of the skeletal muscles. The Contraction of the Muscles of Inspiration. — But some skeletal 96 ^.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. muscles, those of inspiration, regularly add their rhythmic contractions to the continuous pull of the lungs, to reinforce the latter. Each time that the chest expands there is an increased tendency for blood to be sucked into it through the veins. At the beginning of each expiration this increase of suction abruptly ceases. The Respiratory Pulse in the Veins near the Chest, and its Limita- tion. — In quiet breathing the movements of the chest-wall produce no very conspicuous effect. If, however, deep and infrequent breaths be taken, the pressure witliin the veins close to the chest becomes at each inspiration much more negative than before ; and at each inspiration the area of negative pressure may extend to a greater distance from the chest along the veins of the neck, and perhaps of the axilla. As the venous pressure in these parts now falls as the chest rises, and rises as the chest falls, a visible venous pulse presents itself, coinciding, not with the heart-beats, but with the breatliing. At each inspiration the veins diminish in size, as their contents are sucked into the chest faster than they are renewed. At each expiration the veins may be seen to swell under the pressure of the blood coming from the periphery. If the movements of the air in the windpipe be mechanically impeded,, these changes in the veins reach their highest pitch ; for then the muscles of expiration may actually compress the air within the lungs, and produce a positive pressure within the vena cava and its branches, with resistance to the return of venous blood during expiration, shown by the swelling of the veins. These phenomena are suddenly succeeded by suction, and by collapse and disappearance of the veins, as inspiration suddenly recurs. The respiratory venous pulse, when it occurs, diminishes progressively and rapidly as the veins are observed farther and farther from the root of the neck — a fact which results from the flaccidity of the venous wall. Were the walls of the veins rigid, like glass, the successive inspirations would produce obvious accelerations of the flow througliout the whole venous system, and the con- tractions of the muscles of inspiration would rank higher than they do among the causes of the circulation. In fact, the walls of the veins are very soft and thin. If, therefore, near the chest, the pressure of the blood within the veins sinks below that of the atmosphere, the place of the blood sucked into the chest is filled only partly by a heightened flow of blood from the periph- ery, but partly also by the soft venous wall, which promptly sinks under the atmospheric pressure. This is shown by the visible flattening, perhaps disappearance from view, of the vein. This process reduces the visible venous pulse, where it occurs, to a local phenomenon ; for, at each inspira- tion, the promptly resulting shrinkage of all the affected veins together is nearly equivalent to the loss of volume due to the sucking of blood into the chest. Therefore the flow in the more peripheral veins remains but slightly affected, and the pressure within them continues to be positive and without a visible pulse. During expiration the swelling of the veins near the chest, the return of positive pressure within them, may be simply from the return of the ordinary balance of forces after the effects of a deep inspiration have CIRCULATION. 97 disappeared. But, if expiration be violent and much impeded, the positive pressure may rise much above the normal. Here again, however, regurgita- tion •will meet with opposition from the venous valves, though the flow from the periphery may be much impeded. The "Dangerous Region," and the Entrance of Air into a "Wounded Vein. — Quite close to the chest, then, the normal venous pressure is always slightly negative ; and in deep inspiration it may become more so, and this condition may extend farther from the chest along the neck and axilla, through- out a region known to surgeons as " the dangerous region." It is important to understand the reason for this expression. It has already been mentioned that the wounding of a vein in this region may cause intermittent bleeding. It now will easily be understood that such bleeding will occur only when the pressure is positive — that is, during expiration. During deep and difficult breathing, indeed, the venous blood may spring in a jet during expiration instead of merely flowing out, and may wholly cease to flow during inspira- tion. The cessation is due, of course, to the blood being sucked into the chest past the wound rather than pressed out of it. It is not, however, the risks of hemorrhage that have earned the name of " dangerous " for the region where intermittent bleeding may occur. The danger referred to is of the entrance of air into the wounded vein and into the heart, — an accident which is commonly followed by immediate death, for reasons not here to be discussed. Ver)' close to the chest, where the venous pressure is continuously negative and the veins are so bound to the fascise that they may not collapse, this danger is always present. Throughout tlie rest of the dangerous region, the entrance of air into a wounded vein will take place only exceptionally. In quiet breathing the venous pressure is continu- ously positive throughout most of this region ; and then a wounded vein will merely bleed. It is only- in deep breathing that a venous pulse becomes vis- ible here, and that the venous pressure becomes negative in inspiration. But even in forced breathing it is rare for a wounded vein of the dangerous region to do more than bleed. The cause of this lies in the flaccidity of the venous wall. At each expiration the blood may jet from the wound ; but at the fol- lowing deep inspiration the weight of the atmosphere flattens the vein so promptly that the blood is followed down by the wounded wall and no air enters at the opening. It is only when, during deep breathing, the wounded wall for some reason cannot collapse, that the main part of the "dangerous region " justifies its name. Should the tissues through which the vein runs have been stiffened by disease, or should the wall of the vein adhere to a tumor which a surgeon is lifting as he cuts beneath it, in either case the vein will have become practically a rigid tube. Should it be wounded during a deep inspiration, blood will be sucked past the wound, but the atmospheric pressure will fail to make the wall collapse ; air will be drawn into the cut, and blood and air will enter the heart together, probably with deadly effect. Summary. — It appears from what has gone before that the elasticity of the lungs and the contractions of the muscles of inspiration regularly assist in Vol. I.— 7 98 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. unloading the veins in the immediate neighborhood of the heart, and so remove some part of the resistance to be overcome by the contractions of the cardiac muscle. When we come to the detailed study of the heart it will appear also that a slight force of suction is generated by the heart itself, which force adds its effects upon the flow of venous blood to those of the elasticity of the lungs and of the contraction of the muscles of inspiration. Tt must here be repeated, however, that the heart is quite competent to maintain the circulation unaided. This is proven as follows : If in an anaes- thetized mammal a cannula be placed in the windpipe, the chest be widely opened, and artificial respiration be established, the circulation, though modi- fied, continues to be effective. By the opening of the chest its aspiration has been ended, and can no longer assist in the venous return. If, further, the animal be drugged in such a manner as completely to paralyze the skeletal muscles throughout the body, their contractions can exert no influence upon the venous return ; yet the circulation is still kept up by the heart, unaided either by the elasticity of the lungs, by the contractions of the muscles which produce inspiration, or by those of any other skeletal muscles. E. The Speed of the Blood in the Arteries, Capillaries, AND Veins. If we keep as our text, in discussing the circulation, the character of the capillary flow, it will be seen that we have now accounted for the facts that the capillary flow is toward the veins ; that it shows much friction ; that it is continuous, pulseless, and under low pressure. We have not yet accounted for the fact that it is slow. We must now do so, but must first state and account for the speed of the blood in the arteries and veins. The Measurement of the Blood-speed in Large Vessels ; the " Stromr uhr." — The speed of the blood in the larger veins and arteries must be meas- ured indirectly. We can picture to ourselves the volume of blood wliich moves past a given point in a given blood-vessel iu one second, as a cylinder of blood having the same diameter as the interior of the blood-vessel. The length of this cylinder will then be expressed by the same number which will express the velocity with which a particle of the blood would pass the given point in one second, provided that this velocity be uniform and be the same for all the particles. In order, then, to learn the average speed of the blood at a given point of an artery or vein during a certain number of seconds, we have only to measure the calibre of the blood-vessel and the quantity of blood which passes the selected point during the period of observation. From these two measurements the speed-can be obtained by calculation. But these two measurements are not quite easy. The physical properties of the blood-vessels, especially of the veins, make their calibres variable and hard to estimate justly as affected by the conditions present during an experiment. The means adopted for measuring the quantity of blood passing a point in a given time necessarily alters the resistance encountered by the flow, and so of itself affects both the rate of flow and the blood-pressure ; and, with the CIRCULATION. 99 latter, the calibre of the vessel. For these reasons any measurement of the average speed of the blood by the above method is only approximately correct. The best instrument for measuring the quantity of blood driven past a point during an experiment is the so-called '' strom- uhr " or " rheonieter " of Ludwig, a longitu- dinal section of which is given diagrammati- cally in Figure 17.' This is essentially a curved tube shaped like the Greek capital letter n. Each end of the tube is tied into one of the two stumps (a and b) of the divided vessel. These ends of the tube are as nearly as possible of the same calibre as the vessel selected. Each limb of the tube is dilated into a bulb, and the upper part of the tube, including the two bulbs, is of glass ; the lower part of each limb is of metal. At the top, between the bulbs, is an opening for filling the tubes, which can easily be closed when not Fig. 17.— Diagram of longitudinal sec- tion of Ludwig's "Stromuhr." The ar- rows mark the direction of the blood- stream. For further description see the text. in use. Each end of the tube is filled with defibrinated blood before being tied into the blood-vessel. In the limb of the tube {B, (Fig. 17) which is the farther from the heart if an artery be used, or the nearer to the heart if a vein, the defibrinated blood is made to fill the cavity up to the top of the bulb. In the other limb {A, Fig. 17) the blood fills the tube only up to a mark (e. Fig. 17) near the bottom of the bulb. Through the opening between the bulbs the still vacant space, which includes the whole of the bulb A, is filled with oil, all air being excluded. The opening is then closed. If now the clamps be removed from the blood-vessel, the blood of the animal will enter the tube at a and drive before it the contents of the tube. Thus defibrinated blood from B will be driven into the distal stump of the vessel at b, and will enter the circulation of the animal. Oil will at the same time be driven over from A to B. The bulb A has upon it two marks, d and e, one near the top of it, the other near the bottom. The instant when the line between the oil and the advancing blood reaches the mark near the top of A is the instant when a volume of blood equal to that of the displaced oil has entered A, past the mark near the bottom of it. The capacity of the tube between the two marks is accurately known. The time required for this space to be filled with the entering blood is measured by the observer. The calibre of the metal tube at a is accurately known, and is assumed to be equal to the calibre of the blood-vessel. From these measurements the average speed of the blood-stream at a is calculated. ' .J. Dogiel : " Die Ansmessung der stromenden Blutvolumina," Beridite iiber die Verhand- lungen der k. sachsischen Gesetlschaft der Wissenschaften zu Leipzig, Math.-physische Classe, 1867, S. 200. 100 AN AMEBICAX TEXT-BOOK OF PHYSIOLOGY. The metallic lower part of the instrument, which includes both limbs of the tube, is completely divided horizontally at c. The two parts are so built, however, as to be maintained in water-tight apposition. This arrangement permits the whole upper part of the instrument, including the glass bulbs, to be rotated suddenly upon the lower, so that the bulb B may correspond with the entrance for the blood at a, and the bulb A with the exit for the blood at b. If this rotation be effected at the instant when the space between the two marks on A has been filled with blood, the bulb B, now charged with oil, will be filled by the blood which enters next, and the first charge of the ani- mal's own blood will make its exit at b. Oil will now pass over from B to A; when the line between it and the blood which is leaving A has just reached the lower mark on ^, the bulbs are turned back to their original position. Thus, by repeated rotations, each of which can be made to record upon the kymograph the instant of its occurrence, a number of charges of blood can be received and transmitted in succession ; it is always the same space, between the marks on A, which is used for measuring the charge ; and the time of the experiment can be much prolonged. By this procedure the errors due to a single brief observation can be greatly reduced. Indeed, the time of entrance of a single charge of blood would be quite too short to give a satisfactory result. The use of the stromuhr not only affords necessary data for the calcu- lation of the average speed of the blood, but seeks directly to measure the volume of blood delivered in a given time by an artery to its capillary dis- trict. It is evident that this volume is a quantity of fundamental impoi'tance in the physiology of the circulation. Could we ascertain it, by direct meas- urement or by calculation, for the aorta or pulmonary artery, we should know at once the volume of blood delivered to the capillaries in one second, and thus the time taken for the entire blood to enter either those of the lungs or of the system at large. By this knowledge, many important problems would be advanced toward solution. The Measurement of Rapid Fluctuations of Speed. — The stromuhr can give only the average speed of the blood during the experiment. To study rapid fluctuations of speed, another method is needed. If, in a large animal, a vessel, best an artery, be laid bare, a needle may be thrust into it at right angles. If the needle be left to itself, the end which projects from the artery will be deflected toward the heart, because the point will have been deflected toward the capillaries by the blood-stream. The angle of deflection might be read off, could a graduated semicircle be adjusted to the needle. If the stream be arrested, the needle returns to its position at right angles to the artery. The greater the velocity of the stream, the greater is the deflection of the needle. If, later, the same needle be thrust into a tube of rubber through which water flows at known rates of speed, the speed corresponding to each angle of deflection of the needle may be determined. If the needle were made to mark upon a kymograph, variations of the speed would be recorded as a curve. CIRCULATION. 101 An iustrumeut based on the principles jnst described is valuable for the study of rapid changes of velocity.^ In an artery, its needle oscillates rhyth- mically, showing that there the speed of the blood varies during each beat of the. heart, being greatly accelerated by the systole of the ventricle, and retarded by the cessation of the systole. It will be remembered that the microscope directly shows faint rhythmic accelerations in the minute arteries of the frog. In the veins rhythmic changes of speed do not occur except near the heart from respiratory causes. The Speed of the Blood in the Arteries. — The stromuhr shows that the speed of the blood is liable to great variations. This fact, and the range of speed in the arteries, are fairly exhibited by the results obtained by Dogiel from the common carotid artery of a dog, the experiment upon which lasted 127 seconds. During this time six observations were made which varied in length from 14 to 30 seconds each. For one of these periods the average speed was 243 millimeters in one second ; for another period, 520 millimeters. These were the extremes of speed noted in this case.^ The speed in the arteries diminishes toward the capillaries. The Speed of the Blood in the Veins. — The speed in a vein tends to be slower than that in an artery of about the same importance, but is not neces- sarily so.^ It increases from the capillaries toward the heart. The Speed of the Blood in the Capillaries. — The rate of the capillary flow may be measured directly under the microscope. Certain physiologists have also observed the movement of the blood in the retinal capillaries of their own eyes, and have measured its rate there.* Both methods show that in the capillaries the speed is very much less than in the large arteries or large veins. In the capillaries of the web of the frog's foot it is only about 0.5 millimeter in one second. In those of the mesentery of a young dog it has been fonnd to be 0.8 millimeter; in those of the human retina, from 0.6 to 0.9 millimeter. Speed and Pressure of the Blood Compared. — If now we compare the speed with the pressure of the blood in the arteries, in the capillaries, and in the veins, we shall be struck by both similarities and differences. In the arteries both pressure and speed rhythmically rise and fall together ; and both the mean pressure and the mean speed decline from the heart to the capillaries. In the capillaries both pressure and speed are pulseless and low, — very low compared with the great arteries. In the veins, however, the pressure is everywhere lower than in the capillaries and falls from the capillaries to the heart ; the speed is everywhere higher than in the capillaries and rises from ' M. L. Lortet : Recherches sur la mtesse du corns du sang dans les artires du cheval au moyen S!un nouvd htmodromogra'phe, Paris, 1867. ^ J. Dogiel : foe. cit. ' E. Cyon und F. Steinmann : " Die Geschwindigkeit des Blutstroms in den Venen," Bulletin de TAcademie Imperiale des Sciences de St. Petershourg, 1871 ; also in E. Cyon : Gesammelte physio- logische Arbeitm, 1888, S. 110. * K. Vierordt : Die Erseheinungen und Oesetze der Stromgeschwindigkeiten des Blutes, etc., 1862, «. 41, 111. 102 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the capillaries to the heart. It is apparent, therefore, that there is no direct connection between the pressure and the speed of the blood at a given point, inasmuch as they change together along the arteries and change inversely along the veins. How varied the combinations may be of pressure and speed will be seen in studying the regulation of the circulation. In the great veins, as in the arteries, the speed is very high compared with the capillaries. In the capillaries the speed of the blood is least, while in the tubes which supply and which drain them the speed is great. The physi- ological value of these facts is clear. It has already been pointed out that the blood moves slowly through the short and narrow tubes, where its exchanges with tissue and with air are effected, and swiftly through the long tubes of communication. What are the physical conditions which underlie these physiological facts? The speed of the blood varies inversely as the collective sectional area of its path. If the circulation in an animal continue uniform for a time — during several breaths and heart-beats — it is evident that the forces con- cerned must be so balanced that, during that time, equal quantities of blood will have entered and left the heart, the arteries, the capillaries, and the veins, respectively. If the arteries, for instance, lose more blood than the heart transmits to them, this blood must accumulate in the veins till the arteries become drained and the supply to the capillaries fails. The very maintenance of a circulation, then, implies that equal quantities of blood must pass any two points of the coUedive blood-path in equal times, except when a general readjustment of the rate of flow may lead to a temporary disturbance of it. It will be seen at once that this principle is consistent with the widest differ- ences of rate between individual arteries of the same importance, or between individual veins or capillaries. If in one artery the flow be increased by one- half, and in another be diminished by one-half, the total flow in the two arteries collectively will be the same as before. If the principle just stated be considered in connection with the anatomy of the blood-path, the differences of speed in the arterial, capillary, and venous systems will at once be understood. The wider arteries and veins are few. Dissection shows that when an artery or vein divides, the calibre, and, with the calibre, the "sectional area" of the branches taken together, is commonly larger than that of the parent trunk. In general it is a law of the arterial and venous anatomy that the collective sectional area of the vessels of either system increases from the heart to the capillaries. The smaller the individual vessels are, the wider is the blood-path which they make up collectively. AYidest of all is the blood-path where the individual vessels are smallest — that is, in the capillary system. The collective sectional area of the capillaries is several hundred times that of the root of the aorta. The collective sectional area of the veins which enter the right auricle is greater, perhaps twice as great, as that of the root of the aorta. The venous system, regarded as a single tube, is of much greater calibre than the arterial. It is perhaps better to make these general statements than to compare the different figures given CIRCULATION. 103 by different observers. The arterial and venous systems, treated as each a single tube, may be compared roughly to two funnels, each having its nar- row end at the heart. The very wide and very short single tube of the capil- lary system may be imagined to connect the wide ends of the two funnels. Equal quantities of blood pass in equal times any two points of the collec- tive blood-path between the left ventricle and the right auricle. Therefore where the blood-path is wide, these quantities must move slowly, and swiftly where the blood-path is narrow. It is owing, then, to the rapid widening of the arterial path that the speed declines, like the pressure, toward the capilla- ries. It is owing to the huge relative calibre of the path at the capillaries that in them the speed is by far the least while the same volume is passing that passes a point in the narrow aorta in the same time ; it is owing to the steady narrowing of the venous path toward the heart that the venous blood is constantly quickening its speed while its pressure is falling. As the calibre of the venous system is greater than that of the arterial, the average speed iu the veins is probably less than in the arteries. As the collective calibre of the veins which enter the right auricle is greater than that of the aorta, the blood probably moves into the heart less swiftly than out of it ; though of course equal quantities enter and leave it in equal times provided those times are not mere fractions of a beat. In connection with this it is significant that the entrance of blood into the heart takes place during the long auric- ular diastole, while its exit is limited to the shorter ventricular systole. Time Spent by the Blood in a Systemic Capillary. — The width of the path, then, determines the slow movement of the blood in the areas where it is fiiliilling its functions ; the narrowness of the path, the swiftness of move- ment of the blood in leaving and returning to the heart. We have seen (p. 79) that a particle of blood may make the entire round of a dog's circulation in from fifteen to eighteen seconds. If we assume the systemic capillary flow to be at the rate of 0.8 millimeter in one second, the blood would remain about 0.6 of a second in a systemic capillary half a millimeter long. Slow as is the capillary flow, it thus appears that it is none too slow to give time for the usos of the blood to be fulfilled. P. The Flo^w op Blood through the Lungs. The blood moves from the right ventricle to the left auricle under the same general laws as from the left ventricle to the right auricle. Certain dif- ferences, however, are apparent, and must be noted. One difference is that the collective friction is less in the pulmonary than in the systemic vessels, and that therefore the resistance to be overcome by each contraction of the right ventricle is less than that opposed to the left ventricle. Accordingly it appears from dissection that the muscular wall of the right ventricle is much thinner than that of the left. No accurate measurements can be made of the normal pressure and speed of the blood in the arteries, capillaries, and veins of the lungs, because they can be reached only by opening the chest and destroying the mechanism of respiration, and thereby disturbing the normal 104 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tonditious of the pulmouary blood-stream. In the opened chest these cannot be entirely restored by artificial respiration. The thinness of the wall of the pulmouary artery, however, indicates that it has much less pressure to support than that of the" aorta, which fact also is indicated by such roughly approxi- mate results as have been obtained with the manometer after opening the chest. As the pulmonary artery and veins lie wholly within the chest, but outside the lungs, their trunks and larger branches all tend to be dilated continuously by the elastic pull of the lungs — a pull which increases at each inspiration. On the other hand, the pulmonary capillaries lie so close to the surface of each lung that they are exposed to the same pressure, practically, as that surface, and the full weight of the atmosphere may act upon them. These conditions all tend to unload the capillaries and the pulmonary veins, but to weaken the unloading of the pulmonary artery. The two effects can hardly balance one another, however. The wall of the pulmonary artery is so much stiffer than that of the vein, that the actual results should be favorable to the flow. The elasticity of the lungs and the contractions of the muscles of inspiration thus lighten, probably, the work of the right ventricle as well as of the left. The right ventricle, however, like the left, can accomplish its work without assist- ance ; for the entire circulation, including, of course, the flow through the lungs, continues after the chest has been opened, if artificial respiration be maintained. G. The Pulse-volume and the Work done by the Ventricles OF THE Heart. The Cardiac Cycle. — It is assumed that the anatomy of the heart is known to the reader. The general nature and eifects of the heart's beat have been sketched already. Each beat has been seen to comprise a number of phenomena, which occur in regular order, and which recur in the same order during each of the succeeding beats. Each beat is therefore a cycle; and the phrase "cardiac cycle " has become a technical expression for " beat," as it conveys, in a word, the idea of a regular order of events. As each of the four chambers of the heart has its own systole and diastole, there are eight events to be studied in connection with each cycle. The systoles of the two auricles, however, are exactly simultaneous, as are their diastoles; and the same is true of the sys- toles and of the diastoles of the two ventricles. We may, therefore, without confusion, speak of the auricular systole and diastole, and of the ventric- ular systole and diastole, as of four events, each involving the narrowing or widening of two chambers, a right and a left. The heart of the mammal or bird consists essentially of a pair of pumps, the ventricles, each of which acts alternately as a powerful force-pump and as a very feeble suction- pump. To each ventricle is superadded a contractile appendage, the auricle, through which, and to some extent by the agency of which, blood enters the ventricle. CIR C ULA TION. 105 The Pulse-volume. — The central fact of the circulation of the blood is the injection, at intervals, by each ventricle, against a strong resistance, of a charge of blood into its artery, which charge the ventricle has just received out of its veins through its auricle. This quantity must be exactly the same for the two ventricles under normal conditions, or the circulation would soon come to an end by the accumulation of the blood in either the pulmonary or the sys- temic vessels. The blood ejected from each ventricle during the systole must also be equal in volume to the blood which enters each set of capillaries, the pulmonary or systemic, during that systole and the succeeding diastole of the ventricles, provided the circulation be proceeding uniformly. The quantity just referred to is called the "contraction volume" or "pulse-volume" of the heart. "Were it always the same, and could we measure it, we should possess the key to the quantitative study of the circulation. The pulse-volume may vary in the same heart at diifereut times, as is easily shown by opening the chest, causing the conditions of the circulation to change, and noting that under certain conditions the heart during each beat varies in size more than before. This variation of volume is easily possible because the walls of the heart are of muscle, soft and distensible when relaxed. It is probable that at no systole is the ventricle quite emptied ; that most of its cavity may become obliterated by the coming together of its walls, but that a space remains, just below the valves and above the papillary muscles, which is not cleared of blood. It is also probable that not only the blood which is ejected at the systole may vary in amount, but also the residual blood which remains in the ventricle at the end of the systole.' It is therefore clear that it is useless to attempt the measurement of the pulse-volume by measuring the fluid needed to fill the ventricle, even if the heart be freshly excised from the living body and injected under the normal blood-pressure. Rough approx- imations to this measurement may, however, be attempted in at least two ways : In the first place, a modification of the stromuhr has been applied suc- cessfully to the aorta of the rabbit, between the origins of the coronary arteries and of the innominate. This operation requires that the auricles be clamped temporarily so as to stop the flow of blood into the ventricles, and to permit the aorta in its turn to be clamped and divided between the clamp and the ventricle, without serious bleeding. After the circulation has been re-estab- lished, the volume of the blood which passes through the instrument during the experiment, divided by the number of the heart-beats during the same period, gives the pulse-volume. The average result obtained, for the rabbit, ' F. Hesse: "Beitrage zur Mechanik der Herzbewegung," Archiv fur Anatomic und Physiolo- ■gie (anatomische Abtheilung), 1880, S. 328. C. Sandborg und W. Miiller : " Studien fiber den Mechanismns des Herzens," Pfiiiger's Archiv fur die gesammte Phydologie, 1880, xxii. S. 408. C. S. Eoy and J. G. Adarai : " Contributions to the Physiology and Pathology of the Mammalian Heart," Proceedings of the Moyal Society of London, 1891-92, i. p. 435. J. E. Johansson und R. Tigerstedt : " Ueber die gegenseitigen Beziehungen des Herzens und der Gefasse ;" " Ueber die Herzthatigkeit bei verschieden grossem Wiederstand in den Gefassen," Skandinavisches Archiv fiir Physiologic, 1891, ii. S. 409. 106 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. is a volume of blood -the weight of which is 0.00027 of the weight of the animal.^ A second way of attempting to ascertain the pulse-volume is to measure the swelling and the shrinkage of the heart. This is called the " plethysmographic " ^ method. One application of it is as follows : The chest and pericardium of an- animal are opened, and the heart is inserted into a brass case full of oil. The opening through which the great vessels pass is made water-tight by mechanical means which do not impede the movement of the blood into and out of the heart. The top of the brass case is prolonged into a tube, the oil in which rises as the heart swells and falls as it shrinks. Upon the oil a light piston moves up and down, and records its movements upon the kymograph. The instrument is called a " cardiometer." ^ The average pulse-volume of the human ventricle has been very variously estimated upon the basis of observations of various kinds made upon mam- mals of various species. The figures offered range, in round numbers, from 50 to 190 cubic centimeters. If we assume the human pulse- volume to weigh 100 grams, and the blood of a man who weighs 69 kilograms to weigh 5.308 kilograms, or -^ of his body-weight, the pulse-volume will be about -^ of the entire blood, and the entire blood will pass thi'ough the heart, from the veius to the arteries, in only fifty-three beats — that is, in less than one minute. The speed with which a man may bleed to death if a great artery be severed is therefore not surprising. The Work done by the Contracting Ventricles. — Uncertain as is this important quantity of the pulse-volume, the estimation of the work done by the heart in maintaining the circulation must be based upon it, and upon the force with which each ventricle ejects the pulse-volume. A small fractiou of this force is expended in imparting a certain velocity to the ejected blood ; all the rest serves to overcome a number of opposing forces. The force exerted by the muscular contraction is opposed by the weight of the volume ejected, and by the strong arterial pressure, which resists the opening of the semilunar valve and the ejection of the pulse-volume. Moreover, the elasticity of thfr lungs tends at all times to dilate the ventricles, with a force which is increased at each recurring contraction of the muscles of inspiration. Probably there is also in the wall of the ventricle itself a slight elasticity which must be over- come by the ventricle's own contraction in order that its cavity may be effaced. The strong arterial pressure, with which the reader is already familiar, is by far the greatest of these resisting forces — in fact, is the only one of them which is not of small importance in the present connection. Are we obliged to measure the force of the systole indirectly ? Can we not ascertain it by direct experiment? Manometers of various kinds have been^ placed in direct communication with the cavities of the ventricles. The fol- ' K. Tigerstedt: " Studien uber die Bhitvertheilung im Korper." Erste Abhandlung. "Bestimmung der von dem linken Herzen herausgetriebenen Blutmenge," S/candinavisches! Archiv fur Physiohgie, 1891, iii. 8. 145. ' From Tz/.rjdvaiidg, enlargement. ' C. S. Roy and J. G. Adami, op. cit. CIRCULATION. 107 lowiug method, among others, has been employed : A tube open at both ends is introduced through the external jugular vein of an animal into the right ventricle, or, with greater difficulty, through the carotid artery into the left ventricle. In neither case is the valve, whether tricuspid or aortic, rendered incompetent during this proceeding, nor need the general mechanism of the heart and vessels be gravely disturbed. If the outer end of the tube be connected with a recording mercurial manometer, a tracing of the pressure within the right or left ventricle may be written upon the kymograph. It is found, however, that the pressure within the heart varies so much and so rapidly that the inert mercurial column will not follow the fluctuations, and that the attempt to learn the mean pressure by this method fails. A valve, however, may be intercalated in the tube between the ventricle and the man- ometer — a valve so made as to admit fluid freely to the manometer, but to let none out. The manometer will then record, and record not too incorrectly, the maximum pressure within the right or left ventricle during the experiment ; iu other words, it will record the greatest force exerted during that time by the ven- tricle in order to do its work.^ In this way the maximum pressure within the left ventricle of the dog has been found to present such values as 176 and 234 millimeters of mercury, the corresponding maximum pressure in the aorta being 158 and 212 millimeters respectively.^ The maximum pressures obtained from simultaneous observations upon the right and left ventricle of a dog are variously reported. It would perhaps be not far wrong to say that in this animal the pressure in the right ventricle is to that in the left as 1 to 2.6.^ The work done by each ventricle during its systole is found by multiplying the weight of the pulse-volume ejected into the force put forth in ejecting it. That force is equal to the pressure under which the pulse volume is expelled. If we use as a basis of calculation the pressures observed in the dog's heart with the maximum manometer, we may assume as the measure of a given pressure within the contracting human left ventricle 200 millimeters of mercury, and for the human right ventricle 77 millimeters. If for each column of mercury thei-e be substituted the corresponding column of blood, the heights will be 2.567 meters and 0.988 meter respectively. The force exerted by the right or left ventricle upon the pulse-volume might therefore just equal that put forth in lifting it to a height of 0.988 or 2.567 meters. If we assume 100 grams as the weight of a possible pulse-volume ejected by a human ventricle, the work done at each systole of the left ventricle would be 100 X 2.567 = 256.7 gram- meters, and at each systole of the right ventricle 100X0.988=98.8 gram- meters ; a grammeter being the work done in raising one gram to the height of one meter. The work of both ventricles together would be 256.7 + 98.8 = 355.5 grammeters. The foregoing estimates are offered not as statements of what does occur, but as very rough indications of what may occur. Even ' F. Goltz und J. Gaule: "Ueber die Druckverhaltnisse im Innern des Herzens," Archiv fiir die gesammte Phymlogie, 1878, xvii. S. 100. ^ S. de Jager: "Ueber die Saugkraft des Herzens," Pfliiger's Archiv fiir die gesammte Physi- ologie, 1883, S. 504, 505. ' Goltz und Gaule, op. cit, S. 106. 108 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. thus, however, they are of moment. Wlien we think of the vast number of beats executed by the heart every clay, the great amount of energy rendered manifest in maintaining the circulation becomes apparent, and our interest is heightened in the fact that all of this large sum of energy is liberated in the muscular tissue of the heart itself Thus, too, the physiological significance of the diastole is accentuated as a time of rest for the cardiac muscle, as well as a necessary pause for the admission of blood into the ventricle. To disre- gard minor considerations, the work done at a systole will evidently depend upon the amount of the pulse-volume, of the arterial pressure overcome, and of the velocity imparted to the ejected blood. All these are variable. The work of the ventricles therefore is eminently variable. The Heart's Contraction as a Source of Heat. — In dealing with the movement of the blood in the vessels we have seen that the energy of visible motion liberated by the cardiac contractions is progressively changed into heat by the friction encountered by the blood ; and that this change is nearly com- plete by the time the blood has returned to the heart, the kinetic energy of each systole sufficing to drive the blood from the heart back to the heart again, but probably not being much more than is required for this purpose. Practi- cally, therefore, all the energy of the heart's contraction becomes heat within the body itself, and leaves the body under this form. As the heart liberates during every day an amount of energy which is always large but very variable, its contractions evidently make no mean contribution to the heat produced in the body and parted with at its surface. H. The Mechanism op the Valves of the Heart. Use and Importance of the Valves. — The discussion just concluded shows the work of the heart to be the forcible pumping of a variable pulse- volume out of veins where the pressure is low into arteries where the pressure is high. It is owing to the valves that this is possible, and so dependent is the normal movement of the blood upon the valves at the four ventricular apertures that the crippling of a single valve by disease may suffice to destroy life after a longer or shorter period of impaired circulation. The Auriculo-ventricular Valves. — The working of the auriculo-ven- tricular valves (see Fig. 18) is not hard to grasp. "When the pressure within the ventricle in its diastole is low, the curtains hang free in the ventricle, although probably never in close contact with its wall. As the blood pours into the ventricle, the pressure within it rises, currents flow into the space be- tween the wall and the valve, and probably bring near together the edges of the curtains and also their surfaces for some distance from the edges. Thus, upon the cessation of the auricular systole, the supervening of a superior pres- sure within the ventricle probably applies the already approximated edges and surfaces of the curtains to one another so promptly that the commencing contraction of the ventricle is not attended by regurgitation into the auricle. The principle of closure is the same for the tricuspid valve as for the mi- tral. As the forces are exactly equal and opposite which press together the CIRCULATION. 109 opposed parts of the surfaces of the curtains, those parts undergo no strain, and hence are enabled to be exquisitely delicate and flexible and therefore easil)' fitted to one another. Ou the other hand, the parts of the valve which intervene between the surfaces of contact and the auriculo-ventricular ring are tough and much thicker, as they have to bear the brunt of the pressure within the contracting ventricle. As the systole of the ventricle increases, the auric- ulo-ventricular ring probably becomes smaller, and the curtains of the valve probably become somewhat fluted from base to apex, so that their line of con- tact is a zig-zag. At the same time their surfaces of contact may increase in extent. Tendinous Cords and their Uses. — The structure so far described is wonderfully effective because it is combined with an arrangement to prevent a reversal of the valve into the auricle, which otherwise would occur at once. This arrangement consists iu the disposition of the tendinous cords, which act Fig. 18.— The left ventricle and aorta laid open, to show the mitral and aortic semilunar valves (Henle).- as guy-ropes stretched between the muscular wall of the ventricle and the valve, whether mitral or tricuspid. These cords are tough and inelastic, and, like the valve, are coated with the slippery lining of the heart. They are stout where they spring from the muscle, but divide and subdivide into branches, strong but sometimes very fine, which proceed fan-wise from their 110 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. stem to their insertions (see Fig. 18). These insertions are both into the free margin of the valve and into the whole extent of that surface of it which looks toward the wall of the ventricle, quite up to the ring. By means of this arrangement of the cords each curtain is held taut from base to apex through- out the systole of the ventricles, the opposed surfaces being kept in apposition, and the parts of the curtains between these surfaces and the ring being kept from bellying unduly toward the auricle. Each curtain is held sufficiently taut from side to side as well, because the tendinous cords inserted into one lateral half of the curtain spring from a widely different part of the wall of the heart from those of the other lateral half of it (see Fig. 18). At all times, therefore, even when the walls of the ventricle are most closely approximated during systole, the cords may pull in slightly divergent directions upon the two lateral halves of each curtain. This arrangement of the cords may also cause them, when taut, to pull in slightly convergent directions upon the contiguous lateral halves of two neighboring curtains and thus to favor the pressing of them together (see Fig. 18). Papillary Muscles and their Uses. — In the left ventricle the tendinous cords arise in two groups, like bouquets, from two teat-like muscular projec- tions which spring froui opposite points of the wall of the heart, and which are called the "papillary muscles" (see Fig. 18). One of these gives origin to the cords for the right half of the anterior and for the right half of the posterior curtain ; the other papillary muscle gives rise to the cords for the left halves of the two curtains. Each papillary muscle is commonly more or less subdivided (see Fig. 18). The same principles are carried out, but less regularly, for the origins of the tendinous cords of the more complex tricuspid valve. Various opinions have been held as to the use of the papillary muscles. It seems probable that during the change of size and form wrought in the ventricle by its systole, the origins of the tendinous cords and the auriculo- ventrieular ring tend to be approximated and the cords to be slackened in consequence. Perhaps this is checked by a compensatory shortening of the papillary muscles, due to their sharing in the systolic contraction of the mus- cular mass of ^vhich they form a part. Observations have been made which have been interpreted to mean that the papillary muscles begin their con- traction slightly later and end it slightly earlier than the mass of the ven- tricle.' Semilunar Valves. — The anatomy and the working of the semilunar valves are the same in the aorta as in the pulmonary artery, and one account will answer for both valves. Each valve is composed of three entirely sepa- rate segments, set end to end within and around the artery just at its origin from the ventricle. The attachments of the segments occupy the entire cir- cumference of the vessel (Fig. 18). Like the tricuspid and mitral valves, each semilunar segment is composed of a sheet of tissue which is tough, thin, supple, and slippery ; but the semilunar valves differ from the tricuspid and 'C. S. Eoy and J. G. Adami : "Heart-beat and Pulse-wave," The Practitioner, 1890, i. p. 88. CIRCULATION. Ill mitral, not only in the complete distinctness of their segments, but also in their mechanism. The tendinous cords are wholly lacking, and each segment depends upon its direct connection with the arterial wall to prevent reversal into the ventricle during the diastole of the latter. If the artery be carefully laid open by cutting exactly between two of the segments, each of the three is seen to have the form of a pocket with its opening turned away from the heart (see Fig. 18). Behind each segment, the artery is dilated into one of the hol- lows or " sinuses " of Valsalva.^ As the valve lies immediately above the base of the ventricle the segments rest upon the top of the thick muscular wall of the latter, which affords them a powerful support (see Fig. 19). Each segment is attached by the whole length of its longer edge to the artery, while the free margin is formed by the shorter edge. It is this arrangement ^hich renders reversal of a segment impossible (see Fig. 18). Fig. 19.— Diagram to illustrate the mechanism of Fig. 20.— Diagram to illustrate the mechanism of the semilunar valve. the semilunar valve and corpora Arantii. While the blood is streaming from the ventricle into the artery, the three segments are pressed away by the stream from the centre of the vessel, but never nearly so far as to touch its wall. At all times, therefore, a pouch ex- ists behind each segment, which pouch freely communicates with the general cavity of the artery. As the ventricular systole nears its end, the ventricular cavity doubtless becomes narrowed just below the root of the artery, and with it the arterial aperture itself, while currents enter the sinuses of Valsalva. Thus for a double reason the three segments of the valve are approximated, and probably the last blood pressed out of the ventricle issues through a nar- row chink between them. The instant that the pressure in the ventricle falls below the arterial pressure, the three segments must be brought together by -the superior pressure within the artery, and tightly closed by its forcible recoil, without regurgitation having occurred in the process (see Figs. 19, 20).^ Lunnlae and. their Uses. — Each segment of a semilunar valve, when closed, is in firm contact with its fellows not only at its free margin but also over a considerable surface, marked in the anatomy of the segment by the two "lunnlje" or little crescents, each of which occupies the surface of the segment from one of its ends to the middle of its free margin, the shorter edge ' Named from the Italian physician and anatomist Valsalva of Bologna, born in 1666. ' L. Krehl : "Beitrage zur Kenntniss der Fiillung und Entleerung des Herzens,'' Abhand- ■ lungen der math.-phydschen Classe der k. sachskehen Oesellschaft der Wissenschaften, 1891, Bd. xvii. No. 5, S. 360. 112 ^.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. of the lunula being one-half of the free margin of the segment (see Fig. 18). Over the surface of each lunula each segment is in contact with a different one of its two fellows (see Fig. 20). The firmness of closure thus secured is shown by Figure 19, which represents a longitudinal section of the artery, passing through two of the closed segments. The forces which press together the opposed surfaces are equal and opposite, and the parts of the segments which correspond to these surfaces undergo no strain. The luuulse, therefore, like the mutually opposed portions of the mitral or tricuspid valve, are very delicate and flexible, while the rest of each semilunar segment is strongly made, to resist of itself the arterial pressure. Corpora Arantii and their Uses. — At the centre of the free margin of each semilunar segment, just between the ends of the two lunulse, there is a small thickening, more pronounced in the aorta than in the pulmonary artery, called the " body of Aranzi " ' (corpus Arantii). This thickening both rises above the edge and projects from the surface between the lunulse. When the valve is closed, the three corpora Arantii come together and exactly fill a small triangular chink, which otherwise might be left open just in the centre of the cross section of the artery (see Figs. 18, 20). The foregoing shows that the mechanism of the semilunar valves is no less effective, though far simpler, than that of the mitral and tricuspid. That the latter two should be more complex is natural ; for each of them must give free entrance to and prevent regurgitation from a chamber which nearly empties itself, and hence undergoes a very great relative change of volume ; while the arterial system is at all times distended and undergoes a change of capacity which is relatively small while receiving a pulse-volume and trans- mitting it to the capillaries. I. The Changes in Form and Position of the Beating Heart, and THE Cardiac Impulse. General Changes in the Heart and Arteries. — During the brief systole of the auricles these diminish in size while the swelling of the ventricles is completed. During the more protracted systole of the ventricles, which imme- diately follows, these diminish in size while the auricles are swelling and the injected arteries expand and lengthen. During the greater part of the suc- ceeding diastole of the ventricles both these and the auricles are swelling, and all the muscular fibres of the heart are flaccid, up to the moment when a new auricular systole completes the diastolic distention of the ventricles, as above stated. During the ventricular diastole, as the great arteries recoil they shrink and shorten. The changes of size in the beating heart depend entirely upon the changes in the volume of blood contained in it, and not upon changes in the volume of the muscular walls. The muscular fibres of the heart agree with those found elsewhere in not changing their volume appreciably during contraction, but their form only. The cardiac cycle thus runs its course with ■ Named from Julius Csesar Aranzi of Bologna, an Italian physician and anatomist, born in 1530. CIBCULA TION. 113 regularly recurring changes of size in the auricles, the ventricles, and the arteries. These changes of size are accompanied by corresponding changes in the form and position of the heart, which are both interesting in them- selves and important in relation to the diagnosis of disease. The basis of their study consists in opening the chest and pericardium of an animal, and seeing, touching, and otherwise investigating the beating heart. The changes in the beating heart, moreover, underlie the production of the so-called cardiac impulse, or apex-beat, which is of interest in physical diagnosis. Observation of the Heart and Vessels in the Open Chest. — The beat- ing heart may be exposed for observation in a mammal by laying it upon its back, performing tracheotomy, and completely dividing the sternum in the median line, beginning at the ensiform cartilage. Artificial respiration is next established, a tube having been tied into the trachea before the chest was opeued. The two sides of the chest are now drawn asunder and the pericar- dium is laid open to expose the heart. If, in any mammal, the ventricles be lightly taken between the thumb and forefinger, the moment of their systole is revealed by the sudden hardening of the heart produced by it, as the muscular fibres contract and press with force upon the liquid within. On the other hand, the ventricular diastole is mai'ked by such flaccidity of the muscular fibres that very light pressure indents the surface, and causes the finger to sink into it, in spite of care being taken to prevent this. Commonly, therefore, at the systole the thumb and finger are palpably and visibly forced apart, no matter where applied, in spite of the fact that the volume of the ventricles is diminishing. This sinking of the finger or of an instrument into the relaxed wall of the heart has given rise to many errors of observation regarding changes during the beat. The time when the ventricles are hardened beneath the finger coincides with the up-stroke of the arterial pulse near the heart, and, as showu by Harvey,^ with the time \\hen an intermittent jet of blood springs from a wound of either ventricle. The hardening is proven thus to mark the systole of the ventricles. Those changes of size, form, and position of the exposed heart wliich accompany the harden- ing of the ventricles beneath the finger are therefore the changes of the ven- tricular systole ; and the converse changes are those of the ventricular diastole. To interpret all the changes correctlj' by the eye alone, without the aid of the finger or of the jet of blood, is a task of surpassing difficulty in a rapidly beat- ing heart, as was eloquently set forth by Harvey.^ Changes of Size and Form in the Beating Ventricles. — In a mam- mal, lying upon its back, with the heart exposed, the ventricles evidently become smaller during their systole. Their girth is everywhere diminished and their length also, the latter much less than the former ; indeed the dimi- nution in length is a disputed point. Not merely a change of size, but a ' Exercitaiio Anatomica de Motu Cordis et Sanguinis in Animalibus, 1628, p. 23 ; Willis' trans- lation, Bowie's edition, 1889, p. 23. ^ Oj). cii., 1628, p. 20; Willis' translation, Bowie's edition, p. 20. Vol. I.— 8 114 AJV AMERICAN TEXT-BOOK OF PHYSIOLOGY. change of form is thus produced ; the heart becomes a smaller and shorter, but a more pointed cone. The narrowing from side to side is very conspicuous. In the opened chest of a mammal lying on its back this narrowing is accompanied by a change which probably does not occur in the unopened chest, viz., by some increase in the diameter of the heart from breast to back, so that the surface of the ventricles toward the observer becomes more convex (see p. 116). Thus the base of the ventricles, which tended to be roughly elliptical during their relaxation, tends to become circular during their contraction ; and the diameter of the circle is greater than the shortest diameter of the ellipse, which latter diameter extends from breast to back. At the same time, the area of the base when circular and contracted is much less thau when elliptical and relaxed.' Naturally, none of these comparisons to mathematical figures makes any pre- tence to exactness. At the same time that the contracting heart undergoes these changes, the direction of its long axis becomes altered. In animals in which the heart is oblique within the chest, the line from the centre of the base to the apex, that is, the long axis, while it points in general from head to tail, points also toward the breast and to the left. In an animal lying ou its back, the ventricles when relaxed in diastole tend to form an oblique cone, the apex having subsided obliquely to the left and toward the tail. As the ventricles harden in their systole, they tend to change from an oblique cone to a right cone ; the long axis tends to lie more nearly at right angles to the base ; and consequently the apex, unfettered by pericardium or chest-wall, makes a slight sweep obliquely toward the head and to the right, and thus rises up bodily for a little way toward the observer. This movement was graphically called by Harvey the erection of the heart.^ It is accoiiipanied by a slight twisting of the ventricles about their long axis, in such fashion that the left ventricle turns a little toward the breast, the right ventricle toward the back. Changes of Position in the Beating Ventricles. — The changes in form imply changes in position. The oblique movement of the long axis implies that in systole the mass of the ventricles sweeps over a little toward the median line and also a little toward the head. The shortening of the long axis implies that either the apex recedes from the breast, or the base of the ventricles recedes from the back, or both. Of these last three possible cases, the second is the one that occurs. The oblique movement of the apex is accompanied by no recession of it ; but the auriculo-ventricular furrow and the roots of the aorta and pulmonary artery move away from the spinal column as the injected arteries lengthen and expand, and, as the auricles swell, during the contraction of the ventricles. During their diastole the ventricles are soft; they swell; and changes of form and position occur which are simply converse to those of the systole and have been indicated already in dealing with the latter. iC. Ludwig: "Ueber den Ban und die Bewegungen der Herzventrikel," Zeitschrift fur rationdle Medizin, 1849, vii. 8. 189. ^ Op. A, 1628, p. 22. Translation, 1889, p. 22. CIB G ULA TION. 1 1 5 Changes in the Beating Auricles. — Except in small animals, the walls of both the venti-icles are so thick that the color of the two is the same and is unchanging, namely, that of their muscular mass ; but the walls of the auricles are so thin that their color is affected by that of the blood within, so that the right auricle looks bluish and dark and the left auricle red and bright. During the brief systole of the auricles they are seen to become smaller and paler as blood is expelled from them, while their serrated edges and auricular appendages shrink rapidly away frona the observer. The changes of the auricular systole are seen to precede immediately the changes of the systole of the ventricles and to succeed the repose of the whole heart. During the relatively long diastole of the auricles these are seen to swell, whether the ventricles are shrinking in systole or are swelling during the first and greater part of their diastole. Changes in the Great Veins.— In the vense cavse and pulmonary veins a pulse is visible, more plainly in the former than in the latter, which pulse has the same rhythm as that of the heart's beat. The causes of this pulse are complex. It depends in part upon the rhythmic contraction of muscular fibres in the walls of the veins near the auricles, which must heighten the flow into the latter, and which contraction the auricular systole immediately follows.^ This venous pulse will be mentioned again in discussing the details of the events of the cycle (see p. 138). Changes in the Great Arteries. — It is interesting to note that even in so large an animal as the calf the pulse of the aorta or of the pulmonary artery can hardly be appreciated by the eye, so far as the increase in girth of either vessel is concerned. The expansion of the artery affects equally all points in its circumference, and being thus distributed, is so slight in propor- tion to the girth of the vessel that the profile of the latter scarcely seems to change its place. The lengthening of the expanding artery can be more readily seen. Effects of Opening the Chest. — Such are the changes observed in the heart and vessels when exposed in the opened chest of a mammal lying on its back. The question at once arises. Can these changes be accepted as iden- tical wath those which occur in the unopened chest of a quadruped standing upon its feet, or of a man standing erect ? It will be most profitable to deal at once with the case of the human subject. What are the possible, indeed probable, differences between the changes in the heart in the unopened upright chest and in the same when opened and supine ? When air is freely admitted to both pleural sacs, all those complex effects upon the circulation are at once abolished which we have seen to be caused by the elasticity of the lungs and the movements of respiration. The arti- ficial respiration will have an effect upon the pulmonary transit of the blood and so upon the circulation ; but the details of this effect are not the same as those of natural respiration, and, for our present purpose, may be disregarded. 1 T. Lauder Brunton and F. Fayrer : "Note on Independent Pulsation of the Pulmonary Veins and Vena Cava," Proceedings of the Royal Society, 1876, vol. xxv. p. 174. 116 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. "What has been abolished is the continual suction, rhythmically increased in inspiration, exerted by the lungs upon the heart and all the vessels within the chest, which suction at all times favors the expansion and resists the con- traction of the cavities of the heart and of the vessels. On the opening of both pleural sacs the heart and vessels are exposed to the undiminished and unvarying pressure of the atmosphere. Moreover, the heart has ceased to be packed, as it were, between the pleurae and lungs to right and left, the spine, the front of the chest-wall, and the diaphragm. From these considerations it follows that the heart must be freer to change its form and position in the opened than in the unopened chest ; and that these changes must be more modified by simple gravity in the former case than in the latter. Even in the open chest we have studied these changes only in an animal lying on its back. But if we turn the creature to either side, or place it upright in imi- tation of the natural human posture, the ventricles of the exposed heart in any case tend to assume, in systole, the same form, which has been com- pared roughly to a right cone with a circular base. This is the form proper to the hardened structure of branching and connected fibres of which the contracting ventricles consist. But if the exposed ventricles be noted in dias- tole, it will appear that their form depends very largely upon the eifects of gravity upon the exceedingly soft and yielding mass formed by their relaxed fibres. "We have seen them, in diastole, to flatten from breast to back, to spread out from side to side, to gravitate toward the tail and to the left. If the animal is laid on its side, they flatten from side to side, they spread out from breast to back, and gravitate to the right or left, as the case may be.' Probable Changes in the Heart's Form and Position in the Unopened Chest. — It is fair to conjecture that the increase of the relaxed ventricles in girth and in length which is seen in the open chest would not be greatly differ- ent in the closed chest of a man in the upright posture. But it is probable that the flattening of the exposed heart from breast to back, which is seen in diastole, would not occur if the chest were closed. It is precisely in this direc- tion that the flaccid heart exposed in the supine chest would be flattened un- duly by its own weight, when deprived of many of its anatomical supports and of the dilating influence of the lungs. The flattening from breast to back must cause an exaggerated spreading out from side to side and hence an unduly elliptical form of the base, inasmuch as, at the same time, the girth of the ven- tricles is increasing as they enlarge in their diastole. Conversely, it is prob- able, both a 2)riori and from experimental evidence, that in the chest, when closed and upright, the diminution in size of the contracting ventricles pro- ceeds more symmetrically ; that their girth everywhere diminishes through a diminution of the diameter from breast to back as well as of that from side to ' J. B. Haycraft: "The Movements of the Heart within the Chest-cavity, and the Cardio- gram," The Journal of Physiology, vol. xii., Nos. 5 and 6, December, 1891, p. 448 ; J. B. Hay- craft and D. K. Paterson : " The Changes in Shape and in Position of the Heart during the Cardiac Cycle," The Journal of Physiology, vol. xix., Nos. 5 and 6, May, 1896, p. 496. CIBCULA TION. 117 side, aud not through an exaggerated lessening of the latter and an actual iucrease of the former. In this case, too, the base would tend to become more circular during the systole bj' means of a less marked change from the diastolic form/ It has been said that in systole the ventricles are somewhat shortened in the exposed heart, and probably also in the unopened human chest. In the open chest the apex does not recede at all in virtue of this shorten- ing ; on the contrary, the base of the ventricles is seen to move toward the apex, and away, therefore, from the spine. Experiment has proven that the foregoing is true also of the unopened chest.^ It has been noted already that this movement of the base, which in the upright chest would be a descent, is accompanied by a lengthening of the aorta and pulmonary artery as their distention takes place. Very probably it is the thrust of the lengthened arte- ries which largely causes the descent of the base of the contracting ventricles, which descent compensates for the shortening of the ventricles and retains the apex in contact with the chest- wall. The Impulse or Apex-beat. — It must always have been a matter of com- mon knowledge that, in man, a portion of the heart lies so close to the chest- wall that, at each beat, the soft parts of that wall may be seen aud felt to pul- sate over a limited area. This is commonly in the fourth or fifth intercostal space, midway between the left margin of the sternum and a vertical line let fall from the left nipple. A similar pulsation may be observed in other mam- mals. The protrusion of the chest-wall at the site of this " impulse " or " apex- beat " occurs when the arteries expand, and the up-stroke of their pulse is felt ; and the recession of the chest coincides with the shrinking of the arteries away from the finger. The impulse proper, that is the protrusion of the chest-wall, ■occurs, therefore, at the time of the systole of the ventricles. Bj' far the most important factor of the apex-beat is probably the effort of the hardening ven- tricles to change the direction of their long axis against the resistance of the chest-wall. A heart severed from the body and bloodless, if laid upon a table, lifts its apex as it hardens in systole and assumes its proper form. If a finger be placed near enough to the rising apex to be struck by it, the same sensation is received as from the impulse. It is interesting to note that around the point where the soft parts of the chest are protruded by the impulse, they are found to be very slightly drawn in at the time of its occurrence. This drawing-in is called the "negative impulse," and must be caused by the diminution in size of the contracting ventricles. These are air-tight within the chest, and so their forcibly lessened surface must be followed down, in varying degrees, under the pressure of the atmosphere, by the elastic and yielding lungs and by the far less yield- ing soft parts of the chest-wall. The apex-beat can be brought to bear in various ways upon a recording lever, and thus be made to inscribe upon the kymograph a rhythmically fluc- tuating trace, which is called a cardiogram. Considerable attention has been 1 J. B. Haycraft : loc. cit. ' Haycraft : loc. cit. 118 Ay AMERICAN TEXT-_BOOK OF PHYSIOLOGY. given to the elucidation of the curve thus recorded ; but, so far, too little agreement has been reached for the subject to be entered upon here.^ J. The Sounds of the Heart. If the ear be applied to the human chest, at or near the place of the apex- : beat, the heart's pulsation will be heard as well as felt. This fact was known ' to Harvey.^ About two hundred years later than Harvey, in 1819, the French physician Laennec, the inventor of auscultation, made known the fact that each beat of the heart is accompanied not by one but by two separate sounds. He also called attention to their great importance in the diagnosis of the diseases of the heart.'' Relations of the Sounds. — The iirsfc sound is heard during the time when the apex-beat is felt ; it therefore coincides with the systole of the ventricles. The second sound is much shorter, and follows the first immediately, or, to speak more strictly, after a scarcely appreciable interval. The second sound, therefore, coincides with the earlier part of the diastole of the ventricles. The second sound is followed in its turn by a period of silence, commonly longer considerably than the second sound, which silence lasts till the begin- ning of the first sound of the next ventricular beat. The period of silence, therefore, coincides with the later, and usually longer, portion of the diastole of the ventricles, and with the systole of the auricles. It is interesting that the great auscultator, Laennec, offered no explanation of the cause of either sound, while he made and reiterated the incorrect and misleading .statement that the second sound coincides with the systole of the auricles. When the heart beats oftener than usual, each beat must be accomplished in a shorter time ; and it is found that, during a briefer beat, the period of silence is shortened much more than the period during which the two sounds are audi- ble ; which latter period may not be altered appreciably. Characters of the Sounds. — The first sound is not only comparatively loug, but is low-pitched and muffled. The second sound is comparatively short, and is high and clear. The two sounds, therefore, are sharply con- trasted in duration, pitch, and quality. A rough notion of the contrasted characters of the sounds may be obtained by pronouncing the meaningless syllables "lubb dup." In other mammals the sounds have substantially the same characters as in man. Cause of the Second Sound. — Since Laennee's time, the cause of the second sound has been demon.strated by experiment. The second sound is due to the vibrations caused by the .simultaneous closure of the semilunar valves of the pulmonary artery and of the aorta, when the diastole of the ventricles has just begun. This cause was first suggested by the French physician ' M. von Frey : Die Unlersuehung des Pulses, etc., ] 892, S. 102 ; K. Tigerstedt : Lehrbuch der Physiologie des Kreistaufes, Leipzig, 1893, S. 112. '' Exercitatio Anatomica de M(jtu Cordis et Sanguinis in Animalibus, 1628, p. 30 ; Willis's trans- lation, Bowie's edition, 1889, p. 34. ^ E. T. H. Laennec: De I'ausculiation midiate, etc., Paris, 1819. CIR CULA TION. 119 Roua.net in 1832;^ not long afterward it was conclusively pi-oven by experi- ment by the English physician C. J. B. "Williams.^ Dr. Williams's experiment was as follows : In a young ass the chest was opened and the heart was exposed. It Avas ascertained that the second sound was audible through a stethoscope applied to the heart itself. A sharp hook was then passed through the wall of the pulmonary artery, and was so directed as to make the semilunar valve incompetent temporarily. By means of a second hook, the aortic semilunar valve was likewise made incompetent. When both hooks were in position, the heart was auscultated afresh, and the second sound was found to have disappeared, and to be replaced by a hissing murmur. The hooks were withdrawn during auscultation, and at the moment of withdrawal the murmur disappeared and the normal second sound recurred. Subsequent clinical and post-mortem observations have shown that the second sound may be altered by disease which cripples the aortic valves. Causes of the First Sound. — The causes of the first sound have not been proven so clearly by the available evidence, which is partly experimental and partly derived from physical diagnosis followed by post-mortem verifica- tion. The first sound, like the second, was ascribed by Rouanet^ to vibrations depending upon valvular closure, — the simultaneous closure of the tricuspid and mitral valves ; but the persistence of the sound throughout the whole ventricular systole made this cause less probable than in the case of the second sound. Williams,^ on the other hand, ascribed the first sound to the con- traction of the muscular tissue of the ventricles, — an explanation consistent with the muffled quality of the first sound, and with its persistence through- out the systole of the ventricles. It is now believed by many that both of the foregoing explanations are correct, and that the first sound is composite in its origin, and due both to closure of the valves and to muscular contraction. The evidence in favor of these causes is, briefly, as follows : In favor of a valvular element in the first sound, it is maintained: That if the ventricles of a dead heart be suddenly distended with liquid, the mitral and tricuspid valves produce a sound in closing ; and that clinical and post- mortem observations show that the first sound may be altered by disease which cripples the auriculo-ventrieular valves. In favor of an element in the first sound caused by muscular contraction it is maintained : That in a still living but excised heart, the first sound con- tinues to be heard under circumstances which preclude the closure and vibra- tion of the valves, and leave in operation no conceivable cause for the first sound except muscular contraction. Experiments upon the first sound of the excised heart were reported in 1868 by Ludwig and Dogiel," and were ^ .1. Rouanet : Analyse des bruits du ccewr, Paris, 1832. '' C. J. B. Williams : Die. Palhologie und Diaynnxe der Krankheiten der Brust, etc. Nacli der dritten, sehr vermehrten Aufiage aus dem Englischen vibersetzt, Bonn, 1838. (The writer has not seen an English edition.) ' Loc. cit. * Loc. cit. ° J. Dogiel und C. Ludwig: " Ein neuer Versuch fiber den ersten Herzton," Berichte iiher die Verhandlungen der k. sdchsischen Oesettschaft der Wissenschaften zu Leipzig, math.-physiselie Olasse, 1868, S. 89. 120 AJy AMEBICAX TEXT-BOOK OF PHYSIOLOGY. performed upon the dog as follows: The heart was exposed during arti- ficial respiration, aud loose ligatures were placed upon the venae cavse, the pulmonary artery, the pulmonary veins, and the aorta. Next, the loose ligatures were tightened in the order above written, during which process the beating heart necessarily pumped itself as free as possible of blood. The vessels were then divided distally to the ligatures, and the heart was excised and suspended in a conical glass vessel containing freshly drawn defi- brinated blood, in which the heart was fully immersed without touching the glass at any point. Under these conditions the excised heart might execute as many as thirty beats. The conical glass vessel was supported in a " ring- stand." The narrow bottom of the vessel consisted of a thin sheet of india- rubber, with which last was connected the flexible tube aad ear-piece of a stethoscope. By means of the latter any sound produced by the beating heart could be heard through the blood and the sheet of rubber. The second sound was not heard ; but at each contraction of the ventricles the first sound was heard, not of the same length or loudness as normally, but otherwise unal- tered. The conditions of experiment were held to preclude error resulting from adventitious sounds ; moreover, the heart before excision had pumped itself free from all but a fraction of the amount of blood required to close the valves, and had Ijcen so treated that no more could enter. It was therefore believed to be practically impossible that the sound heard could have its origin at the valves ; and no origin remained conceivable other than in the muscular contraction of the ventricular systole. Later experiments, in which the auriculo-ventricular valves have been rendered incompetent by mechani- cal means, have seemed to confirm the importance of muscular contraction as a cause of the first sound.' By the use of a stethoscope combined with a peculiar resonator, the Ger- man physician M'intrich of Erlangen^ satisfied himself that he could analyze the first sound upon auscultation, so as to detect in it two components, one higher pitched, which he attributed to the vibration of the auriculo-ventricular valves, and a component of lower pitch, attributed to the muscular contrac- tion of the heart. The other experiments above referred to, however, which sustain muscular contraction as a cause of the first sound, did not reveal a change of pitch following incompetence of the valves, but only a diminution in loudness and duration. Both the closure of the cuspid valves and the contraction of the muscular tissue of the ventricles are rejected by a recent observer as causes of the first sound, which he ascribes to the opening of the semilunar valves.^ ' L. Krehl : " Ueber den Herznmskelton," Archiv fur Anatomie und Physiologie, Physiolo- gische Abtheilung, 1889, S. 253 ; A. Kasem-Bek : " Ueber die Entstehung des ersten Herztones," Pfliigei's Archiv fiir die gesammte Physiologie, 1890, Bd. xlvii. S. 53. ' Wintrich : " Experimentalstudien iiber Eesonanzbewegungen der Membranen," Silzungs- berichte der phys.^med. Societal eu Erlangen, 1873; Wintrich: "Ueber Causation und Analyse der Herzetone," Ibid., 1875. ' R. Quain : " On the Mechanism by which the First Sound of the Heart is Produced," Proceedings of the Royal Society, vol. Ixi. p. 331. CIRCULATION. 121 K. The Frequency op the Cardiac Cycles.' In a healthy full-grown man, resting quietly in the sitting posture, the heart beats on the average about 72 times a minute. In the full-grown woman the average is slightly higher, perhaps 80 to the miuute. The heart beats less frequently in tall people than in short ones. The difference between men and women largely depends upon this, but cai'eful observation shows that in the case of men and women of the same stature the heart-beats are slightly more frequent in the women. There is, therefore, a real difference as to the pulse between the sexes. Shortly before and after birth the heart-beats are very frequent, from 120 to 140 to the miuute. During childhood and youth, the frequency diminishes gradually, the average falling below 100 to the miu- ute at about the sixth year, and below 80 to the minute at about the eighteenth year. In extreme old age the pulse becomes slightly increased in frequency. It must, however, be borne in mind that there are very wide differences hetween individuals as to the average frequency of the heart-beats. Pulses of 40 and even fewer strokes to the minute, or, on the other hand, of more than 100 to the minute, are natural to some healthy people. In every individual the frequency of the pulse varies decidedly, and may vary very greatly, during each tweuty-four hours. It is least during sleep, tind less in the lying than in the sitting posture. Standing makes the heart beat oftener, the difference being greater between standing and sitting than between sitting and lying. During muscular exercise the pulse-rate is much increased, violent exercise carrying it possibly to 150 or even more. Thermal influences have a marked effect, a hot bath, for instance, heightening the fre- quency of the pulse and a cold bath diminishing it. The taking of a meal also commonly puts up the frequency. The influence of emotion upon the heart's contractions is well known. It may act either to heighten the rate or to lower it. Finally, the practising physician soon learns that the heart's rate is more easily affected by comparatively slight causes, emotional or other- wise, in women, and especially in children, than in men — a fact of some importance in diagnosis. The causes of the differences referred to in this section are partly unknown, and partly belong to the subject of the regulation of the circulation. L. The Relations in Time op the Main Events op the Cardiac Cycle. We have now considered the effects produced by the cardiac pump ; its general mode of working ; and the actual frequency of its strokes. ^Ye must next study certain important details relating to the individual strokes or beats of the ventricles and of the auricles. For this study the basis has already been laid in the sections headed "Causes of the Blood-flow" (p. 77), "Mode of Working of the Pumping ]\Iechanism" (p. 78), "The Cardiac Cycle" (p. 104), and " Use and Importance of the Valves " (p. 108). These sections iTigerstedt: Lehrbuch der Physiologic des Kreidaufes, Leipzig, 1893, S. 25-35; Yierordt : Dalen und Tabdlen zum Oebrauche /iir Medieiner, 1888, 8. 105-109, 259. 122 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. should now be read again in the order just given. Details can best be dealt ■with if we use, instead of the more familiar word " beat," the more technical one " cycle." The Auricular Cycle ; the Ventricular Cycle ; the Cardiac Cycle. — Each systole and succeeding diastole of the auricles constitute a regularly recurring pair of events which may truly be spoken of as an " auricular cycle ;" and so also it is exact to say that the ventricles have their cycle, con- sisting of systole and succeeding diastole. As soon, however, as we strive for clearness, we find that the useful phrase "cardiac cycle" is necessarily arbi- trary and imperfect. A perusal of the account given on p. 78 of the " Mode of Working of the Pumping Mechanism " shows at once that each auricular cycle, consisting of systole followed by diastole, must begin shortly before- the corresponding ventricular cycle begins, and must end shortly before the corresponding ventricular cycle ends. The pumping mechanism is such that the auricular systole is completed just before the ventricular systole begins. The phrase " cardiac cycle " implies a reference to both auricular and ven- tricular events ; if now we assume that the beginning of the auricular sys- tole marks the beginning of the cardiac cycle, this must end either with the end of the auricular diastole or with the end of the ventricular diastole. In the former case the cardiac cycle would coincide with the auricular cycle, but would begin before the end of one ventricular diastole and would end before the end of another, thus containing no one complete ventricular diastole. In the second case, the cardiac cycle would contain one complete ventricular dias- tole and a fraction of another, and would also contain two auricular sys- toles. The second case is clearly even more objectionable than the first. The cardiac cycle had best be defined as consisting of all the events both auricular and ventricular which occur during one complete auricular cycle. The above discussion deals with a phrase which is a constant stumbling-block to stu- dents ; and the question may well be asked, Why should the expression "cardiac cycle" not be abolished? The answer is, that this phrase is indis- pensable in order to accentuate certain important relations of the auricular cycle to the ventricular. During a heart-beat there is a period when the auricles and ventricles are in diastole at the same time. During this period, as we have seen, blood is passing from the veins directly through the auricles into the ventricles, and all the muscular fibres of the heart are resting. This period is therefore called that of "the repose of the whole heart," or the " pause." Whenever the heai-t is not wholly at rest, either auricles or ven- tricles must be in systole. We see, therefore, that each cardiac cycle must coincide with an auricular systole, the instantly succeeding ventricular systole, and a period of repose of the whole heart ; and it is precisely these two systoles and the succeeding universal rest which most engage the attention when the beating heart is looked at in the opened chest. These three phenomena, it will be noted, exactly coincide with one complete auricular cycle, and so do not confuse the definition of the cardiac cycle which has been given already. We see, therefore, that the phrase which seemed at first so CIRCULATION. 123 misleading has a real value, and will cease to confuse if its limitations be care- fully noted. The Brevity and Variability of Bach Cycle. — From the frequency with which the cycles recur, it follows at once that each one, with its complex changes in the walls, chambers, and valves, is very rapidly performed. If, for instance, the heart beat 72 times in one minute, each cycle occupies only a little more thau 0.83 of a second. The brevity of each cycle is both an im- portant physiological fact and a cause of difficulty in studying details. Each cycle, however, necessarily is capable of completion in much less time if the pulse-rate rise ; for instance, during exercise. If repeated 144 times a minute instead of 72 times, each cycle would occupy only one-half of its previous time of completion. With a pulse of less than 60, again, each cycle would occupy over one second. Relative Lengths of the Ventricular Systole and Diastole. — An im- portant question is whether or no there is any fixed relation between the time required for a systole of the ventricles and the time required for a diastole. When the length of the cycle changes from one second to one-half a second,, will the length of the systole be diminished by one-half, and that of the dias- tole also by one-half? Or is a nearly invariable time required for the ventri- cles to do their work of ejection, while the period of rest and of receiving blood can be greatly shortened, for a while at least? The answer is that, while both systole and diastole may vary in length, the length of the systole is much the less variable, while the diastole is greatly shortened or lengthened according as the heart beats often or seldom. These facts have been ascertained as follows: A trained observer^ auscul- tated the sounds of the human heart during a number of cycles, and, at the- instant when he heard the beginning either of the first or of the second sound, made a mark upon the revolving drum of a kymograph by means of a sig- nalling apparatus. Of course, careful account was taken of the time lost between the occurrence of a sound and the recording of it. It was found that the time between the beginning of the first and that of the second sound did not vary to the same degree as the frequency of the beats. Although the interval in question may not be an exact measure of the period of ventricular systole, it is sufficiently near it for the purposes of this observation. A second method ^ depended upon the interpretation of the curve inscribed by a lever pressed upon the skin over a pulsating human artery. Such a curve exhibits two sudden changes of direction, which were taken to indicate approxi- mately the beginning and end of the injection of blood by the ventricle, and, therefore, to afford a rough measure of the duration of its systole. While the interpretation of the curve in question is not wholly settled, it seems, neverthe- ^ F. C. Bonders: " De Khythmus der Hartstoonen,'' Nederlandsch Archief voor Oenees- en Naluurkunde, 1865, p. 141. ^ E. Thurston : " The Length of tlie Systole of the Heart as Estimated from Sphygmographic Tracings," Journal of Anatomy and Physiology, 1876, vol. x. p. 494. 124 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. less, to give a fair basis for conclusions as to the present question. The figures resulting from the second method are especially instructive. It was found that, with a pulse of 47 to the minute, the approximate length of the ventricular systole was 0.347 of a second ; of the diastole, 0.930 of a second.^ With a pulse of 128 to the minute, while the systole was only moderately diminished, viz. to 0.256 of a second, the diastole was I'educed to 0.213 of a second — an enormous decline. These results upon the human subject have been confirmed upon animals by experiments in which were registered the movements of a lever laid across the exposed heart ; ' or the fluctuations of the pressures within the ventricles.^ By whatever means investigated, the ventricular systole is found to be shortened with the cycle, and to be lengthened with it ; the diastole is short- ened or lengthened much more, however. In fact, if the pulse become very frequent, ■ the diastole may be so shortened that the "pause" nearly disap- pears, and the systole of the auricles follows speedily after the opening of the cuspid valves. This signifies that, for a time, the cardiac muscle can do with very little rest, and that effective means exist for a very rapid " charg- ing " of the ventricular cavity when necessary. For the working period of the ventricle, however, a more uniform time is required. For the average human pulse-rate this time of work is decidedly shorter than the time of rest — viz. about 0.3 of a second for the former as against about 0.5 for the latter. Lengths of Auricular Events and of the Pause. — The systole of the auricles is very brief, being commonly reckoned at about 0.1 of a second, as the result of various observations.* At the average pulse-rate, thei-efore, the auricular systole is only about one-third as long as the ventricular, and the length of the auricular diastole is to that of the ventricular as seven to five. Consequently, a cardiac cycle of 0.8 of a second would comprise an auricular systole of 0.1 of a second ; a ventricular systole of 0.3 of a second ; and a pause, or repose of the whole heart, of 0.4 of a second — one-half of the cycle. Practical Application. — The observations above described upon the inter- val between the beginnings of the sounds have a practical bearing upon physical diagnosis ; for they show how faulty are the statements often made which assign regular proportions to the lengths of the sounds and the silences of the heart. The length of the " second silence " must be very fluctuating, as it comprises the longer part of the fluctuating ventricular diastole. The length of the first sound and of the very brief first silence together must be very con- stant, as they nearly coincide with the ventricular systole. ' N. Baxt: "Die Verkiirzung der Systolenzeit durch den Nervns aceelerans cordis," Archiv fiir Anatomie und Physiologie, Physiologische Abtheilung, 1878, S. 122. ' M. von Frey und L. Krehl : " Untersuchungen iiber den Puis," Archiv fur Anatomie UTid Physiologie, Physiologische Abtheilung, 1890, S. 31. W. T. Porter : " Eesearches on the Filling of the Heart," Journal of Physiology, 1892, vol. xiii. p. 531. ' H. Vierordt: Daten und Tabellen zum OebrauchefUr Mediciner, 1888, S. 105. CIRCULATION. 125 M. The Peessdbes within the Ventricles.' We must now approach the study of further details of the working of the ventricuhu- pumps, which details depend for their elucidation upon the measur- ing and recording of the pressures within the ventricles. Absolute Range of Pressure ■within the Ventricles and its Signifi- cance. — In dealing with the work done by the contracting ventricles (p. 106) we have seen that the mercurial manometer, as used for studying the pressure within the arteries, is quite unable to follow the changes of the intra-ventric- ular pressure ; but that, by the intercalation of a valve, this instrument can be converted into a useful " maximum manometer " for the measuring and record- ing of the highest pressure occurring within the ventricle during a given time — that is, during a certain number of cycles. It must now be added that by a simple change of valves this same instrument can at any moment be changed into a "minimum manometer."^ We can thus, by means of the modified mer- curial manometer, learn with fair correctness the extreme range of pressure within the ventricles. As instances of the extent of this range, two observa- tions may be cited upon the left ventricle of the dog, the chest not having been opened. In one animal the maximum was found to be 234 millimeters of mer- cury, the maximum pressure in the aorta being 212 millimeters; and the min- imum in the left ventricle was —38 millimeters — that is to say, 38 millimeters less than the pressure of the atmosphere, the minimum pressure in the aorta ^ The matters connected witli tlie ventricular pressiire-cm-ve may best be studied in the fol- lowing writings, in which citations of other papers may be found : K. Hiirthle, in Pjiuger's Archiv fur die gesammte Physiologie, as follows; "Zur Technik der Untersucliung des Blut- druckes," 1888, Bd. 43, S. 399. "Technische Mittheilungen," 1890, Bd. 47, S. 1. "Ueber den Trsprungsort der sekundaren Wellen der Pulscurve," Bd. 47, S. 17. "Technische Mit- theilungen," 1891, Bd. 49, S. 29. "Ueber den Zusammenhang zwisohen Herzthatigkeit und Pulsform," Bd. 49, S. 51. " Kritik des Lufttransmissionsverfahrens," 1892, Bd. 53, S. 281. '' Vergleichende Priifung der Tonographen von Frey's und Hiirthle's," 1893, Bd. 55, S. 319. J. A. Tschuewsky : " Vergleichende Bestimmung der Angaben des Quecksilber — und des Feder- Manometers in Bezugaufden mittleren Blutdruck," Pflliger' s Archiv fur die gesammte Physiologie, 1898, Bd. Ixxii. S. 5S.5. "Technische Mittheilungen," Ibid., 1898, Bd. Ixxii. S. 566. K. Hiirthle : " Orientirungsversuche iiber die Wirkung des Oxyspartein auf das Herz, Archiv fiir ezperimentelle Pathologie und Pliannakulngie, 1892, Bd. xxx. S. 141. AV. T. Porter: "Researches on the Filling of the Heart," 2'he Journal of Physiology, 1892, vol. xiii. p. 513. "A New Method for the Study of the Intracardiac Pressure Curve," Journal of Experimental Medicine, 1896, vol. i., JSTo. 2. M. von Frey und L. Krehl : " Untersuchungen iiber den Puis," Archiv fiir Anatomic and Physiologie, T?hysio\ogische Abtheilung, 1890,8.31. M. von Frey: "Die Untersuchung des Pulses," Berlin, 1892. " Das Plateau des Kammerpulses," Archiv fiir Anatomic und Physiologie, Physiologische Abtheilung, 1893, S. 1. "Die Ermittlung absoluter Werthe fiir die Leistung von Pulsschreibern," Archiv fiir Anatomic und Physiologie, Physiologische Abtheilung, 1893, S. 17. "Zur Theorie der Lufttonographen," Archiv fiir Anatomic und Physiologic, Physiologische Abtheilung, 1893, IS. 204. " Die Erwiirmung der Luft in Tonographen," Ccntralblatt fiir Phys- iologie vom 30 Jnni, 1S94, Heft 7. O. Frank: " Ein experimentelles Hilfsmittel fiir Fine Kritik der Kammerdnickcurven," Zeitschrift fiir Biologic, 1897, Bd. xxxv. S. 478. R. Rub- brecht : "Recherches cardiographiques chez les Oiseaux," Archives de Biologic, 1898, t. xv. p. 647. J. Waroux : "Du trac^ myographique due cteur exsangue," Ibid., 1898, t. xv. p. 661. ^ F. Goltz und J. Gaule : " Ueber die Druckverhiiltnisse im Innern des Herzens," PJIiiger' s Archiv fur die gesammte Physiologic, 1878, xvii. S. 100. 126 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. being 120 millimeters. In a second dog the figures were 176 and —30 milli- meters for the ventricle, the aortic range being from 158 to 112 millimeters.' In the right ventricle of the dog such ranges as from 26 to —8 millimeters, from 72 to —25, and various intermediate values, have been noted, both in the unopened and the opened chest.^ For reasons already stated (p. 103) no trustworthy figures can be given for the pressures in the pulmonary artery ; but they can never fail to be less than the highest pressures within the right ventricle. The range of pressure, therefore, within either ventricle is in sharp contrast to that within the artery which it supplies with blood ; for the arterial pressure, although it fluctuates, is at all times far above that of the atmosphere, and is able, as we have seen, to maintain the circulation while the semilunar valve is closed and the ventricular muscle is at rest. On the otlier hand, the pressure within the ventricle, when at its highest, rises decidedly above the highest arterial pressure, and thus the ventricle can overcome this and other opposing forces, open the valve, and expel the blood. These facts have been stated already. In falling, however, the pressure within the ventricle not only sinks below that in the artery, and so permits the semilunar valve to close, but sweeps downward to a point, it may be, below the pressure of the atmosphere, and, in so doing, falls below the pressure in the auricle, and permits the open- ing of the auriculo-ventricular valve and the entrance of blood out of the auricle and the veins. As such a great range of pressure occurs in either ventricle of a heart which is repeating its cycles with entire regularity, it is presumable that at every cycle the pressure not only rises above that in the arteries but may sink below that of the atmosphere. Methods of Recording' the Course of the Ventricular Pressure. — It now becomes of interest to ascertain, if possible, not only the range, but the exact course, of these swift variations of pressure ; the causes of them, and the effects which accompany them. It is hard to obtain, by the graphic method, a correct curve of the pressure within either ventricle. We have seen that the mercurial manometer is useless for this purpose ; and it is very difficult to devise any self-registering manometer which shall truly keep pace with fluctu- ations at once so great and so rapid. The true form of this pressure-curve, therefore, still is partially in doubt, and is the subject of controversies which largely resolve themselves into contests between rival instruments. The following characters are common to the manometers with which the most serious attempts have lately been made to obtain a true and minute record of the fluctuations of pressure, even if great and rapid, within the heart or the vessels (see Fig. 21). As in the case of the mercurial manometer, a cannula, open at the end and charged with a fluid which checks the coagulation of the blood, is tied into a vessel, or, if the heart is under observation, is passed down into it through an opening in a jugular vein or a carotid artery. If the chest ' S. de Jager : ' ' IJeber die Saugkraft des Herzens," Pfluger' s ArcUv fur die gesammU Physi- ologic, 1883, Bd. xxxi. S. 491. = S. de Jager: hoc. dt., S. 506, 507 ; Goltz und Gaule: Loe. ciL, S. 106. CIRCULATION. 127 have been opened, the cannula may also be passed into the heart through a small wound in an auricle or even through the walls of the ventricle itself. The end of the cannula which remains without the animal's body is connected, air-tight, with a rigid tube of small, carefully chosen calibre, and as short as the condi- tions of the experiment permit. The other end of this tube is not, as in the mercurial manometer, left as an open mouth, but is connected, air-tight, with a very small metallic chamber, which constitutes, practically, a dilated blind extremity of the system formed by the tube and the cannula together. The roof of this small metallic chamber is a highly elastic disk either of thin metal or of india-rubber. Except for this small disk, all parts of the chamber, tube, and cannula are rigid. In the instruments of some observers, the entire cavity of the system formed by the chamber, tube, and cannula is filled with liquid, viz. the solution which checks coagulation. Other observers introduce this Fig. 21.— Diagram of the elastic manometer : A, auricle ; V, ventricle ; D, drum of the kymograph, revolving in the direction of the arrow, and covered with smoked paper; X, recording lever in contact with the revolving drum. (The working details of the instrument are suppressed for the sake of clear- ness.) liquid only into the portion of the system nearest the blood ; the terminal chamber, and most of the rest of the system, containing only air. In every case the blood in the vessel or in the heart is in free communication, through the mouth of the tied- in cannula, with the cavity common to the tubes and to the terminal chamber. At every rise of blood-pressure a little blood enters this cavity, room being made for it by a displacement of liquid or of air, which in turn causes a slight bulging of the elastic disk. At every fall of blood-pressure a little blood mixed with liquid leaves the tubes as the elastic disk recoils. If the disk is of the right elasticity, its rise and fall are directly proportional to the rise and fall of the blood-pressure, and can be used to measure it. With the centre of the disk is connected a delicate lever which rises and falls with the disk. The point of this lever traces upon the revolving drum of the kymograph a curve which records the fluctuations of the disk and therefore those of the blood-pressure. The elastic disk and the contents, together, of such an apparatus possess less inertia than mer- cury, and therefore follow far more closely rapid fluctuations of pressure. Such instruments may be called " elastic manometers," and are often called *' tonographs," i. e. " tension-writers." They are of several forms. 128 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. It has been indicated already that the pressure of the blood may be communicated to the disk of an elastic manometer either by means of liquid or of air. A given series of fluctuations of blood-pressure may yield decidedly different curves according to the method of " transmission " employed to obtain them ; and the controversies as to the true form of the endocardiac pressure-trace turn upon the question whether such " transmission by air " or " transmission by liquid " yield the truer curve. The objections to the former method depend upon the readier compressibility of air ; the objections to trans- mission by liquid depend upon its greater inertia. The General Characters of the Ventricular Pressure-curve. — What- ever kind of elastic manometer and of transmission be used, the curve dlilUmeters of ■mercury. ine of atmospheric- pressure. Seconds. Fig. 22.— Magnified curve' of the course of pressure within the right ventricle of the dog, the chest being open ; to be read from left to right, fleeorded by the elastic manometer, with transmission by air (von Frey). obtained shows certain characters which are recognized by all as properly belonging to the changes of pressure within the ventricle, whether right or left. These general characters, moreover, persist after the opening of the chest. They are as follows (.see Figs. 22, 23, 24) : The muscular con- traction of the systole begins quite suddenly, and produces a swift and ex- Live of atmospheric pressure. Fig. 23 — Magnified curve of the course of pressure within the left ventricle and the aorta of the dog, the chest being open ; to be read from left to right. Recorded simultaneously by two elastic man- ometers with transmission by liquid. In both curves the ordinates having the same numbers have the following meaning : 1, the instant preceding the closing of the mitral valve ; 2, the opening of the semi- lunar valve ; 3, the beginning of the " dicrotic wave," regarded as marking the Instant of closure of the semilunar valve ; 4, the instant preceding the opening of the mitral valve (Porter). tensive rise of pressure, marked in the curve by a line but slightly inclined from the vertical. In the same way the fall of pressure is nearly as sudden and as swift as the rise, and perhaps even more extensive. The systolic rise begins at a pressure a little above that of the atmosphere ; the diastolic fall continues, toward its end, perhaps, with diminishing rapidity, till a point is CIRCULATION. 129 reached often below the pressure of the atmosphere. The pressure then rises, perhaps continuing negative for a longer or shorter time, but presently becoming equal to that of the atmosphere. Near this it continues, perhaps with a gentle upward tendency, until, near the end of the ventricular diastole, the rise becomes more rapid to the point at which the succeeding ventricular systole is to begin. It is the course of the pressure between its rapid rise and its rapid fall which has been the most disputed. The observers who employ manometers with liquid transmission, have so far found that the high swift rise at the outset of the systole is soon succeeded by a sudden change. According to them the pressure within the manometer now exhibits fluctuations of greater or less extent which are due, partly at least, to the inertia of the transmitting liquid ; but, with due allowance made for these, the cardiac pressure is seen to maintain itself at a high point throughout most of the systole until the rapid fall begins. During this period of high pressure, the height about which the fluctuations occur may remain nearly the same ; or this height may gradually increase, or gradually decrease, up to the beginning of the rapid fall. As is shown by Figure 23, this course of the systolic pressure causes its curve to bend alternately down- ward and upward between the end of its greatest rise and the beginning of its greatest fall ; but between these two points the general direction of the curve approaches the horizontal, and therefore entitles this portion of it to the name Millimeters of mercury. Line of pressure. Tenths of a second. Fig. 24. — Magnified curve of the course of pressure within the left ventricle of the dog, the chest being open ; to be read from left to right. Recorded by the elastic manometer with transmission by air. The ordinates have the following meaning : 1, the closure of the mitral valve ; 2, the opening of the semi- lunar valve ; 3, the closure of the semilunar valve ; 4, the opening of the mitral valve (von Frey). of the "systolic plateau," a name which becomes more truly descriptive when appropriate means are taken to eliminate the fluctuations due to inertia. The best of the manometers with air transmission yields a curve of the pressure within the ventricle which presents a different picture (Figs. 22 and 24). The steeply rising line may diminish its steepness somewhat as it ascends, but its rapid turn at the highest point of the curve is sucoeeded by no plateau. The line simply describes a single peak, and begins the descent which marks the rapid fall of pressure recognized by all observers. In these peaked curves Vol. I.— 9 130 AN AMEBICAN TEXT-BOOK OF PHYSIOLOGY. this descent is often steepest in its middle part. Such a peaked curve would indicate, of course, that there is no such thing as the maintenance, during any large part of the systole of the ventricles, of a varying but high pressure. The experienced observer who is the chief defender of the peaked curve holds the plateau to be a product either of too much friction within the manometer tubes, or of a faulty position of the cannula within the heart, whereby com- munication with the manometer is, for a time, cut oif. The able and more numerous adherents of the plateau, on the other hand, attribute the failure to obtain it to the sluggishness of the instrument employed, or to an abnor- mal condition of the heart. Recent comparative tests of elastic manometers, and other studies, would seem to show that the curves obtained by liquid transmission, and which exhibit the plateau, afford a truer picture of the general course of the jjressure within the ventricles than the peaked curves written by means of air. The Ventricular Pressure-curve and the Auricular Systole. — It is striking testimony to the smoothness of working of the cardiac mechanism, that the curve of intra-ventricular pressure rarely gives any clear indication of the beginning or end of the auricular systole. This event may be expected to increase the pressure within the ventricles ; and, in the curve, the very gentle rise which coincides with the latter and longer part of the ventricular diastole passes into the steep ascent of the commencing ventricular systole by a rounded sweep, which indicates a more rapidly heightened pressure within the ventricle during the auricular systole. As a rule, no angle reveals an instantaneous change of rate to show the beginning or end of the injection of blood by the contracting auricle (see Figs. 22, 23, 24). Occasionally, how- ever, a slight " presystolic " fluctuation of the curve may seem to mark the auricular systole.^ The Ventricular Pressure-curve and the Valve-play. — It is also exceedingly striking that no curve, whether it be pointed or show the sys- tolic plateau, gives a clear indication of the instant of the closing or open- ing of either valve, auriculo-ventricular or arterial (see Figs. 22, 23, 24). These instants, so important for the significance of the curve, can, however, be marked upon it after they have been ascertained indirectly. A method of general apjjlication would be as follows : Two elastic manometers are " absolutely graduated " by causing each of them to record a series of pressures already measured by a mercurial manometer. The two elastic manometers can then be made to mark upon the same revolving drum the simultaneous changes of pressure in a ventricle and in its auricle, or in a ventricle and its artery. The pressure indicated by any point of either curve can then be calculated in terms of millimeters of mercury. That point upon the intra-ventricular curve which marks a rising pressure just higher than the simultaneous pressure in the auricle or artery, may be taken to mark the closing of the cuspid valve or the opening of the semilunar valve, as the case may be. By a converse process, the moment of opening of the cuspid valve, or of closing of the semi- ' von Frey and KreU : op. lAt, p. 61. CIRCULATION. 131 lunar, may also be ascertained. The practical difficulties in the way of applying this method to the ventricle and auricle are mucli greater than to the ventricle and artery. By another application of the principle just described, a " differential manometer " has been devised for the purpose of registering as a single curve the successive differences, from moment to moment, between the ventricular and auricular pressures, or the ventricular and arterial pressures (see Fig. 25). To this end, two elastic manometers are fastened immovably together, and their two elastic disks, instead of bearing upon separate levers, are made to bear upon a single one, which has its fulcrum between the disks, and is a lever not of the third order, but of the first, like a common balance. Fig. 25. — Diagram of the differential manometer: A, artery: V, ventricle; D, drum of kymograph, revolving in the direction of the arrow, and covered with smoked paper; L, recording lever in contact with the revolving drum ; S, a spring hy which the movement of the lever worked by the disks is trans- mitted to the recording lever. (The working details of the instrument are suppressed or altered for the sake of clearness.) As the lever or beam of the balance turns from the horizontal as soon as the scales are pressed upon by unequal weights, so the lever of the differential manometer turns as soon as the disks are unequally affected by the pressures within the ventricle and the auricle, or the ventricle and the artery. As, how- ever, the pressures upon the scales are from above, while those upon the disks are from below, the disk which tends to " kick the beam " is the one acted upon by the greater pressure, instead of by the less, as in the case of the scales. The manometric lever marks its oscillations as a curve upon the kymograph by the help of a second or " writing lever " connected with it. The persistence of exactly equal pressures, no matter what their absolute value, in the two manometers would cause a horizontal line to be drawn by the writing lever. This would serve as a base-line. The differential manometer is a valuable instrument, although it is evident that where such minute differences of space and time are recorded as a curve by such complicated mechanisms, the sources of error must be numerous and difficult to avoid.^ The methods which proceed by the measurement of differences of pressure may sometimes be controlled, or even replaced, by an easier method, as follows : If two manometers simultaneously record on the same kymograph the pressure- ' K. Hiirthle: Pfliiger's Archivfur die. gesammte Physiologic, 1891, Bd. 49, S. 45. 132 AN AMEBICAN TEXT-BOOK OF PHYSIOLOGY. curves of the ventricle and the auricle, or of the ventricle and the artery, any very sudden change of pressure, produced in auricle or artery at the opening or shutting of a cardiac valve, will produce a peak or angle in the curve of pres- sure of the auricle or artery. By the rules of the graphic method the point in the pressure-curve of the ventricle can easily be found which was written at the same instant with the peak or angle in the auricular or arterial curve. That point upon the ventricular curve, when marked, will indicate the instant of opening or shutting of the valve in question. In the pressure-curve ob- tained from the aorta close to the heart, there is a sudden angle which clearly marks the instant when the opening of the semilunar valve leads to the sudden rise of pressure which causes the up-stroke of the pulse (see Fig. 23). Again, the fluctuation of aortic pressure which we shall learn to know as the " dicrotic wave" begins at a moment which many believe to follow closely upon the clos- ure of the semilunar valve. That moment may be indicated by a notch in the aortic curve. So, too, the rise of pressure within the auricle produced by its systole may suddenly be succeeded by a fall, the beginning of which must mark the closure of the cuspid valve, which closure thus may correspond with the apex of the auricular curve. In Figure 23, ordinate 1 indicates the closing, and ordinate 4 the open- ing, of the mitral valve. These two points were found by help of the dif- ferential manometer. Ordinate 2 indicates the opening, and ordinate 3 the closing, of the aortic valve. These two points were marked with the help of the curve of aortic pressure, also shown in Figure 23, each ordinate of which has the same number as the corresponding ordinate of the ventricular curve. In the arterial curve, 2 marks the beginning of the systolic rise, and 3 the beginning of the dicrotic wave, which latter point is treated by the observer as closely corresponding, to the closure of the aortic valve. In Figure 24 each ordinate has the saine number, and, as regards the valve- play, the same significance, as in Figure 23. Ordinate 1 corresponds to the apex of a peak in the auricular curve (not here given) which represents the end of the auricular systole. Ordinate 2 corresponds to the beginning of the systolic ascent in the aortic curve (not here given). Ordinate 3 was found by comparing, by means of two elastic manometers, the simultaneous pressures in the ventricle and the aorta. Ordinate 4 corresponds, on the auricular pressure-curve, to a point which marks the beginning of a decline of pres- sure believed by the observer to succeed the opening of the cuspid valve. In both the figures given of the ventricular curve, and in such curves in general, the points which mark the valve-play occur as follows : The closure .of the cuspid valve corresponds to a point, not far above the line of atmospheric pressure, whei-e the moderate upward sweep of the ventric- ular curve takes on the steepness of the systolic ascent. The systole of the auricle is of little force, and the blood injected by it into the distensible ven- tricle raises the pressure there but little ; that little, however, is more than the relaxing auricle presents, and the cuspid valve is closed. Somewhere on the steep systolic ascent occurs the point corresponding to the rise of the ven- CIBCULA TION. 133 tricular above the arterial pressure, and therefore to the opening of the semi- hinar valve. But other forces beside the arterial pressure must be overcome by the contracting muscle ; and the ventricular pressure mounts higher yet, and either stays high for a while, producing the plateau, or, in a peaked curve, at once descends. In either case, not long after the beginning of the sharp descent, the point occurs at which the ventricular pressure falls below the arte- rial, and the semilunar valve is closed. Beyond this point the curve continues steeply downward, but it is not till a point is reached not far above, or possibly even below, the atmospheric pressure that the pressure in the ventricle falls below that in the auricle, and the cuspid valve is opened. The Period of Reception, the Period of Ejection, and the Two Periods of Complete Closure of the Ventricle. — During the whole of the period when the cuspid valve is open, the pressure is lower in the ventricle than in the artery; the arterial valve is shut; and blood is entering the ventricle. This may be called the " period of reception of blood." During the greater part of the period when the cuspid valve is shut, the arterial valve is open ; the pressure is higher in the ventricle than in the artery; and the ejection of blood from the former is taking place. This may be called the " period of ejection," and lies in Figures 23 and 24 between the ordinates 2 and 3. The careful work which has enabled us to mark the valve-play upon the ventricular curve has demonstrated the interesting fact that there occur two brief periods during each of which both valves are shut, and the ven- tricle is a closed cavity. Of these two periods, one immediately precedes the period of ejection, and the other immediately follows it. The first lies, in Figures 23 and 24, between the ordinates 1 and 2 ; the second, between 3 and 4. The explanation of these two periods is simple. It takes a brief but measurable time for the cardiac muscle, forcibly contracting upon the impris- oned liquid contents of the closed ventricle, to raise the pressure to the high point required to overcome the opposing pressure within the artery and to open the semilunar valve. Again, it takes a measurable time, probably seldom quite so brief as the period just discussed, for the cardiac muscle to relax suffi- ciently to permit the pressure in the closed ventricle to fall to the low point required for the opening of tlie cuspid valve. The ventricular cycle, thus studied, falls into four periods : the first is a brief period of complete closure with swiftly rising pressure; the second is the period of ejection, relatively long, and but little variable ; the third is a period of complete closure, with swiftly falling pressure ; the fourth is the period when the pressure is low and blood is entering the ventricle. This last period is very variable in length, but at the average pulse-rate it is the longest period of all. Phenomena of the Period of Reception of Blood. — "We have already followed the course of the pressure within the ventricle from the moment of opening of the aui'iculo-ventricular valve to that of its closing (p. 128). During this time the ventricle is receiving its charge of blood, the flaccidity of the wall rendering expansion easy and keeping the pressure low. The blood which enters first has been accumulating in the auricle since the closing of the ]34 AN AMJEBICAN TEXT-BOOK OF PHYSIOLOGY. cuspid valve, and now, upon the opening of this, it both flows and is to some slight degree drawn into the ventricle. This blood is followed by that which, during the remainder of the " repose of the whole heart," moves through the veins and the auricle into the ventricle under the influence of the arterial recoil and the other forces which cause the venous flow (p. 93) ; and the charge of the ventricle is completed by the blood which is injected at the auricular systole. The Negative Pressure within the Ventricles. — That the heart, in its diastole, draws something from without into itself is a very ancient belief, and this mode of its working played a great part in the doctrines of Galen and of the :Middle Ages. In 1543, A'esalius, who, on anatomical grounds, questioned some of Galen's views as to the cardiac physiology, fully accepted this one.' On the other hand, in 1628, Harvey rejected it. " It is manifest," he says, "that the blood enters the ventricles not by any attraction or dilatation of the heart, but by being thrown into them by the pulses of the auricles." ^ In this particular, modern research in some degree confirms the opinion of the ancients, while denying to suction within the ventricles any such great effect as was once believed in. As a rule, the cuspid valve is not opened till the pressure in the ventricle has fallen to a point not far from the pressure of the atmosphere ; it may be even below it. In any case the ventricular pressure usually becomes negative very soon after the opening of the cuspid valve. This negative pres- sure is of variable extent and continues for a variable time. It is always small as compared with the positive pressure of the systole. Under some circumstances negative pressure may be absent, but it is so very com- monly present as certainly to be a normal phenomenon (see Figs. 22, 23, and 24). This negative pressure is revealed by the elastic as well as by the minimum mercurial manometer; it is present in both ventri- cles ; and it is present, to a less degree, even after the chest has been opened, and its aspiration destroyed. It is in virtue of the forces which produce the negative pressure in the manometer that blood is drawn into the heart. Passing by disproven or improbable theoi'ies as to the causes of this suction, we shall find the following statements justified : As the heart lies between the lungs and the chest-wall (including in this term the diaphragm), it is subject, like the chest-wall and the great vessels, to the continuous aspiration produced by the stretched fibres of the elastic lungs. At every inspiration this aspiration is increased by the contraction of the inspiratory muscles. We see, therefore, that the ventricle must overcome this aspiration as part of the resistance to its contraction ; and that, as soon as that contraction has ceased, the walls of the ventricle must tend to be drawn asunder by those same forces of elastic recoil in the pulmonary fibres, and of contraction of the muscles of inspiration, which we have seen (p. 95) to produce a slight suction within the great veins in and ' Andraz Vewlil BruxdUnsU, SckolcB medicorum Palavincs professoris, de Humani corporis fahrica Libri septan. Basileje, ex officina loannis Oporini, Anno Salutis reparatae MDXLIII. Page 587. '' Op. cit., 1628, p. 26: Willis's translation, Bowie's edition, 1889, p. 28. CIBCULA TION. 1 35 very near the chest. These same forces produce a slight suction within the ventricles, relaxed in their diastole. But a very slight suction occurs at each ventricular diastole even after the chest has been opened. The causes of this are still obscure; but it is to be borne in mind that the relaxing wall of the ventricle, flabby as it is, possesses some little elasticity, especially at the auriculo- ventricular ring, and therefore may tend to resume a somewhat different form from that due to its contraction. As the result of this slight elastic recoil, a feeble suction may occur. N. The Functions of the Auricles. Connections of the Auricle. — Into the right and left auricles open the systemic and pulmonary veins respectively, and each auricle may justly be re- garded as the enlarged termination of that venous sj'stem with which it is con- nected. Until modern times the terms of anatomy reflected this view, and from the ancient Greeks to a time later than Harvey, the word " heart " com- monly meant the ventricles only, as it still does in the language of the slaughter-house. This termination of the venous system, the auricle, com- municates directly with the ventricle, at the auriculo-ventricular ring, by an aperture so wide that, when the cuspid valve is freely open, auricle and ven- tricle together seem to form but a single chamber. The Auricle a Feeble Force-pump ; the Pressure of its Systole. — The wall of the auricle is thin and distensible ; it is also muscular and contractile. But the slightest inspection of the dead heart shows how little force can be exerted by the contraction of so thin a sheet of muscle. In the wall of the appendix, however, the muscular structure is more vigorously developed than over the rest of the auricle. The auricle, then, should be a very feeble force- pump ; and such in fact, it is ; for the highest pressure scarcely rises above 20 millimeters of mercury in the right auricle of the dog,' and an auricular sys- tole often produces a pressure of only 5 or 10 millimeters.^ This would be but a small fraction of the maximum ventricular pressure of the same heart. The auricle, however, is equal to its work of completing the filling of the ventricle; and the feebleness of the auricle will not surprise us when we consider that, at the beginning of its systole, the pressure exerted by the contents of the relaxed ventricle is but little above that of the atmosphere, and oifers small resistance to the injection of an additional quantity of blood. The systole of the auricles is so conspicuous a part of the cardiac cycle when the beating heart is looked at, that its necessity is easily overrated. Even Har- vey, in attacking the errors of his day, was led by imperfect methods to estimate too highly the work of the auricular systole (see p. 134). The error, although a gross one, is not rare, of considering the systole of the auricles to be as im- portant for the charging of the ventricles as the systole of the ventricles is for the charging of the arteries. On page 98 the proof has already been given ' Goltz und Gaule: op. cit., p. 106. * W. T. Porter : op. at, p. 533. S. de Jager : op. cit., p. 506. 136 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. that the work of the heart may entirely suffice to maintain the circulation with- out aid from any subsidiary source of energy. It must now be added that the ventricles can, for a time, maintain the circulation without the aid of the auric- ular systole — a clear proof that this systole is not a sine qua non for the working of the cardiac pump. If in an animal, not only ansesthetized but so drugged that all its skeletal muscles are paralyzed, artificial respiration be established and the chest be opened, the circulation continues. If the artificial respiration be suspended for a time, the lungs collapse, asphyxia begins, and the blood accumulates conspicuously in the veins and in the heart. Presently the muscular walls of the auricles may become paralyzed by overdistention, and their systoles may cease, while the ventricles continue at work and may maintain a circu- lation, although of course an abnormal one. After the renewal of artificial respiration, it may not be till several beats of the ventricles have succeeded, without help from the auricles, in unloading the latter and the veins, that the auricles recommence their beats.' On the other hand, it is clear that the auricle is not without importance as a force-pump for completing the filling of the ventricle, even if it can be dis- pensed with for a time. In curves of the blood-pressure during asphyxia taken simultaneously from the auricle and the ventricle, there may be noted the influ- ence exerted upon the ventricular curve by ineffectiveness of the auricular sys- tole. It is found that, in this case, that slight but accelerated rise of pressure may fail which normally just precedes, and merges itself in, the large swift rise of the ventricular systole. It is found, too, that, under these circumstances, the total height of this systolic rise may be diminished.^ We shall see pres- ently how, when the pulse becomes very frequent, the importance of the auric- ular systole may be increased, ^^'e have seen already (p. 132) that normally it may probably effect the closure of the cuspid valves. Time-relations of the Auricular Systole and Diastole. — The auricular systole is not only weak, but brief, being commonly reckoned at about 0.1 of a second (see p. 124). If this be correct for man, at the average pulse- rate of 72 the auricular systole would comprise only about one-eighth of the cycle ; would be only one-seventh as long as the auricular diastole ; and only about one-third as long as the ventricular systole which immediately follows that of the auricle. The Auricle a Mechanism for Facilitating the Venous Flow and for the "Quick-charging" of the Ventricle. — Further points in regard to the systole of the auricles can best be treated of incidentally to the general question. What is the principal use of this portion of the heart? The answer is not so obvious as in the case of the ventricles. It may, however, be stated as follows : The auricle is a reservoir, lying at the very door of the ventricle. That door, the cuspid valve, remains shut during the relatively long and un- varying period of the ventricular systole and the brief succeeding period of fall- 1 von Frey und Krehl : op. ciL, pp. 49, 59. G. Colin : Tmite de physiologic comparee den ani- maux, Paris, 1888, vol. ii. p. 424. ■' von Frey und Krehl : op. cit., p. 59. CIRCULATION. 137 ing pressure within the ventricle. These periods coincide with the earlier part of the auricular diastole. During all this time the forces which cause the venous flow are delivering blood iuto the flaccid and distensible reservoir of the auricle, and can thus maintain a continuous flow. But the blood of which the veins are thus relieved during the period of closure of the cuspid valve, accumulates just above that valve to await its opening. When it is opened by the superior auricular pressure, the stored-up blood both flows and is drawn into the ventricle promptly from the adjoining reservoir. From this time on, auricle and ventricle together are converted into a common storehouse for the returning blood during the remainder of the repose of the whole heart, which coincides with the later portion of the long auricular diastole. The next auricular systole completes the charging of the ventricle ; and a second use of this systole now becomes apparent, for the sudden transfer by it of blood from auricle to ventricle not only completes the filling of the latter, but lessens the contents of the auricle, and so prepares it to act as a storehouse during the coming systole of the ventricle. The auricle, then, is an apparatus for the maintenance of as even a flow as possible in tlie veins and for the rapid and thorough charging of the ventricle. It is clear that, for both uses, the auricle's function as a reservoir is certainly no less important than its function as a force-pump. The value of a mechanism for the rapid filling of the ventricle increases with the pulse-rate, and with a very frequent pulse must be of great import- ance, because now time must be saved at the expense of the pause, with its quiet flow of blood through the auricle into the ventricle ; and the auricular systole must follow more promptly than before upon the opening of the cus- pid valve. If the pulse double in frequency, each cardiac cycle must be com- pleted in one-half the former time; but we have seen that the ventricle I'equires for its systole a time which cannot be shortened with the cycle to the same degree as can its diastole. Of heightened value now to the ventricle will be the adjoining reservoir, which is filling while the cuspid valve remains closed, and from which, as soon as that valve is opened, the necessary supply not only flows, but is sucked and pumped into the ventricle, for, when increased demands are made upon the heart, the usefulness of an increased frequency of beat disappears if the volume transferred at each beat from veins to arteries diminish in the same proportion as the frequency increases. No increase of the capillary stream can then follow the more frequent strokes of the pump.^ Neg-ative Pressure within the Auricle ; its Probable Usefulness. — The course of the pressure-curve of the auricle, as shown by the elastic manome- ter, is too complex and variable, and its details are too much disputed, for it to be given here. But certain facts regarding the auricular pressure are of much interest in connection with the use of the auricle which has just been discussed. Once, and perhaps oftener, in each cycle, the pressure in the auricle may become negative, perhaps to the degree of from —2 to —10 millimeters of mercury even in the open chest,^ and of course becomes still more so when ' von Frey und Krehl : op. cit., p. 61. ^ de Jager : op. cit., p. 507. AV. T. Poi-ter : op. cit, p. 533. 138 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the latter is intact, sinking in this case to perhaps— 11.2 millimeters.' What is striking in connection with the " quick-charging " of the ventricle is that the greatest and longest negative pressure in the auricle coincides, as we should expect, with the earlier part of its diastole, and therefore with the systole of the ventricle, when the auricle is cut off from it by the shut valve.^ By this suction within the auricle the flow from the veins into it probably is heightened, and the store of blood increased which accumulates in the reservoir to await the opening of the valve. The quick-charging mechanism itself is quickly charged. Nor should it be forgotten that the work of the ventricle contributes in some degree to this suction within the auricle. The heart is air-tight in the chest, which is a more or less rigid case. At each ventricular systole the heart pumps some blood out of this case, and shrinks as it does so, thus tending to produce a vacuum ; in other words, to increase the amount of negative pressure within the chest, and thus help to expand the swelling auri- cles. Therefore for the suction which helps to charge the auricles during the systole of the ventricles, that systole itself is partly responsible.^ Is the Auricle Emptied by its Systole ? — Authorities differ still as to the extent to which the auricle is emptied by its systole ; some holding the scarcely probable view that, during this time, its contents are all, or nearly all, trans- ferred to the ventricle ; * and others taking the widely different view that the auricle actually continues to receive blood during its systole, which latter simply increases the discharge into the ventricle. According to this latter opinion the flow from the great veins into the auricle is absolutely unbroken." All are agreed, however, that the auricular appendix is the most completely emptied portion of the chamber. Are the Venous Openings into the Auricle closed during- its Systole ? If not, does Blood then regurgitate, or enter ? — As to these questions dif- ferences of opinion are possible, because at the openings of the veins into the auricle no valves exist which are effective in the adult, except at the mouth of the coronary sinus. It is therefore a question, what happens at the mouths of the veins during the auricular systole. These mouths are surrounded by rings composed of the muscular fibres of the auricular wall ; and for some distance from the heart the walls of some of the great veins are rich in circular fibres of muscle. We have seen already (p. 115) that a rhythmic contraction of the venae cavse and pulmonary veins occurs just before the systole of the auricles and must accelerate the flow into the latter. Their swiftly following systole is known to begin at the mouths of the great veins and from these to spread over the rest of each auricle. It is evident at once that the circular fibres must ' Goltz und Gaule : op. cil., p. 109. '' von Frey uud Krehl: op. cit, p. 53; W. T. Porter: op. cit, p. 523. * A. Mosso : Die Diaynostik des Pulses, etc. Zweiter Theil : Ueber den negativen Puis, S. 42. * JI. Foster: A Text-book of Physiology, New York, 1896, p. 182, '" Skoda : " Ueber die Function der Vorkammern des Herzens,'' Silzungsberichte der mathem,.- naiurw. Olasse der kais. Akademie der Wissenschaften in Wim, 1852, Bd. ix. S. 788. L. Her- mann : Lehrbuch der Physiologie, 1900, S. 66. CIB C VLA TION. 139 either narrow or obliterate, like sphincters, the mouths of the veins at the out- set of the systole, and that these fibres thus take the place of valves. If the closure be complete, all the blood ejected by the systole must enter the ventricle, and a momentary standstill of blood and rise of pressure in the veins just with- out the auricle must accompany its brief systole. A recent observer believes the flow into the auricle to be interrupted even more than once during its cycle.^ If the venous openings be not closed but only narrowed during the systole of the auricles, the transfer of all or most of the ejected blood to the ventricle must depend upon the pressure being lower therein than at the venous openings. A slight regurgitation into the veins w^ould, like the complete closing of their mouths, cause a momentary checking of their blood-flow just without the auri- cle, and a slight rise of pressure. Such a checking of the flow has in some cases been observed and ascribed to regurgitation.^ A systolic narrowing with- out closure of the venous mouths would leave room also for the view already given, that so far is regurgitation from taking place, that even during the sys- tole of the auricles blood enters them incessantly, and the venous flow is never checked. In this case the systole of the auricle would still empty it p.artially into the ventricle, owing to the lowness of the pressure there. The time has not arrived for a decision as to all these questions, which are surrounded by practical difficulties ; but fortunately they do not throw doubt upon the functions of the auricle as a reservoir and pump which may be swiftly filled, and may swiftly complete the filling of the ventricle which it adjoins. O. The Abtebial Pulse. Nature and Importance. — The expression " arterial pulse " is restricted commonly to those incessant fluctuations of the arterial pressure which corre- spond with the incessant beatings of the ventricles of the heart. These rhyth- mic fluctuations of the arterial pressure have been explained already (p. 92) to depend upon the rhythmic intermittent injections of blood from the ven- tricles ; upon the resistance to these injections produced by the friction within the blood-vessels ; and upon the elasticity of the arterial walls. It has also been explained that the interaction of these three factors is such that the blood, ■in travei'sing the capillaries, comes to exert a continuous pressure, free from rhythmic fluctuations; in other words, that the pulse undergoes extinction at the confines of the arterial system. It is at once apparent that the pulse may be affected by an abnormal change, either in the heart's beat, in the elas- ticity of the arteries, or in the peripheral resistance, or by a combination of such changes; and that, therefore, the characters of the pulse possess an importance in medical diagnosis which justifies a brief further discus- sion of them. A pulsating artery not only expands, but is lengthened. The sudden > W. T. Porter : (^. cit, p. 534. * Franfois-Franck : "Variations de la vitesse du sang dans les veines sous I'influence de la systole de Toreillette droite," Archives de physiohgie normale el pathologique, 1890, p. 347. 140 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. increase in the contents of an artery which causes the pulse therein, is accom- modated not merely by the increase of calibre which produces the " up-stroke " of the arterial wall against the finger, but also by an increase in the length of the elastic vessel. If the artery be sinuous in its course, this increase in length suddenly exaggerates the curves of the vessel, and thus produces a slight wriggling movement. This is sometimes very clearly visible in the temporal arteries of emaciated persons. On the other hand, the increase in the calibre of the artery is relatively so slight that it is invisible at the profile even of a large artery, dissected clean for a short distance for the purpose of tying it. Such a vessel appears pulseless to the eye, although its pulse is easily felt by the finger, which slightly flattens the artery and thus gains a larger surface of contact. Transmission of the Pulse. — If an observer feel his own pulse, placing the finger of one hand upon the common carotid artery, and that of the other upon the dorsal artery of the foot at the instep, he will perceive that the pulse corresponding to a given heart-beat occurs later in the foot than in the neck. This phenomenon is readily comprehended by considering that room for the " pulse-volume " injected by the heart is made in the root of the arterial system both by local expansion and by a more rapid displacement of blood into the next arterial segment. This next segment, in turn, accommodates its increased charge by local expansion and by a more rapid displacement ; and this same process involves segment after segment in succession, onward toward the capillaries. The expansion of the arterial system, then, is a progressive one, and, as the phrase is, spreads as a wave from the aorta onward to the arteri- oles. The rate of transmission of the " pulse- wave " from a point near the heart to one remote from it, may be calculated. This is done by comparing the time which elapses between the occurrence of the up-stroke of the pulse in the nearer and in the farther artery with the distance along the arterial system which separates the two points of observation. In one case, for exam- ple, that of an adult, the absolute amount of the postponement of the pulse — that is, the time required for the transmission of the pulse-wave from the heart itself to the arteria dorsalis pedis, was 0.193 second.^ The time of transmission of tlie pulse-wave from the heart to the dorsalis pedis is often longer than in this case, amounting to 0.2 second or a little more. If we reckon the duration of the ventricular systole at about 0.3 second, it is evi- dent that the fact of the postponement of the pulse in the artei'ies distant from the heart does not invalidate the general statement that the arterial pulse is synchronous with the systole of the ventricles. The general estimates of the rate, as opposed to the absolute time, of trans- mission of the pulse-wave vary, in different cases, from more than 3 meters to more than 9 meters per second. As the blood in the arteries does not pass onward at a swifter rate than about 0.5 meter per second, it is clear that the wave of expansion moves along the artery many times faster than the blood does ; and that to confound the travelling of the wave with the travelling of ' J. N. Czermak : Oesammelte Schriften, 1879, Bd. i. Abth. 2, S. 711. CIR C ULA TION. 141 the blood would be a very serious error, easily avoided by bearing in mind the causes of the pulse- wave as already given. Investigation by the Finger. — The feeling of the pulse has been a valu- able and constantly used means of diagnosis since ancient times. Indeed, the ancient medicine attached to it more importance than does the practice of to-day. But it is still advisable to warn the beginner that he may not look to the pulse for "pathognomonic" information; that is to say, he may not expect to diagnosticate a disease solely by touching an artery of the patient under examination. The pulse is most commonly felt in the radial artery, which is convenient, superficial, and well supported against an examining finger by the underlying bone. Many other arteries, however, may be util- ized. Frequency and Regularity. — The most conspicuous qualities of the pulse are frequency and regularity. Usually these can be appreciated not merely by a physician but by any intelligent person. The physiological variations in the frequency of the heart's beats have been referred to already (p. 121). In an intermittent pulse the rhythm is usually regular, but, at longer or shorter intervals, the ventricle omits a systole, and therefore, the pulse omits an up- stroke. Either intermittence or irregularity of the cardiac beats may be caused by transient disorder as well as by serious disease. Tension. — AYhen unusual force is required in order to extinguish the pulse by compressing the artery against the bone, the arterial wall, and hence the pulse, is said to possess high tension, or the pulse is called incompressible, or hard. Conversely, the pulse is said to be of low tension, compressible, or soft, when its obliteration is unusually easy. A very hard pulse is sometimes called " wiry ; " a very soft one, " gaseous." High tension, hardness, incompressibil- ity, obviously are dii-ectly indicative of a high blood-pressure in the artery ; and the converse qualities of a low pressure. It follows from what has gone before that the causes of changes in the arterial pressure, and hence in the tension, may be found in changes either in the heart's action, or in the periph- eral resistance, or, as is very common, in both. An instrument called a sphygmomanometer ' or sphygmometer is sometimes applied to the skin over the artery, in order to obtain a better measurement of its hardness or softness, and hence of the blood-pressure within it, than the finger can make. Such instruments are not free from sources of error. Size. — When the artery is unusually increased in calibre at each up-stroke of the pulse, the pulse is said to be large. When, at the up-stroke, the calibre changes but little, the pulse is said to be small. A very large pulse is some- times called " bounding ; " a very small one, " thready." Largeness of the pulse must be distinguished carefully from largeness of the artery. The for- mer phrase means that the fluctuating part of the arterial pressure is large in proportion to the mean pressure. But if the mean pressure be great while the fluctuating part of the pressure is relatively small, the artery, even at the end of the down-stroke, will be of large calibre, while the pulse will be small. ' From avj/i6c, pulse. 142 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. It has been seen that the increased charge of blood which an artery receives at the ventricular systole is accommodated partly by increased displacement of blood toward the capillaries, and partly by that increase in the capacity of the artery which is accompanied by the up-stroke of the pulse. The less the con- tents of the artery the less is the arterial pressure, the less the tension of the wall, and the more yielding is that wall. The more yielding the wall, the more of the increased charge of blood does the artery accommodate by au increase of capacity and the less by an increase of displacement. Therefore, a large pulse often accompanies a low mean pressure in the arteries, and hence may appear as a symptom after large losses of blood. In former days, when bloodletting was practised as a remedial measure, imperfect knowledge of the mechanics of the circulation sometimes caused life to be endangered ; for a "throbbing" pulse in a patient who had been bled already was liable to be taken as an " in- dication " for the letting of more blood. If this were done, an effect was combated by repeating its cause.^ Celerity of Stroke. — When each up-stroke of the pulse appears to be slowly accomplished, requiring a relatively long interval of time, the pulse is called slow, or long. When each up-stroke appears to be quickly accom- plished, requiring a relatively short time, the pulse is called quick or short. These contrasted qualities are among the most obscure of those which the skilled touch is called upon to appreciate. The Pulse-trace. — The rise and fall of a pulsating human artery, if near enough to the skin, may be made to raise and lower the recording lever of a somewhat complicated instrument called a sphygmograph.^ Of this instru- ment a number of varieties are in use. If the fine point of the lever be kept in contact with a piece of smoked paper which is in uniform motion, a " pulse- trace" or "pulse-curve" is inscribed, which shows successive fluctuations, larger and smaller, which tend to be rhythmically repeated, and which depend upon the movements of the arterial wall produced by the fluctuations of blood- pressure. In an auimal, a manometer may be connected with the interior of an artery, and thus the fluctuations of the blood-pressure may be observed more directly. It has been explained (p. 90) that the mercurial manometer is of no value for the study of the finer characters of the pulse, owing to the inertia of the mercury. On the other hand, the best forms of elastic manometer give pulse-traces which are more reliable than those of the sphyg- mograph. This is because the sphygmographic trace is subject to unavoid- able errors dependent upon the physical qualities of the skin and other parts which intervene between the instrument and the cavity of the artery. Nevertheless, the sphygmographic pulse-trace, or " sphygmogram," is the only pulse-trace which can be obtained from the human subject ; ^nd, when obtained from an auimal, it has so much in common with the trace recorded by the elastic manometer, that the sphygmograph has been much used for the study of the human pulse, in health and disease, both by physiologists and by 1 Marshall Hall : Researches principally relative to the Morbid and Ckrative Effecti of Loss of Blood, London, 1830. , 2 From a(i>vyfi6;, pulse, and ypdfeiv, to record. CIRCULATION. 143 medical practitioners. As a means of diagnosis, however, the sphygmogram still leaves much to be desired. The same instrument, applied in immediate succession to different arteries of the same person, gives, as might be expected, pulse-traces of somewhat different forms. The same artery of the same per- son yields to the same instrument at different times different forms of trace, depending upon different physiological states of the circulation. But the same artery yields traces of different form to sphygmographs of different varieties applied to it in immediate succession ; and even moderate changes in adjust- ment cause differences in the form of the successive traces which the same instrument obtains from the same artery. It is no wonder, therefore, that great care must be exercised in comparing sphygmographic observations, and in drawing general conclusions from the information which they impart. The Details of the Sphygmogram. — Figure 26 is a fair example of the sphygmograms commonly obtained from the healthy human radial pulse. When this trace was taken, the subject's heart was beating from 68 to 60 times Fig. 26.— Sphygmogram from a normal human radial pulse beating from 58 to 60 times a minute. To be read from left to riglit (Burdon-Sanderson). a minute. The trace records the effects upon the lever of five successive com- plete pulsations of the artery, which all agree in the general character of their details, while differing in minor respects. By the tracing of each pulsation the up-stroke is shown to be sudden, brief, and steady, while the down-stroke is gradual, protracted, and oscillating. The commencing recoil of the arterial wall succeeds its expansion with some suddenness. In many sphygmograms this is exaggerated by the inertia of the instrument. As shown by the trace rep- resented in the figure, and by most such traces, the recoil soon changes from rapid to gradual, and, in the trace, its protracted line becomes wavy, indicating that the slow diminution of calibre varies its rate, or even is interrupted by one or more slight expansions, before it reaches its lowest, and is succeeded by the up-stroke of the next pulsation. In each of the five successive pulsations the traces of which are shown in Figure 26, the line which represents the more gradual portion of the down-stroke of the pulse is made up of three waves, of which the first is the shortest, the last the longest and lowest, and the mid- dle one intermediate in length, but by far the highest. This middle wave is, in fact, the only one of the three to produce which an actual rise of pressure occurs ; in each of the other two, no rise, but only a diminished rate of decline, is exhibited. The changes of pressure which produce the first and third of the waves just spoken of, in the pulse-trace under consideration, are very obscure in their origin, and are inconstant in their occurrence, sometimes being more numerous than in the trace .shown in Fig. 26, and sometimes failing altogether to appear. The Dicrotic Wave. — The oscillation of pressure, however, which pro- 144 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. duces the middle wave of each of the pulsations of Figure 26, is so constant in its occurrence that it is undoubtedly a normal and important phenomenon, although, in different sphygmograms, the height, and position in the trace, of the wave inscribed by this oscillation may vary. Occasionally this oscillation is morbidly exaggerated, so that it may be not only recorded by the sphygmo- graph, but even felt by the finger, as a second usually smaller up-stroke of the pulse. In such a case the artery is felt to beat twice at each single beat of the ventricle, and is said, technically, to show a " dicrotic " ' pulse. Where a dicrotic pulse can be detected by the finger, it is apt to accompany a mark- edly low mean tension of the arterial wall. The dicrotic pulse was known, and named, long before the sphygmograph revealed the fact that the pulse is always dicrotic, although to a degree normally too slight for the finger to appreciate. The sphygmographic wave which records the slight " dicrotism " of the normal pulse is called the " dicrotic wave." Where dicrotism can be felt by the finger, the sphygmograra naturally exhibits a very conspicuous dicrotic wave. The origin of the dicrotic oscillation has been much discussed, and is not yet thoroughly settled, important as a complete settlement of it would be to the true interpretation and clinical usefulness of the sphygmogram. It is believed by some that this fluctuation of pressure is produced at the smaller arterial branches, as a reflection of the main pulse-wave, and that the dicrotic wave, thus reflected, travels toward the heart, and, naturally, reaches a given artery after the main wave of the pulse has passed over it, travelling in the opposite direction. The weight of probability, however, is in favor of the view that the dicrotic wave essentially depends upon a slight rise of the arterial pressure, or slackening of its decline, due to the closing of the semi- lunar valve ; and that, therefore, this wave follows the main wave of arterial expansion outward from the heart, instead of being reflected inward from the periphery. If the dicrotic wave be caused solely by reflection from the periphery, it ought, in a sphygmogram from a peripheral artery, to begin at a point uearer to the highest point of each pulsation than in the case of an artery near the heart, in which latter vessel, naturally, a reflected wave would undergo postponement. On the other hand, if the dicrotic wave be trans- mitted toward the periphery, and caused solely by the closure of the aortic valve, it ought, in a sphygmogram from a peripheral artery, to occupy very nearly the same relative position as in a sphygmogram taken from an arterv near the heart. But a wave running toward the periphery may be modified by a reflected wave in the same vessel, and a reflected wave may undergo a second reflection at the closed aortic valve, or even elsewhere, and thus give rise to an oscillation which will be transmitted toward the periphery. These statements show with what technical difficulties the subject is beset, whether the sphygmograph be employed, or, in the case of animals, the elastic man- ometer, the traces recorded by which also exhibit the dicrotic wave. As ' From (JiKpoTof, double-beating. CIRCULATION. 145 already stated, however, the probabilities are in favor of the valvular origin of the dicrotic wave. If it be true that the closure of the aortic valve causes the dicrotic wave, the instant marked by the commencement of this wave, in the manometric trace inscribed by the pressure within the first part of the arch of the aorta itself, practically marks the instant of closure of the aortic valve. We have seen (p. 130) that this doctrine has been made use of in the elucidation of the curve of the pressure within the ventricle. The Diagnostic Limitations of the Sphygmogram. — The feeling of the pulse, imperfect as is the most skilled touch, cannot be replaced by the use of the sphygmograph. The presence, between the cavity of the artery and the surface of the body, of a quantity of tissue the amount and elasticity of which differ in different people, and even differ over neighboring points of the same artery, renders it impossible so to adjust the spring of the sphygmo- graph as to be able to obtain a reliable base-line corresponding to the abscissa, or line of atmospheric pressure, in the case of the manometric curve of blood- pressure. The effects produced by slight differences in the placing of the instrument tend to the same result. By the absence of such a base-line the sphygmographic curve is shorn of quantitative value as a curve of blood- pressure, and cannot give information as to whether, in clinical language, the pulse be hard or soft, large or small. Nor can a long or short pulse be iden- tified from the appearance of the sphygmogram.^ The pulse-trace still requires much elucidation ; but when further study shall have rendered clearer the true extent, the normal variations, and the causes of the complex and incessant oscillations of the walls of the arteries, it may well be believed that both physiology and practical medicine will have gained an important insight into the laws of the circulation of the blood. P. The Movement op the Lymph. The Lymphatic System. — The lymph is contained within the so-called lymphatic system, the nature of which may be summarized as follows : The lymph appears first in innumerable minute irregular gaps in the tis- sues, which gaps communicate in various ways with one another, and with minute lymphatic vessels, which latter, when traced onward from their begin- nings, presently assume a structure comparable to that of narrow veins with very delicate walls and extremely numerous valves. These valves open away from the gaps of the tissues, as the valves of the veins open away from the capillaries. The lymphatic vessels unite to form somewliat larger ones, each of which, however, is of small calibre as compared with a vein of medium size, until at length the entire system of vessels ends, by numerous openings, in two main trunks of very unequal importance, the thoracic duct and the right lymphatic duct. The latter is exceedingly short, and receives the ter- minations of the lymphatics of a very limited portion of the body; the termi- nations of all the rest, including the lymphatics of the alimentary canal, are ' M. von Frey ; Die Unlersuchung des Pulses, 1892, S. 35. Vol. I.— 10 146 A^^ AMERICAjS^ TEXT-BOOK OF PHYSIOLOGY. received by the thoracic duct, which runs the whole length of the chest. Both of the main ducts have walls which, relatively, are very thin ; and, like the smaller lymphatics, the ducts are abundantly provided with valves so disposed as to prevent any regurgitation of lymph from either duct into its branches. Each duct terminates on one side of the root of the neck, where, in man, the cavity of the duct joins by an open mouth the confluence of the internal jugular and subclavian veins where they form the innominate vein. At the opening of each duct into the vein a valve exists, which permits the free entrance of lymph into the vein, but forbids the entrance of blood into the duct. It is a peculiarity of the lymphatic system that some of its vessels end and begin by open mouths in the so-called serous cavities of the body — those vast irregular interstices between organs the membranous walls of which interstices are known as the peritoneum, the pleurse, and the like. For present purposes, therefore, these serous cavities may be regarded as vast local expansions of portions of the lymph-path. Another peculiarity of the lymphatic system de- pends upon the presence of the lymphatic glands or ganglia, which also are intercalated here and there between the mouths of lymphatic vessels which enter and leave them. The nature and importance of these bodies have been referred to in dealing with the origin of the leucocytes and the nature of the lymph (p. 47). For the present purposes the ganglia are of interest in this, that the lymph which traverses their texture meets, in so doing, with much resistance from friction. Physiologically, therefore, the lymph-path as a whole, extending from the tissue-gaps to the veins at the root of the neck, both differs from, and in some respects resembles, the blood-path from the capillaries to the same point. The origin of the lymph has been discussed already (p. 71), and has been found to be partly from the blood in the capillaries, and partly from the tis- sues, to say nothing of the products directly absorbed from the alimentary canal during digestion. The quantity of material which leaves the lymph-path and enters the blood during twenty-four hours is undoubtedly large, amount- ing, in the dog, to about sixty cubic centimeters for each kilogram of body- weight. The movement of the lymph is, therefore, of physiological import- ance ; and the causes of this movement must now be considered. DiflFerences of Pressure. — It is a striking fact that in man and the other mammals there exist no "lymph-hearts" for the maintenance of the lymphatic flow. The fundamental causes of the movement of the lymph are that at the beginning of its path in the gaps of the tissues it is under considerable pressure ; that at the end of its path at the veins of the neck it is under very low pressure, which often, if not usually, is negative ; and that throughout the lymph-path the valves are so numerous as to work effectively against regurgitation. The pressure of the lymph in the gaps of the tissues has been estimated at one half, or more, of the capillary blood- pressure,' which latter has been stated (p. 84) to be from 24 to 54 millimeters ^ A. Landerer : Die Gewebsspannung in ihrem Einfiuss auf die ortliehe Blut- und Lymphbeioegung, Leipzig, 1884, S. 103. CIB C ULA TION. 1 47 of mercury. The difference between one half of either of these pressures and the pressure in the veins of the neck, which pressure is not far from zero, is quite enough to prodnce a flow from the one point to the other. To this flow a resistance is caused by the friction along the lymph-path, which resistance causes the lymph to accumulate in the gaps of the tissues, and the pressure there to rise, until the tension of the tissues resists further accumulation more forcibly than friction resists the onward movement of the lymph. The little- known forces which continually produce fresh lymph, and pour it into the tissue-gaps against resistance, cannot be discussed here further than has been done in treating of the origin of the lymph (p. 71). Thoracic Aspiration. — The causes have already been stated fully of that low, perhaps negative, pressure in the veins at the root of the neck which ren- ders possible the continuous discharge of the lymph into the blood (p. 95). It need only be noted here that when inspiration rhythmically produces, or heightens, the suction of blood into the chest, it must also pi-oduce, or heighten, the suction of lymph out of the mouths of the thoracic and right lymphatic duets. Moreover, as the thoracic duct lies with most of its length within the chest, each expansion of the chest must tend to expand the main part of the duct, and thus to suck into it lymph from the numerous lymphatics which join the duct from without the chest ; while the numerous valves in the duct must promptly check any tendency to regurgitation from tlie neck. The Bodily Movements and the Valves. — Like the flow of the blood in the veins, the flow of the lymph in its vessels is powerfully assisted by the pressure exerted upon the thin-walled lymphatics by the contractions of the skeletal muscles ; for the very numerous valves of the lymphatics render it impossible for the lymph to be pressed along them by this means in any other than the physiological direction toward the venous system. Experiment shows that even passive bending and straightening of a limb in which the mus- cles remain relaxed, increases to a very great extent the discharge of lymph from a divided lymphatic vessel of that limb. It is probable, therefore, that movement in any external or internal part of tlie body, however pro- duced, tends to relieve the tension in the tissues by pressing the lymph along its path. Conclusion. — The movement of the lymph produced in these various ways is doubtless irregular ; but a substance in solution, injected into the blood, can be identified in the lymph collected from an opening in the thoracic duct at the neck in from four to seven minutes after the injection.^ The physiological importance of the lymph-movement is shown not only by the large amount of matter which daily leaves the lymphatic system to join the blood, but also by the evil effects which result from an undue accumulation of lymph, more or less changed in character, in the gaps of the tissues. Such an accumulation constitutes dropsy. It may occur in a serous cavity or in the subcutaneous tissue ; in the latter case giving rise to a peculiar swelling which " pits on ' S. Tschirwinsky : "Zur Frage iiber die Schnelligkeit des Lymphstromes und der Lymph- filtration," Oentralblatt fur Physiologie, 1895, Band ix. ,S. 49. 148 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. pressure." Any tissue the meshes of which are thus engorged with lymph is said to be " (edematous." ' PART II.— THE INNERVATION OF THE HEART. ^ It has long been known that the frog's heart can be kept beating for many hours after its removal from the body. In 1881, Martin succeeded in main- taining the beat of the dog's heart after its complete isolation from the central nervous system and the systemic blood-vessels. Ludwig and his pupils have attained the same result in a diiferent way. In 1895, Langendorlf was able by circulating warmed oxygenated, defibrinated blood through the coronary vessels to maintain the hearts of rabbits, cats, and dogs in activity after their total extirpation from the body. Even pieces removed from the ventricle will contract for hours if fed with blood through a cannula in the branch of the coronary artery which supplies them.' It is evident, therefore, that the cause of the rhythmic beat of the heart lies within the heart itself, and not within the central nervous system. Cause of Rhythmic Beat. — It has been much disputed whether the car- diac muscle possesses the power of rhythmical contraction or whether the rhythmic beat is due to the periodic stimulation of the muscle by the discharge of nerve-impulses from the ganglion-cells of the heart. The arrangement of the ganglion-cells and nerves suggests the latter view. 2'/te Intracardiac Ganglion-cells and Nerves. — In the frog the cardiac nerves arise by a single branch from each vagus trunk and run along the great veins through the wall of the sinus venosus, where many ganglion-cells are found, to the auricular septum. Here they unite in a strong plexus richly provided with ganglion-cells. Two nerves of unequal length and thickness leave this plexus and pass along the border^ of the septum to the auriculo-ventrieular junction, where each enters a conspicuous mass of cells known as Bidder's ganglion. Ventricular nerves spring from these ganglia and can be followed with the unaided eye some distance on the ventricle. With the chloride-of- gold method, the raethylene-blue stain, and especially the nitrate-of-silver im- pregnation, the ventricular nerves can be traced to their termination. Some difference of opinion exists regarding the manner of their distribution and the precise nature of their terminal organs. The following facts, however, may be considered established both for the batrachian and the mammalian heart.'' The ventricular nerves form a rich plexus beneath the pericardium and ' From oldri/in, a swelling. '' The literature of the innervation of the heart and blood-vessels is now so large that only references to some of the principal investigations published since 1892 can be given here. For the titles of works prior to that date, the reader may consult Tigerstedt's Lehrbuch cler Physiolo- gie des Kreislaufes, 1893. '' Porter : Journal of Experimental Medicine, 1897, ii. p. 391. * The literature of this subject has been collected by Heymans and Demoor : Archives (Beige) de Biologic, 1895, xiii. p. 619. CIRCULA TION. 1 49 endocardinm. Branches from these plexuses form a third plexus in the myo- cardium or heart muscle, from which arise a vast number of non-medullated terminal nerves, enveloping the muscle-fibres and ending in small enlargements or nodosities of various forms. Similar " varicose " enlargements are observed along the course of the nerves. The nerve-endings are in contact with the naked muscle-substance, the mode of termination resembling in general that observed in non-striated muscle. Ganglion-cells are found chiefly in the auricular septum and the auriculo-ventricular furrow, but are present also beneath the pericardium of the upper half of the ventricle. No ganglia have as yet been satisfactorily demonstrated within the apical half of the ventricle,' and most observers do not admit their presence within the ventricular muscle itself The nerve-cells are unipolar, bipolar, or multipolar. Certain unipolar cells in the frog are distinguished by a spherical form, a pericellular network, and two processes — namely, the axis-cylinder or straight process, and the spiral process. The latter is wound in spiral fashion about the axis-cylinder, ending in the pericellular net. According to Retzius and others, the spiral is not really a process of the cell, but arises in a distant extra- cardiac cell and carries to the heart-cell a nervous impulse which is transmitted from the spiral process to the cell by means of the contact between the peri- cellular net and the cell-body. Section of the cardiac fibres of the vagus causes the spiral " process " and pericellular net to degenerate, the cell-body and axis-cylinder process remaining untouched, showing that the spiral process is the terminal of a nerve-fibre running in the vagus trunk.^ Nerve-theory of Heart-beat. — The theory of the nervous origin of the heart-beat rests in part on the correspondence between the degree of contrac- tility of the various parts of the heart and the number of nerve-cells present in them. Thus the power of rhythmical contraction is greater in the auricle, in which there are many cells, than in the ventricle, in which there are fewer. The properties of the apical half, or " apex," of the ventricle are considered to be of especial importance in the study of this problem, because the apex, as has been said, is believed to contain no ganglion-cells. This part of the ven- tricle stops beating when separated from the heart, while the auricles and the ventricular stump continue to beat. The apex need not be cut away in order to isolate it. By ligating or squeezing the frog's ventricle across the middle with a pair of forceps the tissues at the junction of the upper and the lower half of the ventricle can be crushed to the point at which physiological con- nection is destroyed but physical continuity still preserved. Such frogs have been kept alive as long as six weeks. The apex does not as a rule beat again. The exceptions can be explained as the consequence of accidental stimulation. The conclusion drawn is that the apex, in which ganglion-cells have not been satisfactorily demonstrated, has not the power of spontaneous pulsation which 'Schwartz: Archiv fur mikroskopische Anatomie, 1899, liii. S. 63, Compare Dogiel : Ibid., S. 237. ^Nikolajew : Archiv fur Physiologic, 1893, Suppl. Bd., S. 73. 150 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. distinguishes the remainder of the heart. This view is further supported by the observation that a slight stimulus applied to the base of a resting ventricle will often provoke a series of contractions, while the same stimulus applied to the apex will cause but a single conti'action. Much may be hoped from comparative studies. In the medusse, for ex- ample, the margin of the swimming bell, by the rhythmical contraction of which the animal is driven through the water, is provided with a double nerve-ring and ganglion-cells, while the centre contains only scattered and infrequent ganglion-cells. If the margin is separated from the centre and both are placed in sea-water, only the part containing many nerve-cells beats rhythmically. Loeb concludes that inasmuch as the whole medusa {Gonione- mus) beats in sea-water in the rhythm of the margin, the failure of the iso- lated centre to beat in that medium can only be explained by the lack of nerve-cells.' The fact that the normal contraction begins in the sinus, Howell explains by the greater sensitiveness of that part to chemical stimulation.^ The action of rauscarin on the heart is often held to indicate the nervous origin of the heart-beat. IMuscarin arrests the heart of the frog and other vertebrates, but has no similar action on any other muscle either striped or smooth, nor does it arrest the heart of insects and mollusks. It follows that muscarin does not cause arrest by acting directly upon the contractile material of the heart. The contractile material being excluded, the assumption of a nervous mechanism on tlie integrity of which the heart-beat depends seems necessary to explain the effect of the poison. Further arguments are based on uncertain analogies between the heart and other rhjthmically contracting organs. MiiKcular Theory of Hcart-beaf.^ — The evidence just stated cannot be re- garded as proof of the nervous origin of the heart-beat. The most that can be claimed is that it makes such a ct)nception plausible. The cause of the Ix'at probably lies in the contractile subst;ince rather than the nerve-cells. It is, at all events, certain that the cardiac muscle is capable of prolonged rhythmic contraction. It has been shown that a strip of muscle cut from the apex of the tortoise ventricle and suspended in a moist chamber begins in a few hours to beat apparently of its own accord with a regular but slow rliythm, which has been seen to continue as long as thirty hours. If the strip is cut into pieces and placed on moistened glass slides, each piece will contract rhythmically. Yet in the apex of the heart no nerve-cells have been found. The apex of the batrachian heart will beat rhythmically in response to a constant stimulus. Thus if the apex is suspended in normal saline solution and a constant electrical current kept passing through it, beats will appear after a time, the frequency of pulsation increasing with the strength of the ' Loeb : American Journal of Physiology, 1900, iii. p. 383. ' Howell : Ibid., ii. p. 47. ' A valuable bibliography is given by Engelmann : Archiv fUr die gesammte Physiologic, 1896, Ixv. p. 109; see also Ibid., p. 535. CIBCULA TION. 161 current.* Very strong currents cause tonic contraction. An apex made inac- tive by Bernstein's crushing can be made to beat again by clamping the aorta and thus raising the endocardiac pressure. Chemical stimulation is also effec- tive. Delphinin, quinine, muscarin with atropin, atropin alone, morphin and various other alkaloids, dilute mineral acids, dilute alkalies, bile, sodium chloride, alcohol, and other bodies,^ when painted on the resting ventricle, call forth a longer or shorter series of beats. Stimulation with induction shocks gives a similar result. Other muscles in which no nerve-cells have been discovered can contract rhythmically. Thus the bulbus aortse of the frog beats regularly after its removal from the body, even the smallest pieces showing under the microscope rhythmical contractions. Engelmann, who observed this fact, declares that the entire bulbus is lacking in nerve-cells. This is contradicted by Dogiel ; yet it seems hardly reasonable that these " smallest pieces " which Engelmann mentions were each provided with ganglion-cells. It is more probable that the contractions were the result of a constant artificial stimulus. Curarized stri- ated muscles placed in certain saline solutions may contract from time to time. The hearts of many invertebrates in which ganglion-cells are apparently absent beat rhythmically. Much has been made of the fact that the ganglion-cells grow into the heart long after the cardiac rhythm is established, showing that the embryonic heart muscle has rhythmic contractile powers. The adult heart muscle, it is alleged, retains certain embryonic peculiarities of structure, and as structure and func- tion are correlated, should also retain the embryonic power of contraction without nerve-cells. A positive demonstration that the nerve-cells in the heart are not essential to its contractions is secured by removing the tip of the ventricle of the dog's heart and supplying it with M'arm defibrinated blood through a cannula tied into its nutrient artery. Long-continued, rhythmical, spontaneous contrac- tions are thus obtained.' As the part removed contains no nerve-cells, the observed contractions can only arise in the muscular tissue, provided we make the (at present) safe assumption that the nerve-fibres do not originate im- pulses capable of inducing rhythmic muscular contractions. The demonstra- tion that the nerve-cells are not essential to contraction, places us one step nearer the true cause of contraction. It is some agency acting on the con- tractile substance. Evidence is accumulating that this agent is a chemical substance, or substances, brought to the contractile matter by the blood. For this chemical stimulation calcium is apparently essential, and for rhythmic contraction and relaxation Howell* finds a certain proportion of potassium 'Langendorff: Archivfiir die gesammte Physiologic, 1895,1x1. p. 336. ^ Kaiser : Zeilschrifl fiir Biologie, 1895, xxxii. p. 6. ' Porter : Journal of Experimental Medicine, 1897, ii. p. 391. * Howell: American Journal of Physiology, 1898, ii. p. 47; Loeb: Ibid., 1900, iii. p. 394. The reader is recommended to examine these suggestive papers for himself. 152 AN A3IEBICAN TEXT-BOOK OF PHYSIOLOGY. also necessary. Sodium chloride must be present to preserve the osmotic equilibrium between contractile tissue and surrounding liquid. As phrased by Loeb, it may be assumed that the sodium, calcium, and potassium ions must exist in definite proportions in the tissue which is expected to show rhythmical activity. Only so long as these proportions are preserved does the tissue possess such physical properties and such labile equilibrium as to be capable of rhythmical processes or contractions. The Bxcitation-wave. — The change in form which constitutes what com- monly is called the cardiac contraction is preceded by a change iu electrical potential, supposed to be a manifestation of the unknown process by which the heart-muscle is excited to contract. Both the contraction and the electrical change sweep over the heart in the form of waves, and it has become the cus- tom to speak of the electrical change as the excitation-wave. It should not be forgotten, however, that this usage rests merely on an assumption, for the real nature of the excitation is still a mystery. The contraction-wave begins nor- mally at the great veins, travels rapidly through the auricle, and, after a dis- tinct interval, spreads through the ventricle. The excitation-wave, which pre- cedes and is the cause of the contraction, probably takes the same course,^ and in fact it is possible to show that the change in electrical potential actually begins under normal conditions at the great veins and passes thence over the entire heart. But this sequence is not invariable. The ventricle under abnor- mal conditions has been seen to contract before the auricle, the normal sequence of great veins, auricle, and ventricle being reversed.^ The energy of the ven- tricular muscle-cell may, therefore, be discharged by an excitation arising within the ventricle itself Evidence of this is afforded also by the experi- ment of Wooldridge, who isolated the ventricles by drawing a silk ligature tightly about the auricles at their junction with the ventricles, completely crushing the muscle and nerves of the auricle in the track of the ligature with- out tearing through the more resistant pericardium. This experiment was repeated the following year by Tigerstedt, who devised a special clamp for crushing the auricular tissues. Both observers found that the auricles and ventricles continued to beat. The rhythm, however, was no longer the same. The ventricular beat was slower than before and was independent of the beat of the auricle. Thus the ventricle, no longer connected physiologically with the auricle, develops a rhythm of its own, an idio-ventricular rhythm. It seems improbable that the very small part of the auricular tissue which cannot be included in Wooldridge's ligature for fear of closing the coronary arteries should be able to maintain the ventricular contractions. Independent contraction is said to be secured by properly regulated excita- tion of the cardiac end of the cut vagus nerve. Stimuli of one second duration applied to the vagus at intervals of six to seven seconds arrest the auricles completely, but do not stop the ventricles, except during the second of stimu- lation. The ventricles, now dissociated from the auricles, beat with a rhythm ' Bottazzi: Lo sperimentale, 1898, li. No. 2. ' Kecently studied by Engelmann : Archivfur die gesammte Physiologic, 1895, Ixi. p. 275. CIRCULATION. 153 diiFereut from that which characterized the normal heart. The force of this demonstration is somewhat -weakened by the possibihty that the auricles, although not beating themselves, might still excite the ventricles to contraction. Conduction of the Excitation. — If the points of non-polarizable electrodes are placed on the surface of the ventricle and connected with a delicate galvan- ometer, a variation of the galvanometer needle will be seen with each ventric- ular beat. If one electrode is placed near the base of the heart and the other near the apex it is seen that the former electrode becomes negative before the latter, indicating that the part of the heart muscle on which the basal electrode rests is stimulated before the apical portion, and that the difference in electrical potential, or excitation-wave, according to the prevailing hypothesis, travels as a wave over the ventricle from the base to the apex (see Fig. 27). Burdon- Sanderson and Page have found that the duration of the difference of poten- tial is about two seconds in the frog's heart at ordinary temperatures. Cooling lengthens the period of negativity, warming diminishes it. Some observers believe that the excitation-wave under certain conditions returns toward the base after having reached the apex. The speed of the excitation-wave has been measured by the interval between the appearance of negative variation in the ventricle when the auricle is stimulated first near and then as far as possible Fig. 27.— The electrical variation in the spontaneously contracting heart of the frog, recorded by a 'Capillary electrometer, the apex being connected with the sulphuric acid and the base with the mercury of the electrometer. The changes in electrical potential are shown by the line e, e, which is obtained by throwing the shadow of the mercury in the capillary on a travelling sheet of sensitized paper. The con- traction of the heart is recorded by the line h, h ; time, in ^V second, by t, t. The curves read from left to right. The electrical variation is diphasic ; in the first phase the base is negative to the apex ; in the second, the apex is negative to the base ; the negative variation passes as a wave from base to apex (Waller, 1887, p. 231). from the non-polarizable electrodes. The interval is the time which the excita- tion-wave requires to pass the distance between the two points stimulated. The average rate is at least 50 millimeters per second.^ The negative variation begins apparently instantly after the application of the stimulus. Its phases .and their characteristics have been described by Engelmann. The latent period of a frog's heart muscle is about 0.08 second. ' Burdon-Sanderson and Page {Journal of Physiology, 1880, ii. p. 426) give 125 millimeters per second. 154 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Although the normal course of the excitation-wave is from base to apex, it can be made to travel in any direction. If the frog's ventricle is cut with fine scissors into a number of pieces in such a way as to leave small bridges of heart-tissue between each piece, and any one of the pieces is stimulated, the contraction will begin in the stimulated piece and then run from piece to piece over the connecting bridges until all have successively contracted. The direc- tion in which the excitation-wave travels can thus be altered at the pleasure of the operator. Whether the excitation is propagated from muscle-cell to muscle-cell or by means of nerve-fibres has given rise to much discussion. Anatomical evidence can be adduced on both sides. On the one hand the rich plexus of nerve- fibres everywhere present in the heart-muscle suggests conduction through nerves ; on the other is the intimate contact of neighboring muscle-cells over a part at least of their surface, thus bringing one mass of irritable protoplasm against another and offering a path by whicli the excitation might travel from cell to cell. If the excitation-wave were conducted by means of nerves, the difference between the moment of contraction of the ventricle when the auricle is stimu- lated near the ventricle, and again as far as possible from the ventricle, should be very slight, because of the great speed at which the nervous impulse travels (about 33 meters per second). If, on the contrary, the conduction were by means of muscle, the difference would be relatively much greater, correspond- ing to the much slower conductivity of muscular tissue. It has been found by Engelmann that the ventricle contracts later when the auricle is stimulated far from the ventricle than when it is stimulated near the ventricle. The rate of propagation being calculated from the difi«reuce in the time of ventricular con- traction was found to be 90 millimeters per second, which is about 300 times less than the rate which would have l)een obtained had conduction over the measured distance taken place through nerves.^ Hence the stimulus that trav- els through the auricle to the ventricle and causes its contraction should be propagated in the auricle by muscle-fibres and not by nerves. It is possible to cut the ventricular muscle in a zigzag or sjiii-al fashion that makes probable the severance of all the nerve-fibres in the line of the cut, and yet the contraction will pass from one end to the other of the isolated strip.' Passage of Excitation-wave from Auricle to Ventricle. — The normal con- traction of the heart begins, as has been said, at the junction of the great veins and the auricle, spreads rapidly over the auricle and, after a distinct pause, reaches the ventricle. The normal excitation-wave preceding the con- traction passes likewise from the auricle to the ventricle and is delayed at or • Engelmann : Anhivfur die gesammte Physiologie, 1896, Ixii. p. 549, ' Porter : American Journal of Physiology, 1899, ii. p. 127. The co-ordination of the ven- tricles is discussed in this paper, and also by von Vintscligau : Archiv fur die gesammte Physi- ologie, 1899, Ixxvi. p. 59. CIRCULATION. 155 near the auriculo-ventricular junction. The controversy over the nervous or muscular conduction of the excitation within the auricle and ventricle has been extended to its passage from auricle to ventricle. A path for conduction by nerves is presented by the numerous nerves which go from the auricle to the ventricle. It has been shown recently that muscular connections also exist. In the frog, muscle-bundles pass from the auricle to the ventricle where the auricular septum adjoins the base of the ventricle. Muscular bridges pass also from the sinus venosus to the auricles and from the ventricle to the bulbus arteriosus.^ These muscle-fibres appear to be in intimate con- tact with the muscle-cells of the divisions of the heart which they unite. Gas- kell believes that the connecting fibres are morphologically and physiologically related to embryonic muscle, and therefore possess the power of contracting rhythmically. The delay experienced by the excitation in its passage fi'om the auricle to the ventricle — in other words, the normal interval between the contraction of the auricle and the contraction of the ventricle — is explained by those favoring the nervous conduction as the delay which the excitation experiences in dis- charging the ganglion-cells of the ventricle, in accordance with the well-known hypotheses of the retardation of the nerve-impulse in sympathetic ganglia and the slow passage of the nervous impulse through spinal cells. The explanation given by those who believe in muscular conduction is that the small number of muscular fibres composing the bridge between auricle and ventricle acts as a " block " to the excitation-wave. If the auricle of the tortoise heart is cut into two pieces connected by a small bridge of auricular tissue, the stimulation of one piece will be followed immediately by the con- traction of that piece, and after an interval by the contraction of the other. The smaller the bridge, the longer the interval ; that is the longer the excita- tion-wave will be in passing from one piece to another. The duration of the pause or " block " in the frog has been found to be from ■0.15 to 0.30 second. TJie length of the muscle-fibres connecting auricle and ventricle is about one millimeter. The speed of the excitation-wave in em- bryonic heart muscle is from 3.6 to 11.5 millimeters per .second. The duration of the pause agrees, therefore, with the time which would be required for muscular conduction.^ The extensive extirpations of the auricular nerves which have been made without stopping conduction from auricle to ventricle ' — for example, the ex- tirpation of the entire auricular septum of the frog's heart — are of little importance to this question, since the great number of nerve-cells revealed by recent methods make it improbable that any extirpation short of total removal of both auricles could cut off all the nerve-cells of the auricle. It is possible to explain the occurrence of intermittent or irregular con- ' Engelmann : Arehiv fiir die gesammte Physiologie, 1894, Ivi. p. 158. ''Engelmann : Ibid., p. 159. 'Hofmann: Ihid., 1895, Ix. p. 169. 156 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tractions by alterations in the conductivity or irritability of the several parts of the heart successively traversed by the excitation wave. For example, a lessening of the normal conductivity at the auriculo- ventricular junction might permit only every second sino-auricular impulse to reach the ventricle ;' in this case the ventricle would drop every second beat. The same intcr- mittence would result if the irritability of the ventricle Mere so far reduced that it could not respond to the normal excitation.' Engelmann has recently found that ventricular systole lowers the conductivity of the ventricle for a time.^ Refractory Period and Compensatory Pause. — Schiff found in 1850 that the heart which contracted to each stimulus of a series of slowly repeated mechanical stimuli would not contract to the same stimuli if they followed each other in too rapid succession. Kronecker got a similar result with induction shocks. The heart contracted to every stimulus only when the interval between them was not too brief. The following year Marey published a systematic study of the phenomenon. He observed that the irritability of the heart sank during a part of the systole, but returned during the remainder of the systole and the following diastole. The stimulus which fell between the beginning of the systole and its maximum produced no extra contraction, whilst that which fell between the maximum of one systole and the beginning of the next called forth an extra contraction. During a part of the cardiac cycle therefore the heart is "refractory" toward stimuli. The irritability of the heart is removed for a time by an adequate stimulus. Kronecker and Marey noticed further that stimulation with the induction shock during the non-refractory period did not influence the total number of systoles. The extra systole called forth by the artificial stimulus was followed by a pause the length of which was that of the normal pause plus the interval between the appearance of the extra systole and what would have been the end ■of the cardiac cycle in which the extra systole fell. The extra length of this pause restored the normal frequency or rhythm. It was called the compensa- tory pause (see Fig. 28).' The systole following the extra contraction and its compensatory pause is of marked strength, at least in the surviving mammalian heart (cat). The weaker the extra systole the stronger the first subsequent contraction. The unusual force of this " compensatory systole " may serve to compensate the loss in the output of the heart incident to the disturbance in its rhthym.^ If the heart, or the isolated apex, is beating at a rate so slow that an extra contraction falling in the interval between two normal contractions has time to complete its entire phase before the next normal contraction is due, there will be no compensatory pause.'' ' Oehrwall: SkandiTiavisches Archivfiir Physiologie, 1898, viii. p. 1. ' Engelmaim : Archivfiir die gesammte Physiologie, 1896, Ixii. p. 543. ' Courtade: Archives de Physiologie, 1897, p. 69. * Langendorff: Archivfiir die gesammte Physiologie, 1898, Ixx. p. 473. 'Kaiser: Zeitschrift fur Biologic, 1895, xxxii. p. 449. cm CULA TION. 157 The refractory phase disappears with sufficiently strong stimuli, especially if the heart is warmed. In such a case an artificial stimulus falling in the beginning of a spontaneous contraction produces an extra contraction. This extra contraction, however, comes first after the end of the systole during which the artificial stimulation is made, occurring in fact toward the end of the Fig. 28.— The refractory period and compensatory pause. The curves are recorded by a writing lever resting on the ventricle of the frog's heart. They read from left to right. A break in the horizontal line below each curve indicates the moment at which an induction shock was sent through the ventricle. In curves 1, 2, and 3 the ventricle proved refractory to this stimulus : in the remaining curves, the stimulus having fallen outside the refractory period, an extra contraction and compensatory pause are seen. Many of the phenomena mentioned in the text are illustrated by this figure (Marey, 1876, p. 72). following diastole. The latent period of such a contraction lengthens with the length of the interval between the artificial stimulation and the end of the systole. A refractory period has been demonstrated in the auricle of the frog^ and dog ; ^ in the ventricle of the cat, rabbit, and dog, and in the sinus venosus and bulbus arteriosus of the frog. It is said not to be present in the lobster.^ ' Engelmann: Archivfur die gesammte Physiologic, 1894, lix. p. 322. ^ Meyer : Archives de Physiologie, 1893, p. 185 ; Cushny and Matthews : Journal of Physiology, 1897, xxi. p. 213. ' Hunt, Bookman, and Tierney : Centralblatt fiir Physiologie, 1897, xi. p. 276. 158 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. In some cases, the extra stimulus provokes not merely one, but two or three extra contractions. The amplitude of the extra contraction increases with the length of the interval between the maximum of contraction and the extra stimulus. If the extra stimulus is given at the beginning of relaxation, the extra contraction is exceedingly small ; on the other hand, the extra contraction may be greater than the primary one, when the stimulus falls in the pause between two normal beats. The supplementary systole of the auricle is sometimes followed by a sup- plementary systole and compensatory pause of the ventricle, sometimes by the compensatory pause alone, probably because the excitation wave reaches the ventricle during its refractory period. Multiple extra contractions of the auricle are often followed by the same number of extra contractions of the ventricle. If the frog's heart is made to beat in reversed order, ventricle first, auricle second, extra contractions of the ventricle may be produced, and will cause extra contractions of the auricle with compensatory pause. If the reversed excitation wave travelling from the ventricle to the auricle reaches the latter during auricular systole, the extra auricular contraction is omitted, but a distinct though shortened compensatory pause is still observed. The phenomena with reversed contraction are therefore similar to those seen under the usual conditions.' Kaiser finds in frogs poisoned with muscarin that stimulation of the ven- tricle during the refractory period causes the contraction in which the stimulus falls to be more complete, as shown by the contraction curve rising above its foi-mer level. He concludes that the ventricle is not wholly inexcitable even during the refractory period. The question whether the refractory state and compensatory pause are properties of the muscle-substance or of the nervous system of the heart has excited considerable attention. If the ganglion-free apex of the frog's ven- tricle is stimulated by rapidly repeated induction shocks it can be made to con- tract periodically for a time. By momentarily increasing the strength of any one induction shock an extra stimulus can be given from time to time. When the extra stimulus falls after the contraction maximum or during diastole an extra contraction results, otherwise not. The refractory period exists, there- fore, independently of the cardiac ganglia. The compensatory pause can also, though not always, be secured with the ganglion-free apex.^ The refractory period has been used to show how a continuous stimulus might produce a rhythmic heart-beat. The continuous stimulus cannot affect the heart during the refractory period from the beginning to near the maxi- mum of systole. At the close of the refractory period the constant stimulus ' Kaiser : Zeiisehrift fur Biologic, 1895, xxxii. p. 19. ' Kaiser : Ibid., p. 449 ; for experiments on tlie embryo, see Pickering : Journal of Physi- ology, 1896, XX. p. 165. cm C ULA TION. 159 becomes effective, causing an extra contraction with long latent period. This latent period is, according to this theory, the interval between the first and the second contraction. A tonic contraction' of the heart muscle is sometimes produced by strong, rapidly repeated induction shocks and by various other means, such as filling the ventricle with old blood, by weak sodium hydrate solution, and by certain poisons, such as digitalin and veratrin. A. The Cardiac Nerves. The cardiac nerves are branches of the vagus and the sympathetic nerves. In the dog the vagus arises by about a dozen fine roots from the ventro- lateral aspect of the medulla and passes outward to the jugular foramen in company with the spinal accessory nerve. In the jugular canal the vagus bears a ganglion called the jugular ganglion. The spinal accessory nerve joins the vagus here, the spinal portion almost immediately leaving the vagus to be distributed to certain muscles in the neck, while the medullary portion passes to the heart through the trunk ganglion and thereafter in the substance of the vagus. Directly after emerging from the skull, the vagus presents a second ganglion, fusiform in shape and in a fairly large dog about one centi- meter in length. From the caudal end or middle of this '' ganglion of the trunk " is given off the superior laryngeal nerve, slightly behind which a large nerve is seen passing from the sympathetic chain to the trunk of the vagus. This nerve is in reality the main cord of the sympathetic chain, the sympathetic nerve being bound up with the vagus from the " inferior" cervical ganglion to the point just mentioned. Posterior to the trunk ganglion of the vagus, the vago-sympathetic runs caudalward as a large nerve dorsal to the common carotid artery as far as the first rib or near it, where it enters the so-called inferior cervical ganglion. This ganglion belongs to the sympathetic system and not to the vagus ; from a morphological point of view it is the middle cervical sympathetic ganglion. The true inferior cervical sympathetic ganglion is fused with the first one or two thoracic ganglia to form the gan- glion stellatum, situated opposite the first intercostal space. At the " inferior cervical " ganglion the vagus and the sympathetic part company, the vagus passing caudalward behind the root of the lung and the sympathetic passing to the stellate ganglion, dividing on its way into two portions (the annulus of Yieiissens), which embrace the subclavian artery. In many cases the lower loop of the annulus of Vieussens joins the trunk of the vagus caudal to the ganglion. The cardiac nerves spring from the vagus and the sympathetic nerve in the region of the inferior cervical ganglion. They may be divided into an inner and an outer group. The inner group is composed of one medium, one thick, and two or three slender nerves. The nerve of medium thickness springs from the gan- ' Hunt, Bookman, and Tierney: Centralblati fur Physiologic, 1897, xi. p. 274. 160 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. f glion itself. The thick branch rises from the trunk of the vagus near tiie origin of the inferior laryngeal nerve about 1.25 centimeters caudal to the inferior cervical ganglion. It can be- easily followed to its final distribution. It passes behind the vena cava superior,, perforates the pericardium, and runs parallel with the ascending aorta across the pulmonary artery, on which it lies in the connective tissue already divided into two or three tolerably thick twigs or spread in a fan of smaller branches. These now bend beneath the artery,, pass round its base on the inner side, and reach the anterior inter- ventricular groove. Here they spread over the surface of the ventricle. The slender branches leave the vagus trunk caudal to the branch just described. The outer group comprises two thick branches — namely, an upper nerve,, springing from the ganglion or from the trunk of the vagus near it, and a lower nerve, from the lower loop of the annulus, or from the vagus 1-1 J centimeters lower down. Each of these ceryical ganglion and vagus nerve ; 6, stellate gan- , . , , i j i. glion; 6', 6" 6'", spinal roots of stellate ganglion; thick branches may be replaced by a 7, communication between stellate ganglion and J-jy^^Jlg ^f fingj. branches, and in fact vagus ; 8', 8", 8 ", cardiac nerves. ' the description of the cardiac nerves here given can be regarded as a close approximation only, so frequent are the individual variations.' In the rabbit the cervical sympatlietic and the vagus trunk are not joined, as in the dog, but run a separate course. Cardiac fibres from the spinal cord reach the lower cervical and fir^t thoracic ganglion (ganglion stellatum) along their rami communicantes and pass to the heart by two sympathetic cardiac nerves,, one from the inferior cervical ganglion and one from the ganglion stellatum. The arrangement of the cardiac nerves in the cat is shown in Figure 29. In the frog the cardiac nerves, both vagal and sympathetic, reach the heart through the splanchnic branch of the vagus. The sympathetic fibres pass out of the spinal cord with the third spinal nerve, through the ramus communicans of this nerve into the third sympathetic ganglion,^ up the sympathetic chain to the ganglion of the vagus, and down the vagus trunk to the heart. ' Details concerning the composition of the cardiac plexuses in the dog are given by Lira Boon Keng : Journal of Physiology, 1893, xiv. p. 467. '' It is probable that the fibres of spinal origin end in the sympathetic ganglia, making con- tacts there with sympathetic ganglion-cells, the axis-cylinder processes of which pass up the cervical chain and descend to the heart in company with the vagus. Fig. 29.— Cardiac plexus and stellate ganglion of the cat, drawn from nature after the removal of the arteries and veins ; about one and one-half times natural size (Boehm, 1875, p. 258) : R, right; i, left: 1,1, vagus nerve; 2, cervical sympathetic; 2', annulus of Vieussens ; 2", thoracic sympathetic ; 3, recurrent laryngeal nerve ; 4, de- pressor nerve, entering the vagus on the right, on the left running a separate course to the heart ; 5, middle (often called "inferior") cervical gan- glion : 5', communicating branch between middle CIRCULATION. 161 The connection of the extrinsic cardiac nerves with tlie intracardiac mus- cle and nerve-cells is not yet determined satisfactorily. Certain fibres in the vagus, said to be derived from the spinal accessory nerve, terminate in " end- baskets " embracing sympathetic ganglion-cells, the axis-cylinder processes of which end on the cardiac muscle-fibres. Probalily the inhibitory action of the vagus is exorcised through these cells, as it is lost in animals poisoned Avith nicotine, which is known to paralyze, in other situations, either the end- baskets about sympathetic cells or the body of the cell itself. Other vagus fibres apparently terminate (or arise) in an end-brush in the pericardium and endocardium. The augmentor apjiaratus consists of two, possibly three, neurons. Tlie cell-body of one lies in the spinal cord; its axis-cylinder process leaves the cord in the white ramus and terminates in a ganglion of the sympathetic chain (inferior cervical, stellate ganglion). .The axis-cylinder proee^-s of the sympa- thetic ganglion-cell .passes directly to the cardiac muscle-fil)re on which it ends, or, possibly, terminates in physiological contact \nth the dendrites of a third neuron lying in the heart, the neuraxon of Avhich carries the augment- ing impulse to the muscle-cell. Stimulation of the white ramus causes aug- mentor effects. In nicotine-poisoning, these effects cannot be obtained ; but stimulation on the distal side — the cardiac side — of the cell-l)ody about which the neuraxon ends, still causes augmentation. If nicotine paralyzes the sympathetic cell-body, this experiment proves that there is no cell in this neuron chain between the point stimulated and the muscle-fibre ; if it par- alyzes the end-basket and not the cell-body, the existence of the third (intra- cardiac) neuron in the chain is possible, provided the communication between the second and the third neuron is not by means of an end-basket ; but, as Dogiel and Huber assume, liv a contact with the dendrites, similar to that observed by them in other sympathetic cells, and not sensitive to nicotine. The Inhibitory Xerves. In 1845, Ernst Heinrich and Eduard \\'eber announced that stimulation of the vagus nerves or the parts of the brain where they arise slows the heart even to arrest. When one pole of an induction apparatus was placed in the nasal cavity of a frog and the other on the siDinal cord at the fourth or fifth vertebra, the heart was completely arrested after one or two pulsations and remained motionless several seconds after the interruption of the current. During the arrest, the heart was relaxed and filled gradually with blood. When the stimulus was continued many seconds, the heart began to beat again, at first M'eakly and with long intervals, then more strongly and frequently, until at length the beats were as vigorous and as frequent as before, though all this time the stimulation was uninterrupted. In order to determine from what part of the brain this influence proceeds, the electrodes were brought very near together and placed upon the cerebral hemispheres. The movements of the heart were not affected. Negative results followed also the stimulation of the spinal cord. Not until the medulla oblon- VOL. I.— 11 162 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. gata between the corpora quadrigemina and the lower end of the calamus scrip- torius was stimulated did the arrest take place. Cutting away the spinal cord and the remainder of the brain did not alter the result. Having determined that the inhibitory power had its seat in the medulla oblongata, the question arose through what nerve the inhibitory influence is transmitted to the heart. In a frog in which the stimulation of the medulla had stopped the heart, the vagus nerves were cut and the ends in connection with the heart stimulated. The heart was arrested as before. Thus the fundamental fact of the inhibition of a peripheral motor mechan- ism by the central nervous system through the agency of special inhibitory Fig. 30.— Pulsations of frog's heart, inhibited by the excitation of the left vagus nerve (Tarchanoff, 1876, p. 296) : C, pulsations of heart ; S, electric signal which vibrated during the passage of the stimu- lating current, one vibration for each induction shock. nerves was firmly established. A great number of investigations have demon- strated that this inhibitory power is found in many if not all vertebrates and not a few invertebrates. Tlie effect of vagus stimulation on the heart is not immediate ; a latent 'period is seen extending over one beat and sometimes two, according to the moment of stimulation (see Fig. 30). Fig. 31.— Showing the lengthened diastole and diminished force of ventricular contraction during weak stimulation of the peripheral end of the cut vagus nerve. The heart (cat) was isolated from both systemic and pulmonary vessels, and was kept beating by circulating deiibrinated blood through the coronary arteries : A, Pressure in left ventricle, which was filled with normal saline solution, and com- municated with a Hiirthle membrane manometer by means, of a cannula which was passed through the auricular appendix and the mitral orifice ; B, line drawn by the armature of an electro-magnet in the primary circuit ; the heavy line indicates the duration of stimulation ; C, time in seconds. Changes in the Ventricle. — The jxriodicity of the ventricular contraction is altered by vagus excitation, a weak excitation lengthening the duration of dias- tole, while leaving tlie duration of systole unchanged (see Fig. 31). A stronger excitation,. capably of modifying largely the force of the contraction, lengthens both systole and diastole.' The difficulty of producing a continued ' Meyer: Archives de Physiologic, 1894, p. 698; Arloing : Ibid., p. 88. CIB C ULA TION. 1 6 3 arrest in diastole is much greater in some animals than in others. Even when easily produced, the arrest soon gives away in the manner described by E. H. and E. Weber, the heart beginning to beat in spite of the vagus excitation.^ The force of the contraction, measured by the height of the up-stroke of the intra-ventricnlar pressure curve, or by placing a recording lever on the heart, is lessened, this diminution in force appearing often before any noticeable change in periodicity. The diastolic pressure increases, as is shown by the lower level of the curve gradually rising farther and farther above the atmospheric pressure line. The volume of blood in the ventricle at the close of diastole is increased. So also is the volume at the close of systole (residual blood) — sometimes to such a degree that the volume of the heart at the end of systole may be greater than the volume of the organ at the end of diastole before the vagus was excited. The output and the input of the ventricle, that is, the quantity of blood dis- charged and received, are both diminished by vagus excitation. The ventricular tonus, or state of constant slight contraction on which the systolic contractions are superimposed, is also diminished, as is well shown by an experiment of Stefani.^ In this experiment the pericardial sac is filled with normal saline solution under a pressure just sufficient to prevent the expansion of the heart in diastole. On stimulation of the vagus, the heart dilates fur- ther. A considerably higher pressure is necessary to overcome this dilatation. Stefani finds also that the pressure necessary to prevent diastolic expansion is much greater with intact than with cut vagi. Furthermore, the heart is much more easily distended by the rise of arterial pressure through compression of the aorta when the vagi are severed than when they are intact. Franck has noticed that the walls of the empty ventricle become softer when the vagus is stimulated.' The propagation of the cardiac excitation is more difficult during vagus excitation. Bayliss and Starling demonstrate this on mammalian hearts made to contract by exciting the auricle three or four times per second ; the ven- tricle as a rule responds regularly to every auricular beat. If, then, the vagus is stimulated with a -weak induced current, the ventricle may drop every other beat, or may for a short time cease to respond at all to the auricular contrac- tions. The defective propagation is not due to changes in the auricular con- ti-action, for even an almost inappreciable beat of the auricle can cause the ventricle to contract. Nor is it due to lowered excitability of the ventricle, for the eiFect described is seen with currents too weak to depress the irrita- bility of the ventricle to an appreciable extent. The sino-auricular and auriculo-ventricnlar contraction intervals are usu- ally lengthened by vagus excitation ; sometimes, however, they are dimin- ^ Hough: Journal of Physiology, 1895, xviii. p. 161. The terrapin lieart is said not to es- cape, as a rule, from vagus inhibition. ^ (Compare vStefani : Archives iialiennes de Biulogie, 1895, xxiii. p. 175. ' See plso Fischel : Archiv fiir experimentelle Palhologie und Pharmakologie, 1897, xxxviii. p. 228. 164 AJY AMERICAN TEXT-BOOK OF PHYSIOLOGY. ished ; the one may be increased, while the other is diminished. The vagus effect quickly reaches a maximum and then slowly decreases. The interval between the contractions of different parts of the sinus is sometimes increased by vagus excitation, so that the different parts are dissociated and beat at measurably different times. Attempts have been made to explain the sev- eral actions of the vagus nerve, together with the various forms of intermit- tent and irregular pulse, by variations in the transmission of the cardiac ex- citation ; ' bnt it is probable that alterations in the condition of the muscle-cells in the sinus, auricle, and ventricle are of equal or greater importance.^ The action of the vagus is accompanied jjy an electrical variation. This has been shown in the muscular tissue of the resting auricle of the tortoise (see Fig. 32). The auricle is cut away from the sinus without injuring the coronary nerve, which in the tortoise passes from the sinus to the auricle and contains the cardiac fibres of the vagus. After this operation the auricle and ventricle remain motionless for a time, and this quiescent period is utilized for the experiment. The tip of the auricle is injured by immersion in hot water, and the demarcation current (the injured tissue being negative toward the unin- jured) is led off to a galvanometer. On exciting the vagus in the neck, the demarcation current is markedly increased. No visible change of form is seen in the auricular strip. Fig. 32.— The tortoise heart prepared for the demonstration of the electrical change in the cardiac muscle accompanying the excitation of the vagus nerve : V, vagus nerve ; C, coronary nerve ; S, sinus and part of auricle in connection with it ; 0, galvanometer, in the circuit formed by two non-polarizable electrodes and the part of the auricle between them ; E, induction coil (Gaskell, 1887). Changes in the Sinus and Auricle.— There is little probability that the action of the vagus on the sinus and auricle, or great veins,^ differs essentially from the action on the ventricle. The force of the contraction is diminished. ' Mnskens: American Journal of Physiology, 1898, i. p. 486. '' Hofmann : Archivfiir die gesammte Physiologic, 1898, Ixxii. p. 409. 5 Knoll : Archiv fiir die gesammte Physiologic, 1897, Ixviii. p. 339 ; Engelmann : Ibid., 1896, Ixv. p. 109. CIRCULATION. 165 The diastole is lengthened. The change in force appears earlier than the change in periodicity, and sometimes without it. On the whole, the sinus and auricle are more easily affected by vagus excitation than the ventricle. Action on Bulbus Arteriosus. — If the bulbus arteriosus of the frog's heart is extirpated in such a way as to leave untouched the nerve-fibres that connect it with the auricular septum, the contractions of the isolated bulbus will be arrested when the peripheral end of the vagus is excited.^ Diminished Irritability of Heart. — During vagus excitation with cur- rents of moderate strength, the arrested heart will respond to direct stimula- tion by a single contraction. ^Yith strong vagus excitation, however, the directly stimulated heart contracts not at all or less readily than before. BflFects of Varying the Stimulus. — A single excitation of the vagus does not stop the heart. Morat has investigated the effect of excitations of varied duration, number, and frequency on the tortoise heart.^ With excitations of the same duration, the effect was minimal at 2 per second, maximal at 7 per second, diminishing thereafter as the frequency increased. The longer the stimulation, the longer (within limits) was the inhibition. An excitation that is too feeble or too slow, or, on the contrary, is over-strong or over-frequent, has no effect. Within limits, however, the degree of inhibition increases with the strength of the stimulus. Weak stimuli affect primarily the auricles, diminishing frequency and force of contraction, and secondarily lower the frequency of the ventricle. Stronger stimuli arrest the auricle, the ventricles coutinuing to beat with almost undi- minished force but with altered rhythm. Still stronger stimuli inhibit the ventricles also. The frequency can be kept comparatively small by continued moderate stimulation. Arrest in Systole. — The excitation of the tortoise vagus in the upper or middle cervical region is sometimes followed, according to Rouget,^ by a state of continued, prolonged contraction — in short, an arrest in systole. The same effect is observed in rabbits strongly curarized and in curarized frogs. Arloing * noticed that the mechanical irritation produced by raising on a thread the left vagus nerve of a horse caused the right ventricle to remain contracted during seven seconds. The ventricular curve during this time presented the characters of the tetanus curve of a skeletal muscle. Recent observations by Frank,^ Himt," Walther,' and others make it probable that a kind of summation and superposition of contractions may at times take place in the heart as in ordinary striated muscular tissue. ' Dogiel : Centralblatt fiir die medicinischen Wisxeiischaften, 1894, p. 227. ' Morat ; Archives de Physiologic, 1894, p. 10. »Rouget: Ibid., p. 398. * Arloing: Ibid., 1893, p. 112. 'Frank: Zeitschnft fUr Biologic, 1899, xxxviii. 'Hunt, Bookman, and Tierney: Centralblatt fiir Physiologic, 1897, xi. p. 274. ' Walther ; Archiv/iir die gesammte Physiologic, 1900, Ixxviii. p. 597. 166 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Comparative Inhibitory Power. — One vagus often possesses more inhibi- tory power than the other.^ Septal Nerves in Frog. — The electrical stimulation of the- peripheral stump of either of two large nerves of the inter-auricular septum in the frog alters the tonus and the force of contraction of the ventricle, but not the fre- quency. After section of these nerves, the excitation of the vagus has very little effect on the tonus, and almost none on the force of the ventricular beat, while the frequency is diminished in the characteristic manner. Evidently, therefore, the two large septal nerves take no part in the regulation of fre- quency, but leave this to the nerves diffusely distributed through the auricles. There is then an anatomical division of the septal branches of the frog's vagus, the fibres affecting periodicity running outside the septal nerves, while those modifying the force of contraction and the tonus of the ventricle run within them.^ Nature of Vagus Influence on Heart. — The nature of the terminal apparatus by which the vagus inhibits the heart is unknown. It is probable that the same intracardiac apparatus serves for both nerves, for Hiifler finds that when the heart escapes from the inhibition caused by continued stimula- tion of one vagus, the prolonged diastole growing shorter again, the immediate stimulation of the second vagus has no effect upon the heart.' Dogiel and Grahe have recently observed that the lengthening of diastole which follows stimulation of the peripheral stump of the vagus, the other vagus being intact, is less marked than when both vagi are cut.' The earlier attempts to form a satisfactory theory for the inhibitory power of the vagus met with little success. The statement of the ^yebers' that the vagus inhibits the movements of the heart gave to nerves a new attribute, but is hardly an explanation. The view of Budge and Sehiff, that the vagus is the motor nerve of the heart and that inhibition is the expression of its exhaustion, is now of only historical interest. Nor has a better fate overtaken the theory of Brown-S6quard, who saw in the vagus the vaso-motor nerve of the heart, the stimulation of ^^'hich, by narrowing the coronary arteries, deprived the heart of the blood that, according to Brown-Sequard, is the exciting cause of the contraction. Of recent years, the explanation that has commanded most attention is the one advanced by Stefani ° and Gaskell, namely, that the vagus is the trophic nerve of the heart, producing a dis-assimilation or katabolism in systole and an assimilation or anabolism in diastole. Gaskell supports this theory by the observation that the after-effect of vagus excitation is to strengthen the force of the cardiac contraction and to increase the speed with which the excitation ' Hofmann : Archiv fur die gesammte Physiologic, 1895, Ix. p. 169. ^ For other unusual alterations in the heart-beat in consequence of vagus excitation see Arloing: Archives de Physiologic, 1894, p. 163; and Knoll: Archiv fUr die gesammte Physiologic, 1897, Ixvii. p. 587. ' Hough : Joamal of Physiology, 1895, xviii. p. 198. * Dogiel and Grahe : Archiv fiir Physiologic, 1895, p. 393. Changes in the peripheral effi- ciency of the v.agi are discussed by McWilliams : Proceedings Royal Society, 1893, liii. p. 475. * Stefani: Archives ilcdiennes de Biologic, 1895, xxiii. p. 176. CIRCULATION. 167 wave passes over the heart, while the contrary effects are witnessed after the excitation of the augmentor nerves. Various attempts have been made to prove a trophic action of the vagus on the heart by cutting the nerve in animals kept alive until degenerative changes in the heart-muscle should have had time to appear. The important distribu- tion of the vagus nerve to many organs, and the consequently wide extent of the loss of function following its section, makes it difficult to decide whether the changes produced in the heart are not secondary to the alterations in other tis- sues. The work of Fantino will serve for an example of these investigations. Fantino cut a single vagus to avoid the paralysis of deglutition and the inani- tion and occasional broncho-pneumonia that follow section of both nerves. Young and perfectly healthy rabbits and guinea-pigs were selected. The opera- tion was strictly aseptic, and all cases in which the wound suppurated were excluded. A piece of the nerve about one centimeter long was cut out, so that no reunion could be possible. After the operation the animals were as a rule lively, ate well, and gained weight. Post-mortem examination of animals killed two days or more after section of the vagus nerve disclosed no patho- logical changes in the lungs, spleen, liver, and stomach. In the heart, areas were found in which the nuclei and the striation of the muscle-cells had disap- peared. Eighteen days after section the atrophy of the cardiac muscle in these areas was observed to be extreme. The degenerations following section of the right vagus were situated in a different part of the ventricular wall from those following section of the left nerve. The effects of stimulation of the vagus nerve in the new-born do not differ essentially from those seen in the adult.' The relation between the action of the vagus and the intracardiac pressure has been recently studied by Ste^rart. He finds that an increase in the pressure in the sinus or auricle makes it difficult to inhibit the heart through the vagus. The inhibitory action of the vagus diminishes as the temperature of the heart falls. At a low limit the inhibitory power is lost, but may return when the heart is warmed again. Even when the stimulation of the trunk of the nerve has failed to affect the cooled heart, the direct stimulation of the sinus can still cause distinct inhibition. The power of inhibiting the ventricle is first lost. Loss of inhibitory power does not follow the raising of the heart to high temperatures. The vagus remains active to the verge of heat arrest, and resumes its power as soon as the temperature is lowered. The Augmentor Nerves. V. Bezold observed m 1862 that stimulation of the cervical spinal cord caused an increased frequency of heart-beat. This seemed to him to prove the existence of special accelerating nerves. Ludwig and Thiry, however, soon pointed out that stimulation of the spinal cord in the cervical region excited many vaso-constrictor fibres, leading to the narrowing of many vessels and a corresponding rise of blood-pressure. The acceleration of the heart-beat ' Meyer: Archives de Physioiocjie, 1893, p. 477. 16 a UY A 3T ERIC AN TEXT- BOOK OF PHYSIOLOGY. accompauving this rise in blood-pressure would alone explain the observation of von Bezold. Three years later Bever and von Bezold were more suc- cessful. The influence of the vaso-motor nerves was excluded by section of the spinal cord between the first and second thoracic vertebrae. Stimulation of the cervical cord now caused an increase in the frequency of the heart-beat without a simultaneous increase of blood-pressure. The fibres carrying the accelerating impulse were traced from the spinal cord to the last cervical gan- trlion and from there toward the heart. In the dog the " augmenting " or " accelerating " nerves thus discovered leave the spinal cord mainly by the roots of the second dorsal nerves, and enter the ganglion stellatum, whence they pass through the anterior and posterior loops of the annnlus of A'ieussens into the inferior cervical ganglion, from which they go, in the cardiac branches of the latter, to the heart. Some of the cardiac fibres in the annulus pass directly thence to the cardiac plexus and do not enter the inferior cervical ganglion. In the rabbit, the course of the augmentor fibres is probably closely similar to that in the dog. In the cat, the augmentor nerves spring from the ganglion stellatum, and very rarely from the inferior cervical ganglion as well. The right cardiac sympathetic nerve communicates with the vagus. The stimulation of the sympathetic chain iu the. frog, " between ganglion 1 and the vagus ganglion, and also stimulation of the chain between ganglia 2 and 3, causes marked acceleration and augmentation of the auricular and ven- tricular contractions. Stimulation be- tween ganglia 3 and 4 produces no effect whatever upon the heart." This ex- periment of Gaskell and Gadow's shows that augmentor fibres enter the sympa- thetic from the spinal cord along the ramus commnnicans of the third spinal nerve and pass upward in the sympa- thetic chain. In this animal the sym- pathetic chain, after dividing between the first and second ganglia to form the annulus of Vieussens, joins the trunk of the vagus between the united vagus and glosso-pharyngeal ganglia and the vertebral column (see Fig. 33). Here the sympathetic again divides, some of the fibres passing alongside the vagus into the cranial cavity, the rest accompany- ing the vagus nerve peripherally. The augmentor nerves for the heart ai-e among the latter, for the stimulation of the intracranial vagus results in pure inhibition, while the stimulation of the vagus trunk after it is joined by the sympathetic may give either inhibition or augmentation. We may say, there- fore, that the augmentor nerves of the frog pass out of the spinal cord by the V-Sy Fig. 33.— The cardiac Bympathetio nerves in Eana temporaria (twice natural size): F-Sj/, vago-sympathetic ; A.v, arteria vertebralis ; II, IV, second and fourth spinal nerves (Gaskell and Gadow, 1884). CIBCULATIOX. 169 third spinal nerve, through the ramus communicans of this nerve, into the third sympathetic ganglion, up the sympathetic chain to the ganglion of the vagus, and down the vagus trunk to the heart. Stimulation of Augmentor Nerves. — The most obvious effect of the stim- ulation of the augmentor nerves is an increase of from 7 to 70 per cent, in the frequency of the heart-beat (see Fig. 34). The quicker the heart is beating ■before the stimulation, the less marked is the acceleration. The absolute maxi- ^^ wAwMwAw>Mwwwwv*Wvvwv.vA Fjii. 34. — Curve of blood-pressure in the cat, recorded by a- mercury manometer, showing the increase in frequency of heart-beat from excitation of the augmentor nerves. The curve reads from right to left. The augmentor nerves were excited during thirty seconds, between the two stars. The number of beats per ten seconds rose from 21 to 33 (Boehm, 1875, p. 258). mum of frequency is, however, independent of the frequency before stimulation. The maximum of acceleration is largely independent of the duration of stimula- tion. The duration of stimulation and the duration of acceleration are not related, a long stimulation causing no greater acceleration than a short one. The force of the ventricular beat is increased. The ventricle is filled more -completely by the auricles, the volume of the ventricle being increased. The Fig. 35.— Increase in the force of the ventricular contraction (curve of pressure in right ventricle) from stimulation of angmentor fibres. There is little or no change in frequency (Franek, 1890, p. 819). output of the heart is raised. There is no definite relation between the in- crease of contraction volume or force of contraction and the increase in fre- quency (see Fig. 35). Either may appear without the other, though this is rare. The simultaneous .stimulation of the nerves of both sides does not give a greater maximum frequency than the stimulation of one nerve alone. The strength and the volume of the auricular contractions are also in- creased. The increase in volume is not due to a rise of pressure in the veins — in fact, the pressure falls in the veins — but to a change in the elasticity of the relaxed auricle, a lowering of its tonus. This change is not related to the increase in the force of the auricular contractions that stimulation of the aug- mentor nerves also causes. It varies much in amount and is less constantly met with than the cJiange in force. The changes in the ventricle and auricle 170 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. probably account for the rise of blood-pressure in the systemic arteries and the fall in both systemic and pulmonary veins observed by Roy and Adami. The speed of the cardiac excitation ivave is increased. Its passage across the auriculo-ventricular groove is also quickened, as is shown in the following experiment of Bayliss and Starling. In the dog, the artificial excitation of the ventricle may cause the excitation wave to travel in a reverse direction, namely, from ventricle to auricle. If the ventricles are excited rhythmically and the rate of excitation is gradually increased, a limit will be reached beyond which the auricle no longer beats in response to every ventricular contraction. With intact vagi, a rate of 3 per second is generally the limit. If now the augmentor nerve is stimulated, the " block " is partially removed, and the auricle beats during and for a short time after the stimulation at the same rapid rate as the ventricle. The latent period of the excitation is long. In the dog, about two seconds pass between the beginning of stimulation and the beginning of acceleration, and ten seconds may pass before the maximum acceleration is reached. The after-effect may continue two minutes or more. It consists of a weakening of the contractions and an increase in the difficulty with which the excitation wave passes from the auricle to the ventricle. The return to the former fre- quency is more rapid after short than after long stimulations. The effect upon the heart-rate of simultaneous stimulation of the vagi and accelerator nerves, according to Hunt, is determined by the relative strength of the two .stimulating currents. For sub-maximal stimuli the result for both systole and diastole is approximately the arithmetical mean of the re- sults of stimulating the two nerves separately.' The acceleration that is seen after the stimulation of the vagus is due to the after-effect of the stimulation of accelerating fibres in the vagus. The simultaneous stimulation of the augmentors and the vagi, the strength of the current being sufficient to stop the auricular contractions, causes accel- eration of the ventricular contractions. The acceleration of the li(>art may be more or less intermittent, although the excitation of the augmentor nerves continues. It is probable that this is due to irradiation from the bulbar respiratory centre.' . 2 Other Centrifugal Heart-nerves. In the vago-sym pathetic trunk and the annulus of Vieussens fibres pass to the heart that cannot be classed either with the vagus or the augmentor nerves. The evidence for their existence is furnished by Roy and Adami's observation that when the intracardiac vagus mechanism is acting strongly, so that the auricles are more or less completely arrested, the stimulation of the vago- sympathetic trunk sometimes causes a decided increase in the force both of the ventricles and the auricles, usually accompanied by an acceleration of the rhythm of the heart. These changes are too rapidly produced to be aug- mentor effects. ^Hnnt: American Journal of Physiology, 1899, ii. ji. 422. '' 'Wertliemier and Lepage : Journal de phyaiologie et de pathologic generate, 1899, p. 236. CIRCULATION. 171 Centrifugal inhibitory nerves have been found as an anomaly in the right depressor nerve of a rabbit.^ Pawlow divides the inliibitory and augmentor nerves into four classes — (1) nerves inhibiting the frequency of the beat, (2) nerves inhibiting the force of the contraction, (3) nerves augmenting frequency, and (4) nerves augmenting force. The origin of this subdivision of the two groups generally recog- nized was the observation that, in cer- tain stages of convallaria poisoning, the excitation of the vagus in the neck — all tlie branches of the nerve except those going to heart and lungs being cut — re- duced the blood-pressure without alter- ing the frequency of the beat. Further researches showed that the stimulation of branch 3 (Fig. 36) even in unpoi- soned animals reduced the blood-pres- sure independently of the variable al- teration simultaneously produced in the pulse-rate. Stimulation of branch 5 produced an acceleration of the heart- beat without increase of blood-pressure. Other branches brought about rise of pressure without acceleration, and in- creased discharge by the left ventricle without alteration in the pulse-rate. These results are supported further by Wooldridge's observation that exci- tation of the peripheral ends of certain nerves on the posterior surface of the ventricle raised the blood-pressure without modifying the frequency of contrac- tion, and by Roy and Adami's demonstration that certain branches of the first thoracic ganglion lessen the force of the cardiac contraction without influencing its rhythm. But the matter is as yet far from certain. Fig. 36.— Schema of the centrifugal nerves of the heart according to Pawlow : 1, vago-sympa- thetic nerve ; 2, upper inner branch ; 3, strong inner branch : 4. lower inner branch ; 5, upper and lower outer branches ; 6, ganglion stellatum ; 7, annulus of Vieussens ; 8, middle (inferior) cer- vical ganglion ; 9, recurrent laryngeal nerve. The Centripetal Nerves op the Heart. The Ventricular Nerves. — \Yheu the mammalian heart is freed from blood by washing it out with normal saline solution and the ventricle is painted with pure carbolic acid, liquefied by warming, numerous nerves appear as white threads on a brown background. They are non-medullated, form many plexuses, and run beneath the pericardium obliquely downward from the base to the apex of the ventricle. They may be traced to the cardiac plexus. These fibres are not centrifugal branches of the vagus or the augmentor nerves, for the characteristic effects of vagus and augmentor stimulation are seen after section of the nerves in question. The stimulation of their peripheral ends, moreover, the fibre being carefully dissected out from the subpericardial tissue, 'Hering: ^IrchivfUr die gesammte Physiologie, 1894, Ivii. p. 78. 172 ^;V^ AMERICAN TEXT-BOOK OF PHYSIOLOGY. cut across, and the cut end raised on a thread in the air, is without effect on the blood-pressure and pulse-rate. The stimulation of the central stumps of these nerves, on the contrary, is followed by changes both in the blood-pressure and the pulse, showing that they carry impulses from the heart to the cardiac centres in the central nervous system, or perhaps, according to the views of some recent investigators, to peripheral ganglia, thus modifying the action of the heart reflexly. Sensory Nerves of the Heart. — The stimulation of intracardiac nerves by the application of acids and other chemical agents to the surface of the heart causes various reflex actions, such as movements of the limbs. The afferent nerves in these reflexes are the vagi, for the reflex movements dis- appear when the vagi are cut. On the strength of these experiments the vagus has been believed to carry sensory impressions from the heart to the brain. Direct stimulation of the human heart, in cases in which a defect in the chest-wall has made the organ accessible, give evidence of a dim and very limited recognition of cardiac events — for example, the compression of the heart. Changes in the force, periodicity, and conduction of the contraction- wave may be produced by direct electrical stimulation of the ventricle. The centre of these reflexes probably lies in the bulb.^ Vagus. — The stimulation of the central end of the cut vagus nerve,^ tlie other vagus being intact, causes a slowing of the pulse-rate. The section of the second vagus causes this retardation of the pulse to disappear, indicating that the stimulation of the central end of the one affects the heart reflexly through the agency of the other ^'agus. The blood-pressure is simultaneously affected, being sometimes lowered and sometimes raised, the difference seeming to depend largely on the varying composition of the vagus in different ani- mals and in different individuals of the same species. The stimulation of the pulmonary branches, by gently forcing air into the lungs, loud speaking, singing, etc., is said to increase the frequency of the heart-beat. Yet the chemical stimulation of the mucous membrane of the lungs is alleged to slow the pulse- rate and lower the blood-pressure. Observers differ as to the results of stim- ulation of the central end of the laryngeal branches of the vagus on the pulse- rate and blood-pressure. Depressor Nerve. — The earlier stimulations of the nerves that pass between the central nervous system and the heart, with the exception of the vagus, altered neither the blood-pressure nor the pulse-rate. Ludwig and Cyon suspected that the negative results were owing to the fact that the stimulations were confined to the end of the cut nerve in connection with the heart. Some of the nerves, they thought, should carry impulses from the heart to the brain, and such nerves could be found only by stimulation of the brain end of the cut nerve. They began their research for these afferent nerves with the branch which springs from the rabbit's vagus high in the neck and passes downward to the ganglion stellatum. Their suspicion was at once confirmed. The stimu- 'Muskens: Archivfiir die gesammle Physiologic, 1897, Ixvi. p. 328. "Hunt: Journal of Physiology, 1895, xviii. p. 381. C IRCULA TION. 1 73 lation of the central end of this nerve, called by Ludwig and Cyon the depres- sor, caused a considerable fall of the blood-pressure. The depressor nerve arises in the rabbit by two roots, one of which comes from the trunk of the vagus itself, the other from a branch of the vagus, the superior laryngeal nerve. Frequently the origin is single ; in that case it is usually from the nervus laryngeus.^ The nervus depressor runs in company with the sympathetic nerve to the chest, where communications are made with the branches of the ganglion stellatum. The stimulation of the peripheral end of the depressor nerve is without effect on the blood-pressure and heart-beat. The stimulation of the central end, im the contrary, causes a gradual fall of the general blood-pressure to the half or the third of its former height. After the stimulation is stopped, the blood-pressure returns gradually to its previous level. Simultaneously with the fall in blood-pressure a lessening of the pulse-rate sets in. The slowing is most marked at the beginning of stimulation, and after rapidly reaching its maximum gives way gradually until the rate is almost what it was before the stimulation began. After stimulation the frequency is commonly greater than previous to stimulation. After section of both vagi, the stimulation of the depressor causes no change in the pulse-rate, but the blood-pressure falls as usual. Tiie alteration in fre- quency is therefore brought about through stimulation of the cardiac inhibitory centre, acting on the heart through the vagi. The experiment teaches, further, that the alteration in pressure is not dejjendent on the integrity of the vagi. Poisoning with curare paralyzes all motor mechanisms except the heart and the muscles of the blood-vessels. Yet curare-poisoning does not affect the result of depressor stimulation. The cause of the fall in blood-pressure must be sought then either in the heart or the reflex dilatation of the blood-vessels. It cannot be in the heart, for depressor stimulation lowers the blood-pressure after all the nerves going to the heart have been severed. It must therefore lie in the blood-vessels. Ludwig and Cyon knew that the dilatation of the intestinal vessels could produce a great fall in the blood-pressure and turned at once to them. Section of the splanchnic nerve caused a dilata- tion of the abdominal vessels and a fall in the blood-pressure. Stimula- tion of the peripheral end of the cut splanchnic caused the blood-pressure to rise even beyond its former height. Ludwig and Cyon reasoned that if the depressor lowers the blood-pressure cliieHy by affecting the splanchnic nerve reflexly, the stimulation of the central end of the depressor after section of the splanchnic nerves ought to have little effect on the blood-pressure. This proved to be the case. The investigators concluded that the depressor re- duces the blood-pressure chiefly by lessening the tonus of the vessels governed by the splanchnic nerve, thus allowing their dilatation and in consequence lessening the peripheral resistance. The fallacy in this argument has re- cently been pointed out by Porter and Beyer.^ The stimulation of the de- ' Tschirwinsky : Centralblail fur I'hysiologie, 1896, ix. p. 778, gives a somewhat different account. ^ Porter and Beyer : American Joarnal of Physiology, 1900, xxiii. 174 AN AMERICAN TEXT- BO OK OF PHYSIOLOGY. pressor after section of the splanchnic nerves has little effect, because the blood-pressure is alread}- so low \\-hen the stimulation is made that it can sink but little more. When, however, the pressure is restored to its normal level, after section of the splanchnic nerves by the stimulation of their peripheral ends, or by the injection of normal saline solution into the vessels and the depressors then stimulated, the fall in blood-pressure is nearly and some- times quite as great as that obtained by the stimulation of the depressor nerve when the splanchnic ner\-es are intact. It is improbable, therefore, that the depressor acts chiefly through the splanchnic nerves. It probably acts on all the vasomotor nerves connected with the vasomotor centre. Tliis view is somewhat strengthened by the observations of Bayliss (Fig. 37). It has already been said that the depressor fibres pass from the heart to the vaso-motor mechanism in the central nervous system. The cardiac fibres are probably stimulated when the heart is overfilled through lack of expulsive force or through excessive venous inflow, and, by reducing the peripheral resist- ance, assist the engorged organ to empty itself. The depressor nerve is not in continual action ; it has no tonus ; for the sec- tion of both depressor nerves causes no alteration in the blood-pressure. Sewall and Steiner have obtained in some cases a permanent rise in blood- pressure following section of both depressors, yet they hesitate to say that the depressor exercises a tonic action. Spallita and Consiglio have stimulated the depressor before and after the Fig. 37.— Showing the fall in blood-pressure and the dilatation of peripheral vessels from stimula- tion of the central end of the depressor nerve (Bayliss) : A, curve of hlood-pressure in the carotid artery ; B, volume of hind limh, recorded by a plethysmograph ; C, electro-magnet line, in which the elevation shows the time of stimulation of the nerve ; D, atmospheric pressure-line ; E, time in seconds. section of the spinal accessory nerve near its junction with the vagus. They find that after section of the spinal accessory, the stimulation of the depressor does not affect the pulse, whence they conclude that the depressor fibres that affect the blood-pressure are separate from those that affect the rate of beat, the latter being derived from the spinal accessory nerve. A recent study by Bayliss ' brings out several new facts. If a limb is placed ' Bayliss : JoumaJ, of Physiology, 1893, xiv. p. 303. The relation between the depressor nerve and the thyroid is pointed out by v. Cyon : CentralblaU fur Physiologie, 1897, ii. pp. 279, 357. CIBCULA TION. 175 in Mosso's plethysmograph and the central end of the depressor stimidated, the vohime of the limb increases, showing an active dilatation of the vessels that supply it. The latent period of this dilatation varies greatly. The vessels of the skin play a large part in its production. A similar local action is seen on the vessels of the head and neck (see Fig. 37). The depressor fibres vary much in size in different animals. When the nerve is small, a greater depressor effect can be obtained by stimulating the central end of the vagus than from the depressor itself But the course of the fall is different in the two cases. With the depressor, the fall is maintained at a constant level during the whole excitation, however long it lasts, whereas in the case of the vagus the pressure very soon returns to its original height although the excitation still continues. Bayliss believes, therefore, that there is a considerable difference between the central connections of the depressor nerve itself and the depressor fibres sometimes found in other nerves. The left depressor nerve usually produces a greater fall of pressure than the right. The excitation of the second nerve during the excitation of the first produces a greater fall than the excitation of one alone. The fibres of the depressor, in part at least, end in the wall of the ventricle. A similar nerve has been demonstrated in the cat, horse, dog, sheep, swine, and in man. Sensory Nerves. — The first and usually the only effect of the stimulation of the central end of a mixed nerve like the sciatic, according to Roy and Adami, is an increase in the force and the frequency of the heart-beat. Other observers have sometimes found quickening and sometimes slowing of the pulse- rate, so that sensory nerves, as Tigerstedt suggests, appear to affect both the inhibitory and the augmenting heart-nerves. When a sensory nerve is weakly excited the augmentor effect predominates, when strongly excited the inhibi- tory. A well-known demonstration of the reflex action of the sensory nerves on the heart is seen in the slowing of the rabbit's heart when the animal is made to inhale chloroform. The superior laryngeal and the trigeminus nerves, especially the latter, convey the stimulus to the nerve-centres. The stimulation of the nerves of special sense, optic, auditory, olfactory and glosso-pharyngeal nerves, also sometimes slows and sometimes quickens the heart. Sympathetic. — The reflex action of the sympathetic nerve upon the heart is well shown by the celebrated experiment of F. Goltz. In a medium-sized frog, the pericardium was exposed by carefully cutting a small window in the chest-wall. The pulsations of the heart could be seen through the thin peri- cardial membrane. Goltz now began to beat upon the abdomen about 140 times a minute with the handle of a scalpel. The heart gradually slowed, and at length stood still in diastole. Goltz now ceased the rain of little blows. The heart remained quiet for a time and then began to beat again, at first slowly and then more rapidly. Some time after the experiment, the heart beat about five strokes in the minute faster than before the experiment was begun. The effect cannot be obtained after section of the vagi. 176 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Bernstein found that the afferent nerves in Goltz's experiment were branches of the abdominal sympathetic, and discovered that the stimulation of the cen- tral end of the abdominal sympathetic in the rabbit was followed also by reflex inhibition of the heart. The stimulation of the central end of the splanchnic produces a reflex rise of blood-pressure and, perhaps secondarily, a slowing of the heart. In some cases acceleration has been observed. According to Roy and Adami splanch- nic stimulation sometimes produces a combination of augmentor and vagus effects, the augmentation appearing during stimulation and giving place abruptly to well-marked inhibitoiy slowing at the close of stimulation. The results of stimulating various abdominal viscera have been studied by ]\Iayer and Pribram. One of the most interesting of the reflexes observed by them was the inhibition of the heart called forth by dilating the stomach. The stimulation of the cervical sympathetic does not give any very constant results on the action of the heart. B. The Centres of the Heaet-nbrves. Inhibitory Centre. — It has been already mentioned that the brothers AVeber localized the cardiac inhibitory centre in the medulla oblongata. The efforts to fix the exact location of the centre by stimulation of various parts, either mechanically, by thrusting fine needles into the medulla, or electrically, cannot inspire great confidence because of the difficulty of distinguishing between the results that follow the excitation of a nerve-path from or to the centre and those following the excitation of the centre itself. According to Laborde, who also used this method, the cardiac inhibitory centre is situated at the level of the mass of cells known as the accessory nucleus of the hypoglossus and the mixed nerves (vagus, spinal accessory, glosso-pharyngeal). The localization of the centre by the method of successive sections is per- haps more trustworthy. Franck has found that the separation of the bulb from the spinal cord cuts off the reflexes called forth by nerves that enter the spinal cord, while leaving undisturbed the reflex produced by stimulation of the trigeminus nerve. On the whole, there seems to be no doubt that the cardiac inhibitory centre is situated in the bulb. Tonus of Cardiac Inhibitory Centre. — The cardiac inhibitory centre is prob- ably always in action, for when the vagus nerves are cut, the heart-beat becomes more frequent.^ The source of this continued or " tonic " activity may lie in the continuous discharge of inhibitory impulses created by the liberation of energy in the cell independent of direct external influences, or the cells may be discharged by the continuous stream of afferent impulses, that must constantly play upon them from the multitude of afferent nerves. This latter theory, the conception of a reflex tonus, is made probable by the observations that section of the vagi does not increase the rate of beat after the greater part of the afferent impulses have been cut off by division of the ' Hunt : American Journal of Physiology, 1899, ii. p. 397. CIRCULA TION. 177 spinal cord near its junction with the bulb, and that the sudden decrease in the number of afferent impulses caused by section of the splanchnic nerve quickens the pulse-rate. Irradiafion.-^The slowing of the rate of beat observed chiefly during the expiratory portion of respiration disappears after the section of both vagus nerves. The slowing may perhaps be due to the stimulation of the cardiac inhibitory centre by irradiation from the respiratory centre.' Origin of Cardiac Inhibitory Fibres. — Since the researches of "Waller and others, it has been generally believed that the cardiac inhibitory fibres enter the vagus from the spinal accessory nerve, for the reason that cardiac inhibi- tion was not secured in animals in which the fibres in the vagus derived from the spinal accessory nerve were made to degenerate by tearing out the latter before its junction with the vagus. These results have lately been called in question by Grossmann.^ The method employed by his predecessors, according to him, probably involved the destruction of vagus roots as well as those of the spinal accessory. Grossmann finds that the stimulation of the spinal accessory nerve before its junction with the vagus does not inhibit the heart. Nor does inhibition follow the stimulation of the bulbar roots supposed to be contributed to the mixed nerve by the spinal accessory. Augrnentor Centre. — The situation of the centre for the augmeutor nerves of the heart is not definitely known, although from analogy it seems probable that it will be found in the bulb. That this centre is constantly in action is indicated by the lowering of the pulse-rate after section of the vagi followed by the bilateral extirpation of the inferior cervical and first thoracic ganglia.' The division of the spinal cord in the upper cervical region after the section of the vagi has the same effect. Vagus inhibition, moreover, is said to be more readily produced after section of the augmeutor nerves. jNlcWilliam * has remarked that the latent period and the character of the acceleration often accompanying the excitation of afferent nerves may differ entirely from the characteristic effects of the excitation of augmentor nerves. The stimulation of the latter is followed by a long latent period, after which the rate of beat gradually increases to its maximum and, after excitation is over, as gradually declines. The excitation of an afferent nerve, on the con- trary, causes often, with almost no latent period, a remarkably sudden accel- eration, that reaches at once a high value and often suddenly gives way to a slow heart-beat. These facts seem to show that reflex acceleration of the heart- beat is due to changes in the cardiac inhibitory centre, and not to augmentor excitation. This view is strengthened by the fact that if the augmentor nerves are cut, the vagi remaining intact, the stimulation of afferent fibres, for exam- ple in the brachial nerves, can still cause a marked quickening of the pulse- rate. In short, the action of afferent nerves upon the rate of beat is essentially 'Laulani6; Comples rendm Soclcte de Biologic, 1893, p. 723. Compare Wood; American Journal of Physiologxj, 1899, ii. p. 352. ^ Grossmann : Archiv/Ur die gcsammte Physiologic, 1895, lix. p. 6. ' Hunt: American Journal of Physiology, 1899, ii. p. 397. "• Mc\\'illiam : Proceedings Royal Society, 1893, liii. p. 472. Vol. I.— 12 178 JX AMERICAN TEXT-BOOK OF PHYSIOLOGY. the same, according to this observer, whether the augmentor nerves are divided or intact. Roy and Adami believe that the stimulation of afferent nerves, such as the sciatic or the splanchnic, excites both augmentor and vagus centres. The augmentor centre is almost always the more strongly excited of the two, so that augmentor effects alone are usually obtained. Action of Higher Parts of the Brain on Cardiac Centres. — Repeated efforts have been made to find areas in the cortex of the brain especially related to the inhibition or augmentation of the heart, but with results so con- tradictory as to warrant the conclusion that the influence on the heart-beat of the parts of the brain lying above the cardiac centres does not differ essen- tially from that of other organs peripheral to those centres. Voluntary control of the heart, by which is meant the power to alter the rate of beat by the exercise of the will, is impossible except as a rare indi- vidual peculiarity, commonly accompanied by an unusual control over muscles, such as the platysma, not usually subject to the will. Cases are described by Tarchanoff and Pease, in which acceleration of the beat up to twenty-seven in the minute was produced, together with increase of blood-pressure, from vaso-constrictor action. The experiments are dangerous.^ Peripheral Reflex Centres. — It is now much discussed whether the periph- eral ganglia can act as centres of reflex action. According to Frauck^ the excita- tion of the central stump of the divided left anterior limb of the annulus of Vieussens is transformed within the first thoracic ganglion, isolated from the spinal cord by section of its rami communicantes, into a motor impulse trans- mitted by the posterior limb of the annulus. This motor impulse causes, inde- pendently of the bulbo-spinal centres, a reflex augmentation in the action of the heart, and a reflex constriction of the vessels in the external ear, the submaxil- lary gland, and the nasal mucous membrane. This experiment, in conjunction with the facts in favor of other sympathetic ganglia acting as reflex centres,' seems to demonstrate that some afferent impulses are transformed in the sym- pathetic cardiac ganglia into efferent impulses modifying the action of the heart. If this conclusion is confirmed by future investigations it will pro- foundly modify the views now entertained regarding the innervation of the heart. Tiie experiments of Stannius, published in 1852, have been the starting- point of a very great number of researches on the innervation of the frog's heart. Stannius observed, among other facts, that the heart remained for a time arrested in diastole when a ligature was tied about the heart precisely at the junction of the sinus venosus with the right auricle. No sufficient explanation of this result has yet been given, nor is one likely to be found until the innervation of the iieart is better understood. Stannius further ' Van de Velde : Archivfur die (jemmmte Pliysiologie, 1897, Ixvi. p. 232. ^ Fraiick : Archives de PhysioJogie, 1894, p. 721. ' Langley and Anderson : Journal of Physiology, 1894, xvi. p. 43.5. Tlie attempt of Prof. Kronecker to demonstrate a co-ordinating centre in the ventricles may be mentioned liere (Zeil- sclirift fiir Biologie, 1896, xxxiv. p 529). CIRCULATION. 179 observed that after the ligature just described had been drawn tight, thus arresting the heart, the placing of a second ligature around the heart at the junction of the auricle and ventricle caused the latter to begin to beat again, while the auricle remained at rest. This second ligature, it is generally admitted, stimulates the ganglion of Bidder, and the ventricle responds by rhythmic contractions to the constant excitation thus produced. Loosening the ligature and so interrupting the excitation stops the ventricular beat. PAET III.— THE NUTRITION OF THE HEART. The cells of which the heart-wall are composed are nourished by contact with a nutrient fluid. In hearts consisting of relatively few cells no special means of bringing the nutrient fluid to the cells is required. The walls of the minute globular heart of the small crustacean Daphnia, for example, are com- posed of a single layer of cells, each of which is bathed by the fluid which the heart pumps. In larger hearts with thicker walls only the innermost cells could be fed in this way. Special means of distributing the blood throughout the substance of the organ are necessary here. Passages in the Frog's Heart. — In the frog this distribution is accom- plished chiefly through the irregular passages which go out from the cavities of the heart between the muscle-bundles to within even the fraction of a milli- meter of the external surface. These passages vary greatly in size. Many are mere capillaries. They are lined by a prolongation of the endothelium of the heart. Filled by every diastole and emptied by every systole, they do the work of blood-vessels and carry the blood to every part of the cardiac muscle. Henri ^Martin ' describes a coronary artery in the frog, analogous to the coronary arteries of higher vertebrates. This artery supplies a part of the auricles and the upper fourth of the ventricle. In the rabbit, cat and dog, and in man a well-developed system of cardiac vessels exists, the coronary arteries and veins. Their distribution in the dog deserves especial notice, because the physiological problems connected with these vessels have been studied chiefly in this animal. Coronary Arteries in the Dog. — In the dog the coronary arteries and their larger branches lie upon the surface of the heart, covered as a rule only by the pericardium and a varying quantity of connective tissue and fat. The left coronary artery is extraordinarily short. A few millimeters after its origin from the aorta it divides into the large ramus circumflex and the descen- dens, nearly as large. The former runs in the auriculo-ventricular furrow around the left side of the heart to the posterior surface, ending in the pos- terior inter-ventricular furrow. The left auricle and the upper anterior and the posterior portion of the left ventricle are supplied by this artery. The descen- dens runs downward in the anterior inter- ventricular furrow to the apex. Close to its origin the descendens gives off' the arteria septi, which at once enters the ' Martin Comptes rendus Societe de Bioloyie, 1893, p. 754. 180 AN A3IERICAN TEXT-BOOK OF PHYSIOLOGY. inter-ventricular septum and passes, sparsely covered \yith muscle-bundles, obliquely downward and backward on the right side of the septum. The descendens in its farther course gives off numerous branches to the left ventricle and the anterior part of the septum. Only a few small branches go to the right ventricle. Thus the descendens supplies the septum and the inferior anterior part of the left ventricle. The right coronary arterj^, imbedded in fat, runs in the right auriculo-ventricular groove around the right side of the heart, sujDplying the right auricle and ventricle. It is a much smaller artery than either the circulnflex or descendens. Each coronary artery keeps to its own boundaries and does not, in the dog, jjass into the field of another artery, as sometimes happens in man.^ Terminal Nature of Coronary Arteries. — The coronary arteries in the dog, as in man, are terminal arteries, that is, the anastomoses which their branches have with neighboring vessels do not permit the making of a collateral circula- tion. Their terminal nature in the human heart is shown by the formation of infarcts in the areas supplied by arteries which have been plugged by embo- lism or thrombosis. That part of the heart-wall supplied by the stopped artery speedily decays. The bloodless area is of a dull white color, often faintly tinged with yellow; rarely it is red, being stained by haemoglobin from the neighboring capillaries. The cross section is coarsel}' granular. The nuclei of the muscle-cells have lost their power of staining. The muscle-cells are dead and connective tissue soon replaces them.^ This loss of function and rapid decay of cardiac tissue would not take place did anastomoses permit the establislimeut of collateral circulation between the artery going to the part and neigliboring arteries. The terminal nature of the coronary arteries in the dog has been placed beyond doubt by direct experiment. It is possible to tie them and keep the animal alive until a distinct infarct has formed.^ The objection that one of the coronary arteries can be injected from another,* and that therefore they are not terminal, is based on the incorrect premise that terminal arteries cannot be thus injected, and has no weight against the positive evidence of the complete failure of nutrition following closure. The passage of a fine injection-mass from one vascular area to another proves nothing concerning the possibility of the one area receiving its blood-supply from the other. Such supply is impossible if the resistance in the communi- cating vessels is greater than the blood-pressure in the smallest branches of the artery through which the supply must come. It is the fact of this high resist- ance, due to the small size of the communicating branches, which makes the artery "terminal." This condition of high resistance is really present during life, or infarction could not take ])lace. The terminal nature of the coronary arteries is of great importance with regard to the part taken by them in the nutrition of the heart. Being ter- ' Baumgarten : American Jonrnal of Physiology, 1899, ii. p. 243. 'See also the description by Kolster: Hkmiflinarixches Archiv fiir Physiologic, 1893, iv. p. 14, of the infarctions produced experimentally in the dog's heart. ' Porter: Archiv fUr die gesammte Physiologic, 1893, Iv. p. 366. * Michaelis : Zeitschrift fiir klinische Merlicin, 1894, xxiv. p. 289. CIR C ULA TION. 181 minal, their experimental closure enables us to study the effects of the sudden stopping of the blood-supply (ischtemia) of the heart muscle upon the action of the heart. Results of Closure of the Coronary Arteries. — The sudden closure of one of the large coronary branches in the dog has as a rule either no effect upon the action of the heart beyond occasional and transient irregularity/ or is fol- lowed after the lapse of seconds, or of minutes, by the arrest of the ventricu- lar stroke, the ventricle falling a moment later into the rapid, fluttering. Fig. 38. — A, curve of intra-ventricular pressure, written by a manometer connected with tlie interior of the left ventricle ; B, atmospheric pressure ; C, time in two-second intervals. At the first arrow the ramus circumflexus of the left coronary artery was ligated ; at the second arrow the heart fell into fibril- lary contractions. The lessening height of the curve shows the gradual diminution of the force of con- traction after ligation. The rise of the lower line of the curve above the atmospheric pressure Indicates a rise of intra-ventricular pressure during diastole. The small elevations in the pressure-curve after the second arrow are caused by the left auricle, which continued to beat after the arrest of the ventricle (Porter, 1893). undulatory movements known as fibrillary contractions and produced by the inco-ordinated, confused shortenings of individual muscle-cells, or groups of cells. The auricles continue to beat for a time, but the power of the ventricles to execute co-ordinated contractions is lost. The Frequency of Arrest.— The frequency with which closure is fol- lowed by ventricular arrest depends on at least two factors — namely, the size of the artery ligated and the irritability of the heart. That the size of the artery is of influence appears from a series of ligations performed on dogs, arrest being never observed after ligation of the arteria septi alone, rarely observed (14 per cent.) with the right coronary artery, more frequently (28 per cent.) with the descendens, and still more frequently (80 per cent.) with the arteria circumflexa.^ The irritability of the heart is an important factor. In animals cooled by long artificial respiration, or by section of the spinal cord at its junction with the bulb, the ligation of the descendens arrests the heart less frequently than in vigorous animals which have been operated upon quickly. The frequency of arrest is increased by the use of morphia and curare.^ Changes in the Heart-heat. — Ligation destined to arrest the heart is fol- lowed almost immediately by a continuous fall in the intra-ventricular pressure during systole and a gradual rise in the pressure during diastole (see Fig. 38). The contraction and relaxation of the ventricle are often slowed. The force of the ventricular stroke is diminished. As arrest draws near, irregularities in the force of the ventricular beat are seldom absent. The frequency of beat is sometimes unchanged throughout, but is usually diminished toward the end ; ' The changes produced by subsequent degeneration are not considered here. 2 Porter: Journal of Physiology, 1893, xv. p. 131. ' Porter : Journal of Experimental Medicine, 1896, i. p. 49. 182 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Fig. 39.— Showing fall in arte- rial pressure and diminished out- put of left ventricle in consequence of the ligation of the eircumfiex artery. The curve reads from left to right. It Is one-half the original size. The upper curve is the pres- sure in the carotid artery. The unbroken line is atmospheric pres- sure. The next curve is the meas- urement of the outflow from the left ventricle, each rise and each fall indicating the passage of 50 c.cm. of blood into the aorta. The lower line is a time-curve in sec- onds. At * the circumflex artery was ligated (Porter, 1896, p. 51). occasionally the frequency is increased. Both ven- tricles as a rule cease to beat at the same instant. The work done by the heart, measured by the blood thrown into the aorta in a unit of time, is lessened by ligation when followed by arrest (see Fig. 39). The Exciting Cause of Arrest. — There are two opinions concerning the exciting cause of the changes following closure of a coronary artery, some investigators holding for ansemia and others for mechanical injury of the cardiac muscle or its nerves in the operation of ligation. The latter base their claim on the frequent failure of ligation of even a main branch to stop the heart ; on the fact that the heart of the dog has been seen to beat from 115 to 150 seconds after the blood-pres- sure in the aorta was so far reduced, by clamping the auricle and opening the carotid artery, as to make a continuance of the coronary circulation very improbable;' on the revival of the arrested heart by the injection of defibrinated blood into the coronary arteries from the aorta, by which means the dog's heart and even the human heart has been made to beat again many minutes after the total arrest of the circulation,^ — it being as- sumed, incorrectly, that the dog's heart cannot be made to beat after arrest with fibrillary contrac- tions; and, finally, on the arrest with fibrillary contractions which some experimenters have caused by mechanical injury to the heart. To sum up, the argument in favor of explain- ing arrest with fibrillary contractions simply by the mechanical injury done the heart in the pro- cess of ligation consists of two propositions : first, anemia without mechanical injury does not cause arre.st with fibrillary contractions; and second, me- chanical injury without anemia does cause arrest. jVgainst the second of these propositions must be jilaced the extreme infrequency of arrest from mechanical injuries.' In more than one hundred ' Tigerstedt: Slcandinavisehes Archiv fiir Physiologic, 1893, V. p. 71 ; Michaelis : Zeitschrift fiir Minische Medicin, 1894, xxiv. p. 270. ^ Langendorft': Archiv fiir die gesammte Physiologic, 1895, Ixi. p. 320 ; 1898, Ixx. p. 281 ; Batke : Ibid., 1898, Ixxi. p. 412. ' Rodet and Nicolas : Archives de Physiologic, 1896, p. 167. CIR C UL A TION. 183 ligations Porter' observed not a single arrest in consequence of laying the artery bare and placing the ligature ready to be drawn, the only effect of the mechanical procedure being an occasional slight irregularity in force. Ligation of the periarterial tissues in ten dogs, the artery itself being excluded from the ligature, directly injured both muscular and nervous substance, but was only once followed by arrest. Nor does arrest follow the ligation of a vein, although the mechanical injury is possibly as great as in tying an artery. The direct stimulation of the superficial ventricular nerves exposed to injury in the opera- tion of ligation does not produce the effects that appear after the ligation of coronary arteries. Against the remaining proposition stated above — namely, that ansemia with- out mechanical injury does not cause arrest with fibrillary contractions — it should be said that the frequency of arrest after ligation is in proportion to the size of the artery ligated, and hence to the size of the area made anaemic, and is not in proportion to the injury done in the preparation of the artery. The circumflex and descendens may be prepared without injuring a single muscle-fibre, yet their ligation frequently arrests the heart, while the ligation of the arteria septi, which cannot be prepared without injuring the muscle- substance, does not arrest the heart. It is, moreover, possible to close a coro- nary artery without mechanical injury. Lycopodium spores mixed with de- fibrinated blood are injected into the arch of the aorta during the momentary closure of that vessel and are carried into the coronary arteries, the only way left open for the blood. The lycopodium spores plug up the finer branches of the coronary vessels. The coronary arteries are thus closed without the operator having touched the heart. Prompt arrest with tumultuous fibrillary contractions follows. There seems, then, to be no doubt that fibrillary contrac- tions can be brought on by sudden ansemia of the heart muscle.^ The gradual interruption of the circulation in the coronary vessels — by bleeding from the carotid artery, for example — is followed by feeble inco- ordinated contractions not essentially different in kind from those commonly termed fibrillary contractions. The manner of interruption probably explains the difference in result. In the former case, namely, ligation or other sudden closure, the supply of blood to the heart muscle is suddenly stopped while the heart continues to work against a high peripheral resistance ; in the latter, the ansemia is gradual and the heart works against little or no peripheral resistance. Recovery from Fibrillary Contractions. — Fibrillary contractions brought on by clamping the left coronary artery in the rabbit's heart are often gradually replaced by normal contractions when the clamp is removed. The isolated cat's heart after showing marked fibrillary contractions during forty-five minutes has given strong regular beats for more than an hour. McWilliam and others have seen a number of spontaneous regular beats after the termi- nation of fibrillary contraction. The dog's heart can be recovered by cool- ing the ventricles until all trace of fibrillation has disappeared, and then bringing the heart back to normal temperature by circulating warmed defi- ' Porter ; Journal of Experimental Medicine, 1896, 1. p. 65. 184 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. brinated blood through the coronary vessels.' Recovery has also been obtained by passing immediately (within 15 seconds) a very rapid alternating current of not too great intensity.^ Closure of the Coronary Veins. — Closure of all the coronary veins in the rabbit produced fibrillary contractions after from fifteen to twenty minutes had passed. Their closure in the dog is said to be without effect'— a negative result perhaps to be explained by the fact that a portion of the coronary blood finds its way to the cavities of the heart through the venaj Thebesii. Volume of Coronary Circulation. — Bohr and Henriques/ taking the average of six experiments on dogs, found that 16 cubic centimeters of blood passed through the coronary arteries per minute for each 100 grams of heart muscle. The quantity passing through both coronary arteries varied in dif- ferent animals from 20 to 64 cubic centimeters per minute; the quantity passing through the left coronary artery varied from 22.5 to 60 cubic centi- tf ■IffFT U|flf(Jpj)j|/U!Jf/i|/!/(())4i|*ill|lj!i«fto^^ Fig. 40.— Diminution of the force of contraction of tlie ventricle of the isolated cat's heart in con- sequence of diminishing the supply of blood to the cardiac muscle : A, blood-pressure at the root of the aorta, recorded by a mercury manometer; B, intra-ventricular pressure-curve, left ventricle: the indi- vidual beats do not appear, beca\ise of the slow speed of the smoked surface ; C, time in seconds ; D, the number" of drops of blood passing through the coronary arteries, each vertical mark recording one drop. As the number of drops of blood passing through the coronary arteries diminishes, the contractions of the left ventricle become wealicr, but recover again when the former volume of the coronary circula- tion is restored. meters per minute. The hearts weighed from 51 to 350 grams. The method which Bohr and Henriques found it necessary to employ placed the heart under such abnormal conditions that their results can be regarded as only approximate. Porter" supplied the left coronary artery of the dog with blood diluted one-half with sodium chloride solution (0.6 per cent.) by means of a tube (lumen 2.75 millimeters) inserted into the aortic opening of the left coro- ' Porter : American Journal of Physiology, 1898, i. p. 71. ' Prevost and Battelli : Journal de physiologie et de pathologie generate, 1900, p. 440. ^ Michaelis : Zeitschrift fur klinische Medidn, 1894, xxiv. p. 291. * Bohr and Henriques: Skandinavisches Archiv fiir Physiologie, 1895, v. p. 2.32. * Porter : Journal of Ex.perimental Medicine, 1896, i. p. 64. CIRCULATION. 185 nary artery aud connected with a reservoir placed 150 centimeters above the heart. In one dog, weighing 11,500 grams, 318 cubic centimeters flowed through in eight minutes. In a second dog, weighing 9500 grams, 114 cubic centimeters passed through in four minutes. In the isolated heart of the cat strong and regular contractions are made on a circulation of about 4 cubic centimeters per minute, or even less, through the coronary system. The quantity passing through the veins of Thebesius into the left auricle and ventricle is very slight. The supply of blood to the heart-muscle is modified by ventricular con- traction, not only in that the mean blood-pressure in the aorta is a function of the force of the heart-beat, but directly by the compression of the intra- mural vessels during systole. Thus, when a piece of the mammalian ven- tricle is kept beating by supplying it with defibrinated blood through its nutrient artery at a constant pressure, each beat can be seen to force the blood out of the severed vessels in the margin of the fragment. The effect of the contractions on the contents of the intramural vessels can also be demon- strated in the living animal by incising a vein, or a ligated artery on the distal side of the ligature, and slowing the heart by stimulation of the vagus. At each systole of the ventricle blood is forced from the vessel. I\Iore ■ over, lessening the frequency of contraction diminishes the volume of the coro- nary circulation — ;'. c, the outflow from the coronary veins, as may be shown in a record similar to that illustrated by Fig. 40. It is conceivable that the emptying of the intramural vessels by the contraction of the heart may favor the flow of blood through the heart-walls in two ways : first, by the diminished resistance which the empty patulous vessels should offer to the inflow of blood from the aorta when the heart relaxes ; and, secondly, by the suction which might accompany the sudden expansion of the compressed vessels — expanding either by virtue of their intrinsic elasticity, or because of the pull of the surrounding tissues upon their walls, as the heart quickly regains its diastolic form. The problem thus raised may be attacked by sud- denly connecting the distal portion of a coronary artery in the strongly beat- ing heart of the living animal with a small reservoir of normally warm de- fibrinated blood at the atmospheric pressure. The connection can be made through a cannula tied into the artery (ramus descendens of the dog) or through a tube passed into the left coronary artery by way of the innominate artery and aorta. If each compression of the deeper branches of the artery were followed by an expansion sufficient to cause a noteworthy suction, the blood in the reservoir should be drawn into the artery, for this blood is the sole source of supply throughout the experiment, as the " terminal " nature of the coronary arteries prevents any material backflow from the distal branches. The results of these experiments showed that no appreciable suc- tion can be demonstrated in the larger coronary arteries, even when a very sensitive minimum valve is interposed between the artery and the reservoir in order to prevent the possible masking of the suction by rising pressure accompanying the contraction of the ventricle. It is, therefore, necessary 186 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. to conclude that the emptying of the intraruiral vessels by the contraction of the heart favors the flow of blood through the heart-walls chiefly by the diminished resistance which the empty patulous vessels offer to the inflow from the aorta when the heart relaxes.' The Vessels of Thebesius and the Coronary Veins. — The vessels of Thebesius probably have a part in the nutrition of the heart. If a glass tube two or three inches long is tied into the ventricle of the extirpated heart of the cat and filled with warm defibrinated blood, the heart will begin to beat, and, if the blood is oxygenated from time to time, may continue its contrac- tions for many hours, although its only supply is through the vessels of The- besius. If a vein on the surface of the ventricle is incised, the blood which enters the ventricle arterial, in color will emerge from the cut vein a dark venous hue, showing that it has given up its oxygen and presumably other nutrient substances on its way through the heart-wall. This experiment also demonstrates a connection between the coronary vessels and the vessels of Thebesius ; the same may be shown by corrosion preparations of hearts, the veins of which have been injected with celloidin. The extirpated heart may be kept contracting a longer time, when to the supply received through the vessels of Thebesius is added that which may reach the heart from the auricle by backflow through the coronary veins, the valves of which are incompetent. It is evident that these accessory channels of nutrition must be of impor- tance when the main supply through the arteries is diminished, as in arterio- sclerosis.^ Blood-supply and Heart-beat. — The relation between the volume of blood passing through the coronary arteries and the rate and force of the ventricular contraction has been studied by Magrath and Kennedy.' Varia- tions in the volume of the coronary circulation in the isolated heart of the cat, unless very considerable, are not accompanied by changes in the rate of beat. The force of contraction, on the contrary, appears to be closely dependent on the volume of the coronary circulation (Fig. 40). Distention of the ventricle diminishes the volume of blood flowing through the coronary vessels, except when this effect is compensated by the distention stimulating the ventricle to contract more forcibly, and thus to pump more blood through its walls by alternate compression and expansion of the intramural vessels.' Lymphatics of the Heart. — A rich plexus of lymphatic vessels has been demonstrated in the heart.^ Valuable information concerning the nutrition of the heart could probably be gained by the systematic study of these vessels. 'Porter: American Journal of Physiology, 1898, i. p. 145; consult also von Vintscligau : Archiv fiir die gesammte Physiologie, 1896, Ixlv. p. 79. "Pratt: Ibid., -p. 86. ' Magrath and Kennedy: Journal of Experimental 3Micine, 1897, ii. p. 13. * I. H. Hyde: Amei-ican Journal of Physiology, 1898, i. p. 215. 'Nystrora: Archiv fiir Physiologie, 1897, p. 361. CIRCULATION. 187 0. Solutions which Maintain the Beat of the Heart. The beat of the heart is maintained duiing life by a constant supply of oxygenated blood. The blood, however, is a very complex fluid, and it can hardly be supposed that all of its constituents are of equal value to the heart. The systematic search for those constituents of the blood which are of import- ance to the nutrition of the heart was begun in Ludwig's laboratory in 1875 by Merunowicz. The first step toward the method used by Merunowicz and his successors was taken by Cyon. Cyon tied cannulas in the vena cava inferior and in one of the aortse of the extirpated heart of the frog, and joined them by a bowed tube filled with serum. The ventricle pumped the serum through the aortic cannula and the bowed tube into the vena cava, whence it reached the ventricle again. The force of the contraction was measured by a mercury manometer which was joined by a side branch to one limb of the bowed tube. The frog heart manometer method thus introduced by Ludwig and Cyon has undergone various modifications at the hands of Blasius and Pick, Bow- ditch, Luciani, Kronecker, and others. Blasius and Fick were the first to register changes in the volume of the heart by the plethysmographic method, the organ being enclosed in a vessel filled with normal saline solution and connected with a manometer. This idea reappears in the Strassburg apparatus described below. A valuable improvement was made by Kronecker, who invented a double cannula, through one side of which the " nutrient " fluid enters the ventricle while it passes out through the other (Fig. 4 1 ). The contents of the ventricle are thus contin- ually renewed. In 1878, Roy constructed the instrument shown in Figure 42, by means of which the changes in the volume of the heart at each contraction are recorded on a moving cylin- der. A great advance was made by Williams, in the invention known as " Williams's valve," which is the essential feature of the apparatus devised by this investigator and others in Schmiedeberg's laboratory at Strassburg. The present form of this apparatus is illustrated in Figure 43. A perfusion cannula is introduced into the ventricle through the aorta. Through one tube of the cannula the heart is fed from a reservoir placed above it. Through the other the heart pumps its contents into a higher reser- voir or into the same reservoir. Thus the heart is " loaded " with a colunui of liquid of known height and pumps against a measurable resistance. A Williams valve in the inflow tqbe prevents any flow except in the direction of the heart. A similar valve reversed in the outflow tube prevents any flow Fig. 41.— The perfusion cannula of Kronecker. The ventricle is tied on the cannula at d, a ring being placed here to prevent the ligature from slipping. The double tube, shown in cross-section at e, divides into the large branch a and the small branch b. The nutrient solu- tion enters the heart through h and escapes through a. The silver wire c can be connected with one pole of a battery, the cannula serving as one electrode, and the fluid surrounding the heart as the other. 188 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. except away from the heart. The ventricle is filled and emptied alternately as is the normal heart, the artificial valves replacing the heart-valves, which are often necessarily rendered useless by the introduction of the cannula and are at best less certain in their action than the artificial valve. The changes in the volume of the heart are shown by the movements of a liquid column in a Fig. 42. — Roy's apparatus; the heart is tied on a perfusion cannula and enclosed in a bell glass rest- ing on a brass plate, 6, the centre of which presents an opening covered by a rubber membrane. Vari- ations in the volume of the heart cause the mem- brane to rise and fall. The movements of the membrane are recorded by a lever. Fig. 43.— Williams's apparatus; H, frog's heart; F, V\ Williams's valves ; j¥S, millimeterscale. The apparatus is arranged to feed the heart from the reservoir into which the heart is pumping. horizontal tube which communicates with the bottle filled with "nutrient" fluid in which the heart is enclosed. In the original method of Cyon the ventricle is left in connection with the auricle, the ganglion-cells of the ventricle and the neighboring portions of the auricle being kept intact. This " whole heart " preparation is to be distin- guished from the " apex " preparation of Bowditch, which has also been used in studies of the effects of nutrient solutions on the heart. In Bowditch's " apex " preparation, the ventricle is bound to the cannula by a thread tied at the junction of the upper and middle thirds of the ventricle. By this means the lower two-thirds of the ventricle, which contains no ganglion-cells, is cut off from any physiological connection with the base of the ventricle and a " ganglion-free apex " secured. The isolated " apex " at first stands still, but after from ten to sixty minutes commences to beat again and can then be kept beating for several hours. In the use of the.se various methods certain general precautions should be kept in mind. Special attention should be directed to the difficulty of remov- ing the blood from the capillary fissures in the wall of the frog's heart. A small amount of blood remaining in these passages is frequently a source of error. It should be remembered that, as Cyon pointed out, a change in the nutrient solution is of itself a stimulus to the heart, increa.sing or diminishing the frequency of contraction and obliging the investigator to wait until the heart CIRCULATION. 189 has become accustomed to the new solution before making an observation. The heart should, as a rule, be constantly supplied with fresh fluid, as in the natural state. The resistance against which the heart works is also a factor of import- ance. The water with which the solutions are made should be distilled in glass, as the minutest trace of the compounds of heavy metals in non-colloidal solu- tions affects the heart.' Nutrient Solutions. — Cyon found that the beat of the extirpated frog's heart is very dependent on the nature of the solution with which the heart is fed. Hearts supplied with normal saline solution (NaCl, 0.6 per cent.) ceased to beat much sooner than those left empty. The serum of dog's blood seemed almost poisonous. Rabbit's serum, on the contrary, postponed the exhaustion of the heart for many hours, provided the limited quantity contained in the apparatus was renewed from time to time. Serum used over and over again caused the beats to lose force after an hour or two. The renewal of the serum seemed a stimulus to the heart, causing it to contract very strongly during a half minute or more, after which the contractions became less energetic. Cyon's immediate successors, Bowditch, Luciani, and Rossbach, confirmed his observations. None of these investigators, however, was concerned pri- marily with the nutrition of the heart. The first systematic work on this sub- ject was done, as has been said, by Merunowicz, who attempted to maintain the beat of the heart with normal saline solution containing various quantities of blood, with normal saline alone, with a watery solution of the ash of an alcholic extract of serum, and with a normal saline solution containing a minute amount of sodium carbonate. The direction taken by him has been pursued to the present day, the chief objects of study being the importance to the heart of sodium carbonate or other alkali, sodium and potassium chloride, the salts of calcium, oxygen, proteids and some other organic bodies such as dextrose, and, finally, of fluids possessing the physical characteristics of the blood. The outcome of this work we must now consider. The value of an alkaline reaction has been generally recognized. Sodium carbonate is the alkali commonly preferred. The favorable influence of this salt probably does not depend on any specific action, but simply upon its alkalinity. The alkali promotes the beat of the heart by neutralizing the carbon dioxide and other acids formed in the metabolism of the contracting muscle; this, however, may not be its only use. Certain of the salts normally present in the blood are necessary to main- tain the beat of the heart. Sodium chloride is one of these. The solution employed should contain a " physiological quantity." Such a solution is said to be " isotonic." The amount required to make a sodium chloride solution "normal" or "isotonic" for the frog is 0.6 per cent., for the mammal nearly 1 per cent. Enough of a calcium salt to prevent the washing out of lime from the tissues is also essential for prolonged maintenance of the contractions. A heart fed with normal saline solution is before long brought to a stand ; the addition of a calcium salt to the solution postpones the arrest. The character ' Locke : Journal of Physiology, 1895, xviii. p. 331. 190 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. of the contraction, however, is altered by the calcium, the relaxation of the ventricle being sometimes so much delayed that the next contraction takes place before the relaxation from the previous contraction has commenced, the ventricle falling thereby into a state of persistent or "tonic" contraction. The addition of a potassium salt restores the normal character of the contraction, calcium and potassium having an antagonistic action on the heart.^ The importance of calcium to the heart is said to be demonstrated by the disap- pearance of the spontaneous contractions of the heart which follows the pre- cipitation of the calcium in the circulating fluid by the addition to it of an equivalent quantity of a soluble oxalate, and by the return of spontaneous contractions which is seen when ihe calcium is restored to the solution. The antagonistic action of calcium and the oxalates was first pointed out by Cyon. According to Ringer, the substances tlius far mentioned are effective in the following order: normal saline is the least effective; next is saline containing sodium bicarbonate ; then saline containing tricalcium phosphate ; and best of all, saline containing tricalcium phosphate together with potassium chloride. He recommends the following mixture : Sodium chloride solution 0.6 per cent., saturated with tribasic calcium phosphate, 100 cubic centimeters; solu- tion potassium chloride 1 per cent., or acid potassium phosphate (HKjPOJ 1 per cent., 2 cubic centimeters.^ There has been considerable dispute over the part played by oxygen in the beat of the frog's heart. McGuire and Klug were of opinion that the beat is largely independent of the amount of oxygen in the circulating fluid. Yeo concluded that the contracting heart uses more oxygen than the resting heart, and that the consumption of oxygen increases with the work done. Kronecker and Handler, on the contrary, believe that the oxygen con- sumption is increased by an increase in the rate of beat, but is independent of the work done. More recent observers are united on the necessity of oxygen to the working heart. Oehrwall's studies in this field are especially interesting. He finds that a volume of blood sufficient to fill the frog's ventricle will main- tain contractions for hours pi'ovided the heart is surrounded by an atmosphere of oxygen. The heart is brought to a stand by lack of oxygen and may be made to beat again, even after an arrest of twenty minutes, by giving it a fresh sup- ply. The heart fails in oxygen-hunger probably because the chemical process by which the stimulus to contraction is called forth no longer takes place, and not because of a failure in contractility, for even after long inaction a gentle touch on the pericardium will cause a vigorous contraction.'' Haldane* discovered that the corpuscles of the blood are not essential to the contractions of the warm-blooded heart, provided the oxygen whicli the ' Bottazzi : Archires de Physiologic, 1S96, xxviii. p. 882. '' Einger : Journal of Physiology, 1893, xiv. p. 128. The bibliography has recently been given by Howell : American Journal of Physiology, 1898, ii. p. 47 ; and Greene : Ibid., p. 82 ; consult also Wliite : .Journal of Physiology, 1896, xix. p. 344. ' 'Oehrwall: Skamlinamsches Archivfiir Physiologie, 1898, viii. p. 1. *IIal(lane; Journal of Physiology , 1895, xviii. p. 211. CIRCULATION. 191 heart needs is supplied by increasing the tension of tlie gas in the plasma. Haldane kept his animals alive in oxygen at a pressure of two atmospheres after the oxygen-carrying function of the red corpuscles had been destroyed with carbon monoxide. The experiment has been repeated with the extir- pated mammalian heart by Porter/ Locke,^ and Rusch.' Scrum and even saline solutions will serve, if the oxygen tension is high or if the volume of oxygen reaching the tissues is increased simply by causing the nutrient liquid to circulate more rapidly. Carbon dioxide* is injurious to the heart when present in the circulating fluid in considerable quantities. The force of the contraction is reduced before the rate of beat. The heart poisoned with carbon dioxide often falls into irregular contractions, exhibiting at times "grouping" and the "staircase" phenomenon, a series of beats regularly increasing in strength. Oir/aaic Substaitcn^. — An unsuccessful effort has been made to prove that only solutions containing proteids, for example blood-serum, chyle, and milk, can keep the heart active. Recent observers have shown the incorrectness of this claim. A mixture of the inorganic salts, sodium chloride, potassium chloride, and calcium chloride, alone suffices. Locke" found that the addi- tion of 0.1 per cent, of dextrose to a suitable inorganic solution kept a frog's heart working under a load of 3.5 centigrams, and under an " after-load " of 3 centigrams in spontaneous activity for more than twenty-four hours. The sustaining action which dextrose appears to exercise is shared, according to him, by various other organic substances. Physical Characteristics. — Heffier and Albanese,^ having observed that the addition of gum-arabic to the circulating fluid was of advantage, declared that the nutrient solutions should possess the viscosity of the blood. The favorable action of gum-arabic may, however, more probably be ascribed to the compounds which it contains rather than to its physical properties.^ Mammalian Heart. — The success attained within the past two years in the isolation of the mammalian heart opens up an hitherto unexplored region in which systematic investigation will surely bring to light facts of wide interest and value. At present, however, little is known as to the constituents of the blood which are essential to the life of the mammalian heart. An abundant supply of oxygen is certainly highly important.* ' Porter: American Journal of Physiology, 1898, i. p. 511. ^ Locke: Centralblatt fUr Pliysiologie, 1898, xii. p. 568. ' Rusch : Archivfur die gesammte Physiologic, 1898, Ixxiii. p. 535. * Langendorff ; Archivfur Physiologie, 1893, p. 417 ; Ide : Ibid., p. 492 ; Oehrwall : Skandin- avisches Archivfiir Physiologie, 1897, vii. p. 222. ° Locke: Journal of Physiology, 1895, xviii. p. 332. ^Albanese: Archiv fur experimentelle Pathologic und Pharmakologie, 1893, xxxii. p. 311; Archives iialiennes de Biologic, 1896, xxv. p. 308. ' Howell and Cooke: Journal of Physiology, 1893, xiv. p. 216. * Literature is given by Magrath and Kennedy : Jow-nal of Experimental Medicine, 1897, ii. p. 13 ; and Hedbom : Skandinavisches Archiv fu,r Physiologie, 1898, viii. p. 147. See also Hering : Archiv fUr die gesammte Physiologie, 1898, Ixxii. p. 163; Bock: Archiv fur experimentelle Path- ologic und Pharmakologie, 1898, xli. p. 158 ; and Cleghorn : American Journal of Physiology, 1899, ii. p. 273. 192 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Blood of Various Animals. — Eoy gives some data as to the effect on the frog's ventricle of the blood of various animals. The blood of the various her- bivora (rabbit, guinea-pig, horse, cow, calf, sheep), as well as that of the pigeon, were found to have nearly the same nutritive value in each case. That of the dog, of the cat, and more especially of the pig, while in some instances equal in effect to that from the horse or rabbit, were in other examples (from the newly killed animals) apparently almost poisonous. Cyon's early observation of the in- jurious action of dog's blood on the frog's ventricle has already been mentioned.' Regarding the mammalian heart, experience has shown that it is best to supply the heart with blood from the same species of animal. The difficulties attending the use of blood from a different species are seen in the case of the dog's heart supplied with calf's blood. The heart dies sooner ; oedema of the lungs takes place, impeding the pulmonary circulation and leading to engorge- ment of the right heart and paralysis of the right auricle ; exudation into the pericardium often seriously interferes with the beat of the heart; and, finally, the elastic modulus of the cai'diac muscle is apparently altered, permitting the heart to swell until it tightly fills the pericardium, when the proper filling of the heart is no longer possible through lack of room for diastolic expansion. PART IV.— THE INNERVATION OF THE BLOOD-VESSELS.' About the middle of the eighteenth century more or less sagacious hypotheses concerning the contractility of the blood-vessels began to appear in znedical literature, but it was not until Henle demonstrated the existence of muscular elements in the middle coats of the arteries in 1840 that a secure foundation was laid for the present knowledge of the mechanism by which that contractility is made to control the distribution of the blood. More than a hundred years before, indeed, Pourfour du Petit had shown that redness of the conjunctiva was one of the consequences of the section of the cervical sympathetic, but had called the process an inflammation, in which false idea he was supported by Cruikshank and others ; and Dupuy of Alfort had noted redness of the con- junctiva, increased warmth of the forehead, and sweat-drops on ears, forehead, and neck following his extirpation of the superior cervical ganglia in the horse ; Brachet, also, cutting the cervical sympathetic in the dog, had gone so far as to attribute the resulting congestion to a paralysis of the blood-vessels. But these were merely clever speculations, for the anatomical basis necessary for a real knowledge of this subject was wanting as yet. Henle furnished this basis, and at the same time reached the modern point of view. " The part taken by the contractility of the heart and the blood-vessels in the circulation," said Henle, " can be expressed in two words : the movement of the blood depends on the heart, but its distribution depends on the vessels." Nor did Henle stop here. It was now known that the vessels possessed contractile walls ; it was ' See also Bardier : Comptes rendus Sociele de Biologie, 1898, p. 548. ''See footnote to Part 11., p. 148. CIRCULATION. 193 known further that these walls contracted when mechanically stimulated; for example, by scraping them with the point of a scalpel ; and various observers had traced sympathetic nerves from the greater vessels to the lesser until lost in their finest ramifications. It was therefore easy to construct a reasonable hypothesis of the control of the blood-vessels by the nerves. Henle declared that the vessels contract because their nerves are stimulated, either directly, or reflexly through the agency of a sensory apparatus. The ground was thus prepared for the physiological demonstration of the existence of " vaso- motor" nerves, as Stilling began to call them. Four names are associated with this great achievement — Schiff, Bernard, Brown-Sequard, and Waller, each of whom worked independently of the others. Foremost among them is Claude Bernard, though not the first in point of time, for it was he who put the new doctrine on a firm basis. In his first publication Bernard stated that section of the cervical sympathetic, or removal of the superior cervical ganglion, in the rabbit, causes a more active circulation on the correspond- ing side of the face together with an increase in its temperature. The greater blood-supply manifests itself in the increased redness of the skin, particularly noticeable in the skin of the ear. The elevation of temperature may be easily felt by the hand. A thermometer placed in the nostril or in the ear of the operated side shows a rise of from 4° to 6° C. The elevation of temperature may persist for several months. Similar results are obtained in the horse and the dog. The following year Brown-Sequard announced that "if galvanism is applied to the superior portion of tlie sympathetic after it has been cut in the neck, the dilated vessels of the face and of the ear after a certain time begin to contract ; their contraction increases slowly, but at last it is evident that they resume their normal condition, if they are not even smaller. Then the temperature diminishes in the face and the ear, and becomes in the palsied side the same as in the sound side. When the galvanic current ceases to act, the vessels begin to dilate again, and all the phenomena discovered by Dr. Bernard reappear." Brown-S6quard concludes that " the only direct effect of the section of the cervical part of the sympathetic is the paralysis, and consequently the dilata- tion, of the blood-vessels. Another evident conclusion is that the cervical sympathetic sends motor fibres to many of the blood-vessels of the head." While Bi-own-S6quard was making these important investigations in America, Bernard, in Paris, quite unaware of Brown-S^quard's labors, was reachiufic the same result. The existence of nerve-fibres the stimulation of which causes constriction of the blood-vessels to which they are distributed was thus established. A considerable addition to this knowledge was presently made by Schiff, who pointed out in 1856 that certain vaso-motor nerves take origin from the spinal cord. The destruction of certain parts of the spinal cord causes the same vascular dilatation and rise of temperature that follows the section of the vaso-motor nerves outside the spinal cord. At this time Schiff also offered evidence of vaso-diiator nerves. When Vol. I.— 13 194 AjV AMERICAN TEXT-BOOK OF PHYSIOLOGY. the left cervical sympathetic is cut in a dog, and the animal is kept in his kennel, the left ear will always be found to be 5° to 9° warmer than the right. If the dog is now taken out for a run in the warm sunshine, and allowed to heat himself until he begins to pant with outstretched tongue, the temperature of both ears will be found to have increased. The right ear is now, however, the warmer of the two, being from 1° to 5° warmer than the left. The blood-vessels of the right ear are, moreover, now fuller than those of the left. When the animal is quiet again the former condition returns, the redness and warmth in the right becoming again less than in the left ear. The increase of the redness and warmth of the right ear over the left, in which the vaso-constrictor nerves were paralyzed, must be the result of a dilatation of the vessels of the right ear by some nervous mechanism. For if the dilatation of the vessels was merely passive, the vessels in the right ear could not dilate to a greater degree than those in the left ear which had been left in a passive state by the section of their nerves. This experiment, however, is by no means con- clusive. The existence of vaso-dilator fibres was placed beyond doubt by the follow- ing experiment of Bernard on the chorda tympani nerve, new facts regarding the vaso-constrictor nerves being also secured. Bernard exposed the submax- illary gland of a digesting dog, removed the digastric muscle, isolated the nerves going to the gland, introduced a tube into the duct, and, finally, sought out and opened the submaxillary vein. The blood contained in the vein was dark. The nerve-branch coming to the gland from the sympathetic was now ligated, whereupon the venous blood from the gland grew red and flowed more abundantly ; no saliva was excreted. The sympathetic nerve was now stimu- lated between the ligature and the gland. At this the blood in the vein became dark again, flowed in less abundance and finally stopped entirely. On allow- ing the animal to rest the venous blood grew red once more. The chorda tympani nerve, coming from the lingual nerve, was now ligated, and the end in connection with the gland stimulated. Then almost at once saliva streamed into the duct, and large quantities of bright scarlet blood flowed from the vein in jets, synchronous with the pulse. This experiment may be said to close the earlier history of the vaso-motor nerves. It was now established beyond question that .the size of the blood- vessels, and thus the quantity of blood carried by them to different parts of the body, is controlled by nerves which when stimulated either narrow the blood vessels (vaso-constrictor nerves) and thus diminish the quantity of blood that flows through them, or dilate the vessels (vaso-dilator nerves) and increase the flow. The section of vaso-constrictor nerves, for example those found in the cervical sympathetic, causes the vessels previously constricted by them to dilate. The section of a vaso-dilator nerve, for example the chorda tympani, running from the lingual nerve to the submaxillary gland, does not, however, cause the constriction of the vessels to which it is distributed. And finally, it was now determined that vaso-motor fibres are found in the sympathetic system as well as in the spinal cord and the cerebro-spinal nerves. CIRCULATIOX. 195 It remained for a later day to show that vaso-motor nerves are present in the veins as well as in the arteries. Mall has found that when the aorta is compressed below the left subclavian artery, the portal vein receives no more blood from the arteries of the intestine, yet remains for a time moderately full, because it cannot immediately empty its contents through the portal capil- laries of the liver against the resistance which they otfer. If the peripheral end of the cut splanchnic nerve is now stimulated, the portal vein contracts visibly and may be almost wholly emptied. Thompson ' has extended the discovery of Mall to the superficial veins of the extremities. He finds that the stimulation of the peripheral end of the cut sciatic nerve, the crural artery being tied, causes the constriction of the superficial veins of the hind limb. The contraction begins soon after the commencement of the stimulation, and usually goes so far as to obliterate the lumen of the vein. Often the contrac- tion begins nearer the proximal portion of the vein and advances toward the periphery. More commonly, however, it is limited to band-like constrictions between which the vein is filled with blood. After stimulation ceases the constrictions gradually disappear. A second and third stimulation produce much less constriction. The superficial veins of the rabbit's abdomen are constricted by the stimulation of the cervical spinal cord at the second ver- tebra. The observations of Bernard and his contemporaries led to a very great number of researches on the general properties and the distribution of the vaso-motor nerves, in the course of which a variety of ingenious methods of observation have been devised. Methods of Observation. — One fruitful method of research has been already incidentally mentioned, namely, the direct inspection of the vessel, or region, the vaso-motor nerves of which are being studied. A second method consists in accurately measuring the outflow from the vein. If the blood-vessels of the area drained by the vein are constricted by the stimulation of a vaso-motor nerve, the quantity escaping from the vein in a given period previous to constriction will be greater than that escaping in an equal period during constriction. This well-known method is especially avail- able where an artificial circulation is kept up through the organ studied, as the blood drained from the vein does not then weaken the animal and thus disturb the accuracy of the observations.^ A third method is founded on the principle in hydraulics that the lateral pressure at any point in a tube through which a liquid flows depends, other things being equal, on the resistance to be overcome below the point at which the pressure is measured. In the animal body the resistance to be overcome by the blood-stream varies with the state of contraction of the smaller vessels, and thus the variations in the lateral pressure of a given artery may, under certain restrictions, be used to determine variations in the size of the smaller ' Thompson : ArchivfUr Physiologic, 1893, p. 104 ; Bancroft : American Journal of Physiology, 1898, i. p. 477. ^Cavazzani and INIanca: Archives itcdiennes de Biologic, 1895, xxiv. p. 33. 196 AN AMERICAX TEXT-BOOK OF PHYSIOLOGY. vessels distal to the artery. The restrictions are, that the variations in the lateral pressure in the artery are indicative of changes iu the size of the distal vessels only when the general blood-pressure remains uoaltered, or alters in a direction opposite to the change in the artery investigated. An example will make this plain. Dastre and ^Nlorat, in order to demonstrate the presence of vaso-motor fibres for the hind limb in the sciatic nerve, connected a manometer with the central end of the left femoral artery, and a second manometer with the peripheral end of the right femoral artery, distal to the origin of the pro- funda femoris. The anastomoses between the principal branches of the fem- oral artery are so numerous and so large that the circulation in the limb can be maintained by the profunda femoris alone. Dastre and Morat could there- fore compare the general blood-pressure with the blood-pressure in the right hind limb. On stimulating the peripheral end of the right sciatic nerve, the blood-pressure rose in the arteries of the limb, but remained stationary in the arteries of the trunk, connected with the first manometer through the central end of the left femoral artery. The rise of blood-pressure in the operated limb, while the blood-pressure in the rest of the body remained unchanged, proved that the vessels in the operated limb were constricted. Many investigators have studied vaso-motor phenomena by means of the plethysmograph, an apparatus invented by Mosso for recording the changes in the volume of the extremities. The member, the vaso-motor nerves of which are to be studied, is placed within a cylinder tilled with water, from which a tube leads to a recording tambour. An increase in the volume of the member, such as would be brought about by the expansion of its vessels, causes a corre- sponding volume of water to enter the tambour tube, thus raising the pressure in the tambour and forcing its lever to rise. A constriction of the vessels, on the contrary, causes the recording lever to fall. In addition to these general methods, special devices have been employed in the researches into the vaso-motor nerves of the brain. In considering the observations made with these various methods it will be advisable to begin with the differences between the two kinds of vaso-motor nerves. Differences between Vaso-constrictor and Vaso-dilator Nerves. — The differences between vaso-constrictor and vaso-dilator nerves are particularly interesting for the reason that both vaso-constrictor and vaso-dilator fibres are often found in one and the same anatomical nerve. The sciatic nerve is a good example of this. By taking advantage of these differences the investi- gator may determine whether one or both kinds of fibres are present in any anatomical nerve ; whereas, without this knowledge, the effects produced by the stimulation of the one might be wholly masked by the effects produced by the stimulation of the other. The vaso-constrictors are less easily excited than the vaso-dilators. The simultaneous and equal stimulation of the dilator and constrictor nerves going to the submaxillary gland causes vaso-constriction, dilatation appearing after the stimulation ceases, for the after-effect of excitation is of shorter duration CIRCULATION. 197 with the constrictors than with the dilators. "Warming increases and cooling diminishes the excitability of the vaso-constrietors to a greater degree than is the case with the vaso-dilators. Thus if the hind limb of an animal be warmed, the stimulation of the sciatic nerve will cause vaso-constrietion ; while if it be cooled the same stimulation will cause vaso-dilatation.^ Vaso- constrictors are more sensitive to rapidly repeated induction shocks (tetaniza- tion) and less sensitive to single induction shocks than are vaso-dilators. Thus if the sciatic nerve is stimulated with induction shocks of the same strength, it will be found that a rapid repetition of the stimuli will give vaso-constriction, while with single shocks at intervals of five seconds vaso-dilatation is the result. Vaso-constrictors degenerate more rapidly than vaso-dilators after separation from their cells of origin. The stimulation of the peripheral end of the frog's sciatic nerve immediately after section causes constriction. Several days later the same stimulation causes vaso-dilatation, the constrictor nerves having already degenerated (see Fig. 44, B). The maximum effect of stimulation is more quickly reached with the vaso-constrietor than with the vaso-dilator nerves. There is also a difference in the latent period, or interval between stimulation \.-y\ ..-.-—^ V _*.-,- A B Fig. 44— Curves obtained by enclosing tlie hind limb of a cat in the plethysmograph and stimu- lating the peripheral end of the cut sciatic nerve (Bowditch and Warren, 1886, p. 447). The curves read from right to left. In each case the vertical lines show the duration of the stimulus— namely, fifteen induction shoolis per second during twenty seconds. Curve A shows the contraction of the vessels pro- duced by the excitation of the freshly-divided nerve ; curve B, the dilatation produced by an equal excitation of the nerve of the opposite side four days after section, the vaso-constrictor nerves having degenerated more rapidly than the vaso-dilators. and response. Bowditch and Warren have found the latent period of the vaso-constrictor fibres in the sciatic to be about 1.5 seconds, while that of the vaso-dilators is 3.5 seconds. Finally, the two sorts of nerves have been said to differ in the manner in which they are distributed. The vaso-constrictor nerves leave the cord as medullated fibres, enter the sympathetic chain of gan- glia and end in terminal branches probably in contact with a sympathetic ganglion-cell. The constrictor impulse is forwarded to the vessel by a process of this cell, either directly or by means of still other sympathetic ganglion-cells. The vaso-dilator fibre, on the contrary, was thought to run directly from the cord to the blood-vessel ; but recent investigations make it probable that all spinal vaso-motor fibres end in sympathetic ganglia. Orig-in and Course. — The vaso-motor nerves the general properties of which have just been studied are axis-cylinder proce.sses of sympathetic gan- glion-cells. They follow, for a time at least, the course of the corresponding 'Howell, Budgett, and Leonard: Journal of Physiology, 1894, xvi. p. 298. 198 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. spinal nerve. According to Langley/ they do not diiFer from the pilo-motor and secretory nerves except in the nature of the structure in which they termi- nate. They are not interrupted by other nerve-cells on their course. The action of the sympathetic vaso-motor cells is influenced by the vaso-motor cells of the spinal cord and bulb. These are probably small cells situated at various levels in the anterior horn and lateral gray substance. Their axis- cylinder processes leave the cerebro-spinal axis by the anterior roots ^ of certain spinal and by certain cranial nerves, and enter sympathetic gangliaj where they end in terminal twigs probably in contact with the sympathetic vaso-motor cells. The vaso-motor cells lying at various levels in the cerebro- spinal axis are iu turn largely controlled by an association of cells situated in the bulb and termed the vaso-motor centre. The neuraxons (axis-cylinder processes) of the cells composing this "centre" pass in part to the nuclei of certain cranial nerves and in part down the lateral columns of the cord, to end in contact with the spinal vaso-motor cells. The vaso-motor apparatusi consists, then, of three classes of nerve-cells.' The cell-bodies of the first classi lie in sympathetic ganglia, their neuraxons passing directly to the smooth mus-.' cles in the walls of the vessels ; the second are situated at different levels in the cerebro-spinal axis, their neuraxons passing thence to the sympathetic gan*- glia by way of the spinal and cranial nerves; and the third are placed in th6 bulb and control the second through intraspinal and intracranial paths. The nerve-cell of the first class lies wholly without the cerebro-spinal axis, the third wholly within it, while the second is partly within and partly without, and binds together the remaining two. The evidence for the existence of these vaso-motor nerve-cells must now be considered. We shall begin with those of the third class, constituting the so-called bulbar vaso-motor centre. Bulbar Vaso-motor Centre. — The section of the spinal cord near its junction with the bulb is followed by the general dilatation of the blood- vessels of the trunk and limbs. The dilated vessels are again constricted when the severed fibres in the spinal cord are artificially stimulated. Hence the section caused the dilatation by interrupting the vaso-constrictor impulses passing from the bulb to parts below. The position of the bulbar vaso- constrictor centre has been determined by Owsjannikow and Dittmar. The former observer divided the bulb transversely at various levels. When the section fell immediately caudal to the corpora quadrigemina, only a slight temporary rise in blood-pressure was observed. When, however, the section fell a millimeter or two nearer the cord, a considerable and permanent fall in the blood-pressure was noted. Further lowering was seen as the sections were carried still farther toward the spinal cord, until at length, about four millimeters from the corpora quadrigemina, no further fall took place. The ' Langley : Journal of Physiology, 1894, xvii. p. 314. "Compare Werziloff: Centralblati fiir Physiologie, 1896, x. p. 194. ^By "nerve-cells" is meant the cell-body with all its processes, namely, the neiiraxon, or axis-cylinder process, and the dendrites, or protoplasmic processes. CIRCULATION. 199 area from M'hich the vaso-constrictor nerves receive a constant excitation extends, therefore, in the rabbit, over about three millimeters of the bulb not far from the corpora quadrigemina. Two years after tliis investigation Ditt- mar added to the observations of Owsjannikow the fact that the vaso-con- strictor centre is bilateral, lying in the anterior part of the lateral columns on both sides of the median line. At this site is found a group of ganglion-cells known as the antero-lateral nucleus of Clarke. It is possible, though far from certain, that these are the cells of the vaso-constrictor centre. The vaso-constrictor centre in the bulb is always in a state of action, or "tonic" excitation, as is shown by the dilatation of the vessels when deprived of their constrictor impulses through the section of the spinal cord. It is not definitely known whether a vaso-dilator centre is present in the bulb. Spinal Centres. — A complete demonstration of the existence of vaso-motor centres in the spinal cord, first suggested by Marshall Hall, was made by Goltz and Freusberg in their experiments on dogs which had been kept alive after the division of the spinal cord at the junction of the dorsal and the lumbar regions. This operation cuts off both sensory and motor communication between the parts lying above and below the plane of section, and divides the animal physiologically into a fore dog and a hind dog, to use the author's expression. The investigator can now explore the lumbar cord unvexed by cerebral impulses. A great number of motor reflexes formerly thought to have their centres exclusively in the brain are by this means found to take place in the absence of the brain.^ That vaso-motor reflexes were among them was discovered by accident. It was noticed that the mechanical stimulation of the skin of the abdomen and penis while the animal was being washed provoked erection, which, as Eckhard had discovered some years before, is a reflex action due to the dilatation of the arteries of the penis through impulses conveyed by the nervi erigentes. Pressure on the bladder, or the walls of the rectum, also had this efi^ect. After the destruction of the lumbar cord this I'eflex was no longer possible. The vessels of the hind limb are also connected with vaso- motor cells in the lumbar cord. Soon after the section of the cord in the dorsal region the hind paws are observed to be warmer than the fore paws, and the arteries of the hind limb are seen to beat more strongly. This is the result of cutting off the vaso-constrictor impulses from the bulbar centre to the vessels in question. If the animal survives a considerable time the hiud paws will be observed to grow cooler from day to day until they are again no warmer than the fore paws. Destruction of the lumbar cord now causes the tempera- ture of the hind limbs to rise again. The conclusion drawn from these observations is that vaso-motor cells are present in the spinal cord. It is probable that they are normally subordinated to the bulbar nerve-cells and require a certain time after separation from the bulb in order to develop their previously rudimentary powers. Hence the ' Later experiments by Goltz and Ewald, showing the degree of independence of the spinal cord possessed by sympathetic vaso-motor neurons, will presently be cited. 200 AX AMERICAN TEXT-BOOK OF PHYSIOLOGY. interval of many days between the section and the return of arterial tone in areas distal to the section. It has been suggested that during this period the power of the spinal nerve-cell is inhibited by impulses proceeding from the cut sur- face of the cord/ but this long inhibition is questionable in view of the fact that transverse section of the cord in rabbits and dogs does not inhibit the phrenic nuclei.^ The spinal nerve-cell takes part in vaso-motor reflexes. Thus the stimu- lation of the central end of the brachial nerves after section of the spinal cord at the third vertebra causes a dilatation of the vessels of the fore limb. The stimulation of the central end of the sciatic nerve after the division of the spinal cord causes a general rise of blood-pressure indicating the constriction of many vessels. The sensory stimulation of one hind limb may cause reflexly a narrowing of the vessels in the other, after the spinal cord is severed in the mid-thoracic region. In asphyxia, after the separation of the cord from the brain, vascular constriction is produced reflexly through the spinal centres. This constriction is not observed if the cord is previously destroyed. Goltz and Ewald find that the tonic constriction of the vessels of the hind limbs returns after the extirpation of the lower part of the spinal cord. Sympathetic Vaso-motor Centres. — Gley ' finds that after the destruc- tion of both bulbar and spinal centres some degree of vascular tone is still maintained. The extraordinary experiments of Goltz and Ewald place this fact beyond question. These physiologists remove the lower part of the spinal cord completely, taking away 80 millimeters or more. For a few days after the operation the hind limbs are hot and red, from dilatation of their blood- vessels. Soon, however, the hind limbs become as cool, and sometimes even cooler, than the fore limbs, their arterial tonus being re-established and main- tained without the help of the spinal cord. The sympathetic ganglia are probably also centres of reflex vaso-motor action. The fact that these ganglia act as centres for other motor reflexes would itself suggest this possibility. Evidence of the vaso-motor reflex function of the first thfiracic ganglion has been offered recently by Franjois- Franck.'' The two branches composing the annulus of Vieussens contain both afferent and efferent fibres. If one of the branches is cut, and the end in con- nection with the first thoracic ganglion is stimulated, the ganglion having been (Separated from the spinal cord by the section of the communicating branches, a constriction of the vessels of the ear, the submaxillary gland, and the nasal mucous membrane may be observed. This evidence, together with the probability that the neuraxons of all the spinal vaso-motor cells end in sympathetic ganglia,'' makes it fairly credible that the sympathetic vaso-motor nerve-cell possesses central functions. ' Goltz and Ewald : Archiv fiir die gesammte Physiolocjie, 1896, Ixiii. p. 397. ' Porter : Journal of Physiology, 1895, xvii. p. 459. " Gley : Archives de Physiologie, ] 894, p. 704. *Franck: Archives de Physiologic, 1894, p. 721. ^See the statement of Langley's results with the nicotin method on page 208. CIRCULATION. 201 There has been much discussion over the meaning of the rhythmic con- tractions observed in certain blood-vessels apparently independent of the cen- tral nervous system/ The median artery of the rabbit's ear, the arteria saphena in the same animal, and the vessels in the frog's web and frog's mes- entery, slowly contract and relax. This rhythmic contraction is easily seen in the ear of a white rabbit. The movements are possibly of purely muscular origin, but are more probably the result of periodical discharges by vaso-motor nerve-cells. Rhythmical variations in the tonus of the vaso-constridor centres are often held to explain the oscillations seen in the blood-pressure curve after the influence of thoracic aspiration has been eliminated by opening the chest and cutting the vagus nerves. These oscillations" are of two sorts. In the one, the blood-pressure sinks with every inspiration and rises with every expiration, though the rise and fall are not precisely synchronous with the respiratory movements ; in the other, the so-called Traube-Hering waves, the oscillations embrace several respirations. It has also been suggested that these phenomena are due to periodical changes in the respiratory centre affecting the vaso-con- strictor centre by "irradiation." Vaso-motor Reflexes. — The vaso-motor nerves can be excited reflexly by afferent impulses conveyed either from the blood-vessels themselves or from the end-organs of sensory nerves in general. The existence of reflexes from tlie blood-vessels may be shown by Heger's experiment. Heger observed a rise of general blood-pressure with a subsequent fall, and at times a primary fall, after the injection of nitrate of silver into the peripheral end of the crural artery of a rabbit. The limb, with the exception of the sciatic nerve, was severed from the trunk. The quantity injected was so small that it probably was decomposed before passing the capillaries or escaping from the blood- vessels. Thus the effect exerted by the nitrate of silver on the general blood- pressure was probably caused by afferent impulses set up in the blood-vessels themselves and transmitted through the sciatic nerve to the vaso-motor cen- tres. Vaso-motor reflexes are, however, much more commonly produced by the stimulation of sensory nerves other than those present in the blood- vessels. The reflex constriction or dilatation ^ appears usually in the vascular area from which the afferent impulses arise. For example, the stimulation of the central end of the posterior auricular nerve in the rabbit causes a passing con- striction followed by dilatation, or a primary dilatation often followed by constriction of the vessels in the ear. The stimulation of the nervi erigentes causes dilatation of the vessels of the penis. Gaskell found that the vessels of the mylo-hyoid muscle widened on stimulating the mucous membrane at the entrance of the glottis. ' Franck : Archives de Physiologic, 1893, p. 729 ; Lui : Archives italiennes de Biolofjie, 1894, xxi. p. 416 ; Goltz and Ewald : Archivfiir die gesammte Physiologic, 1896, Lxiii. p. 396. "Hegglin: Zeitschrifl fUr klinische Medicin, 1894, xxvi. p. 25. 202 AjV AMERICAX TEXT-BOOK OF PHYSIOLOGY. The vascular reflex ^ may appear in a part associated in function with tlie sensory surface stimulated. Thus the stimulation of the tongue causes dilata- tion of the blood-vessels in the submaxillary gland. Frequently the vascular reflex is seen on both sides of the body. The stimulation of the mucous membrane on one side of the nose may cause vascular dilatation in the ^hole head ; the effect in this case is usually more marked on the side stimulated. The vessels of one hand contract when the other hand is put in cold water. Sometimes distant and apparently unrelated parts are affected. Yulpian noticed that the stimulation of the central end of the sciatic caused the vessels of the tongue to contract.^ The vascular changes produced reflexly in the splanchnic area are of especial importance because of the great number of vessels innervated through these nerves and the great changes in the blood-pressure that can follow dilata- tion or constriction on so large a scale. There is in some degree an inverse relation between the vessels of the akin and deeper parts on reflex stimulation of the vaso-motor centres. The super- ficial vessels are often dilated while those of deeper parts are constricted.'' Thus the stimulation of the central end of the sciatic nerve may cause a dilata- tion of the vessels of the lips, hand in hand with a rise in general blood-pres- sure.'' Exposing a loop of intestine dilates the intestinal vessels in the rabbit, but constricts those of the ear. In asphyxia, the superficial vessels of the ear, face, and extremities dilate, while the vessels of the intestine, spleen, kidneys and uterus are constricted. Relation of Cerebrum to Vaso-motor Centres. — A rise of general blood- pressure has been produced by the stimulation of different regions of the cortex and of various other parts of the brain ; for example, the crura cerebri and corpora quadrigemina. Vaso-dilatation has also been observed. The motor area of the cortex especially seems closely connected with the bulbar vaso- motor centres. There is, however, no conclusive evidence that special vaso- motor centres exist in the brain aside from the bulbar centres already described. At present the safer view is that the changes in blood-pressure called forth by the stimulation of various parts of the brain are reflex actions, the afferent im- pulse starting in the brain as it might in any other tissue peripheral to the vaso-motor centres. Pressor and Depressor Fibres. — The stimulation of the same afferent nerve sometimes causes reflex dilation of the vessels of a part, instead of the more usual reflex constriction. Two explanations of this fact have been sug- gested. The first assumes that the condition of the vaso-motor centre varies in such a way that the same stimuli might produce contrary effects, depending on the relation between the time of stimulation and the condition of the centre. ' The general arrangement of the matter in this paragraph is that given by Tigerstedt, Der Kreislauf, 1893, p. 519. ^ Compare Sergejew : CentralblaU far die mediainische Wissenschaft, 1894, p. 162. " Wertheimer : Comptes rmdn^, 1893, cxvi. p. 595 ; Hallion and Franck : Archives de Phyd- oloyie, 1896, p. 502; Bayliss and Bradford : Journal of Physiology, 1894, xvi. p. 17. ' Isergin : Archivfiir Physiologic, 1894, p. 448. CIBCULA TION. 203 The second assumes the existence of special reflex constrictor or " pressor " fibres, and reflex dilator or "depressor" fibres. The existence of at least one depressor nerve is beyond question, namely the cardiac depressor nerve, which it will be remembered runs from the heart to the bulb and when stimulated causes a dilatation of the splanchnic and other vessels reflexly througli the bulbar vaso-motor centre. Evidence of otlier reflex vaso-dilator nerves and of reflex vaso-constrictor fibres as well has been offered by Latschenberger and Deahna, Howell,^ and others. Howell, for example, has found that if a part of the sciatic nerve is cooled to near 0° C. and the central end stimulated periph- erally to this part, the blood-pressure falls, instead of rising, as it does when the nerve is stimulated without previous cooling. Howell's experiments have been recently extended by Hunt, who finds that the stimulation of the sciatic -during its regeneration after section gives at first vaso-dilatation only, but when regeneration has progressed still further, vaso-constriction is secured. These results point to the existence of both pressor and depressor fibres, the latter being the first to regenerate after section. A reflex fall in blood-pressure is also produced by stimulating various mixed nerves with weak currents and by the mechanical stimulation of the nerve-endings in muscle. The fall is more readily obtained when the animal is under ether, chloroform, or chloral, Jess readily under curare. Topography. — We pass now to the vaso-motor nerves of various regions. Brain} — The study of the innervation of the intracranial vessels is ren- dered exceptionally difficult by the fact that the brain and its blood-vessels are placed in a closed cavity surrounded by walls of unyielding bone. The funda- mental difference created by this arrangement between the vascular phenomena ■of the brain and those of other organs was recognized in part at least by the younger Monro as long ago as 1783. Monro declared that the quantity of blood within the cranium is almost invariable, " for, being enclosed in a case of bone, the blood must be continually flowing out of the veins that room may be given to the blood which is entering by the arteries, — as the substance of the brain, like that of the other solids of our body, is nearly incompress- ible." Further differences between the circulation in the brain and in other organs are introduced by the presence of the cerebro-spinal fluid in the ventri- cles and in the arachnoidal spaces at the base of the brain. This fluid may pass out into the spinal canal and thus leave room for an increase in the amount of blood in the cranium. Finally, a rise of pressure in the arteries too great to be compensated by the outflow of cerebro-spinal fluid may lead to com- pression of the venous sinuses and a decided change in the relative distri- bution of the blood in the arteries, capillaries and veins — conditions which are not present in extracranial tissues. It is evident, therefore, that the methods ■employed in the search for vaso-motor nerves within the cranium must take ' Howell, Budgett, and Leonard ; Journal of Physiology, 1894, xvi. p. 310 ; Bayliss : Ibid., 1893 xiv. p. 317 ; Bradford and Dean : Ibid., 1894, xvi. p. 67 ; Hunt: Ibid., 1895, xviii. p. 381. ^ Cavazzani : Archives italiennes de Bioloyie, 1893, xviii. p. 54, xix. p. 214 ; Bayliss and Hill : Journal of Physiology, 1895, xviii. p. 334; Gulland: Ibid., p. 361. 204 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. into account many sources of error that are absent in vaso-motor studies of other regions. It is^ indeed, probable that incompleteness of method will go far toward explaining the disagreement of authors as to the presence of vaso- motor nerves in the brain. According to Bayliss and Hill, who have recently studied this subject, it is necessary to record simultaneously the arterial pressure, the general venous pressure, the intracranial pressure and the cerebral venous pressure, the cranium as in the normal condition being kept a closed cavity. In their experiments, " a cannula was placed in the central end of the carotid artery. A second long cannula was passed down the external jugular vein, and on the same side, into the right auricle. The torcular Herophili was trephined, and a third cannula, this time of brass, was screwed into the hole thus made." The intracranial pressure was recorded by a cannula connected through another trephine-hole with the subdural space. Bayliss and Hill could find no evidence of the existence of cerebral vaso- motor nerves. The cerebral circulation, according to them, passively follows the changes in the general arterial and venous pressure. Gulland has examined the cerebral vessels by the Golgi, Ehrlich, and other methods, to determine whether nerve-fibres could be demonstrated in them. None were found. It is probable that the blood-supply to the brain is regulated through the bulbar vaso-constrictor centre. Anaemia or asphyxia of the brain stimulates the cells composing this centre, vascular constriction of many vessels follows, and more blood enters the cranial cavit}'. The vessels of the splanchnic area play a chief part in this regulative process.' Their importance to the circulation in the brain is shown by the fatal effect of the section of the splanchnic nerve.s in the rabbit. On placing the animal on its feet, so much blood flows into the relaxed abdominal vessels that death may follow from anaemia of the brain. Vaso-motor Nerves of Head. — ^The cervical sympathetic contains vaso-con- strictor fibres for the corresponding side of the face, the eye, ear, salivary glands and tongue, and possibly the brain. The spinal vaso-constrictor fibres for the vessels of the head in the eat and dog leave the cord in the first five thoracic nerves ; in the rabbit, in the second to eighth thoracic, seven in all. Vaso-dilator fibres for the face and mouth have been found in the cervical sympathetic by Dastre and INIorat, leaving the cord in the second to fifth dorsal nerves, and uniting (at least for the most part) with the trigeminus by passing, according to Morat, from the superior cervical sympathetic ganglion to the ganglion of Gasser. Other dilator fibres for the skin and mucous membrane of the face and mouth arise apparently in the trigeminus, for the stimulation of this nerve between the brain and Gasser's ganglion causes dila- tation of the vessels of the face,^ and in the nerve of Wrisberg. The vaso-motor nerves of the tongue have been recently studied by Isergin.' ' Wertheiraer : Archives de Physiologic, 1893, p. 297. 'Langley: Philosophicd Transactions, iSy2, p. 104 ; Piotrowsky: Cmtralblatt fiir Physiologie.- 1892, vi. p. 464. 3 jgergin : Archiv fiir Physiologic, 1894, p. 441. CIRCULA TION. 205 The lingual and the glosso-pharyngeal nerves are recognized by all authors as dilators of the lingual vessels. The sympathetic and the hypoglossus contain constrictor fibres for the tongue. It is possible that the lingual contains also a small number of constrictor fibres. Most if not all these vaso-motor fibres arise in the sympathetic and reach the above-mentioned nerves by way of the superior cervical ganglion. They degenerate in from three to five weeks after the extirpation of the ganglion. Morat and Doyon cut the cervical sympathetic in a curarized rabbit and examined the retinal arteries with the ophthalmoscope. They were found dilated. The excitation of the cervical sympathetic caused constriction, the excitation of the thoracic sympathetic dilatation of these vessels. The retinal fibres leave the sympathetic at the superior cervical ganglion and pass along the communicating ramus to the ganglion of Gasser, whence they reach the eye through the ophthalmic branch of the fifth nerve, the gray root of the ophtlialmic ganglion, and the ciliary nerves. Most, or all, of the fibres foi- the anterior part of the eye are found in the fifth nerve. Lungs. — The methods ordinarily employed for the demonstration of vaso- motor nerves cannot without danger be used in the study of the innervation Pr.A.P.Hjf. u PrA.F.Hrt ^ ,/ IIIlllMMIllMMInf •■ ' mllimillllnHIIIIIIMIIII Fig. 45.— The excitation of the central end of the inguinal branch of the crural (sciatic) nerve causes a rise in the aortic pressure (Pr A.F.), a rise in the pressure in the pulmonary artery (Pr.A.P.) of 10 to 16 mm. Hg, accompanied hy a falling pressure in the left auricle (Pr.O.G.) (Franck, 1896, p. 184). The rise of pressure in the pulmonary artery, together with the fall in the left auricle, demonstrate, according to Franck, a constriction of the pulmonary vessels. of the pulmonary vesfsels.' A fall in the blood-pressure in the pulmonary artery, for example, produced by stimulating any nerve cannot be taken as final evidence that the stimulation caused the constriction of the pulmonary vessels. The lesser circulation is so connected that changes in the calibre of the vessels of a distant part, the liver for example, may alter the quantity of blood in the luugs. The method of Cavazzani avoids these difficulties. Cavazzani establishes an artificial circulation tiirough one lobe of a lung in ^ Doyon : Archives de Physiologic, 1893, p. 101 ; Henriqiies : Skandinavmhes Archivfiir Physi- ologic, 1893, iv. p. 229 ; Bradford and Dean : Journal of Physiology, 1894, xvi. p. 34 ; Franck : Archives de Physiologic, 1896, p. 178. 206 A.r AMEBICAJSr TEXT-BOOK OF PHYSIOLOGY. a living animal, and measures the outflow per unit of time. An increase in the outflow means a dilatation of the vessels, diminution means constriction. He finds that the outflow diminishes in the rabbit when the vagus is stimulated in the neck, and increases when the cervical sympathetic is stimulated. Franck measures the pressure simultaneously in the pulmonary artery and left auricle, a method apparently also trustworthy. The stiaiulation of the inner surface of the aorta causes a rise of pressure in the pulmonary artery and a simul- taneous fall in the left auricle, indicating, according to Franck, the vaso-con- strictor power of the sympathetic nerve over the pulmonary vessels. A reflex constriction is also produced by the stimulation of the central end of a branch of the sciatic, intercostal, abdominal pneumogastric, and abdominal sympa- thetic nerves (see Fig. 45). Heart. — Vaso-motor fibres for the coronary arteries of the heart have been described.' Intestines.^ — The mesenteric vessels receive vaso-constrictor fibres from the- sympathetic chiefly through the splanchnic nerve. The vaso-constrictors of the jejunum, as a rule, begin to be found in the rami of the fifth dorsal nerves ; a little lower down, those for the ileum come off"; and still lower down, those for the colon; none arise below the second lumbar pair. According to Hal- lion and Franck, vaso-dilator fibres are present in the same sympathetic nerves that contain vaso-constrictors. The dilator fibres are most abundant or most powerful in the rami of the last three dorsal and first two lumbar nerves. There is some evidence of the presence of vaso-dilator fibres in the vagus. The excitation of the vaso-constrictor centres by the blood in asphyxia pro- duces constriction of the abdominal vessels. The vaso-dilator as well as the vaso-constrictor fibres of the splanchnic probably end in the solar and renal plexuses. Liver. — Cavazzani and Manca ^ have recently attempted to show the pres- ence of vaso-motor fibres in the liver. Their method consists in passing warm normal saline solution from a Mariotte's flask at a pressure of 8 to 10 milli- meters Hg through the hepatic branches of the portal vein and measuring the outflow in a unit of time from the ascending vena cava. On stimulating the splanchnic nerve they observed that the outflow was usually diminished though sometimes increased, indicating perhaps that the splanchnics contain both vaso-constrictor and vaso-dilator fibres for the hepatic branches of the portal vein. The vagus appeared to contain vaso-dilator fibres. Further studies are necessary, however, before pronouncing definitely upon these questions. ' Porter : Boston Medical and Surgical Journal, 1896, cxxxiv. 39 ; Porter and Beyer : Ameri- can Journal of Physiology, 1900, ili. p. xxiv. ; Maass : Archiv fur die gesammie Physiologie, 1899, Ixxiv. p. 281. ' Hallion and Franck : Archives de Physiologie, 1896, xxviii. pp. 478, 493 ; Bunch : Journal of Physiology, 1899, xxiv. p. 72. ■'Cavazzani and Manca: Archiveji itali^mies de Biologic, 1895, xxiv. p. 33; Franpois-Franek and Hallion: Archives de Physiologie, 1896, pp. 908, 923; 1897, pp. 434, 448. Cim 'UL. 1 TIOK. 207 Kidney} — The vaso-motor nerves of the kidney leave the cord from the sixth dorsal to the second lumbar nerve. In the dog, most of the renal vaso- motor fibres are found in the eleventh, twelfth, and thirteenth dorsal nerves. The stimulation of the nerves entering the hilus of the kidney between the artery and vein causes a marked and sudden renal contraction, but the organ soon regains its former volume. Constriction follows also the stimulation of the peripheral end of the cut splanchnic nerve. Bradford has demonstrated renal vaso-dilator fibres for certain nerves by stimulating at the rate of one induction shock per second. For example, the excitation of the thirteenth dorsal nerve with 50 to 5 induction shocks per second gave always a constric- tion of the kidney, but when a single shock per second was employed, the kidney dilated. If the cells connected with the renal vaso-motor fibres are stimulated directly by venous blood as in asphyxia, the animal being curarized, a decided constriction of the kidney results. The reflex excitation of these cells is of especial importance. The stimulation of the central end of the sciatic or the splanchnic nerves causes renal constriction. The same effect is easily produced by stimulating the skin, for example, by the application of cold. The stimulation of the sole of the foot in a curarized dog caused contraction of the renal vessels. There is some evidence that the splanchnic vaso-motor fibres for the kidney end in the cells of the renal plexus. Spleen. — The stimulation of the peripheral end of the splanchnic nerves causes a sudden and large diminution in the volume of the spleen.^ It is, however, not certain whether the constriction of the spleen is to be referred primarily to a constriction of its blood-vessels or to the contraction of the intrinsic muscular fibres which play so large a part in the changes of volume of this organ. The doubt is strengthened by the fact that section of the splanchnic nerves does not alter the volume of the spleen ; dilatation would be expected were these nerves the pathway of vaso-constrictor fibres for the spleen. Pancreas. — Frangois-Franck and Hallion find vaso-constrictor fibres in the sympathetic chain between the sixth and eleventh ribs ; they leave the .spinal cord from the fifth dorsal to the second lumbar ramus communicans, pass into the greater and lesser splanchnic nerves, and reach the gland along the pancreatic artery. A few dilator fibres were found in the sympathetic ; more in the the vagus.^ External Generative Organs.* — The recent history of the vaso-motor nerves of the external generative organs — namely, those developed from the urogenital sinus and the skin surrounding the urogenital opening — begins vvith Eck- ' Wertheimer . Archives de Physiologie, 1894, p. 308; Bayliss and Bradford: Journal of Physiology, 1894, xvi. p. 17. ^ Schafer and Moore : Journal of Physiology, ] 896, xx. p. 1. ' Franck and Hallion : Archives de Physiologie, 1896, pp. 908, 923. *Pranck: Archives de Physiologie, 1895, p. 122; Langley and Anderson: Journal of Physi- ology, 1895, xix. p. 76. 208 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. hard, who showed that the stimulation of certain branches of the first and second, and occasionally the third, sacral nerves (dog) caused a dilatation of the blood-vessels of the penis and erection of that organ, and with Goltz, who found an erection centre in the lumbo-sacral cord. Numerous researches in recent years, among which the reader is referred especially to the work of Langley and Langley and Anderson, have shown that the vaso-motor nerves of the externa] generative organs of both sexes may be divided into a lumbar and a sacrak group. The lumbar fibres pass out of the cord in the anterior roots of the second, third, fourth, and fifth lumbar nerves, and run in the white rami communi- cantes to the sympathetic chain, from which they reach the periphery either by way of the pudic nerves or by the pelvic plexus. The greater number take the former course, running down the sympathetic chain to the sacral ganglia, and passing from these ganglia through the gray rami communicantes to the sacral nerves. None of the fibres thus derived enter the nervi erigentes of Eckhard. Of the various branches of the pudic nerves (rabbit), the nervus dorsalis causes constriction of the blood-vessels of the penis and the peri- neal nerve contraction of the blood-vessels of the scrotum. The course by way of the pelvic plexus is taken by relatively few fibres. They run for the most part in the hypogastric nerves, a few sometimes joining the plexus from the lower lumbar or upper sacral sympathetic chain, or from the aortic plexus. The presence of vaso-dilator fibres in the lumbar group is disputed. The sacral group of nerves leave the spinal cord in the sacral nerve roots. Their stimulation causes dilatation of the vessels of the penis and vulva. Internal Generative Organs (those developed from the Miillcrian or the Wolffian ducts). — Langley and Anderson find vaso-constrictor fibres for tiie Fallopian tubes, uterus, and vagina in the female, and the vasa deferentia and seminal vesicles in the male, in the second, third, fourth, and fifth lumbar nerves. The internal generative orgaus receive no afferent, and probably no efferent, fibres from the sacral nerves. The position of the sympathetic ganglion-cells, the processes of which carry to their peripheral distribution the efferent impulses brought to them by the efferent vaso-motor fibres of the spinal cord, may be determined by the nicotin method of Langley. About 10 milligrams of nicotin injected into a vein of a cat prevent for a time, according to Langley,' any passage of nerve-impulses through a sympathetic cell. Painting the ganglion with a brush dipped in nicotin solution has a similar effect. The fibres peripheral to the cell, on the contrary, are not paralyzed by nicotin. Now, after the injection of nicotin the stimulation of the lumbar nerves in the spinal canal has no effect on the vessels of the generative organs. Hence all the vaso-motor fibres of the lumbar nerves must be connected with nerve-cells somewhere on their course. The lumbar fibres which run outward to the inferior mesenteric ganglia are for the most part connected with the cells of these ganglia. A lesser number is con- ' Langley and Anderson : Journal of Physiology, 1894, xvi. p. 420. CIRCULATION. 209 nected with small ganglia lying as a rule near the organs to which the nerves are distributed. The remaining division of lumbar fibres running downward in the sympathetic chain, and including the majority of the nerve-fibres to the external generative organs are connected with nerve-cells in the sacral gan- glia of the sympathetic. The sacral group of nerves enter ganglion-cells scattered on their course, most of the nerve-cells for any one organ being in ganglia near that organ. Bladder. — Neither lumbar nor sacral nerves send vaso-motor fibres to the vessels of the bladder. Portal System. — It has already been said that vaso-constrictor fibres for the portal vein were discovered by Mall in the splanchnic nerve. Constrictor fibres have been found by Bayliss and Starling^ in the nerve-roots from the third to the eleventh dorsal inclusive. INIost of the constrictor nerves pass out from the fifth to the ninth dorsal. Back.^The dorsal branches of the lumbar and intercostal arteries, issuing from the dorsal muscles to supply the skin of the back,^ can be seen to con- tract when the gray ramus of the corresponding sympathetic ganglia are stimulated. Limbs.^ — The vaso-motor nerves of the limbs in the dog leave the spinal cord from the second dorsal to the third lumbar nerves. The area for the hind limb, according to Bayliss and Bradford, is less extensive than that for the fore limb, the former receiving constrictor fibres from nine roots, namely the third to the eleventh dorsal, the latter from six roots, the eleventh dorsal to third lumbar. Langley finds that the sympathetic constrictor and dilator fibres for the fore foot are connected with nerve-cells in the ganglion stella- tum ; while those for the hind foot are connected with nerve-cells in the sixth and seventh lumbar, and the first, and possibly the second, sacral ganglia. Thompson and Bancroft have studied the nerves to the superficial veins of the hind limb. The latter finds that in general the arrangement of the vaso-motor nerves corresponds to that of the arterial vaso-motor nerves and the sweat fibres. The fibres to the superficial veins originate from the lower end (first to fourth lumbar nerves) of the region of the spinal cord supplying all the vaso-motor nerves for the hind limbs. Tail.^ — Stimulation of any part of the sympathetic from about the third lumbar ganglion downward almost completely stops the flow of blood from wounds in the tail. The vaso-motor fibres for the tail leave the cord chiefly in the third and fourth lumbar nerves. Their stimulation may cause primary dilatation followed by constriction. Iliiseles. — According to Gaskell, the section of the nerve belonging to ' Bayliss and Starling : Journal of Physiology, 1894, xvii. p. 125. ^Langley : Journal of Physiology, 1894, xvii. p. 314. ■'Thompson: Archiv fur Physiologie, 1893, p. 104; Wertheimer : Archives de Physiologic 1894, p. 724 ; Bancroft : American Jniirnal of Physiology, 1898, i. p. 477 ; Bayliss and Bradford : Journal of Physiology, 1894, xvi. p. 16; Langley: Journal of Physiology, 1894, xvii. p. 307; Piotrowski : Archiv fur die gesammte Physiologie, 1893, Iv. p. 258. * Langley : Journal of Physiology, 1894, xvii. p. 311. Vol. I.— 14 210 AN AMEBICAJV TEXT-BOOK OF PHYSIOLOGY. any particular muscle or group of muscles causes a temporary increase in the amount of blood which flows from the muscle vein. The stimulation of the jjeripheral end of the nerve also increases the rate of flow through the muscle. The same increase is seen on stimulation of the nerve when the muscle is kept from contracting by curare, provided the drug is not used in amounts sufiicient to paralyze the vaso-dilator nerves. Mechanical stimulation by crimping the peripheral end of the nerve gives also an increase. The existence of vaso- dilator nerves to muscles must therefore be conceded. The presence of vaso-con- strictor fibres is shown by the diminution in outflow from the left femoral vein which followed Gaskell's stimulation of the peripheral end of the abdominal sympathetic in a thoroughly curarized dog, but the supply of constrictor fibres is comparatively small. In curarized auimals reflex dilatation apparently follows the stimulation of the nerves the excitation of which would have caused the contraction of the muscles observed, had not the occurrence of actual contrac- tion been prevented by the curare. The stimulation of the central end of nerves not capable of calling forth reflex contractions in the muscles observed — for example, the vagus — seems to cause constriction of the muscle-vessels. IV. SECRETION. A. General Considerations. The term secretion is meant ordinarily to apply to the liquid or semi- liquid products formed by glandular organs. On careful consideration it becomes evident that the term gland itself is widely applied to a variety of structures differing greatly in their anatomical organization — so much so, in fact, that a general definition of the term covering all cases becomes very indefinite, and as a consequence the conception of what is meant by a secretion becomes correspondingly extended. Considered from the most general standpoint we might define a gland as a structure composed of one or more gland-cells, epithelial in character, which forms a product, the secretion, that is discharged either upon a free epithelial surface such as the skin or mucous membrane, or upon the closed epithelial surface of the blood- and lymph-cavities. In the former case — that is, when the secretion appears upon a free epithelial surface communi- cating with the exterior, the product forms what is ordinarily known as a secretion ; for the sake of contrast it might be called an external secretion. In the latter case the secretion according to modern nomenclature is designated as an internal secretion. The best-known organs furnishing internal secretions are the liver, the thyroid, and the pancreas. It remains possible, however, that any organ, even those not possessing an epithelial structure, such as the muscles, may give off substances to the blood comparable to the internal secretions — a possibility that indicates how indefinite the distinction between the processes of secretion and of general cell-metabolism may become if the analysis is carried sufficiently far. If we consider only the external secretions definition and generalization become much easier, for in these cases the secret- ing surface is always an epithelial structure which, when it possesses a certain organization, is designated as a gland. The type upon which {'TlJVTi[^VF^ these secreting surfaces are con- .J^^^^^^'^^^S-^^^ structed is illustrated in Figure . - _M • . ^ Fici- 46.— Plan of a secreting membrane. 46. Ihe type consists oi an epithelium placed upon a basement membrane, while upon the other side of the membrane are blood-capillaries and lymph-spaces. The secretion is derived ultimately from the blood and is discharged upon the free epithelial surface, which is supposed to communicate with the exterior. The mucous membrane of the alimentary canal from stomach to rectum may be considered, 211 212 .4^V A2IERICAJV TEXT-BOOK OF PHYSIOLOGY. if we neglect the existence of the villi and crypts, as representing a secreting surface constructed on this type. If we suppose such a membrane to become Fig. 47.— To illustrate the simplest form of a tubular and a racemose or acinous gland. invaginated to form a tube or a sac possessing a definite lumen (see Fig. 47), we have then what may be designated technically as a gland. It is obvious that in this case the gland may be a simple pouch, tubular or saccular in shape (Fig. 48), or it may attain a varying degree of complexity by the elongation of the involuted portion and the development of side branches Fig. 48.— Simple alveolar gland of the amphibian skin (after Flemming). Fig. 49.— Schematic representation of a lobe of i compound tubular gland (after Flemming). (Fig. 49). The more complex structures of this character are known sometimes as compound glands, and are further described as tubular, or racemose (saccular), or tubulo-racemose, according as the terminations of the invaginations are tubular, or saccular, or intermediate in shape.^ As a matter of fact we iind the greatest variety in the structure of the glands imbedded in the cutaneous and mucous surfaces, a variety extending from the simplest form of crypts or tubes to very complicated organs possessing an anatomical independence and definite vascular and nerve-supplies as in the case of the salivary glands or the kidney. In compound glands it is generally assumed that the terminal portions of the tubes alone form the secretions, and these are designated as the the acini or alveoli, while the tubes connecting the alveoli with the exterior are known as the ducts, and it is supposed that their lining epithelium is devoid of secretory activity. The secretions formed by these glands are as varied in composition as the glands are in structure. If we neglect the case of the so-called reproductive ' Flemming has called attention to the fact that most of the so-called compound racemose glands, salivary glands, pancreas, etc., do not contain terminal sacs or acini at the ends of the system of ducts ; on the contrary, the final secreting portions are cylindrical tubes, and such glands are better designated as compound tubular glands. SECBETIOX. 213 glands, the ovary and testis, whose right to the. designation of glands is doubt- ful, we may say that the secretions in the mammalian body are liquid or semi- liquid in character and are composed of water, inorganic salts, and various organic compounds. With regard to the last-mentioned constituent the secre- tions differ greatly. In some cases the organic substances present are not found in the blood, and furthermore they may be specific to a particular secretion, so that we must suppose that these constituents at least are produced in the gland itself. In other cases the organic elements may be present in the blood, and are merely eliminated from it by the gland, as in the case of the urea found in the urine. Johannes Miiller long ago made this distinction, and spoke of secre- tions of the latter kind as excretions, a term which we still use and which car- ries to our minds also the implication that the substances so named are waste products whose retention would be injurious to the economy. Excretion as above defined is not a term, however, that is capable of exact application to any secretion as a whole. Urine, for example, contains some constituents that are probably formed within the kidney itself, e. g., hippuric acid ; while, on the other hand, in most secretions the water and inorganic salts are derived directly from the blood or lymph. So, too, some secretions — for example, the bile — carry off waste products that may be regarded as mere excretions, and at the same time contain constituents (the bile salts) that are of immediate value to the whole organism. Excretion is therefore a name that we may apply conveniently to the process of removal of waste products from the body, or to particular constituents of certain secretions, but no fundamental distinc- tion can be made between the method of their elimination and that of the formation of secreted products in general. Owing to the diversity in com- position of the various external secretions and the obvious difference in the extent to which the glandular epithelium participates in the process in different glands, a general theory of secretion cannot be formulated. The kinds of activity seem to be as varied as is the metabolism of the tissues in general. It was formerly believed that the formation of the secretions was de- pendent mainly if not entirely upon the physical processes of filtration, osmosis, and diffusion. The basement membrane with its lining epithelium was supposed to constitute a membrane through which various products of the blood or lymph passed by filtration and diffusion, and the variation in com- position of the secretions was referred to differences in structure and chemical properties of the dialyzing membrane. The significant point about this view is that the epithelial cells were supposed to play a passive part in the process ; the metabolic processes within the cytoplasm- of the cells were not believed to affect the composition of the secreted product. As compared with this view the striking peculiarity of modern ideas of secretion is, perhaps, the import- ance attributed to the living structure and properties of the epithelial cells. It is believed generally now that the glandular epithelium takes a direct part in the production of some at least of the constituents of the secretions. The reasons for this view will be brought out in detail further on in describing the secreting processes of the separate glands. Some of the general facts, how- 214 AX A3IEBICAN TEXT-BOOK OF PHYSIOLOGY. ever, which influenced physiologists in coming to this conclusion are as follows : Microscopic examination has demonstrated clearly that in many cases parts of the epithelial oell-substance can be followed into the secretion. In the sebaceous secretion the cells seem to break down completely to form the mate- rial of the secretion ; in the formation of mucus by the goblet cells of the mucous membrane of the stomach and intestines a portion of the cytoplasm after undergoing a mucoid degeneration is extruded bodily from the cell to form the secretion ; in the mammary glands a portion of the substance of the epithelial cells is likewise broken off and disintegrated in the act of secretion, while in other glands the material of the secretion is deposited within the cell in the form of visible granules which during the act of secretion may be observed to disappear, apparently by dissolution in tiie stream of water passing through the cell. Facts like these show that some at least of the products of secretion arise from the substance of the gland-cells, and may be considered as representing the results of a metabolism within the cell-substance. From this standpoint, therefore, we may explain the variations in the organic constituents of the secretions by referring them to the different kinds of metabolism existing in the different gland-cells. The existence of distinct secretory nerves to many of the glands is also a fact favoring the view of an active participation of the gland-cells in the formation of the secretion. The first discovery of this class of nerve-fibres we owe to Ludwig, who (in 1851) showed that stimulation of the chorda tympani nerve causes a strong secretion from the submaxillary gland. Later investigations have demon- strated the existence of similar nerve-fibres to many other glands — for example, the lachrymal glands, the sweat-glands, the gastric glands, the pancreas. Recent microscopic work indicates that the secretory fibres end in a fine plexus between and around the epithelial cells, and we may infer from this that the action of the nerve-impulses conducted by these fibres is exerted directly upon the gland-cells. The formation of the water and inorganic salts present in the various secretions offers a problem the general nature of which may be referred to appropriately in this connection, although detailed statements must be reserved until the several secretions are specially described. The problem involves, indeed, not only the well-recognized secretions, but also the lymph itself as well as the various normal and pathological exudations. Formerly the occur- rence of these substances was explained Ijy the action of the physical processes of filtration, diffusion, and osmosis through membranes. With the blood under a considerable pressure and with a certain concentration in salts on one side of the basement membrane, and on the other a liquid under low pressure and differing in chemical composition, it would seem inevitable that water should filter through the membrane and that processes of osmosis and diffusion should be set up, further changing the nature of the secretion. Upon this theory the water and salts in all secretions were regarded merely as transudatory prod- ucts, and so far as they were concerned the epithelium was supposed to act SECRETION. 215 simply as a passive membrane. This theory has not proved entirely acceptable for various reasons. It has been shown that living membranes offer consider- able resistance to filtration even when the liquid pressure on one side is much greater than on the other. Tigerstedt' and Santessen, for instance, found that a lung taken from a frog just killed gave no filtrate when its cavity was distended by liquid under a pressure of 18 to 20 centimeters, provided the liquid used was one that did not injure the tissue. If, however, the lung- tissue was killed by heat or otherwise, filtration occurred readily under the same pressure. In some glands, also, the formation of the water and salts, as has been said, is obviously under the control of nerve-fibres, and this fact is difficult to reconcile with the idea that the epithelial cells are merely pas- sive filters. In glands like the kidney, and in other glands as well, it has not, as yet, been shown conclusively that the amount of water and salts increases in proportion to the rise of blood-pressure within the capillaries, as should happen if filtration were the sole agent at work ; and furthermore, certain chemical substances when injected into the blood may increase the flow of urine to an extent that it is difficult to explain by the use of the filtration and diffusion theor)' alone. " While, therefore, it cannot be denied that the anatomical conditions pre- vailing in the glands are favorable to the processes of filtration and osmosis, and while we are justified in assuming that these processes do actually occur and serve to account in part for the appearance of the water and inorganic salts, it seems to be clear that in the present condition of our knowledge theories based on these factors alone do not suffice to explain all the phe- nomena connected with the secretion of water and salts. Until the contrary is definitively proved we may suppose that the epithelial cells are actively con- cerned in the process. The way in which they act is not known ; various hypotheses have been advanced, but none of them meets all the facts to be explained, and at present it is customary to refer the matter to the vital properties of the cells — that is, to the peculiar physical or chemical properties connected with their living structure. We may now pass to a consideration of the facts known with regard to the physiology of the different glands considered merely as secretory organs. The functional value of the secretions will be found described in the sections on Digestion and Nutrition. B. Mucous AND Albuminous (Serous) Types of G-lands ; Salivary Glands. Mucous and Albuminous Glands. — Heidenhain recognized two types of glands, the mucous and the albuminous, basing his distinction upon the character of the secretion and upon the histological appearance of the secreting cells. The classification as originally made was applied only to the salivary glands and to similar glands found in the mucous membranes of the mouth ' MMieil. vom physiol. Lab, des Carol, med.-chir. Instituts in Slockholm, 1885. 216 ^^Y AJIEBICAX TEXT-BOOK OF PHYSIOLOGY. and oesophagus, the air-passages, conjunctiva, etc. The chemical difference iu the secretions of the two types consists in the fact that tlie secretion of tlie albuminous (or serous) glands is thin and watery, containing in addition to possible enzymes only water, inorganic salts, and small quantities of albumin ; while that of the mucous glands is stringy and viscid owing to the presence of mucin. As examples of the albuminous glands we have the parotid in man and the mammalia generally, the submaxillary in some animals (rabbit), some of the glands of the mucous membrane of the mouth and nasal cavities, and the lachrymal glands. As examples of the mucous glands, the submaxil- lary in man and most mammals, the sublingual, the orbital, and some of the glands of the mucous membrane of the mouth-cavity, oesophagus, and air- passages. The histological appearance of the secretory cells in the albuminous glands is in typical cases markedly different from that of the cells in the mucous glands. In the albuminous glands the cells are small and densely filled with granular material, so that the cell outlines, in preparations from the fresh gland, cannot be distinguished (see Figs. 53 and 55). In the mucous glands, on the contrary, the cells are larger and much clearer (see Fig. 56). In microscopic preparations of the fresh gland the cells, to use Langley's expression, present the appearance of ground glass, and granules are only indistinctly seen. Treatment with proper reagents brings out the granules, ^vhich are, however, larger and less densely packed than in the albuminous glands, and are imbedded in a clear homogeneous substance. Histological examination shows, moreover, that in some glands, e. g. the submaxillary gland, cells of both types occur. Such a gland is usually spoken of as a mucous gland, since its secretion contains mucin, but histologically it is a mixed gland. The terms mucous and albuminous or serous, as applied to the entire gland, are not in fact perfectly satisfactory, since not only do the mucous glands usually contain some secretory cells of the albuminous type, but albu- minous glands, such as the jiarotid, may also contain cells belonging to the mucous type. The distinction is more satisfactory when it is a[)plied to the individual cells, since the formation of mucin within a secreting cell seems to present a definite histological picture, and we can recognize microscopically a mucous cell from an albuminous cell although the two may occur together in a single alveolus. Goblet Cells. — The goblet cells found in the epithelium of the intestine afford an interesting example of mucous cells. The epithelium of the intes- tine is a simple columnar epithelium. Scattered among the columnar cells are found cells containing mucin. These cells are originally columnar in shape like the neighboring cells, but their protoplasm undergoes a chemical change of such a character that mucin is produced, causing the cell to become swollen at its free extremity, whence the name of goblet cell. It has been shown that the mucin is formed within tlie substance of the protoplasm as distinct granules of a large size, and that the amount of mucin increases gradually, forcing the nucleus and a small part of the unchanged protoplasm toward the base of the SECRETION. 217 -cell. Eventually the mucin is extruded bodily into the lumen of the intestine, leaving behind a partially empty cell with the nucleus and a small remnant of protoplasm (see Fig. 50). The complete life-history of these cells is imper- FiG. 50.— Formation of secretion of mucus in the goblet cells : A, cell containing mucin ; B, escape of the mucin ; C, after escape of the mucin (after Paneth). fectly known. According to Bizzozero^ they are a distinct variety of cell and are not genetically related to the ordinary granular epithelial cells by which they are surrounded. According to others, any of the columnar epithelial cells may become a goblet cell by the formation of mucin within its interior, and after tiie mucin is extruded the cell regenerates its protoplasm and becomes again an ordinary epithelial cell. However this may be, the interesting fact from a physiological standpoint is that these goblet cells are genuine unicellular mucous glands. Moreover, the deposition of the mucin in the form of definite granules within the protoplasm gives histological proof that this material is produced by a metabolism of the cell-substance itself. It will be found that the mucin cells in the secreting tubules of the salivary glands exhibit similar appearances. So far as is known, the goblet cells do not possess secretory nerves. Salivary Glands. Anatomical Relations. — The salivary glands in man are three in num- ber on each side — the parotid, the submaxillary, and the sublingual. The parotid gland communicates with the mouth by a large duct (Stenson's duct) which opens upon the inner surface of the cheek opposite the second molar tooth of the upper jaw. The submaxillary gland lies below the lower jaw, and its duct (Wharton's duct) opens into the mouth-cavity at the side of the fr^num of the tongue. The sublingual gland lies in the floor of the mouth to the side of the frsenum and opens into the mouth-cavity by a number (8 to 20) of small ducts, known as the ducts of Eivinus. One larger duct that runs parallel with the duct of "Wharton and opens separately into the mouth- cavity is sometimes present in man. It is known as the duct of Bartholin and occurs normally in the dog. In addition to these three pairs of large glands a number of small glands belonging both to the albuminous and the mucous types are found imbedded in the mucous membrane of the mouth and ' A rchiv fiir mikroskopische Anatomie, 1893,' Bd. 42. S. 82. 218 AjY A3IEBICAX TEXT-BOOK OF PHYSIOLOGY. tongue. The secretions of these glands contribute to the formation of the' saliva. The course of the nerve-fibres supplying the large salivary glands is interest- ing in view of the physiological results of their stimulation. The description here given applies especially to their arrangement in the dog. The parotid gland receives its fibres from two sources — first, cerebral fibres that originate in the glosso-pharyngeal or ninth cranial nerve, pass into a branch of this nerve known as the tympanic branch or nerve of Jacobson, thence to the small superficial petrosal nerve, through which they reach the otic ganglion. From this gan- glion they pass by way of the auriculo-temporal branch of the inferior max- Inferior maxillary ■ branch of fifth Glosso-pharyngeal nerve Petrous ganglion Pig. 51.— Schematic representation of the course of the cerebral fibres to the parotid gland. illary division of the fifth cranial nerve to the parotid gland. (A schematic diagram showing the course of these fibres is given in Figure 51.) A second Inferior maxillary branch of fifth •igual ganglion Branches to tongue Branches to submaxiT- lary and sublingual Fig. 52.— Schematic representation of the course ^f the chorda tympani nerve to the submaxillary gland. supply of nerve-fibres is obtained from the cervical sympathetic nerve, the fibres reaching the gland ultimately in the coats of the blood-vessels. The submaxillary (and the sublingual) glands receive their nerve-fibres also from SECRETION. 219 two sources. The cerebral fibres arise from the brain in the facial nerve and pass out in the chorda tympaui branch (Fig. 52). This latter nerve, after emerging from the tympanic cavity through the Glaserian fissure, joins the lingual nerve. After running with this nerve for a short distance, the secre- tory (and vaso-dilator) nerve-fibres destined for the submaxillary and sublin- gual glands branch off and pass to the glands, following the course of the ducts. Where the chorda tympani fibres leave the lingual there is a small ganglion which has received the name of submaxillary ganglion. The nerve- fibres to the glands pass close to this ganglion, but Langley has shown that only those destined for the sublingual gland really connect with the nerve- cells of the ganglion, and he suggests therefore that it should be called the sublingual instead of the submaxillary ganglion. The nerve-fibres for the submaxillary gland make connections with nerve-cells mainly within the hilus of the gland itself. The submaxillary and sublmgual glands receive also sympathetic nerve-fibres, which after leaving the superior cervical gan- glion pass to the glands in the coats of the blood-vessels. Histological Structure. — The salivary glands belong to the type of com- pound tubular glands, as Flemming has pointed out. That is, the secreting portions are tubular in shape, although in cross sections these tubes may present various outlines according as the plane of the section passes through them. The parotid is described usually as a typical serous or albuminous gland. Its secreting epithelium is composed of cells which in the fresh con- dition as well as in preserved specimens contain numerous fine granules (see Figs. 53 and 55, A). Heidenhain states that in exceptional cases (in the dog) some of the secreting cells may belong to the mucous type. The base- ment membrane is composed of flattened branched connective-tissue cells, the interstices between which are filled by a thin membrane. The submaxillary gland differs in histology in different animals. In some, as the dog or cat, all the secretory tubes are composed chiefly or exclusively of epithelial cells of the mucous type (Fig. 56). In man the gland is of a mixed type, the secretory tubes containing both mucous and albuminous cells. The sublingual gland in man also contains both varieties of cells, although the mucous cells predominate. It follows from these histological characteristics that the secre- tion from the submaxillary and sublingual glands is thick and mucilaginous as compared with that from the parotid. In the mucous glands another variety of cells, the so-called demilunes or crescent cells, is frequently met with ; and the physiological significance of these cells has been the subject of much discussion. The demilunes are cres- oent-shaped granular cells lying between the mucous cells and the basement membrane, and not in contact, therefore, with the central lumen of the tube (see Fig. 56). According to Heidenhain these demilunes are for the purpose of replacing the mucous cells. In consequence of long-continued activity the mucous cells may disintegrate and disappear, and the demilunes then develop into new mucous cells. The most probable view at present is that the demi- lunes represent distinct secretory cells of the albuminous type. 220 AJV AMERICAN TEXT-BOOK OF PHYSIOLOGY. The secreting tubules of the salivary glands possess distinct lumens round which the cells are arranged. In addition a number of recent observers, making use of the Golgi method of staining, have apparently demonstrated that in the albuminous glands the lumen is continued as fine capillary spaces running between the secreting cells.^ The statement is also made that from these secretion capillaries small side-branches are given off that penetrate into the substance of the cell, making an intracellular origin of the system of ducts; this point, however, needs confirmation. In the mucous glands similar secretion capillaries are found only in connection with the demilunes. This latter fact supports the view that the demilunes are not simply inactive forms of mucous cells, but cells with a specific functional activity. It is an un- doubted fact that the salivary glands possess definite secretory nerves which M'hen stimulated start the formation of secretion. This fact indicates that there must be a direct contact of some kind between the gland-cells and the terminations of the secretory fibres. The nature of this connection has been the subject of numerous investigations, the results of which were for a long time negative or untrustworthy. More recently, however, the application of the useful Golgi method has led to satisfactory results. The ending of the nerve- fibres in the submaxillary and sublingual glands has been described by a num- ber of observers.^ The accounts differ somewhat as to details of the finer anatomy, but it seems to be clearly established that the secretory fibres from the chorda tympani end first round the intrinsic nerve-ganglion cells of the glands, and from these latter cells axis-cylinders are distributed to the secreting cells, passing to these cells along the ducts. The nerve-fibres termi- nate in a plexus upon the membrana propria of the alveoli, and from this plexus fine fibrils pass inward to end on and between the secreting cells. It would seem from these observations that tiie nerve-fibrils do not penetrate or fuse with the gland-cells, as was formerly supposed, but form a terminal network in contact with the cells, following thus the general schema for the connection between nerve-fibres and peripheral tissues. Composition of the Secretion. — The saliva as it is found in the mouth is a mixed secretion from the large salivary glands and the numerous smaller glands scattered over the mucous membrane of the mouth. It is w colorless or opalescent, turl)id, and mucilaginous liquid of weakly alkaline re- action and a specific gravity of about 1003. It may contain numerous flat cells derived from the epithelium of the mouth, and the peculiar spherical cells known as salivary corpuscles, which seem to be altered leucocytes. The im- portant constituents of the secretion are mucin, a diastatic enzyme known as ptyalin, traces of albumin and of potassium sulphocyanide, and inorganic salts such as potassium and sodium chloride, potassium sulphate, sodium carbonate, and calcium carbonate and phosphate. The average proportions of these con- iitituents is given in the following anal)-sis by Hammerbacher : ' Laserstein: Pfliiger's Archiv fur die gesammte Physiologie, 1893, Bd. 55, S. 417. ^ See Huber : Journal of Experimental Medicine, 1896, vol. i. p. 281. SECRETION. 221 Water, , .... 994.203 Solids : Mucin and epithelial cells, 2.202 Ptyalin and albumin, . . . 1.390 Inorganic salts, .... . ... 2.205 5.797 (Potassium sulphocyanide, 0.041.) Of the organic constitueuts of the saliva the proteid exists in small and varia- ble quantities, and its exact nature is not determined. The mucin gives to the saliva its ropy, mucilaginous character. This substance belongs to the group of combined proteids, glyco-proteids (see section on Chemistry), consisting of a proteid combined with a carbohydrate group. The physiological value of this constituent seems to lie in its physical properties, as described in the section on Digestion. The most interesting constituent of the mixed saliva is the pty- alin. This body belongs to the group of enzymes or unorganized ferments, whose general and specific properties are described in the section on Digestion. It suffices here to say only tiiat ptyalin belongs to the diastatic group of enzymes, whose specific action consists in a conversion of the starches into sugar by a proc- ess of hydrolysis. In some animals (dog) ptyalin seems to be normally absent from the fresh saliva. An interesting fact with reference to the saliva is the large quantity of gases, particularly C'0„, which may be obtained from it \^'hen freshly secreted. In an analysis by Pfliiger of the saliva from the submaxil- lary gland the following figures were obtained : COj, 65 per cent., of which 42.5 per cent, was in the form of carbonates; N, 0.8 per cent. ; O, 0.6 per cent. For the parotid secretion Kiilz reports : COj, 66.7 per cent., of which 62 per cent, was in combination as carbonate ; N, 3.8 per cent. ; O, 1.46 per cent. The secretions of the parotid and submaxillary glands can be obtained easily by inserting a cannula into the openings of the ducts in the mouth. The secre- tion of the sublingual can only be obtained in sufficient quantities for analysis from the lower animals. Examination of the separate secretions shows that the main difference lies in the fact that the parotid saliva contains no mucin, while that of the submaxillary and especially of the sublingual gland is rich in mucin. The parotid saliva of man .seems to be particularly rich in ptyalin as compared with that of the submaxillary, while the secretion of the latter and that of the sublingual gland give a stronger alkaline reaction than the parotid saliva. The Secretory Nerves. — -The existence of secretory nerves was discovered by Ludwig in 1851. He found that stimulation of tlie chorda tympani nerve caused a flow of saliva from the submaxillary gland. He established also several important facts with regard to the pressure and composition of the secretion which will be referred to presently. It was afterward shown that the salivary glands receive a double nerve-supply, in part by way of the cervical sympathetic and in part through cerebral nerves, as briefly described on p. 218. It was discovered also that not only are secretory fibres carried 222 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. to the glands by these paths, but that the vaso-motor fibres are contained in the same nerves, and the arrangement of these latter fibres is such that the cerebral nerves contain vaso-dilator fibres that cause a dilatation of the small arteries in the glands and an accelerated blood-flow, while the sympathetic carries vaso-constrictor fibres whose stimulation causes a constriction of the small arteries and a diminished blood-flow. The effect upon the secretion of stimulating these two sets of fibres is found to vary somewhat in different animals. For purposes of description we may confine ourselves to the effects observed on dogs, since much of our fundamental knowledge upon the subject is derived from Heidenhain's* experiments upon this animal. If the chorda tympani nerve is stimulated by weak induction shocks, the gland begins to secrete promptly, and the secretion, by proper regulation of the stimuli, may be kept up for hours. The secretion thus obtained is thin and watery, flows freely, is abundant in amount, and contains not more than 1 or 2 per cent, of total solids. At the same time there is an increased flow of blood through the gland. The whole gland takes on a redder hue, the veins are distended, and if cut the blood that flows from them is of a redder color than in the resting gland, and may show a distinct pulse — all of which points to a dilata- tion of the small arteries. If now the sympathetic fibres are stimulated, quite different results are obtained. The secretion is relatively small in amount, flows slowly, is thick and turbid, and may contain as much as 6 per cent, of total solids. At the same time the gland becomes pale, and if the veins be cut the flow from them is slower than in the resting gland, thus indicating that a vaso-constriction has occurred. The increased vascular supply to the gland accompanying the abundant flow of " chorda saliva " and the diminished flow of blood during the scanty secretion of " sympathetic saliva " suggest naturally the idea that the whole process of secretion may be at bottom a vaso-motor phenomenon, the amount of secretion depending only on the quantity and pressure of the blood flowing through the gland. It has been shown conclusively that this idea is erro- neous and that definite secretory fibres exist. The following facts may be quoted in support of this statement : (1) Ludwig showed that if a mercury manometer is connected with the duct of the submaxillary gland and the chorda is then stimulated for a certain time, the pressure in the duct may ! become greater than the blood-pressure in the gland. This fact shows that~ the secretion is not derived entirely by processes of filtration from the blood. (2) If the blood-flow be shut off" completely from the gland, stimulation of the chorda will still give a secretion for a short time. (3) If atropin is injected into the gland, stimulation of the chorda will cause vascular dilata- tion but no secretion. This may be explained by supposing that the atropin paralyzes the secretory but not the dilator fibres. (4) Hydrochlorate of qui- nine injected into the gland gives vascular dilatation but no secretion. In ' Pfliiger's Arehiv fur die gesammte Physiologic, 1878, Bd. xvii. S. 1 ; also in Hermann's Hand- buch der Physiologie, 1883, Bd. v. Th. 1. SECRETION. 223 this case the secretory fibres are still irritable, since stimulation of the chorda gives the usual secretion. A still more marked difference between the effect of stimulation of the ■cerebral and the sympathetic fibres may be observed in the case of the parotid gland in the dog. Stimulation of the cerebral fibres alone in any part of their course (see Fig. 51) gives an abundant thin and watery saliva, poor in solid constituents. Stimulation of the sympathetic fibres alone (provided the cerebral fibres have not been stimulated shortly before (I^anglay) and the tym- panic nerve has been cut to prevent a reflex effect) gives usually no perceptible secretion at all. But in this last stimulation a marked effect is produced upon ■the gland, in spite of the absence of a visible secretion ; this is shown by the fact that subsequent or simultaneous stimulation of the cerebral fibres gives a secretion very unlike that given by the cerebral fibres alone, in that it is very rich indeed in organic constituents. The amount of organic matter in the secretion may be tenfold that of the saliva obtained by stimulation of the cerebral fibres alone. Another important and suggestive set of facts with regard to the action of the secretory nerves is obtained from a study of the differences in composition of the secretion following upon variations in the strength of stimulation of the nerves. Relation of the Composition of the Secretion to the Strength of Stimula- tion. — If the stimulus to the chorda is gradually increased in strength, ■care being taken not to fatigue the gland, the chemical composition of the secretion is found to change with regard to the relative amounts of the water, the salts, and the organic material. The water and the salts increase in amount with the increased strength of stimulus up to a certain maximal limit, which for the salts is about 0.77 per cent. It is important to observe that this effect may be obtained from a perfectly fresh gland as well as from a gland which had previously been secreting actively. With regard to the organic constituents the precise result obtained depends on the con- dition of the gland. If previous to the stimulation the gland was in a resting condition and unfatigued, then increased strength of stimulation is followed at first by a rise in the percentage of organic constituents, and this rise in the beginning is more marked than in the case of the salts. But with continued stimulation the increase in organic material soon ceases, and finally the amount begins actually to diminish, and may fall to a low point in spite of the stronger stimulation. On the other hand, if the gland in the beginning of the experiment had been previously worked to a considerable extent, then an increase in the stimulating current, while it increases the amount of water and salts, may have either no effect at all upon the organic constituents or cause only a temporary increase, quickly followed by a fall. Similar results may be obtained from stimulation of the cerebral nerves of the parotid gland. The above facts led Heidenhain to believe that the con- ditions determining the secretion of the organic material are different from 224 A^'' AMERICAJS"^ TEXT-BOOK OF PHYSIOLOGY. those controlling the water and salts, and he gave a rational explanation of the diiferences observed, in his tlieory of trophic and secretory fibres. Theory of Trophic and Secretory Nerve-fibres. — This theory supposes that two physiological varieties of nerve-fibres are distributed to the salivary glands. One of these varieties controls the secretion of the water and inor- ganic salts and its fibres may be called secretory fibres proper, while the other, to which the name trophic is given, causes the formation of the organic con- stituents of the secretion, probably by a direct influence on the metabolism in the cell. Were the trophic fibres to act aloue, the organic products would be formed within the cell but there would be no visible secretion, and this is the hypothesis which Heidenhain uses to explain the results of the experi- ment described above upon stimulation of the sympathetic fibres to the parotid of the dog. In this animal, apparently, the sympathetic branches to the parotid contain exclusively or almost exclusively trophic fibres, while in the cerebral branches both trophic and secretory fibres proper are present. The results of stimulation of the cerebral and sympathetic branches to the submaxillary gland of the same animal may be explained in terms of this theory by supposing that in the latter nerve trophic fibres preponderate, and in the former the secretory fibres proper. It is obvious that this anatomical separation of the two sets of fibres along the cerebral and sympathetic paths may be open to individual variations, and that dogs may be found in which the sympathetic branches to the parotid glands contain secretory fibres proper, and therefore give some flow of secretion on stimulation. These variations might also be expected to be more marked when animals of different groups are compared. Thus Langley^ finds that in cats the sympathetic saliva from the submaxillary gland is less viscid than the chorda saliva, just the reverse of what occurs in the dog. To apply Heidenhain's theory to this case it is necessary to assume that in the cat the trophic fibres run chiefly in the chorda. An interesting fact with reference to the secretion of the parotid in dogs has been noted by Langley and is of special interest, since, although it may be reconciled with the theory of trophic and secretory fibres, it is at the same time suggestive of an incompleteness in this theory. As has been said, stimulation of the sympathetic in the dog causes usually no secretion from the parotid. Langley ^ finds, however, that if the tympanic nerve is stimulated just previously, stimulation of the sympathetic causes an abundant but brief flow from the parotid. One may explain this in terms of the theory by assuming that the sympathetic does contain a few se- cretory fibres proper, but that ordinarily their action is too feeble to start the flow of water. Previous stimulation of the tympanic nerve, however, leaves the gland-cells in a more irritable condition, so that the few secretory fibres proper in the sympathetic branches are now effective in producing a flow of water. ^Journal of Physiology, 1878, vol. i. p. 96. 'Ibid., 1889, vol. X. p. 291. SECBETIOK. 225 Theories of the Action of Trophic and Secretory Fibres. — The way in which the trophic fibres act has been briefly indicated. They may be sup- posed to set up metabolic changes in the protoplasm of the cells, leading to the formation of certain definite products, such as mucin or ptyalin. That such changes do occur is abundantly shown by microscopic examination of the rest- ing and the active gland, the details of which will be given presently. In general these changes may be supposed to be katabolic in nature ; that is, to consist in a disassociation or breaking down of the complex living material with the formation of the simpler and more stable organic constituents of the secretion. There is evidence to show that these gland-cells during activity form fresh material from the nourishment supplied by the blood ; that is, that anabolic or building-up processes occur along with the katabolic changes. The latter are the more obvious and are the changes which are usually associated with the action of the trophic nerve-fibres. It is possible, also, that the anabolic or growth changes may be under the control of separate fibres for which the name anabolic fibres would be appropriate. Satisfactory proof of the existence of a separate set of anabolic fibres has not yet been furnished. The method of action of the secretory fibres proper is difficult to under- stand. At present the theories suggested are very speculative, and a detailed account of them is scarcely appropriate in this place. Heidenhain's own view may be mentioned, but it should be borne in mind that it is only an hy- pothesis, the truth of which is far from being demonstrated. The theory starts from the fact that no more water leaves the blood-capillaries than afterward appears in the secretion ; that is, no matter how long the secretion continues, the gland does not become cedematous nor does the velocity of the lymph- stream in the lymphatics of the gland increase. This being the case, we must suppose that the stream of water is regulated by the secretion, that is, by the activity of the gland-cells. If we suppose that some constituent of these cells has an attraction for water, or, to use the modern expression, exerts a high osmotic pressure, tiien, while the gland is in the resting state, water will diffuse from the basement membrane ; this in turn supplies its loss from the surrounding lymph, and the lymph obtains the same amount of water from the blood. As the amount of water in the cell increases a point is reached at which an equilibrium is established, and the osmotic stream from blood to cells comes to a standstill. The water in the cells does not escape into the lumen of the tubule or of the secretion capillaries, because the periphery of the cell is modified to form a layer offering considerable resistance to filtra- tion. The action of the secretory fibres proper consists in so altering the structure of this limiting layer of the cells that it offers less resistance to filtra- tion ; consequently the water under tension in the cells escapes into the lumen, and the osmotic pressure of its substance again starts up a stream of water from capillaries to cells, which continues as long as the nerve-stimulation is effective. Vol. I.— 15 226 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Recent work by Ranvier, Drasch, Biedermann, and others has called atten- tion to an interesting phenomenon occurring in gland-cells during secretion which when better known will possibly throw light upon the formation of the water stream under the influence of nerve-stimulation. Ranvier^ describes in both serous and mucous cells the formation of vacuoles within the proto- plasmic substance. These vacuoles are particularly abundant after nerve- stimulation. They seem to contain water, and if they behave as they do in the protozoa — and this is indicated by the observations of Drasch ^ upon the glands in the nictitating membrane in the frog — they would seem to form a mechanism sufficient to force water from the cells into the lumen. Histological Changes during Activity. — The cells of both the albu- minous and mucous glands undergo distinct histological changes in conse- quence of prolonged activity, and these changes may be recognized both in preparations from the fresh gland and in preserved specimens. In the parotid gland Heidenhaiu studied the changes in stained sections after hardening in alcohol. In the resting gland (Fig. 53) the cells are compactly filled with ^i Fig. 53.— Parotid of the rabbit, in the resting condition (after Heidenhain). granules that stain readily and are imbedded in a clear ground substance that does not stain. The nucleus is small and more or less irregular in out- line. After stimulation of the tympanic nerve the cells show but little altera- tion, but stimulation of the sympathetic produces a marked change (Fig. 54). The cells become smaller, the nuclei more rounded, and the granules more closely packed. This last appearance seems, however, to be due to the hard- ening reagents used. A truer picture of what occurs may be obtained from a study of sections of the fresh gland. Langley,^ who first used this method, ' Comptes renins, cxviii., 4, p. 168. ^ Archivfur Anatomic und Physiologie, 1889, 8. 96. ^Journal of Physiology, 1879, vol. ii. p. 260. SECRETION. 227 describes his results as follows : When the animal is in a fasting condition the cells have a granular appearance throughout their substance, the outlines of Fig. 54,— Parotid of the rabbit, after stimulation of the sympathetic (after Heiaenhain). the different cells being faintly marked by light lines (Fig. 55, A). When the gland is made to secrete by giving the animal food, by injecting pilocarpin, or by stimulating the sympathetic nerves, the granules begin to disappear from. C D Fig. 55.— Parotid gland of the rabbit in a fresh state, showing portions of the secreting tubules : A, in a resting condition; B, after secretion caused by pilocarpin; C, after stronger secretion, pilocarpin and stimulation of sympathetic ; X>, after long-continued stimulation of sympathetic (after Langley). the outer borders of the cells (Fig. 55, B), so that each cell now shows an outer clear border and an inner granular one. If the stimulation is continued the granules become fewer in number and are collected near the lumen and the mar- 228 AiX A2IEB1CAN TEXT-BOOK OF PHYSIOLOGY. gins of the cells, the clear zone increases in extent and the cells become smaller (Fig. 55, G, D). Evidently the granular material is used up in some way to make the organic material of the secretion. Since the ptyalin is a conspicuous organic constituent of the secretion, it is assumed that the granules iu the rest- ing gland contain the ptyalin, or rather a preliminary material from which the ptyalin is constructed during the act of secretion. On this latter assumption the granules are frequently spoken of as zymogen granules. During the act of secretion two distinct processes seem to be going on in the cell, leaving out of consideration for the moment the formation of the water and the salts. In the first place the zymogen granules undergo a change such that they are forced or dissolved out of the cell, and, second, a constructive metabolism or an- abolism is set up, leading to the formation of new protoplasmic material from the substances contained in the blood aud lymph. The new material thus formed is the clear, non-granular substance, which appears first toward the basal sides of the cells. We may suppose that the clear substance during the resting periods undergoes metabolic changes, whether of a katabolic or anabolic character cannot be safely asserted, leading to the formation of new granules, and the cells are again ready to form a secretion of normal composition. It should be borne in mind that in these experiments the glands were stimulated beyond normal limits. Under ordinary conditions the cells are probably never depleted of their granular material to the extent represented in the figures. In the cells of the mucous glands changes equally marked may be observed after prolonged activity. In stained sections of the resting gland, according to Heidenhain, the cells are large and clear (Fig. 56), with flattened nuclei Fig. 56.— Mucous gland : eubmaxiUary of dog ; rest- Fig. 67.— Mucous gland ; submaxillary of dog ing stage. after eight hours' stimulation of the chorda tym- pani. placed well toward the base of the cell. When the gland is made to secrete the nuclei become more spherical and lie more toward the middle of the cell, aud the cells themselves become distinctly smaller. After prolonged secretion the changes become more marked (Fig. 57) and, according to Heidenhain, some of the mucous cells may break down completely. According to most of the later observers, however, the mucous cells do not actually disintegrate, but SECRETION. 229 form again new material during the period of rest as was described for the goblet cells of the intestine. In the mucous as in the albuminous cells ob- servations upon pieces of the fresh gland seem to give more reliable results than those upon preserved specimens. Langley ' has shown that in the fresh mucous cells of the submaxillary gland numerous large granules may be discovered, about 125 to 250 to a cell. These granules are comparable to those found in the goblet cells, and may be interpreted as consisting of mucin or some preparatory material from which mucin is formed. The granules are sensitive to reagents ; addition of water causes them to swell up and disappear. It may be assumed that this happens during secretion, the gran- ules becoming converted to a mucin-mass which is extruded from the cell. Action of Atropin, Pilocarpin, and Nicotin upon the Secretory Nerves. — The action of drugs upon the salivary glands and their secretions belongs properly to pharmacology, but the eifects of the three drugs men- tioned are so decided that they have a peculiar physiological interest. Atro- pin in small doses injected either into the blood or into the gland-duct prevents the action of the cerebral fibres (tympanic nerve or chorda tympani) upon the glands. This effect may be explained by assuming that the atropin paralyzes the endings of the cerebral fibres in the glands. That it does not act directly upon the gland-cells themselves seems to be assured by the inter- esting fact that with doses sufficient to throw out entirely the secreting action of the cerebral fibres, the sympathetic fibres are still effective when stimulated. Pilocarpin has directly the opposite effect to atropin. In minimal doses it sets up a continuous secretion of saliva, which may be explained upon the supposition that it stimulates the endings of the secretory fibres in the gland. Within certain limits these drugs antagonize each other — that is, the effect of pilocarpin may be removed by the subsequent application of atropin and viae versa. Nicotin, according to the experiments of Langley,^ prevents the action of the secretory nerves, not by action on the gland-cells or the endings of the nerve-fibres round them, but by paralyzing the connections between the nerve- fibres and the ganglion cells through which the fibres pass on their way to the gland. If, for example, the superior cervical ganglion is painted with a solu- tion of nicotin, stimulation of the cervical sympathetic below the gland will give no secretion ; stimulation, however, of the fibres in the ganglion or between the ganglion and gland will give the usual effect. By the use of this drug Langley is led to believe that the cells of the so-called submaxillary ganglion are really intercalated in the course of the fibres to the sublingual gland, while the nerve-cells with which the submaxillary fibres make con- nection are found chiefly in the hilus of the gland itself. Paralytic Secretion. — A remarkable phenomenon in connection with the salivary glands is the so-called paralytic secretion. It has been known for a long time that if the chorda tympani is cut the submaxillary gland after a cer- tain time, one to three days, begins to secrete slowly and the secretion contin- ' Journal of Physiology, 1889, vol. x. p. 433. ' Proceedings of the Royal Society, London, 1889, vol. xlvi. p. 423. 230 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. ues uninterruptedly for a long period — as long, perhaps, as several weeks — and eventually the gland itself undergoes atrophy. Langley ' states that section of the chorda on one side is followed by a continuous secretion from the glands on both sides ; the secretion from the gland of the opposite side he designates as the antiparalytic or antilytic secretion. After section of the chorda the nerve-fibres peripheral to the section degenerate, the process being com- pleted within a few days. These fibres, however, do not run directly to the gland-cell ; they terminate in end-arborizations round sympathetic nerve-cells placed somewhere along their course, in the sub-lingual ganglion, for instance, or within the gland substance itself. It is the axons from these second nerve units that end round the secreting cells. Langley ^ has accumulated some facts to show that within the period of continuance of the paralytic secretion (5 to 6 weeks) the fibres of the sympathetic cells are still irritable to stimula- tion. He is inclined to believe therefore that the continuous secretion is due to a continuous excitation, from some cause, of the local nervous mechanism in the gland. On the other hand, it is possible that the mere cessation of the normal action of the chorda fibres is followed by an altered metabolism in the gland cells of such a nature as to cause a continuous feeble secretion. Normal Mechanism of Salivary Secretion. — Under normal conditions the flow of saliva from the salivary glands is the result of a reflex stimulation of the secretory nerves. The sensory fibres concerned in this reflex must be chiefly fibres of the glosso-pharyngeal and lingual nerves supplying the mouth and tongue. Sapid bodies and various other chemical or mechanical stimuli applied to the tongue or mucous membrane of the mouth will produce a flow of saliva. The normal flow during mastication must be effected by a reflex of this kind, the sensory impulse being carried to a centre and thence trans- mitted through the efferent nerves to the glands. It is found that section of the chorda prevents the reflex, in spite of the fact that the sympathetic fibres are still intact. No satisfactory explanation of the normal functions of the secretory fibres in the sympathetic has yet been given. Various authors have suggested that possibly the three large salivary glands respond normally to different stimuli. This view has lately been supported by Pawlow, who reports that in the dog at least the parotid and the submaxillary may react quite differently. When fistulas were made of the ducts of these glands it was found that the submaxillary responded readily to a great number of stimuli, such as the sight of food, chewing of meats, acids, etc. The parotid, on the contrary, seemed to react only when dry food, dry powdered meat, or bread was placed in the mouth. Drjmess in this case seemed to be the efficient stimulus. Since the flow of saliva is normally a definite reflex, we should expect a distinct salivary secretion centre. This centre' has been located by physiological means in the medulla oblongata ; its exact position is not clearly defined, but possibly it is represented by the nuclei of origin of ' Proceedings of the Royal Society, London, 1885, No. 236. '' Text-book of Physiology, edited by Schiifer, 1898. SECRETION. 231 the secretory fibres which leave the medulla by way of the facial and glosso- pharyngeal nerves. Owing to the wide connections of nerve-cells in the central nervous system we should expect this centre to be affected by stimuli from various sources. As a matter of fact, it is known that the centre and through it the glands may be called into activity by stimulation of the sensory fibres of the sciatic, splanchnic, and particularly the vagus nerves. So, too, various psychical acts, such as the thought of savory food and the feeling of nausea preceding vomiting, may be accompanied by a flow of saliva, the effect in this case being due probably to stimulation of the secretion centre by nervous impulses descending from the higher nerve-centres. Lastly, the medullary centre may be inhibited as well as stimulated. The well-known effect of fear, embarrassment, or auxiety in producing a parched throat may be supposed to arise in this way by the inhibitory action of nerve-impulses arisiug in the cerebral centres. Electrical Changes in the Gland during Activity. — It has been shown that the salivary as well as otiier glands suffer certain changes in electric potential during activity which are comparable in a general way to the " action currents " observed in muscles and nerves (see section on Muscle and Nerve). The theories bearing upon the causes of these electrical changes are too intricate and speculative to enter upon here. The reader is referred to an account given by Biedermann ^ for further details. C. Pancreas ; Glands op the Stomach and Intestines. Anatomical Relations of the Pancreas. — The pancreas in man lies in the abdominal cavity behind the stomach. It is a long, narrow gland, its head lying against the curvature of the duodenum and its narrow extremity or tail reaching to the spleen. The chief duct of the gland (duct of Wirsung) usually opens into the duodenum, together with the common bile-duct, about eight to ten centimeters below the pylorus. In some cases, at least, a smaller duct may enter the duodenum separately some%vhat lower down. The points at which the ducts of the pancreas open into the duodenum vary considerably in different animals. For instance, in tiie dog there are two ducts, the larger of which enters the duodenum separately about six to seven centimeters below the pylorus, while in the rabbit the main duct opens into the duodenum over thirty centimeters below the pylorus. The nerves of the pancreas are derived from the solar plexus, but physiological experiments which will be described presently show that the gland receives fibres from at least two sources, through the vagus nerve and through the sympathetic system. Histological Characters. — The pancreas, like the salivary glands, belongs to the compound tubular type. The cells in the secreting portions of the tubules, the so-called alveoli, belong to the serous or albuminous type, and are usually characterized by the fact that the outer portion of each cell, that is, the part toward the basement membrane, is composed of a clear oon-glandular ' Elekirophysiologie, Jena, 1 895. 232 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. substance that takes stains readily, while the inner portion turned toward the lumen is filled with conspicuous granules. In addition to this type of cell, which is the characteristic secreting element of the organ, the pancreas contains a number of irregular masses of cells of a different character (bodies of Langerhans). These latter cells are clear and small, frequently have ill- defined cell-bodies, but contain nuclei which stain readily with ordinary reagents. By some these cells are supposed to be immature secreting cells of the ordinary pancreatic type. By others it is thought that they are a separate type of cell and take some special part in the secretory functions of the pan- creas. Nothing definite, however, is known as to their physiological import- ance. Composition of the Pancreatic Secretion. — The pancreatic secretion is a clear alkaline liquid which in some animals (dog) is thick and mucilaginous. Its physical characters seem to vary greatly, even in the same animal, accord- ing to the duration of the secretion or the time since the establishment of the fistula by which it is obtained (see p. 300). In a newly made fistula in the dog the secretion is thick, but in a permanent fistula it becomes much thinner and more watery. The main constituents of the secretion are three enzymes, a large percentage of proteid material the exact nature of which is not known, some fats, soaps, a slight amount of lecithin, and inorganic salts. The strongly alkaline nature seems to be due chiefly to sodium carbonate, which may be present in amounts equal to 0.2 to 0.4 per cent. The three enyzmes are known respectively as trypsin, a proteolytic ferment; amylopsin, a diastatic ferment, and steapsin, a fat-spliting ferment. The action of these enzymes in digestion is described in the section on Digestion. Action of the Nerves on the Secretion of the Pancreas. — In animals like the dog, in which the process of digestion is not continuous, the secretion of the pancreas is also supposed to be intermittent. A study of the flow of secretion as observed in cases of pancreatic flstula indicates that it is connected with the beginning of digestion in the stomach, and is therefore probably a reflex act. Until recently, however, little direct evidence had been obtained of the existence of secretory nerves. Stimulation of the medulla was known to increase the flow of pancreatic juice and to alter its composition as regards the organic constituents, but direct stimulation of the vagus and the sympa- thetic nerves gave only negative results. Lately, however, Pawlow' and some of his students have been able to overcome the technical difficulties in the way, and have given what seems to be perfectly satisfactory proof of the existence of distinct secretory fibres comparable in their nature to those described for the salivary glands. The results that they have obtained may be stated briefly as follows : Stimulation of either the vagus nerve or the sympathetic causes, after a considerable latent period, a marked flow of pancreatic secretion. The failure of other experimenters to get this result was due apparently to the sensitive- ness of the gland to variations in its blood-supply. Either direct or reflex ^Pawlow: Du Bois-ReymoncCs Archiv fur Physiohgie, 1893, Suppl. Bd. ; Mett: Ibid., 1894; Kudrewetsky: i6id., 1894 ; Pawlow : Die Arbeit der Verdauungsdriisen, Wieshaden, 1858. 8ECBETION. 233 vaso-constriction of the pancreas prevents the action of the secretory nerves upon it. Thus stimulation of the sympathetic gives usually no effect upon the secretion, because vaso-constrictor fibres are stimulated at the same time, but if the sympathetic nerve is cut five or six days previously, so as to give the vaso-constrictor fibres time to degenerate, stimulation will cause, after a long latent period, a distinct secretion of the pancreatic juice. A similar result may be obtained from stimulating the undegenerated nerve if mechani- cal stimulation is substituted for the electrical. The long latent period elapsing between the time of stimulation and the efi^ect upon the flow is not easily understood. The authors quoted do not give an entirely satisfactory explanation of this curious fact, but suggest that it may be due to the presence of definite inhibitory fibres to the gland, which are stimulated simultaneously with the secretory fibres and thus hold the secretion in check for a time. The existence of inhibitory fibres is rendered probable by several interesting experiments, for an account of which the original sources must be consulted.^ Histological Changes during Activity. — The morphological changes in the pancreatic cells have long been known and have been studied satisfac- torily in the fresh gland as well as in pi-eserved specimens. The general nature of the changes is the same as that described for the salivary gland, and is illustrated in Figures 58, 69, and 60. If the gland is removed from a dog which has been fasting for about twenty-four hours and is hardened in alcohol and sectioned and stained, it will be found that the cells are filled with granules except for a narrow zone toward the basal end, which is marked off more clearly because it stains more deeply than the granular portion (Fig. 58). If, on the contrary, the gland is taken from a dog which had been fed Fig. 68.— Pancreas of the dog during hunger ; preserved in alcohol and stained in carmine (after Heidenhain). six to ten hours previously, the non-staining granular zone is much reduced in size, while the clearer non-granular zone is enlarged (Fig. 59). The increase in size of the non-granular zone does not, however, entirely compensate for ' Pawlow: Die Arbeit der Verdauungsdriisen, p. 78, Wiesbaden, 1898. 234 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the loss of the granular material, so that the cell as a whole is smaller in size than in the gland from the fasting animal. It seems evident that during the hours immediately following a meal — that is, at the time when we know Fig. 59.— Pancreas of dog during first stage of digestion ; alcohol, carmine (after Heidenhain). that the gland is discharging its secretion, the granular material is being used up. After the cessation of active secretion — that is, during the tenth to the twentieth hour after a meal in the case of a dog fed once in twenty-four Fig. 60.— Pancreas of dog during second stage of digestion; alcohol, carmine (after Heidenhain). hours — the gland-cells return to their resting condition (Fig. 60). New gran- ules are formed, and finally, if the gland is left unstimulated they fill the entire cell except for a narrow margin at the basal end. Similar results are reported by Kiihne^ and Lea from observations made upon the pancreas cells in a living rabbit. In the inactive gland the outlines ' Vnterguchungen aus dem physiologischen Institut des Universitiits Heidelberg, 1882, Bd. ii. SECBETION. 235 of the individual cells are not clearly distinguishable, but it can be seen that there are two zones, one clear and homogeneous on the side toward the basement membrane, and one granular on the side toward the lumen. During activity the secretory tubules show a notched appearance corresponding to the positions of the cells, the outlines of the cells become more distinct, the granular zone becomes smaller, and the homogeneous zone increases in width. It should be stated also that in this latter condition the basal zone of the cells shows a dis- tinct striation. From these appearances we must believe that, as in the case of the salivary gland, a part at least of the organic material of the secretion is formed from the granules of the inner zone, and that the granules in turn are formed within the cells from the homogenous material of the outer zone. Enzyme and Zymogen. — The observations just described indicate that the enzymes of the pancreatic secretion are derived from the granules in the cells, but other facts show that the granules do not contain the enzymes as such, but a preparatory material or mother-substance to which the name zymogen (enzyme-maker) is given. This belief rests upon facts of the following kind : If a pancreas is removed from a dog that has fasted for twenty-four hpurs, when, as we have seen, the cells are heavily loaded with granules, and a glycerin extract is made, very little active enzyme will be found in it. If, however, the gland is allowed to stand for twenty-four hours in a warm spot before the extract is made, or if it is first treated with dilute acetic acid, the glycerin ex- tract will show very active tryptic or amylolytic properties. Moreover, if an inactive glycerin extract of the perfectly fresh gland is treated by various methods, such as dilution with water or shaking with finely divided platinum- black, it becomes converted to an active extract capable of digesting proteid material. These results are readily explained upon the hypothesis that the granules contain only zymogen material, which during the act of secretion, or by means of the methods mentioned, may be converted into the corresponding enzymes. As the three enzymes of the pancreatic secretion seem to be distinct substances, one may suppose that each has it own zymogen to which a distinc- tive name might be given. The zymogen that is converted into trypsin is frequently spoken of as trypsinogen. Normal Mechanism of Pancreatic Secretion. — After the establishment of a pancreatic fistula it is possible to study the flow of secretion in its rela- tions to the ingestion of food. Experiments of this kind have been made. They show that in animals like the dog, in which sufficient food may be taken in a single meal to last for a day, the flow of secretion is intimately connected with the reception of food into the stomach and its subsequent digestive changes. The time relations of the secretion to the ingestion of food are shown in the accompanying chart (Fig. 61). The secretion begins immedi- ately after the food enters the stomach, and increases in velocity up to a cer- tain maximum which is reached some time between the first and the third hour after the meal. The velocity then diminishes rapidly to the fifth or sixth hour, after which there may be a second smaller increase reaching its maxi- mum about the ninth to the eleventh hour. From this point the secretion 236 AN AMEBICAX TEXT-BOOK OF PHYSIOLOGY. diminishes in quantity to the sixteenth or seventeenth hour, when it has practically reached the zero point. In man, in whom the meals normally occur at intervals of five to six hours, this curve of course would have a dif- ferent form. The interesting fact, however, that the secretion starts very soon Or % 3 't S 6 > a ^ 10 It IZ li in Wli Tf Fig. 61.— Curve of the secretion of pancreatic juice during digestion. The figures along the abscissa represent hours after the beginning of digestion ; the figures along the ordinate represent the quantity of this secretion in cubic centimeters. Curves of two experiments are given (after Heidenhaln). after the beginning of gastric digestion is probably true for human beings, and gives strong indication that the secretion is a reflex act. Recently a number of experiments have been reported which strengthen the view that the normal secretion of the pancreas is reflexly excited by stimuli acting upon the mucous membrane of the stomach or duodenum. Dolinsky,^ working upon dogs by Pawlow's methods, finds that acids are particularly effective in arousing the pancreatic flow ; on the contrary, alkalies in the stomach diminish the pancreatic secretion. Dolinsky believes that the normal acidity of the gastric secretion is perhaps the most effective stimulus to the pancreatic gland, and that in this way the flow of gastric juice in ordinary digestion starts the pancreatic gland into activity. Whether the acid acts after absorption into the blood, or stimulates the sensory fibres of the mucous membrane, and thus reflexly affects the pancreas through its secretory nerves, is not definitely known, but the probabilities are in favor of the latter view. It is probable also that the acid acts upon the sensory fibres of the mucous membrane of the duodenum rather than upon the gastric membrane. In addition to acids, it has been found that oils and water introduced into the stomach also cause a flow of pancreatic juice, the stimulation occurring prob- ' Arthivts des Sciences biologiques, St. Petersburg, 1895, t. iii.'p. 399. SECRETION. 237 ably after these substances have reached the duodenum. Moreover, Pawlow has given proof that the secretion of the pancreas varies in both quantity and quality with the nature of the food. Indeed, there seem to be indications of a specific relationship between the food and the composition of the secretion, albuminous food giving a secretion with a greater digestive action on pro- teids; oily foods, a secretion with a larger amount of fat-splitting enzymes, and so on. If this relationship is shown to exist, it forms an adaptation whose mechanism is very obscure.' Glands of the Stomach. Histological Characteristics. — The glands of the gastric mucous mem- brane belong practically to the type of simple tubular glands ; for, although two or more of the simple tubes may possess a common opening or mouth, there is no system of ducts such as prevails in the compound glands, and the divergence from the simplest form of tubular gland is very slight. Each of these glands possesses a relatively wide mouth, lined with the columnar epi- thelium found on the free surface of the gastric membrane, and a longer, nar- rower secreting part, which penetrates the thickness of the mucosa and is lined by cuboidal cells. The glands in the pyloric end of the stomach differ in gen- eral appearance from those in the fundic end, and are especially characterized by the fact that they possess only one kind of secretory cell, while the fundic glands contain two apparently distinct types of cells (Fig. 64). The lumen in the latter glands is lined by a continuous layer of short cylindrical cells to which Heideuhain gave the name of chief-cells. These cells are apparently concerned in the formation of pepsin, the proteolytic enzyme contained in the gastric secre- tion. In addition there are present a number of cells of an oval or triangular shape which are placed close to the basement membrane and do not extend quite to the main lumen of the gland. These cells are not found in the pyloric glands ; they are known by various names, such as border-cells, parietal cells, oxyntic cells, etc. The last-mentioned name has been given to them because of their supposed connection with the formation of the acid of the gastric secretion. The nature and function of these border-cells have been the subject of much discus- sion. From the histological side they have been interpreted as representing either immature forms of the chief-cell, or else the active modification of this cell. Eecent work, however, seems to have demonstrated that they form a specific type of cell, and probably therefore have a specific function. An interesting histological fact in connection with the parietal cells is that, in the human stomach at least, they frequently contain several nuclei, five or six, and some of these seem to be derived from ingested leucocytes. They are interesting also is the fact that they contain distinct vacuoles that seem to appear some time after digestion has begun, reach a maximum size, and then gradually grow smaller and finally disappear. Like the similar phenomenon ' For other interesting facts bearing upon the mechanism of pancreatic secretion, see Walter : Archives des Sciences biologiques, 1899, t. vii. p. 1. 238 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. described for other gland-cells (p. 226), this appearance is possibly connected with the formation of the secretion. The duct of a gastric gland was formerly supposed to be a simple tube extending the length of the gland. A number of recent observers, however, have shown, by the use of the Golgi stain, that this view is not entirely correct, at least not for the glands in the fundus in which border-cells are present. In these glands the central lumen sends off side channels that pass to the border-cells and there form a net- work of small capillaries lying either in or round the cell.' An illustration of the duct-system of a fundic gland is given in Figure 62. If this work is correct it would seem that the chief-cells com- FiG. 62.— Ducts and secretion muuicatc directly with the central lumen, but that capiuaries to parietal cells. ^^^ border-cells have a System of secretion capillaries Gland from the fundus of cats ... stomach (after Langendorff of their owu, resembling in this respect the demi- and Laserstein). j^^^^ ^f ^^^ mucous salivary glands (p. 220). This fact tends to corroborate the statement previously made, that the border-cells form a distinct type of cell whose function is probably diiferent from that of the chief-cells. Composition of the Secretion of the Gastric Mucous Membrane. — The secretion as it is poured out on the surface of the mucous membrane is composed of the true secretion of the gastric glands together with more or less mucus, which is added by the columnar cells lining the surface of the mem- brane and the mouths of the glands. In addition to the mucus, water, and inorganic salts, the secretion contains as its characteristic constituents hydro- chloric acid and two enzymes — namely, pepsin which acts upon proteids, and rennin which has a specific coagulating effect upon the casein of milk. For an analysis of the gastric secretion of the dog see p. 288. According to Heiden- hain,^ the secretion from the pyloric end of the stomach is characterized by the absence of hydrochloric acid, although it still contains pepsin. This statement rests upon careful experiments in which the pyloric end was entirely resected and made into a blind pouch which was then sutured to the abdominal wall to form a fistula. In this way the secretion of the pyloric end could be obtained free from mixture with the secretion of any other part of the alimentary canal. By this means Heidenhain found that the pyloric secretion is an alkaline liquid containing pepsin. This fact forms the strongest evidence for Heidenhain's hypothesis that the HCl of the normal gastric secretion is produced by the " border-cells " of the fundic glands and the pepsin by the " chief-cells," since HCl is formed only in parts of the stomach containing border-cells, whereas the pepsin is produced in the pyloric end, where only chief-cells are present. Evidence of this character is naturally not very convincing, and the hypoth- ■ Langendorff and Laserstein : Pfliiger's Anhiv fur die gesammte PhysMogie, 1894, Bd. Iv. S. 578. ' Anhiv jur die gesammte Physiologie, 1878, Bd. xviii. S. 169, also Bd. xix. 8ECBETION. 239 esis, especially that part connecting the border-cells with the formation of HCI, can only be accepted provisionally until further investigation confirms or disproves it. It should be stated that the alkalinity of the secretion obtained from the pyloric glands by Heideuhain's method has been attributed by some authors to the abnormal conditions prevailing, especially to the section of the vagus fibres that necessarily results from the operation. Contejean ' asserts that the reaction of the pyloric membrane under normal conditions is acid in spite of the absence of border-cells. Influence of the Nerves upon the Gastric Secretion. — It has been very difficult to obtain direct evidence of the existence of extrinsic secretory nerves to the gastric glands. In the hands of most experimenters, stimulation of the vagi and of the sympathetics has given negative results, and, on the other hand, section of these nerves does not seem to prevent entirely the formation of the gastric secretion. There are on record, however, a number of observations that point to a direct influence of the central nervous system on the secre- tion. Thus Bidder and Schmidt found that in a hungry dog with a gastric fistula (page 288) the mere sight of food caused a flow of gastric juice ; and Richet reports a case of a man in whom the oesophagus was completely oc- cluded and in whom a gastric fistula was established by surgical operation. It was then found that savory foods chewed in the mouth produced a marked flow of gastric juice. There would seem to be no clear way of explaining the secretions in these cases except upon the supposition that they were caused by a reflex stimulation of the gastric mucous membrane through the central nervous system. These cases are strongly supported by some recent experimental work on dogs by Pawlow ^ and Schumowa-Simanowskaja. These observers used dogs in which a gastric fistula had been established, and in which, more- over, the oesophagus had been divided in the neck and the upper and lower cut surfaces brought to the skin and sutured so as to make two fistulous openings. In these animals, therefore, food taken into the mouth and subse- quently swallowed escaped to the exterior through the upper oesophageal fistula, without entering the stomach. Nevertheless this " fictitious meal," as the authors designate it, brought about a secretion of gastric juice. If in such animals the two vagi were cut, the " fictitious meal " no longer caused a secretion of the gastric juice, and this fact may be considered as showing that the secretion obtained when the vagi were intact was due to a reflex stimulation of the stomach through these nerves. In later experiments ' from the same laboratory the secretion caused in this way by the act of eating is designated as a " psychical secretion," on the assumption, for which consider- able evidence is given, that the reflex must involve psychical factors such as the sensations accompanying the provocation and gratification of the appetite. In favorable cases the fictitious feeding was continued for as long as five to six hours, with the production of a secretion of about 700 c.c. of pure gastric ' Archives de Physiologic, 1892, p. 554. ' Du Bois-Reymond' s ArchivfUr Physiologie, 1895, S. 53. 'Die Arbeit der Verdauungsdriisen, Wiesbaden, 1898. 240 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. juice. Finally, these observers were able to show that direct stimulation of the vagi under proper conditions causes, after a long latent period (four and a half to ten minutes), a marked secretion of gastric juice. The long latent period is attributed to the simultaneous stimulation of inhibitory fibres. Taking these results together, we must believe that the vagi send secretory fibres to the gastric glands, and that these fibres may be stimulated reflexly through the sensory nerves of the mouth, and probably also by psychical states. Normal Mechanism of Secretion of the Gastric Juice. — Our knowl- edge of the means by which the flow of gastric secretion is caused during normal digestion, and of the varying conditions which influence the flow, is as yet quite incomplete. The notable experiments recently made by Pawlow ' and his pupils, together with older experiments by Heidenhain,^ have, however, thrown some light upon this difficult problem, and have, moreover, opened the way for further experimental study of the matter. Heidenhain cut out a part of the fundus of the stomach, converted it into a blind sac, and brought one end of the sac to the abdominal wall so as to form a fistulous opening to the exterior. The continuity of the stomach was established by suturing the cut ends, but the fundic sac was completely separated from the rest of the alimentary canal. This operation has since been modified by Pawlow in such a way that the isolated fundic sac retains its normal nerve supply. Heiden- hain found that under these conditions the ingestion of ordinary food caused a secretion in the isolated and empty fundic sac, the secretion beginning fifteen to thirty minutes after the food was taken, and continuing until the stomach was empty. The ingestion of water caused a temporary secretion in the fundus, while indigestible material such as ligamentum nuchse gave no secretion at all. Heidenhain's interpretation of these experiments as applied to normal secretion was that in ordinary digestion we must distinguish between a primary and a secondary secretion. The primary secretion depends upon the mechanical stimulus of the ingested food, and is confined to the spots directly stimulated ; the secondary secretion begins after absorption from the stomach is in progress, and involves the whole secreting surface. The first part of this theory is in accord with a belief which heretofore has been very generally held by physiologists, namely, that the gastric glands may be made to secrete by direct mechanical excitation. Pawlow has shown, however, by what seem to be most convincing experiments, that this belief is erroneous. Mechanical stimulation, strong or weak, circumscribed or general, seems to be totally without effect in arousing a secretion. Pawlow has been led by his interesting experiments to give a different explanation of the normal mechan- ism of secretion. The first effect of eating is the production of the " psychical secretion," before referred to. This secretion is effected through the action of secretory fibres in the vagus, and possibly also in the sympathetic nerve. It begins usually within five minutes, is, in a general way, proportional in amount ' Archives des Scimces biologiques, St. Petersburg, 1895, t. iii. p. 461 ; t. v. p. 425. ^Hermann's Handbnch der Physiologie, 1883, Bd. v. S. 114. SECRETION. 241 to the intensity of the appetite or enjoyment of the food, and may last for several hours even though the actual period of eating has been short (five min- utes). It is this secretion that first acts upon the food received into the stomach. Later its action is supplemented by an augmented secretion, caused by stimuli of a chemical nature originating in the food ingested. Some foods contain substances ready formed that are capable of acting in this way. Investigation of various articles of diet showed that meat extracts, juices, and soups contain these substances in largest amounts. Milk and aqueous solutions of gelatin act in the same way, although less powerfully. Water also, if in sufficient quantity, acts as a direct stimu- lant. Other common articles of food, such as bread or white of egg, do not contain these stimulating substances. Food of the latter character, when introduced directly into a dog's stomach through a fistula, pro- vokes not a drop of secretion and undergoes no digestion, if it has been introduced in such a way as to avoid arous- ing the psychical secretion, as, for instance, at times when the animal is dozing. If, how- ever, this latter class of foods undergo digestion, as would happen in normal feeding in consequence of the action of the " psychical secretion," sub- stances capable of stimulating the stomach to secretion are developed, and their action keeps up the flow of secretion after the effect of the psychical factor has become weakened. The nature of these chemical stimuli remains entirely undetermined. Pawlow's first statement that pep- tone constituted at least one member of this group he now finds is erroneous. It is assumed that these substances act through the secretory nerves, and it has been shown also that other substances may have the contrary effect of retarding or inhibiting the gastric secretion. This has been proved for fats at least. Oils of various kinds decrease the secretion of gastric juice, while they augment the pancreatic secretion. Another most suggestive result of Pawlow's work is the proof tliat the quantity and characteristics of the secre- tion vary with the food. Apparently the quantity of the secretion varies, other Vol. I.— 16 2 1 1 ■^ d Milk, Meat, Beead, 600 c.c. 100 gr. 100 gr. 10 8 6 4 2 0.576 0.528 0.4S0 0.432 0.384 0.336 0.288 0.240 0.192 0.144 0.096 0.048 18 16 14 12 10 8 6 4 2 _ / s \ \ 1 \ 1 \ 1 \ 1 \ ; ' \ I 1 ^^ ! \ 1 \ \ \ \ \ \ _, , \ y ^ 1 / k \ '^ / \ J S. S Ji. d 6 7 8 y wini - Quantity of secretioi 1. -r ii est IV ei o\ ve r. Fig. 63.— Diagram showing the variation in quantity of gastric secretion in the dog after a mixed meal ; also the variations in acidity and in digestive power (after Khigine). 242 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. conditions being the same, with the amount of the food to be digested. By some means the apparatus is adjusted in this respect to work economically. Different l^inds of food produce secretions varying not only as regards quan- tity, but also in their acidity and digestive action. The secretion produced by bread, though less in quantity than that caused by meat, possesses a greater digestive action. On a given diet the secretion will assume certain charac- teristics, and Pawlow is convinced that further work will disclose the fact that the secretion of the stomach is not caused normally by general stimuli all affecting it alike, but by specific stimuli contained in the food or produced during digestion, whose action is of such a kind as to produce the secretion best adapted for the food ingested. One of the curves showing the effect of a mixed diet (milk, 600 cubic centimeters ; meat, 100 grams ; bread, 100 grams) upon the gastric secretion, as determined by Pawlow's method, is reproduced in Fig. 6o. It will be noticed, that the secretion began shortly after the ingestion of the food (seven minutes), and increased rapidly to a maximum that was reached in two hours. After the second hour the flow decreased rapidly and nearly uniformly to about tlie tenth hour. The acidity rose slightly between the first and second hours, and then fell gradually. The digestive power showed an increase between the second and third hours. Histological Changes in the Gastric Glands during Secretion. — The cells of the gastric glands, especially the so-called chief-cells, show distinct changes as the result of prolonged activity. Upon preserved specimens taken from dogs fed at intervals of twenty-four hours, Heidenhain found that in the fasting condition the chief-cells were large and clear, that during the first six hours of digestion the chief-cells as well as the border-cells increased in size, but that in a second period extending from the sixth to the fifteenth hour, the chief-cells became gradually smaller, while the border-cells remained large or even increased in size. After the fifteenth hour tlie chief-cells increased in size, gradually passing back to the fasting condition (see Fig. 64). Langley' has succeeded in following the changes in a more satisfactory way by observations made directly upon the living gland. He finds that the chief-cells in the fasting stage are charged with granules, and that during digestion the granules are used up, disappearing first from the base of the cell, which then becomes filled with a non-granular material. Observations similar to those made upon the pancreas demonstrate that these granules represent in all probability a preliminary material from which the gastric enzymes are made during the act of secretion. The granules, therefore, as in the other glands, may be spoken of as zymogen granules, the preliminary material of the pepsin being known as pepsinogen and that of the rennin sometimes as pexinogen. Glands of the Intestine. — At the very beginning of the intestine in the immediate neighborhood of the pylorus is found a small area of mucous mem- brane containing distinct tubular glands, known usually as the glands of ^ Journal of Physiology, 1880, yol. ill. p. 269. SECRETION. 243 Brunuer. These glands resemble closely in arrangement those of the pyloric end of the stomach, with the exception that the tubular duct is more branched. The secreting cells are similar to those of the pyloric glands of the stomach. Little is known of their secretion. According to some authors it contains pepsin. The amount of secretion furnished by these glands would seem to be too small to be of great importance in digestion. Throughout the length Fig. 64.— Glands of the fundus (dog) : A and A^, during hunger, resting condition ; B, during the first stage of digestion; C and X>, the second stage of digestion, showing the diminution in the size of the "chief" or central cells (after Heidenhain). of the small and large intestine the well-known crypts of Lieberkiihn are found. These structures resemble the gastric glands in general appear- ance, but not in the character of the epithelium. The epithelium lining the crypts is of two varieties — the goblet cells, whose function is to form mucus, and columnar cells with a characteristic striated border. The changes in the goblet cells during secretion and the probability of a relationship between them and the neighboring epithelial cells has been discussed (see p. 216). Whether or not the crypts form' a definite secretion has been much debated. Physiologists are accustomed to speak of an intestinal juice, " succus entericus," as being formed by the glands of Lieberkiihn, but practically nothing is known as to the mechanism of the secretion. The succus entericus itself, however it may be formed, can be collected by isolating small loops of the intestine and 244 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. bringing the ends to the abdominal wall to form fistulous openings. The secretion thus obtained contains diastatic and also inverting ferments, the action of which is described on p. 308. Histological!}-, the cells in the bottom of the crypts do not possess the general characteristics of secreting cells. D. LivEB; Kidney. The liver is a gland belonging to the compound tubular type. The hepatic cells represent the secretory cells and the bile-ducts carry off the external secretion, which is designated as bile. In addition it is known that the liver-cells occasion important changes in the material brought to them in the blood, and that two important compounds, namely, glycogen and urea, are formed under the influence of these cells and afterward are given off to the blood-stream. The liver, then, furnishes a conspicuous example of a gland that forms simultaneoublv an external and an internal secretion. In this section we have to consider only certain facts in relation to the external secretion, the bile. Histological Structure. — The general histological relations of the hepatic lobules need not be repeated in detail. It will be remembered that in each lobule the hepatic cells are arranged in columns radiating from the central vein, and that the intralobular capillaries are so arranged with reference to these columns that each cell is practically brought into contact with a mixed blood derived in part from the portal vein and in part from the hepatic artery. As a gland making an external secretion, the relations of the liver-cells to the ducts and to the nervous system are important points to be determined. The bile-ducts can be traced without difficulty to the fine interlobular branches running round the periphery of the lobules, but the finer branches or bile- capillaries springing from the interlobular ducts and penetrating into the in- terior of the lobules have been difficult to follow with exactness, especially as to their connection with the interlobular ducts on the one hand, and with the liver-cells on the other. The bile-capillaries have long been known to pene- trate the columns of cells in the lobule in such a way that each cell is in con- tact with a bile-capillary at one point of its periphery, and with a blood-capil- lary at another, the bile- and blood-capillaries being separated from each other by a portion of the cell-substance. But whether or not intracellular branches from these capillaries actually penetrate into the substance of the liver-cells has been a matter in dispute. Kuppfer contended that delicate ducts arising from the capillaries enter into the cells and end in a small intracellular vesicle. As this appearance was obtained by forcible injections through the bile-ducts, it was thought by many to be an artificial product ; but recent observations with staining reagents tend to substantiate the accuracy of Kuppfer's obser- vations and confirm the belief that normally the system of bile-ducts begins within the liver-cells in minute channels that connect directly with the bile- capillaries. Two questions with reference to the bile-ducts have given rise to considerable SECRETION. 245 discussion and investigation : first, tiie relationship existing between the liver- cells and the lining epithelium of the bile-ducts; second, the presence or ab- sence of a distinct membranous wall for the bile-capillaries. Different opin- ions are still held upon these points, but the balance of evidence seems to show that the bile-capillaries have no proper wall. They are simply minute tubular spaces penetrating between the liver-cells and corresponding to the alveolar lu- men in other glands. "Where the capillaries join the interlobular ducts the liver- cells pass gradually or abruptly, according to the class of vertebrates examined, into the lining epithelium of the ducts. From this standpoint, then, the liver- cells are homologous to the secreting cells of other glands in their relations to the general lining epithelium. Several observers (MaCallum,^ Berkley,'* and Korolkow^) have claimed that they are able to trace nerve-fibres to the liver-cells, thus furnishing histological evidence that the complex processes oc- curring in these cells are under the regulating control of the central nervous system. According to the latest observers (Berkeley, Korolkow) the terminal nerve-fibrils end between the liver-cells, but do not actually penetrate the sub- stance of the cells, as was described in some earlier papers. If these observa- tions prove to be entirely correct they would demonstrate the direct effect of the nervous system on some at least of the manifold activities of the liver- cells. So far as the formation of the bile is concerned we have no satisfactory physiological evidence that it is under the control of the nervous system. Composition of the Secretion. — The bile is a colored secretion. In most carnivorous animals it is golden red, while in the herbivora it is green, the difference depending on the character and quantity of the pigments. In man the bile is usually stated to follow the carnivoi'ous type, showing a red- dish or brownish color, although in some cases apparently the green predomi- nates. The characteristic constituents of the bile are the pigments, bilirubin in carnivorous bile and biliverdin in herbivorous bile, and the bile acids or bile- salts, the sodium salts of glycocholic or taurocholic acid, the relative proportions of the two acids varying in different animals. In addition there is present a considerable quantity of a mucoid nucleo-albumin, a constituent which is not formed in the liver-cells, but is added to the secretion by the mucous membrane of the bile-ducts and gall-bladder; and small quantitiesofcholesterin, lecithin, fats, and soaps. The inorganic constituents comprise the usual salts — chlorides, phosphates, carbonates and sulphates of the alkalies or alkaline earths. Iron is found in small quantities, combined probably as a phosphate. The secre- tion contains also a considerable though variable quantity of COj gas, held in such loose combination that it can be extracted with the gas-pump without the addition of acid. The presence of this constituent serves as an indication of the extensive metabolic changes occurring in the liver-cells. Quantitative analyses of the bile show that it varies greatly in composition even in the same species of animal. Examples of this variability are given in the analyses I MaCalluro : Quarterly Journal of the Microscopical Sciences, 1887, vol. xxvii. p. 439. '' Berkley : Anatomischer Ameicjer, 1893, Bd. viii. S. 769. ' Korolkow: Ibid., S. 750. 246 AJV AMERICAN TEXT-BOOK OF PHYSIOLOGY. quoted in the section on Digestion (p. 322), where a brief account will also he found of the origin and physiological significance of the different constituents. The Quantity of Bile Secreted. — Owing to the fact that a fistula of the common bile-duct or gall-bladder may be established upon the living animal and the entire quantity of bile be drained to the exterior without serious detri- ment to the animal's life, we possess numerous statistics as to the daily quantity of the secretion formed. Surgical operations upon human beings (see p. 321 for references), made neces.-ary by occlusion of the bile-passages, have furnished similar data for man. In round numbers the quantity in man varies from 600 to 800 cubic centimeters per day, or, taking into account the weight of the individuals concerned, about 8 to 16 cubic centimeters for each kilogram of body-weight. Observations upon the lower animals indicate that the secretion is proportionally greater in smaller animals. This fact is clearly shown in the following table, compiled by Heidenhain' for three herbivorous animals: Sheep. Eabbit. Guinea-pig. Ratio of bile-weight for 24 hours to body-weight . . 1 : 37.5 1 : 8.2 1 : 5.6 Eatio of bile-weight for 24 hours to liver-weight . 1.507 : 1 4.064 : 1 4.467 : 1 There seems to be no doubt that the bile is a continuous secretion, although in animals possessing a gall-bladder the secretion may be stored in this reser- voir and ejected into the duodenum only at certain intervals connected with the processes of digestion. The movement of the bile-stream within the system of bile-ducts — that is, its actual ejection from the liver, is also probably intermittent. The observations of Copeman and Winston on a human patient with a biliary fistula showed that the secretion was ejected in spirts, owing doubtless to contractions of the muscular walls of the larger bile-ducts. But though continuously formed within the liver-cells, the flow of bile is subject to considerable variations. According to most observers the activity of .secre- tion is definitely connected with the period of digestion. Somewhere from the third to the fifth hour after the beginning of digestion there is a very marked acceleration of the flow, and a second maximum at a later period, ninth to tenth hour (Hoppe-Seyler), has been observed in dogs. The mechanism con- trolling the accelerated flow during the third to the fifth hour is not perfectly understood. It would seem to be correlated with the digestive changes occur- ring in the intestine, but whether the relationship is of the nature of a reflex nervous act, or whether it depends on increased blood-flow through the organ or upon some action of the absorbed products of secretion remains to be deter- mined. It has been shown that the presence of bile in the blood acts as a stimulus to the liver-cells, and it is highly probable that the absorption of bile from the intestine which occurs during digestion serves to accelerate the secre- tion ; but this circumstance obviously does not account for the marked increase observed in animals with biliary fistula.s, since in these cases the bile does not reach the intestine at all. Therapeutically various substances have been stated by different authors to act as true cholagogues — that is, to stimulate the ' Hermann's Handbuch der Physiologie, Bd. v. Thl. 1, S. 253. SECRETION. 247 secretion of bile. Of these substances the one whose action is most undoubted is bile itself or the bile acids. When given as dried bile, in the form of pills, a marked increase in the flow is observed.' Relation of the Secretion of Bile to the Blood-flow in the Liver. — Numerous experiments have shown that the quantity of bile formed by the liver varies more or less directly with the quantity of blood flowing through the organ. The liver-cells receive blood from two sources, the portal vein and the hepatic artery. The supply from both these sources is probably essen- tial to the perfectly normal activity of the cells, but it has been shown that bile continues to be formed, for a time at least, when either the portal or the arterial supply is occluded. However, there can be little doubt that the material actually utilized by the liver-cells iu the formation of their external and internal secre- tions is brought to them mainly by the portal veiq, and that variations in the quantity of this supply influences directly the amount of bile produced. Thus, occlusion of some of the branches of the portal vein diminishes the secretion ; stimulation of the spinal cord diminishes the secretion, since, owing to the large vascular constriction produced thereby in the abdominal viscera, the quantity of blood in the portal circulation is reduced ; section of the spinal cord also dimin- ishes the flow of bile or may even stop it altogether, since the result of such an operation is a general paralysis of vascular tone and a general fall of blood- pressure and velocity ; stimulation of the cut splanchnic nerves diminishes the secretion because of the strong constriction of the blood-vessels of the abdom- inal viscera and the resulting diminution of the quantity of the blood in the portal circulation ; section of the splanchnics alone, however, is said to increase the quantity of bile, in dogs, since in this case the paralysis of vascular tone is localized in the abdominal viscera. The effect of such a local dilatation of the blood-vessels would be to diminish the resistance along the intestinal paths, and thus lead to a greater flow of blood to that area and the portal circulation. In all these cases one might suppose that the greater or less quantity of bile formed depended only on the blood-pressure in the capillaries of the liver lobules — that so far at least as the water of the bile is concerned it is produced by a process of filtration and rises and falls with the blood-pressure. That this simple mechanical explanation is not sufficient seems to be proved by the fact that the pressure of bile within the bile-ducts, although comparatively low, may exceed that of the blood in the portal vein. The Existence of Secretory Nerves to the Liver. — The numerous experiments that have been made to ascertain whether or not the secretion of bile is under the direct control of secretory nerves have given unsatisfactory results. The experiments are difficult, since stimulation of the nerves supply- ing the liver, such as the splanchnic, is accompanied by vaso-raotor changes which alter the blood-flow to the organ and thus introduce a factor that in itself influences the amount of the secretion. So far as our actual knowledge goes, the physiological evidence is against the existence of secretory nerve- 1 Journal of Experimental Medicine, 1897, vol. ii. p. 49. 248 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. fibres controlling the formation of bile. On the other hand, there are some experiments/ although they are not perfectly conclusive, which indicate that the glycogen formation within the liver-cells is influenced by a special set of glyoo-secretory nerve-fibres. This fact, however, does not bear directly upon the formation of bile. Motor Nerves of the Bile-vessels. — Doyon ^ has recently shown that the gall-bladder as well as the bile-ducts is innervated by a set of nerve-fibres comparable in their general action to the vaso-constrictor and vaso-dilator fibres of the blood-vessels. According to this author, stimulation of the peripheral end of the cut splanchnics causes a contraction of the bile-ducts and gall-bladder, while stimulation of the central end of the same nerve, on the contrary, brings about a reflex dilatation. Stimulation of the central end of the vagus nerve causes a contraction of the gall-bladder and at the same time an inhibition of the sphincter muscle closing the opening of the common bile-duct into the duodenum. These facts need confirmation, perhaps, on the part of other observers, although they are in accord with what is known of the actual movement of the bile-stream. The ejection of bile from the gall- bladder into the duodenum is produced by a contraction of the gall-bladder, and it is usually believed that this contraction is brought about reflexly from some sensory stimulation of the mucous membrane of the duodenum or stomach. The result of the experiments made by Doyon would indicate that the afferent fibres of this reflex pass upward in the vagus, while the efferent fibres to the gall-bladder run in the splanchnics and reach the liver through the semilunar plexus. Normal Mechanism of the Bile-secretion. — Bearing in mind the fact that our knowledge of the secretion of bile is in many respects incomplete, and that any description of the act is therefore partly conjectural, we might picture the processes concerned in the secretion and ejection of bile as follows : The bile is steadily formed by the liver-cells and turned out into the bile-capil- laries ; its quantity varies with the quantity and composition of the blood flowing through the liver, but the formation of the secretion depends upon the activities taking place in the liver-cells, and these activities are independ- ent of direct nervous control. During the act of digestion the formation of bile is increased, owing probably to a greater blood-flow through the organ and to the generally increased metabolic activity of the liver-cells occasioned by the inflow of the absorbed products of digestion. The bile after it gets into the bile-ducts is moved onward partly by the accumulation of new bile from behind, the secretory force of the cells, and partly by the contractions of the walls of the bile-vessels. It is stored in the gall-bladder, and at inter- vals during digestion is forced into the duodenum by a contraction of the muscular walls of the bladder, the process being aided by the simultaneous relaxation of a sphincter-like layer of muscle that normally occludes the bile-duct at its opening into the intestine ; both these last acts are under the control of a nervous reflex mechanism. ' Morat and Dufoiirt: Archives de Physiologic, 1894, p. 371. ^Archives de Physiologic, 1894, p. 19 ; see also Oddi : Arch. ital. de Biologie, t. xxii., cvi. SECRETION. 249 In a very interesting research by Bruno ^ it has been shown that the actual passage of bile into the intestine is occasioned, reflexly no doubt, by the passage of the chyme from stomach to intestine. As long as the stomach is empty no bile flows into the duodenum ; the flow commences when the stomach begins to empty its contents into the intestine, and ceases as soon as this process is completed. The author endeavored to ascertain tlie substances in the chyme that serve as the stimulus in this reaction. As far as his experi- ments go, they show that fats and the digested products of proteids (peptones and proteoses) are the most efficient stimuli. Acid."^, alkalies, and starch or the substances formed from it during salivary digestion are ineffective. Pre- sumably the fats and the products of proteid digestion act on the sensory fibres of the duodenal membrane. Effect of Complete Occlusion of the Bile-duct. — It is an interesting fact that when the flow of bile is completely prevented by ligation of the bile- duct, the stagnant liquid is not reabsorbed by the blood directly, but by the lymphatics of the liver. The bile-pigments and bile-acids in such cases may be detected in the lymph as it flows from the thoracic duct. In this way they get into the blood, producing a jaundiced condition. The way in which the bile gets from the bile-ducts into the hepatic lymphatics is not definitely known, but possibly it is due to a rupture, caused by the increased pressure, at some point in the course of the delicate bile-capillaries. Kidney. Histology. — The kidney is a compound tubular gland. The constituent uriniferous tubules composing it may be roughly separated into a secreting part comprising the capsule, convoluted tubes, and loop of Heule, and a col- lecting part, the so-called straight collecting-tube, the epithelium of which is assumed not to have any secretory function. Within the secreting part the epithelium differs greatly in character in different regions; its peculiarities may be referred to briefly here so far as they seem to have a physiological bearing, although for a complete description reference must be made to some work on Histology. The arrangement of the glandular epithelium in the capsule with reference to the blood-vessels of the glomerulus is worthy of special attention. It will be remembered that each Malpighian corpuscle consists of two principal parts, a tuft of blood-vessels, the glomerulus, and an enveloping expansion of the uriniferous tubule, the capsule. The glomerulus is a remarkable structure (see Fig. 65, A). It consists of a small afferent artery which after entering the glomerulus breaks up into a number of capillaries, which, though twisted together, do not anastomose. These capillaries unite to form a single efferent vein of a smaller diameter than the afferent artery. The whole structure, therefore, is not an ordinary capillary area, but a rde mirabile, and the phys- ical factors are such that within the capillaries of the rete there must be a greatly diminished velocity of the blood-stream, owing to the great increase ' Archives des sciences biologiques, 1899, t. vii. p. 87. 250 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. in the width of the stream-bed, and a high blood-pressure as compared with ordinary capillaries. Surrounding this glomerulus is the double-walled capsule. One wall of the capsule is closely adherent to the capillaries of the glomerulus; it not only covers the structure closely, but dips into the interior between the small lobules into which the glomerulus is divided. This layer of the capsule is composed of flattened endothelial-like cells, the glomerular epithelium, to which great importance is now attached in the formation of the secretion. It will be noticed that between the interior of the blood-vessels of the glomerulus and Fig. 65.— Portions of the various divisions of the uriniferous tubules drawn from sections of human kidney : A, Malpighian body ; x, squamous epithelium lining the capsule and reflected over the glomer- ulus ; y, z, afferent and efferent vessels of the tuft ; e, nuclei of capillaries ; n, constricted neck marking passage of capsule into convoluted tubule ; B, proximal convoluted tubule ; C, irregular tubule ; D and F, spiral tubules ; M, ascending limb of Henle's loop ; iJ, straight collecting tubule (Piersol). the cavity of the capsule, which is the beginning of the uriniferous tubule, there are interposed only two very thin layers, namely, the epithelium of the capil- lary wall and the glomerular epithelium. The apparatus would seem to afford most favorable conditions for filtration of the liquid parts of the blood. The epithelium clothing the convoluted portions of the tubule, including under this designation the so-called irregular and spiral portions and the loop of Henle, is of a character quite different from that of the glomerular epithelium (Fig. 65, B, C, D, E, F, G). The cells, speaking generally, are cuboidal or cylindrical, proto- plasmic, and granular in appearance ; on the side toward the basement mem- brane they often show a peculiar striation, while on the lumen side the extreme periphery presents a compact border which in some cases shows a cilia-like striation. These cells have the general appearance of active secretory struc- tures, and recent theories of urinary secretion attribute this importance to them, Composition of Urine. — The chemical composition of the urine is very complex, as we should expect it to be when we remember that it contains most of the end-products of the varied metabolism of the body, its importance in this respect being greater than the other excretory organs such as the lungs, skin, and intestine. The secretion is a yellowish liquid which in carnivorous ani- mals and in man has normally an acid reaction, owing to the presence of acid SECRETION. 251 salts (acid sodium and acid calcium phosphate), and an average specific gravity of 1017 to 1020. The quantity formed in twenty-four hours is about 1200 to 1700 cubic centimeters. In the very young the amount of urine formed is proportionately much greater than in the adult. Tlie normal urine contains about 3.4 to 4 per cent, of solid matter, of which over half is organic mate- rial. Among the important organic constituents of the urine are the follow- ing: urea, uric acid, hippuric acid, xauthin, hypoxanthin, guanin, creatinin and aromatic oxy- acids (para-oxypheuyl propionic acid and para-oxyphenyl acetic acid, as simple salts or combined with sulphuric acid) ; phenol, paracre- sol, pyrocateohiu and hydrochinon, these four substances being combined with sulphuric or glycuronic acid ; iudican or indoxyl sulphuric acid ; skatol sul- phuric acid ; oxalic acid ; sulphocyauides, etc. These and other organic con- stituents occurring under certain conditions of health or disease in various animals, are of the greatest importance in enabling us to follow the metab- olism of the body. Something as to their origin and significance will be found in the section on Nutrition, while their purely chemical relations are described in the section on Chemistry. Among the inorganic constituents of the urine may be mentioned sodium chloride, sulphates, phosphates of the alkalies and alkaline earths, nitrates, and carbon dioxide gas partly in solution and partly as carbonate. In this section we are concerned only with the general mechanism of the secretion of urine, and in this connection have to consider mainly the water and soluble inorganic salts and the typical nitrogenous excreta, namely, urea and uric acid. The Secretion of Urine. — The kidueys receive a rich supply of nerve- fibres, but most histologists have been unable to trace any connection between these fibres and the epithelial cells of the kidney tubules. Berkley^ has, how- ever, described nerve-fibres passing through the basement membrane and ending between the secretory cells. The majority of purely physiological experiments upon direct stimulation of the nerves going to the kidney are adverse to the theory of secretory fibres, the marked effects obtained in these experiments being all explicable by the changes produced in the blood-flow through the organ. Two general theories of urinary secretion have been proposed. Ludwig held that the urine is formed by the simple physical processes of filtration and diffusion. In the glomeruli the conditions are most favorable to filtration, and he supposed that in these struc- tures water filtered througli from the blood, carrying with it not only the in- organic salts, but also the specific elements (urea) of the secretion. There was thus formed at the beginning of the uriuiferous tubules a complete but diluted urine, and in the subsequent passage of this liquid along the convoluted tubes it became concentrated by diffusion with the lymph surrounding the outside of the tubules. So far as the latter part of this theory is concerned it has not been supported by actual experiments ; recent histological work (see below) seems to indicate that the epithelial cells of the convoluted tubules have a ' The Johns Hopkins Hospital Bulletin, vol. iv., No. 28, p. 1. 252 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. distinct secretory function, and that they give material to the secretion rather than take from it. Bowman's theory of urinary secretion, which has since been vigorously supported and extended by Heideuhain, was based apparently mainly on his- tological grounds. It assumes that in the glomeruli water and inorganic salts are produced, while the urea and related bodies are eliminated through the activity of the epithelial cells in the convoluted tubes. Elimination of Urea and Related Bodies. — Numerous facts have been discovered whicli tend to support the latter part of Bowman's theory — namely, the participation of the cells of the convoluted tubules in the secretion of the specific nitrogenous elements. In birds the main nitrogenous element of the secretion is uric acid instead of urea, and it is possible, owing to the small solu- bility of the urates, to see them as solid deposits in mici'oscopic sections of the kidney. When the ureters are ligated the deposition of the urates in the kid- ney may become so great as to give the entire organ a whitish appearance. Nevertheless histological examination of a kidney in this condition shows that the urates are found always in the tubes and never in the Malpighian corpus- cles. From this result we may conclude that the uric acid is eliminated through the epithelial cells of the tubes. Heidenhain has shown by a striking series of experiments that the cells of the tubes possess an active secretory power. In these experiments a solution of indigo-carmine was injected into the circulation of a living animal after its spinal cord had been cut to reduce the blood-pressure and therefore the rapidity of the secretion. After a certain interval the kidneys were removed and the indigo-carmine precipitated in situ in the kidney by injecting alcohol into the blood-vessels. It was found that the pigment granules were deposited in the convoluted tubes, but never in the Malpighian corpuscles. Still further proof of definite secretory functions on the part of the cells of the tubules is given by the results of recent histological work upon the changes in the cells during activity. Van der Stricht,' Disse,^ and Trambusti^ describe definite morphological changes in the epithelial cells of tlie convoluted tubes and ascending loop of Plenle which they connect with the functional activity of the cells. The details of the descriptions differ, but the authors agree in finding that the material of the secretion collects in the interior of the cell to form a vesicle wliich is afterward discharged into the lumen of the cell. According to Disse the inactive cells are small and granular, and toward the lumen show a striated border of minute processes, while the lumen of the tube is relatively wide. As the fluid secretion accumulates in the cells it may be distinguished as a clear vesicular area near the nucleus. The cells enlarge and project toward the lumen, which becomes smaller ; the striated border dis- appears. Finally the swollen cells fill the entire canal, and the liquid secre- ' Comptes remdus, 1891, and Travail du Laboratoire d' Hislnlogie de t Vniverxite de Oand, 1892. '' Referate und Beiirdge zur Anatomie und Entv-'ickelungsgeschichie (anatomische Hefte), Merkel and Bonnet, 1893. ' Archives ilaliennes de Biologic, 1898, t. 30, p. 426. SECRETION. 253 tion is emptied from the cells by filtration. A'an der Stricht believes that the vesicles rupture and thus empty into the lumen. In longitudinal sections various stages in the process may be seen scattered along the length of a single tubule. Secretion of the Water and Salts. — There seems to be no question that the elimination of water together with inorganic salts, and probably still other soluble constituents, takes place chiefly through the glomerular epithelium. This supposition is made in both the general theories that have been men- tioned. It has, however, long been a matter of controversy, in this as in other. glands, whether the water is produced by simple filtration or whether the glomerular epithelium takes an active part of some character in setting up the stream of water. The problem is perhaps simpler in this case than iu the salivary glands, since the direct participation of secretory nerves in the process is e.xcluded. On the filtration theory the quantity of urine should vary directly with the blood-pressure in the glomerulus. This relationship has been accepted as a crucial test of the validity of the filtration theory, and numerous experiments have been made to ascertain whether it iuvariablv exists. Speaking broadly, any general rise of blood-pressure in the aorta will occasion a greater blood-flow and greater pressure in the glomerular vessels provided the kidney arteries themselves are not simultaneously constricted to a sufficient extent to counteract this favorable influence ; whereas a general fall of pressure should have the opposite influence both on pressure and velocity of flow. It has been shown experimentally that if the general arterial pressure falls below 40 or 50 millimeters of mercury, as may happen after section of the spinal cord in the cervical region, the secretion of the urine will be greatly slowed, or suspended completely. Constriction of the small arteries in the kidney, whether effected through its proper vaso-coustrictor nerves or by par- tially clamping its arteries, causes a diminution in the secretion and at the same time in all probability a fall of pressure within the glomeruli and a diminution in the total flow of blood. On the other hand, dilatation of the arteries of the kidney, whether produced through its vaso-dilator fibres or by section or inhibition of its constrictor fibres, augments the flow of urine and at the same time probably increases the pressure within the glomerular capil- laries, and also the total quantity of blood flowing through them in a unit of time. From these and other experimental facts it is evident that the amount of secretion and the amount of pressure within the glomerular vessels do often vary together, and this I'elationship has been used to prove that the water of the secretion is obtained by filtration from the blood-plasma. But it will be observed that the quantity of secretion varies not only with the pressure of the blood within the glomeruli, but also with the quantity of blood flowing through them. Heidenhain has insisted that it is this latter factor and not the intracapillary pressure which determines the quantity of water secreted. He believes that the glomerular epithelial cells possess the property of actively secreting water, and that they are not simply passive filters ; that the forma- tion, in other words, is not a simple mechanical process, but a more complex 254 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. one depending upon the living structure and properties of the epithelial cells. In support of this view he quotes the fact that partial compression of the renal veins quickly slows or stops altogether the flow of urine. Compression of the veins should raise the pressure within the vessels of the glomeruli, and upon the filtration hypothesis should increase rather than diminish the secre- tion. It has been shown also that if the renal artery is compressed for a short time so as to completely shut off the blood-flow to the kidney the secretion is not only suspended during the closure of the arteries but for a long time after the circulation is re-established. According to Tiegerstedt, if the renal artery is ligated for only half a minute the activity of the kidney is suspended for three-quarters of an hour. This fact is difficult to understand if the glomerular epithelium is regarded simjily as a filtering mem- brane, but it is explicable upon the hypothesis that the epithelial cells are actively concerned in the production of the water. The uncertainty as to the mechanism of production of the water and salts renders it difficult to give a theciretical explanation of the action of diuretics. Various saline substances, such as NaCl and KNO3, increase the flow of urine. According to Starling,' these substances increase the bulk of water in the blood by drawing water from the tissues. A condition of hydremic plethora ensues, causing a greater volume of blood in the kidney capillaries and a rise of capillary pressure, conditions that favor greater filtration and account in part for the increased amount of urine. Experiments seem to show, however, that the condition of hydrjemic plethora ]iasses off before the increased secre- tion of urine ceases, so that the diuretic action of the salts is not due to -this factor alone. Tiie adherents of the filtration theory assume that in addition the salts cause a vaso-dilatation in the kidney, and thus produce a rise in blood-pressure in the glomeruli. vVceording to the other point of view, these substances may be considered as having a specific stimulating effect upon the glomerular epithelium. So the action of cafl^ein may be referred either to a sjaecific action ''' on the secreting cells or possibly to an indirect effect exerted through the circulation of the kidney. It seems clear that at present we are not justified in asserting more than that the glomeruli control in some way the production of the water and salts of the secretion. The extent of the activity seems to be correlated with the quantity of blood flowing through the glomeruli. It must be borne in mind, however, that some water and probably also some of the inorganic salts are secreted at other parts of the tubule along with the nitrogenous wastes. It is of interest to add that the most important of the abnormal constituents of the urine under pathological conditions, such as the albumin in albuminuria, the haemoglobin in hsemoglobinuria, and the sugar in glycosuria, seem likewise to escape from the blood into the kidney tubules through the glomerular epithelium. ^Joumul of Physiology, 1899, vol. 24, p. 317. " See Von Schroeder : Archiv. fiir exper. Pathologie und PharmakoL, Bd. xxiv. S. 80 ; and Dreser, Ibid., 1892, Bd. xxix. S. 303. SECRETION. 255 The normal stimulus to the epithelial cells of the convoluted tubules, using the term convoluted to include the actively secreting parts, seems to be the presence of urea and related substances in the blood (lymph). That the elimination of the urea is not a simple act of diffusion seems to be clearlv shown by the fact that its percentage in the blood is much less than in the urine. In some way the urea is selected from the blood and passed into the lumen of the tubule, and although we have microscopic evidence that this process involves active changes in the substance of the cells, there is no ade- quate theory of the nature of the force which attracts the urea from the sur- rounding lymph. The whole pi'ocess must be rapidly effected by the cell, since there is normally no heaping- up of urea in the kidnev-cells ; the material is eliminated into tlie tubules as quickly as it is received from the blood. The rate of elimination increases normally with the increase in the urea in the blood, as would be expected upon the assumption that the urea itself acts as the physiological stimulus to the epithelial cells. The Blood-flow through the Kidneys. — It will be seen from the dis- cussion above that, other conditions remaining the same, the secretion of the kidney varies with the quantity of blood flowing through it. It is therefore important at this point to refer briefly to the nature and especially the regula- tion of the blood-flow through this organ, although the same subject is referred to in connection with the general description of vaso-motor regulation (see Circulation). It has been shown by Landergren ^ and Tiegerstedt that the kidney is a very vascular organ, at least when it is in strong functional activ- ity such as may be produced by the action of diuretics. They estimate that in a minute's time, under the action of diuretics, au amount of blood flows through the kidney equal to the weight of the organ ; this is au amount from four to nineteen times as great as occurs in the average supply of the other organs in the systemic circulation. Taking both kidneys into account, their figures show that (in strong diuresis) 5.6 per cent, of the total quantity of blood sent out of the left heart in a minute may pass through the kidneys, although the combined weight of these organs makes only 0.56 per cent, of that of the body. The nature of the supply of vaso-motor nerves to the kidney and the con- ditions which bring them into activity are fairly well known, owing to the use- ful invention of the oncometer by Roy.^ This instrument is in principle a plethysmograph especially modified for use upon the kidney of the living animal. It is a kiduey-shaped box of thin brass made in two parts, hinged at the back, and with a clasp in front to hold them together. lu the interior of the box thin peritoneal membrane is so fastened to each half that a layer of olive oil may be placed between it and the brass walls. There is thus formed in each half a soft pad of oil upon which the kidney rests. When the kidney, freed as far as possible from fat and surrounding connective tissue, but with the blood-vessels and nerves entering at the hilus entirely uninjured, is laid in ' Skandinrivisches ArchivfUr Physiologie, 1892, Bd. iv. S. 241. ^ See Cohnheim and Roy : Virchou/s Arehiv, 1883, Bd. xcii. S. 424. 256 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. one-half of the oncometer, and the other half is shut down upon it and tightly fastened, the organ is surrounded by oil in a box which is liquid-tight at every point except one, where a tube is led off to some suitable recorder such as a tambour. Under these conditions every increase in the volume of the kidney ■will cause a proportional outflow of oil from the oncometer, which will be measured by the recorder, and every diminution in volume will be accompa- nied by a reverse change. At the same time the flow of urine during these changes can be determined by inserting a cannula into the ureter and measur- ing directly the outflow of ui'ine. By this and other means it has been shown that the kidney receives a rich snpplv of vaso-constrictor nerve-fibres that reach it between and round the entering blood-vessels. These fibres emerge from the spinal cord chiefly in the lower thoracic spinal nerves (tenth to thir- teenth in the dog), pass through the sympathetic system, and reach the organ as non-medullated fibres. Stimulation of these nerves causes a contraction of the small arteries of the kidney, a shrinkage in volume of the whole organ as measured by the oncometer, and a diminished secretion of urine. When, on the other hand, these constrictor fibres are cut as they enter the hilus of the kidnej', the arteries are dilated on account of the removal of the tonic action of the constrictor fibres, the organ enlarges, and a greater quantity of blood passes through it, since the resistance to the blood-flow is diminished while the general arterial jjressure in the aorta remains practically the same. Along with this greater flow of blood there is a marked increase in the secretion of urine. Under normal conditions we must suppose that these fibres are brought into play to a greater or less extent by reflex stimulation, and thus serve to control the blood-flow through the kidney and thereby influence its functional activity. It has been shown, too, that the kidney receives vaso-dilator nerve- fibres, that is, fibres which when stimulated directly or reflexly cause a dilata- tion of the arteries, and therefore a greater flow of blood through the organ. According to Bradford,' these fibres emerge from the spinal cord mainly in the anterior roots of the eleventh, twelfth, and thirteenth spinal nerves. Under normal conditions these fibres are probably thrown into action by reflex stimula- tion and lead to an increased functional activity. It will be seen, therefore, that the kidneys possess a local nervous mechanism through which their secretory activity may be increased or diminished by corresponding alterations in the blood-supply. So far as is known, this is the only way in which the secretion in the kidneys can be directly affected by the central nervous system. It should be borne in mind, also, that the blood-flow through the kidneys, and therefore their secretory activity, may be affected by conditions influ- encing general arterial pressure. Conditions such as asphyxia, strychnin- poisoning, or painful stimulation of sensory nerves, which cause a general vaso- constriction, influence the kidney in the same way, and tend, therefore, to diminish the flow of blood through it; while conditions which lower general arterial pressure, such as genei'al vascular dilatation of the skin ^Journal of Physiology, 1889, vol. x. p. 358. SECRETION. 257 vessels, may also depress the secretory action of the kidney by diminishing the amount of blood flowing through it. In what way any given change in the vascular conditions of the body will influence the secretion of the kidney depends upon a number of factors, and their relations to one another ; but any change which will increase the differ- ence in pressure between the blood in the renal artery and the renal vein will tend to augment the flow of blood unless it is antagonized by a simultaneous constriction in the small arteries of the kidney itself. On the contrary, any vascular dilatation of the vessels in the kidney will tend to increase the blood- flow through it unless there is at the same time such a general fall of blood- pressure as is sufiicient to lower the pressure in the renal artery and reduce the driving force of the blood to an extent that more than counteracts the favoi'a- ble influence of diminished resistance in the small arteries. Movements of the Ureter and the Bladder. — (See Micturition, p. 389.) E. Cutaneous Glands ; Internal Secretions. The sebaceous glands, sweat-glands, and mammary glands are all true epider- mal structures, and may therefore be conveniently treated together. Sebaceous Secretion. — The sebaceous glands are simple or compound alveolar glands found over the cutaneous surface usually in association with the hairs, although in some cases they occur separately, as, for instance, on the pre- puce and glans penis, and on the lips. When they occur with the hairs the short duct opens into the hair-follicle, so that the secretion is passed out upon the hair near the point where it projects from the skin. The alveoli are filled with cuboidal or polygonal epithelial cells, which are arranged in several lay- ers. Those nearest the lumen of the gland are filled with fatty material. These cells are supposed to be cast off bodily, their detritus going to form the secretion. Xew cells are formed from the layer nearest the basement mem- brane, and thus the glands continue to produce a slow but continuous secretion. The sebaceous secretion, or sebum, is an oily semi-liquid material that sets upon exposure to the air to a cheesy mass, as is seen in the comedones or pim- ples which so frequently occur upon the skin from occlusion of the opening of the ducts. The exact composition of the secretion is not known. It contains fats and soaps, some cholesterin, albumiuous material, part of which is a nucleo-albumin often described as a casein, remnants of epithelial cells, and inorganic salts. The cholesterin occurs in combination with a fatty acid and is found in especially large quantities iu sheep's wool, from which it is extracted and used commercially under the name of lanolin. The sebaceous secretion from different places, or in different animals, is probably somewhat variable in composition as well as in quantity. The secretion of the prepuce is known as the smegma prcepntii ; that of the external auditory meatus, mixed with the secretion of the neighboring sweat-glands or ceruminous glands, forms the well-known ear-wax or eemmen. The secretion iu this place con- tains a reddish pigment of a bitterish-sweet taste, the composition of which has not been investigated. Upon the skin of the newly-born the sebaceous ma- VoL. I.— ir 258 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. terial is accumulated to form the vernix caseosa. The well-known uropygal gland of birds is homologous with the mammalian sebaceous glands, and its secretion has been obtained in sufficient quantities for chemical analysis. Physiologically it is believed that the sebaceous secretion affords a protectioa to the skin and hairs. Its oily character doubtless serves to protect the hairs from becoming too brittle, or, on the other hand, from being too easily satu- rated with external moisture. In this way it probably aids in making the hairy coat a more perfect protection against the effect of external changes of temperature. Upon the surface of the skin also it forms a thin protective layer that tends to prevent undue loss of heat from evaporation, and possi- bly is important in other ways in maintaining the physiological integrity of the external surface. Sweat. — The sweat or perspiration is a secretion of the sweat-glands. These latter sti'uctures are found over the entire cutaneous surface except in the deeper portions of the external auditory meatus. They are particularly abundant upon the palms of the hands and the soles of the feet. Krause estimates that their total number for the whole cutaneous surface is about two millions. In man they are formed on the type of simple tubular glands ; the terminal portion contains the secretory cells, and at this part the tube is usually coiled to make a more or less compact knot, thus increasing the extent of the secreting surface. The larger ducts have a thin muscular coat of invol- untary tissue that may possibly be concerned in the ejection of the secretion. The secretory cells in the terminal portion are columnar in shape, they possess a granular cytoplasm and are arranged in a single layer. The amount of secretion formed by these glands varies greatly, being influenced by the con- dition of the atmosphere as regards temperature and moisture, as well as by various physical and psychical states, such as exercise and emotions. The average quantity for twenty-four hours is said to vary between 700 and 900 grams, although this amount may be doubled under certain conditions. According to an interesting paper by Schierbeck,^ the average quantity of sweat in twenty-four hours may amount to 2 to 3 liters in a person clothed, and therefore with an a^■erage temperature of 32° C. surrounding the skin. This author states that the amount of sweat given off from the skin in the form of insensible perspiration increases proportionately with the tempera- ture until a certain critical point is reached (about 33° C. in the person investigated), when there is a marked increase in the water eliminated, the increase being simultaneous with the formation of visible sAveat. At the same time there is a more marked and sudden increase in the COj eliminated from the skin, from 8 grams to 20 grams in twenty -four hours. It is possible that the sudden increase in COj is an indication of greater metabolism in the sweat- glands in connection with the formation of visible sweat. Composition of the Src-refioii. — The precise chemical composition of sweat is difficult to determine, owing to the fact that as usually obtained it is liable '^Archivfiir Anatomic und Pht/siologie (Physiol. Abtheil), 1893, S. 116. SECRETION. 259 to be mixed with the sebaceous secretion. Normally it is a very thin secre- tion of low specific gravity (1004) and an alkaline reaction, although when first secreted the reaction may be acid owing to admixture with the sebaceous material. The larger part of the inorganic salts consists of sodium chloride. Small quantities of the alkaline sulphates and phosphates are also present. The organic constituents, though present in mere traces, are quite varied in num- ber. Urea, uric acid, creatinin, aromatic oxy- acids, ethereal sulphates of phenol and skatol, and albumin, are said to occur when the sweating is pro- fuse. Argutiusky has shown that after the action of vapor-baths, and as the result of muscular work, the amount of urea eliminated in this secretion may be considerable (see p. 360). Under pathological conditions involving a diminished elimination of urea through the kidneys it 'has been observed that the amount found in the sweat is markedly increased, so that crystals of it may be deposited upon the skin. Under perfectly normal conditions, how- ever, it is obvious that the organic constituents are of minor importance. The main fact to be considered in the secretion of sweat is the formation of water. Secretory Fibres to the Siceat-glands. — Definite experimental proof of the existence of sweat-nerves was first obtained by Goltz^ in some experiments upon stimulation of the sciatic uerve in cats. In the cat and dog, in which sweat-glands occur on the balls of the feet, the jsresence of sweat-nerves may be demonstrated with great ease. Electrical stimulation of the peripheral end of the divided sciatic nerve, if sufficiently strong, will cause visible drops of sweat to form on the hairless skin of the balls of the feet. When the elec- trodes are kept at the same spot on the nerve and the stimulation is maintained the secretion soon ceases, but this effect seems to be due to a temporary injury of some kind to the nerve-fibres at the point of stimulation, and not to a genuine fatigue of the sweat-glands or the sweat-fibres, since moving the elec- trodes to a new point on the nerve farther toward the periphery calls forth a new secretion. The secretion so formed is thin and limpid, and has a marked alkaline reaction. The anatomical course of these fibi-es has been worked out in the cat with great care by Laiigle_y.^ He finds that for the hind feet they leave the spinal cord chiefly in the first and second lumbar nerves, enter the sympathetic chain, and emerge from this as non-medullated fibres in the gray rami proceeding from the sixth lumbar to the second sacral ganglion, but chiefly in the seventh lumbar and first sacral, and then join the nerves of the sciatic plexus. For the fore feet the fibres leave the spinal cord in the fourth to the tenth thoracic nerves, enter the sympathetic chain, pass upward to the first thoracic ganglion, whence they are continued as non-medullated fibres that pass out of this ganglion by the gray rami communicating with the nerves forming the brachial plexus. The action of the nerve-fibres upon the sweat-glands cannot be explained as an indirect effect — for instance, as a result of a variation in the blood-flow. Experiments have repeatedly shown that, iu the cat, stimulation of the sciatic still calls forth a secretion after the ' Archiv fur die gesammte Physwlogie, 1875, Bd. xi. S. 71. ^ Journal of Physiology, 1891, vol. xii. p. 347. 260 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. blood has been shut off from the leg by ligation of the aorta, or indeed aft«r the leg has been amputated for as long as twenty minutes. So in human beings it is known that profuse sweating may often accompany a pallid skin, as in terror or nausea, while on the other hand the flushed skin of fever is characterized by the absence of perspiration. There seems to be no doubt at all that the sweat-nerves are genuine secretory fibres, causing a secretion in consequence of a direct action on the cells of the sweat-glands. In accord- ance with this physiological fact histological wcjrk has demonstrated that special nerve-fibres are supplied to the glandular epithelium. According to Arnstein ^ the terminal fibres form a small branching varicose ending in con- tact with the epithelial cells. The sweat-gland may be made to secrete in many ways other than by direct artificial excitation of the sweat-fibres ; for example, by external heat, dyspnoea, muscular exercise, strong emotions, aud by the action of various drugs such as pilocarpin, muscarin, strychnin, nicotin, picrotoxin, and physostigmin. In all such cases the effect is supposed to result from an action on the sweat-fibres, either directly on their terminations, or indirectly upon their cells of origin in the central nervous system. In ordinary life the usual cause of profuse sweating is a high external temper- ature or muscular exercise. With regard to the former it is known that the high temperature does not excite the sweat-glands immediately, but through the intervention of the central nervous system. If the nerves going to a limb be cut, exposure of that limb to a high temperature does not cause a secretion, showing that the temperature change alone is not suflBcient to excite the gland or its terminal nerve-fibres. We must suppose, therefore, that the high temperature acts upon the sensory cutaneous nerves, possibly the heat-fibres, and reflexly stimulates the sweat-fibres. Although external temperature does not directly excite the glands, it should be stated that it affects their irritability either by direct action on the gland-cells or upon the terminal nerve-fibres. At a sufficiently low temperature the cat's paw does not secrete at all, and the irritability of the glands is increased by a rise of temperature up to about 45° C. Dyspnoea, muscular exercise, emotions, and many drugs affect the secretion, probably by action on the nerve-centres. Pilocarpin, on the contrary, is known to stimulate the endings of the nerve-fibres in the glands, while atropin has the opposite effect, completely paralyzing the secretory fibres. Sweat-centres in the Central Nervous Sysfem. — The fact that secretion of sweat may be occasioned by stimulation of afferent nerves or by direct action upon the central nervous system, as in the case of dyspnoea, implies the exist- ence of physiological centres controlling the secretory fibres. The precise loca- tion of the sweat-centre or centres has not, however, been satisfactorily deter- mined. Histologically and anatomically the arrangement of the sweat-fibres resembles that of the vaso-constrictor fibres, and, reasoning from analogy, one might suppose the existence of a general sweat-centre in the medulla compara- ble to the vaso-constrictor centre, but positive evidence of the existence of such ' Anaiomisclier Ameiyer, 1895, Bd. x. SECRETION. 261 an arrangement is lacking. It lias been shown than when the medulla is separated from the cord by a section in the cervical or thoracic region the action of dyspncea, or of various sudorific drugs supposed to act on the cen- tral nervous system, may still cause a secretion. On the evidence of results of this character it is assumed that there are spinal sweat-centres, but whether these are few in number or represent simply the various nuclei of origin of the fibres to different regions is not definitely known. It is possible that in addi- tion to these spinal centres there is a general regulating centre in the medulla. ^lAMjrAEY Glands. The mammary glands are undoubtedly epidermal structures comparable in development to the sweat- or the sebaceous glands. Whether they are to be homologized with the sweat- or with the sebaceous glands is not clearly deter- mined. In most animals they are compound alveolar glands, and their acinous structure and the rich albuminous and fatty constituents of their secretion would seem to suggest a relationship to the sebaceous glands. But the histo- logical structure of the alveolus with its single layer of epithelium points rather to a connection with the sweat-glands. "\Miatever may have been their exact origin in the priinitive mammalia, there seems to be no question that they were derived in the first place from some of the ordinary skin-glands which at first simply opened, without a distinct mamma or nipple, on a defi- nite area of the skin, as is seen now in the case of the monotremes. Later in the phylogenetic history of the gland the separate ducts united to form one or more larger ones, and these opened to the exterior upon the protrusion of the skin known as the nipple. The number and position of the glands vary much in the different mammalia. In man they are found in the thoracic region and are normally two in number. The milk-ducts do not unite to form a single canal, but form a group of fifteen to twenty separate systems, each of which opens separately upon the surface of the nipple. Before preg- nancy the secreting alveoli are incompletely formed, but during pregnancy and at the time lactation begins the formation of the alveoli is greatly acceler- ated by proliferation of the epithelial cells. Composition of the Secretion. — The general appearance and composi- tion of the milk are well known. Microscopically milk consists of a liquid portion, or plasma, in which float an innumerable multitude of fine fat-drop- lets. The latter elements contain the milk-fat, which consists chiefly of neutral fats, stearin, palmitin, and olein, but contains also a small amount of the fats of butyric and caproic acid as well as slight traces of other fatty acid com- pounds and small amounts of lecithin, cholesterin, and a yellow pigment. Upon standing, a portion of these elements rises to the surface to form the cream. The milk-plasma holds in solution important proteid and carbohydrate compounds as well as the necessary inorganic salts. The proteids are casein, belonging to the group of nucleo-albumins ; lactalbumin, which closely resembles the serum- albumin of blood, and lacto-globulin, which is similar to the paraglobulin of blood : the two latter proteids occur in much smaller quantities than the casein. 262 .-l.T AMERICAN TEXT-BOOK OF PHYSIOLOGY. The chief carbohydrate in milk is the milk-sugar or lactose. Hammarsten ^ has succeeded in isolating from the mammary gland a nucleo-proteid contain- ing a reducing group. He designates this substance as nucleo-glyco-proteid. It seems possible that a compound of this character might serve as the parent substance for both the casein and the lactose of the secretion. The mineral constituents are varied and, considered quantitatively, show an interesting rela- tionship to the mineral composition of the body of the suckling (see p. 357). The fact that the inorganic salts of the milk vary so widely in quantitative composition from those of the blood has been used to show that they are not derived from the blood by the simple mechanical processes of filtration and diffusion, but are secreted by the epithelial cells of the glands. Traces of nitrogeneous excreta, such as urea, creatin, and ereatinin, are also found in the milk-plasma, together with some lecithin and cholesterin and a small amount of citric acid occurring as citrate of calcium. Histological Changes during Secretion. — The simple fact that sub- stances are found in the milk which do not occur in the blood or lymph is sufficient proof that the epithelial cells are actively concerned in the process of secretion. Histological examination of the gland during lactation confirms fully this a priori deduction, and enables us to understand the probable origin of some of the important constituents.^ In the resting gland during the period of gestation, or in certain alveoli during lactation, the alveoli are lined by a single layer of flattened or cuboidal cells, which have only a single nucleus, present a granular appearance, and have few or no fat-globules in them (Fig. 66). "When such alveoli enter into the active formation of milk the epithelial cells increase in height, projecting in toward the lumen, the nuclei divide, and as a Fig. 66.— Section through the middle of two alyeoli of the mammary gland of the dog ; con- dition of rest (after Heidenhain). A B Fig. 67.— Mammary gland of dog, showing the formation of the secretion : A, medium condition of growth of the epithelial cells ; B, a later condition (after Heidenhain). rule (Steinhaus*) each cell contains two nuclei (Fig. 67). Fat-droplets de- velop in the cytoplasm, especially in the free end of the cell, and according to ' Zeitschrift fur phy/fiologische Chemie, 1894, Bd. xix. S. 19. ^ See Heidenhain : Hermann's Handbuch da- Physdologie, 1883, Bd. v. 8. 381. ■'' Du Bois-Reymond's Archiv fur Physiolngie, 1892, Suppl. Bd., S. 54. SECRETION. 263 • Steiahaus the nucleus nearest the lumen undergoes a fatty metamorphosis. According to the same author the granular material in the cytoplasm also undergoes a visible change; the granules, which in the resting cell are spherical, elongate during the stage of activity to threads that take on a spirochseta-like form. The acme of this phase of development is reached by the solution or disintegration of a portion of the end of the cell, the frag- ments being discharged into the lumen of the alveolus. The debris of this disintegrated portion of the cell helps to form the secretion ; part of it goes into solution to form, probably, the albuminous and carbohydrate constituents, while the fat-droplets are set free to form the milk-fat. Apparently the basal portion of the cell regenerates its cytoplasm and thus continues to form new material for the secretion. In some cases, however, the whole cell seems to undergo dissolution, and its place is taken by a new cell formed by karyo- kinetic division of one of the neighboring epithelial cells. The origin of the peculiar colostrum corpuscles found in the milk during the first few days of its secretion has been explained differently by different observers. Heid- enhaiu traces them to certain epithelial cells of the alveoli which at this time become rounded, develop numerous fat-droplets, and are finally dis- charged bodily into the lumen, although he was not able to actually trace the intermediate steps in the process. Steinhaus, on the contrary, thinks that these corpuscles are derived from the wandering cells of the connective tissue (llastzellen) which at the beginning of lactation are very numerous, but seem to undergo fatty degeneration and elimination in the secretion of the newly active gland. Control of the Secretion by the Nervous System. — There are indica- tions that the secretion of the mammary glands is under the control, to some extent at least, of the central nervous system. For instance, iu women during the period of lactation cases have been recorded iu which the secretion was altered or perhaps entirely suppressed by strong emotions, by an epileptic attack, etc. This indication has not received satisfactory confirmation from the side of experimental physiology. Eckhard ' found that section of the main nerve- trunk supplying the gland in goats, the external spermatic, caused no dif- ference in the quantity or quality of the secretion. Rohrig^ obtained more positive results, inasmuch as he found that some of the branches of the exter- nal spermatic supplj' vaso-motor fibres to the blood-vessels of the gland and influence the secretion of milk by controlling the local blood-flow in the gland. Section of the inferior branch of this nerve, for example, gave in- creased secretion, while stimulation caused diminished secretion, as in the ease of the vaso-constrictor fibres to the kidney. These results have not been confirmed by others — in fact, they have been subjected to adverse criticism — and they cannot, therefore, be accepted unhesitatingly. Mironow ' reports a number of interesting experiments made upon goats. ' See Heidenhain : Hermann's Handbuch der Physiologic, Bd. v. Thl. 1. S. 392. ^ Virchov/s Archiv fur pathologische Anatomic, etc., 1876, Bd. 67, S. 119. ' Archives des Sciences biologiques, St. Petersburg, 1894, t. iii. p. 353. 264 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. * He found that artificial stiniulatiou of sensory nerves causes a diminution in the amount of secretion, thus confirming the opinion based upon observations upon the human being, that in some way the central nervous system exerts an influence on the mammary gland. When the mammary glands are com- pletely isolated from their connections with the central nervous system, stimu- lation of an afferent nerve no longer influences the secretion. Mironow states also that although section of the external spermatic on one side does not influence the secretion, section of this nerve on both sides is followed by a marked diminution, and the same result is obtained when the gland on one side is completely isolated from all nervous connections. The diminution of the secretion in these cases comes on very slowly, after a number of days, so that the effect canuot be attributed to the removal of definite secretory fibres. Moreover, after apparently complete separation of the gland from all its extrinsic nerves, not only does the secretion, if it was previously present, con- tinue to form although in less quantities, but in operations of this kind upon pregnant animals the glands increase in size during pregnancy and become functional after the act of parturition. Experiments, therefore, as far as they have been carried, indicate that the gland is under the regulating control of the central nervous system, either through secretory or vaso-motor fibres, but that it is essentially an automatic organ. The bond of connection between it and the uterus seems to be, in part if not entirely, through the blood rather than through the nervous system. It should be added that Arnstein ^ has described a definite connection between the nerve-fibres and the epithelial ceils of the gland. If this fact is corrobo- rated it would amount to an histological proof of the existence of special secretory fibres, but the physiological evidence for the same fact is either negative or unsatisfactory. Normal Secretion of the Milk. — As was said in speaking of the his- tology of the gland, the secreting alveoli are not fully formed until the first pregnancy. During the period of gestation the epithelial cells multiply, the alveoli are formed, and after parturition secretion begins. At first the secre- tion is not true milk, but a liquid difffering in composition and known as the colostrum ; this secretion is characterized microscopically by the existence of the colostrum corpuscles, which seem to be wandering cells that have under- gone a complete fatty degeneration. After a few days the true milk is formed in the manner already described. According to Eohrig the secretion is con- tinuous, but this statement needs confirmation. As the liquid is formed it accumulates in the enlarged galactophorous duets, and after the tension has reached a certain point further secretion is apparently inhibited. If the ducts are emptied, by the infant or otherwise, a new secretion begins. The emptying of the ducts, in fact, seems to constitute the normal physiological stimulus to the gland-cells, but how this act aifects the secreting cells, whether reflexly or directly, is not known. When the child is weaned the secretion under normal conditions soon ceases and the alveoli undergo retrograde changes, although ^ Anatomischer Anzeiger, 1895, Bd. j^. S. 410. 8.ECBETI0N. 265 they do not return completely to the condition they were iu before the first pregnancy. Internal Secretions. According to the definition proposed on p. 211, the term internal secretion is here used to mean a specific substance or substances formed within a gland- ular organ and given off to the blood or lymph. As was said before, it is difficult to make a distinction between these internal secretions and the waste products of metabolism generally so far as method and place of formation and elimination are concerned. Every active tissue gives off waste products that are borne off in the lymph and blood, but as generally employed the term internal secretion is not meant to include all such products, but only the materials produced in distinctly glandular organs wliich are more or less specific to those organs, and which are supposed to have a general value to the body as a whole. The idea of an internal secretion seems to have been suggested by Bernard, but was first seriously forced upon the attention of physiologists by Brown-Sequard in the course of some work upon extracts ■of the testis. AYithin the last few years the term has been frequently used, especially in connection with the valuable and interesting work done upon the pancreas and the so-called blood-vascular or ductless glands, the thyroids, adrenals, pituitary body, and spleen. In almost all cases our knowledge of the nature and importance of these internal secretions is in a formative stage ; the literature, however, of the subject is already very great, and is increasing rapidly, while speculations are numerous, so that constant contact with current literature is necessary to keep pace with the advance in knowledge. Liver. — It has not been customary to speak of the liver as furnishing an internal secretion, but two of the products formed within this organ are so clearly known and their method of production is so typical of what is sup- posed to be the mechanism of internal secretion, that it is desirable both for the sake of convenience and consistency to include them under this general heading. Glycogen (CgH,|,05)n is formed within the liver-cells from the sugars and proteids brought to them in the blood of the portal vein, and in many cases the presence of this glycogen can be demonstrated microscopically within the cells. From time to time, however, the glycogen within the cell is converted into dextrose by a process of hydration, and the sugar so formed is by a secretory process of some kind given off to the blood to serve for the metabolism of the other tissues of the body, es- pecially the muscles. This elimination of its stored glycogen on the part of the liver may be regarded as a case of internal secretion. (For further details concerning glycogen, its properties and functions, see p. 326 and the section on Chemistry.) A second substance which is formed under the influence of the liver-cells and is then eliminated into the blood is urea. Urea constitutes the chief nitrogenous end-product of the metabolism of the proteid tissues; it 266 AS AMERICAN TEXT-BOOK OF PHYSIOLOGY. is eliminated from the bocl\' by the kidneys, but it is known not to be formed in these organs. Modern investigations have seemed to show conclusively that this substance is formed mainly within the liver from some ante- cedent body (ammonia compound) which arises in the proteid tissues generally, but is not prepared for final elimination until in the liver or else- where it is converted into urea. Here again the liver-cells perform a metab- olism for the good of the organism as a whole, and the act of passing out the urea into the blood may be regarded as an internal secretion. It is quite possible that in still other ways the liver-cells add to the blood elements of importance to the tissues of the body — as, for example, in the conservation and distribution of the iron of broken-down htemoglobin (see p. 323), or in the syn- thetic combination of the products of putrefaction formed in the intestines (indoU skatol, phenol, etc.) with sulphuric acid (see p. 340) ; but concerning these mat- ters our knowledge is not yet sufficiently definite to make positive statements. Pancreas. — The importance of the external secretion, the pancreatic juice,, of the pancreas has long been recognized, but it was not until 1889 that von Mehring' and Minkowski proved that it furnishes also an equally important internal secretion. These observers succeeded in extirpating the entire pan- creas without causing the immediate death of the animal, and found tliat in all cases this operation was followed by the appearance of sugar in the urine in considerable quantities. Further observations of their own and other experi- menters ^ have corroborated this result and added a number of interesting facts to our knowledge of this side of the activity of the pancreas. It has been shown that when the pancreas is completely removed a condition of glycosuria inevitably follows, even if carbohydrate food is excluded from the diet. More- over, as in the similar pathological condition of glycosuria or diabetes mellitus in man, there is an increase in the quantity of urine (polyuria) and of urea,, and an abnormal thirst and hunger. Acetone also is present in the urine. These symptoms in cases of complete extirpation of the pancreas are followed by emaciation and muscular weakness, which finally end in death in two to four weeks. If the pancreas is incompletely removed, the glycosuria may be serious, or slight and transient, or absent altogether, depending upon the amount of pancreatic tissue left. According to the experiments of von Mehring and Minkowski on dogs, a residue of one-fourth to one-fifth of the gland is STifficient to prevent the appearance of sugar in the urine, although a smaller fragment may suffice apparently if its physiological condition is favorable. The portion of pancreas left in the liody may suffice to prevent glycosuria, partly or completely, even though its connection with the duo- denum is entirely interrupted, thus indicating that the suppression of the pancreatic juice is not responsible for the glycosuria. The same fact is shown more conclusively by the following experiments : Glycosuria after complete removal of the pancreas from its normal connections may be prevented par- ' Archil' fiir exper. Pathologie und Pharmakologie, 1S90, Bd. xxvi. S. 371. See also Minkow- ski, Ibid., 1893, Bd. xxxi. S. 85, for a more complete account. ^ See H^don : Diabite pancreatiyue, Travaux de Physiologie Universiii de Montpellier, 1898. SECRETION. 267 tially or completely by grafting a portion of the pancreas elsewhere in the abdominal cavity or even nnder the skin. The dncts of the gland may be completely occluded by ligature or by injection of paraffin without causing a condition of permanent glycosuria. The condition of glycosuria produced by removal of the pancreas is desig- nated frequently as pancreatic diabetes and oflFers many analogies to the similar pathological condition in man known as diabetes mellitus. The cause of the glycosuria is obscure. It has been shown that in severe cases sugar appears in the urine even when the animal is deprived of food, although the quantity is increased by feeding and especially by carbohydrate food. Examination of the blood shows that the percentage of sugar in it is increased above the normal, from 0.15 per cent, to 0.3 or 0.5 per cent. In the liver, on the con- trary, the supply of glycogen disappears. Carbohydrate foods when fed cause no deposition of glycogen in the liver, and apparently escape consumption in the body, being eliminated in the urine. It is said, however, that one form of sugar, levulose, offers an exception to this general rule, since it causes a formation of liver glycogen and seemingly is consumed in the body. AVe may believe from these experiments that the pancreas produces a substance of some kind that is given off to the blood or lymph, and is either necessary for the normal consumption of sugar in the body, or else, as is held bv some/ normally restrains the output of sugar from the liver and other sugar-producing tissues of the body, ^\'llat this material is and how it acts has not yet been determined satisfactorily. The most plausible theory suggested is that the internal secretion produced contains a special enzyme, glycolytic enzvme (Lupine), whose presence in the blood is necessary for the consumption of the sugar. Such an enzyme may be obtained from blood (p. 354), but it is not proved whether it is a normal constituent or M'hether it is produced after the blood is shed by the disintegration of some of its cor- puscular elements. This theory therefore cannot be considered as more than a possibility. It is interesting and suggestive to state in this connection that post-mortem examination in cases of diabetes mellitus in the human being has shown that this disease is associated in some instances with obvious alterations in the structure of the pancreas. The Thyroid Body. — The thyroids are glandular structures found in all the vertebrates. In the mammalia they lie on either side of the trachea at its junction with the larynx. In man they are united across the front of the trachea by a narrow band or isthmus, and hence are sometimes spoken of as one structure, the thyroid body. In some of the lower mammals (e. g. dog) the isthmus is often absent. The thyroids in man are small bodies measuring about 50 millimeters in length by 30 millimeters in width ; they have a distinct glandular structure but possess no ducts. Histological examination shows that they are composed of a number of closed vesicles vary- ing in size. Each vesicle is lined by a single layer of cuboidal epithelium, while its interior is filled by a homogeneous glairy liquid, the colloid substance ' See Kaufrnann: Archives de Physiologie normnle et pathologique, 1895, p. 210. 268 AiY AMERICAN TEXT-BOOK OF PHYSIOLOGY. which is fouud also in the tissue between the vesicles lying in the lympli- spaces. This colloid substance is regarded as a secretion from the epithelial cells of the vesicles, and Biondi/ Langendorff/ and Hiirthle^ claim to have followed the development of the secretion in the epithelial cells by micro- chemical reactions. While the interpretation of the microscopical appearances given by these authors is not the same, they agree in believing that the colloid material is formed within some or all of the epithelial cells, and is eliminated into the lumen with or without a disintegration of the cell-substance. More- over, Langendorif and Bioudi believe that the colloid material is finally dis- charged into the lymphatics by the rupture of the vesicles. The composition of the colloid is incompletely known. Parathi/rnifly. — The parathyroids are small bodies, two on each side, lying lateral or posterior to the thyroids. One of them may be enclosed within the substance of the thyroid, and is then known as the internal parathyroid, the other being the external parathyroid. They are quite unlike the thyroids in structure, consisting of solid masses or columns of epithelial-like cells which are not arranged to form acinous vesicles. According to Schaper,* these bodies are not always paired, but may have a multiple origin extending along the common carotid in the neighborhood of the thyroids. Accessory Thyroids. — In addition to the parathyroids, a variable number of accessory thyroids have been described by different observers, occurring in the neck or even as far down as the heart. These bodies possess the structure of the thyroid, and presumably have the same function. After removal of the thyroids they may suffice to prevent a fatal result. Functions of the Thyroids and Parathyroids.-^Y ery great interest has been excited within recent years with regard to the functions of the thyroids. In 1856 8chifF showed that in dogs complete extir])ation of the two thyroids is followed by the death of the animal ; and within the last few years similar results have been obtained by numerous observers. Death is preceded by a number of characteristic symptoms, such as muscular tremors, which may pass into spasms and convulsions, cachexia, emaciation, and a more or le.ss marked condition of apathy. The muscular phenomena seem to proceed from the central nervous system, since section of the motor nerves protects the muscles from the irritation. The metabolic changes may also be due primarily to an alteration in the condition of the cord and brain. Similar results have been obtained in cats. Among the herbivorous animals it was at first stated that removal of the thyroids does not cause death ; but so far as the rabbit is concerned Gley ^ has shown that if care be taken to remove the parathyroids also, death is as certain and rapid as in the case of the carnivora ; a similar result has been obtained upon rats by Cliris- tiani. Cases have been reported in which dogs recovered after complete 1 Berliner klinhche Wochensehrift, 1888. ' ArchivfUr Pfiysiologie, 1889, Suppl. Bd. ' Pjiiiger's Archivfur die gesammte Physioloffie,.189'i, Bd. Ivi. S. 1. * Archiv fiir mikrostcopische Anatomic, 1895, Bd. xlvi. S. 500. ' Archives de Physiologie noi-male et palhologique, 1892, p. 135. SECRETION. 269 thyroidectomy, but these cases are rare and may be explained probably by the presence of accessory thyroids which remain after the operation. It has been observed, too, that the operation is more rapidly and certainly fatal in young animals than in old ones. In the monkey as well as in man the evil results following the removal of the glands develop more slowly than in the lower animals, and give rise to a series of symptoms resembling those of myxcfidema in man. Among these symptoms may be mentioned a pronounced anaemia, diminution of muscular strength, failure of the mental powers, abnor- mal dryness of the skin, loss of hairs, and a peculiar swelling of the subcu- taneous connective tissue. Physiologists have shown that in the case of dogs the fatal results following thyroidectomy may be mitigated or entirely obviated by grafting a portion of the gland under the skin or in the peritoneal cavity. If the piece grafted is sufficiently large, the animal recovers apparently com- pletely from the operaticm. Sn also in removing the thyroids, if a small portion of the gland, or the parathyroids, be left undisturbed the fatal s}mp- toms do not develop. In human beings suffering from myxcEdema as the result of loss of function of the tliyroids it has l)een abundantly shown that injection of thyroid extracts, or feeding the fresh gland, restores the indi- vidual to an approximately normal condition. In the earlier experiments on thyroidectomy no distinction was made between the effects of removal of the thyroids and parathyroids, although, as said above, it was noticed that in some animals a fatal result failed to follow the operation unless care was taken to extirpate the parathyroids as ■well as the thyroids. It was supposed by some that the parathyroids represented an immature or embryonic form of thyroid tissue, and that after the removal of the thyroids the parathyroids took on their function and assumed a thyroid structure. Histological evi- dence seemed to favor this view, but the latest physiological experiments, on the contrary, have indicated that the parathyroids are not to be regarded as immature structures, but as bodies possessing a definite functional value, dis- tinct from, but not less important than, that of the thyroids themselves. Moussou,' whose work has been confirmed in part by others,^ makes the fol- lowing distinction in regard to the effect of extirpation of these bodies. Removal of the thyroids and accessory thyroids is followed by a slowly developing general trophic disturbance, a progressive cachexia that produces a condition resembling myxredema. In young animals the effect is more marked and causes a condition of cretinism. The animals, therefore, may survive complete thyroidectomy, for long periods at least. Removal of all the parathyroids, on the contrary, is followed l)y acute disturbances and rapid death, the symptoms being the same as those formei'ly described as resulting from complete thvroidectomy. It would seem from these results that both the thyroids and the parathyroids play an important part in the general metabolism of the body. ' Proceedings of Fourth International Physiological Cniigrcsx, Cambridge, 1898. ' Gley : Archiv fiir 'die gesammie Physiologic, 1897, Bd. Ixvi. S. 308. 270 A^" AMERICAN TEXT-BOOK OF PHYSIOLOGY. Two views prevail as to the general nature of their function.' According to some, the office of these bodies is to remove some toxic substance or sub- stances which normally accumulate in the blood as the result of the body- metabolism. If the thyroids or parathyroids are extirpated, the corresjDond- ing substance then increases in quantity and produces the observed symptoms by a process of auto-intoxication. In support of this view there are numerous observations to show that the blood, or urine, or muscle-juice of thyroid- ectomized animals has a toxic effect upon sound animals. These latter results, however, do not appear to be marked or invariable, and in the hands of some experimenters have failed altogether. The second view is that the thyroids and parathyroids secrete each a material, a true internal secretion, which after getting into the blood plays an imjDortant and indeed essential part in the metabolic changes of some or all of the organs of the body, but especially the central nervous system. In support of this view A\-e have such facts as these : Injections of properly prepared thyroid extracts have a beneficial and not an injurious influence ; there is microscopic evidence to show that the epithelial cells participate actively in the formation of the colloid secretion, and that this secretion eventually reaches the blood by way of the lymph-vessels; the beneficial material in the tliyroid extracts may be obtained from the gland by methods which prove that it is a distinct and stable substance formed in the gland, as we might suppose would be the case if it formed part of a definite secretion. This latter fact, indeed, amounts to a proof that the important function of the thyroids is connected with a material secreted within its substance ; but it may still be questioned, per- haps, whether this material acts by antagonizing toxic substances produced elsewhere in the body or by directly influencing the body metabolism. For a more specific tlieory of the functional vahie of the thyroids proposed by Cyon ^ reference must be made to original sources. Much work has been done to isolate the beneficial material of the tliyroid, particularly in relation to the therapeutic use of the gland in myxoedcma and goitre. The mere fact that feeding the gland acts as "well as injecting its extracts shows the resistant nature of the substance, since it is evidently not injured by the digestive secretions. It has been shown also by Baumann ^ that the gland material may be boiled for a long period with 10 per cent, sulphuric acid without destroying the beneficial substance. This observer has succeeded in isolating from the gland a substance to which the name iodothyrin is given, wliich is characterized by containing a relatively large percentage (9.3 per cent, of the dry weight) of iodine, and which preserves in large measure the beneficial influence of thyroid extracts in cases of myxoedema and parenchymatous goitre. In the parathyroid tissue the same material is contained in relatively larger quantities. This notable discovery shows that thyroid tissue has the ' See Schaefer: "Address on Physiology," annual meeting of the British Medical Associa- tion, London, July-Augu.st, 1895. '^ Archives de Physiologie, 1898, p. 618. " Zeitschrift fiir physiologische Chemie, 189B, Bd. xxi. S. 319. SECRETION. 271 power of forming a specific organic compound of iodine, and it is possible that its iniiuence upon body-metabolism may be connected with this fact. Baumann and Roos ' state that the iodothjrin is contained within the gland mainly in a state of combination with proteid bodies, from which it may be separated by digestion with gastric juice or by boiling with acids. Most of the substance is combined with an albuminous proteid, while a smaller part is united with a globulin-like proteid. There can be little doubt that the authors have succeeded in isolating at least (nie of the really effective substances of thyroid extracts. If the distinction made between the functions of the thyroids and jxirathyroids proves to be correct, and if each of these glands exercises its functions by means of an internal secretion, we may hope that future work will be able to isolate the distinctive substance or sub- stances characteristic of each gland. Adrenal Bodies. — The adrenal bodies — or, as they are frequently called in human anatomy, the suprarenal capsules — belong to the group of ductless glands. Their histology as well as their physiology is incompletely known. It was shown first by Brown-S^quard (1856) that removal of these bodies is followed rapidly by death. This result has been confirmed by many experi- menters, and so far as the observations go the effect of complete removal is the same in all animals. The fatal effect is more rapid than in the case of removal of the thyroids, death following the operation usually in two to three ■days, or, according to some accounts, within a few hours. The sj^mptoms preceding death are great prostration, muscular weakness, and marked dimi- nution in vascular tone. These symptoms are said to resemble those occurring in Addison's disease in man, a disease which clinical evidence has shown to be associated with pathological lesions in the suprarenal capsules. It has been expected, therefore, that the results obtained for thyroid treatment of myx- oedema might be repeated in cases of Addison's disease by the use of adrenal extracts. These expectations seem to have been realized in part, but complete and satisfactory reports are yet lacking. The physiology of the adi'enals has usually been explained upon the auto-intoxication theory. Thedeath thatcohies after their removal has been accounted for upon the supposition that during life they remove or destroy a toxic substance produced elsewhere in the body, possibly in the muscular system. Oliver ^ and Schaefer, and, about the same time, Cybulski and Szyinonowicz,' have given reasons for believing that this organ forms a peculiar substance that has a very definite physiological action especially upon the circulatory system. They find that aqueous extracts of the medulla of the gland when injected into the blood of a living animal have a remarkable influence upon the heart and blood-vessels. If the vagi are intact, the adrenal extracts cause a very marked slowing of the heart-beat together with a rise of blood-pressure. "When the inhibiting fibres of the vagus are thrown out of action by section or by the use of atropin the heart- ' Zeitschrift fur physiologische Chemie, 1896, Bd. xxi. S. 481. ^Journal of Physiology, 1895, vol. xviii. p. 230. ^ ArchivfUr die gesammte Physiologie, 1896, Bd. Ixiv. >S. 97. 272 AN AMERICAN TEXT- BOOK OF PHYSIOLOGY. rate is accelerated, while the blood-pressure is increased sometimes to an extraordinary extent. These facts are obtained with very small doses of the extracts. Schaefer .states that as little as 5^ milligrams of the dried gland may produce a maximal effect upon a dog weighing 10 kilograms. The effects produced by such extracts are quite temporary in character. In the course of a few minutes the blood-pressure returns to normal, as also the heart-beat, sho-^ving that the substance has been destroyed in some way in the body, although where or how this destruction occurs is not known. Accord- ing to Schaefer, the kidneys and the adrenals themselves are not responsible for this prompt elimination or destruction of the injurious substance. The constriction of the blood-vessels seems to be due to a direct effect on the muscles in the walls of the vessels, in part at least, since it is present after de- struction of the vaso-motor centre and most or, indeed, all of the spinal cord. Several observers ' have shown satisfactorily that the material producing this effect is pi-esent in perceptible quantities in the blood of the adrenal vein, si> that there can be but little doubt that it is a distinct internal secretion of the adrenal. Dreyer has shown, moreover, that the amount of this substance in the adrenal blood is increased, judging from the physiological effects of its injection, by stimulation of the splanchnic nerve. Since this result was obtained independently of the amount of blood-flow through the gland, I)rever makes the justifiable assumption that the adrenals possess secretory nerve fibres. Abel ^ has succeeded in isolating the substance that produces the effect on blood-pressure and heart-rate, and proposes for it the name epinephrin. He assigns to it the formula C,;H,5NO^, and describes it as a peculiar unstable basic body. Salts of epinephrin were obtained which when injected into the circulation caused the typical effects produced by injection of extracts of the gland. It is possible that the substance in question may be continually secreted under normal conditions by the adrenal bodies and play a very important part with reference to the functional activity of the muscular tissues. Pituitary Body. — ^This body is usually described as consisting of two parts, a large anterior lobe of distinct glandular structure, and a much smaller posterior lobe, whose structure is not clearly known, although it contains nerve-cells and also apparently some glandular cells. Embryologically the two lobes are entirely distinct. The anterior lobe, which it is preferable to call the hypophysis cerebri, arises from the epithelium of the mouth, while the posterior lobe, or the infundibular body, develops as an outgrowth from the infundibulum of the brain, and in the adult remains connected with this portion of the brain by a long stalk. Howell^ and others have shown that extracts of the hypophysis when injected intravenously have little or no physiological effect, while extracts of the infundibular body, on the contrary, ^American Journal of Physiology, 1899, vol. ii. p. 203. ' Zeitschrift fiir physiotogische Chemie, 1899, Bd. xxviii. S. 318. ' Journal of Experimental Medicine, 1898, vol. iii. p. 24.5 ; also Schaefer and Vincent : Journal of Physiology, 1899, vol. xxv. p. 87. 8ECRETI0N. 273 cause a marked rise of blood-pressure and slowing of the heart-beat. These effects resemble in general those obtained from adrenal extracts, but differ in some details. They seem to warrant the conclusion that the infundibular body is not a mere rudimentary organ, as has been generally assumed, but produces a peculiar substance, an internal secretion, that may have a distinct physiological value. A number of observers, especially \"assale and Sacchi, have succeeded in removing the entire pituitary body. They report that the operation results eventually in the death of the animal with a certain group of symptoms, such as muscular tremors and spasms, apathy and dyspncea, that resemble the results of thyroidectomy. It has been suggested therefore that the pituitary body may be related in function to the thjroids and may be able to assume vicariously the functions of the latter after thyroidectomy. There is no satisflictory evidence, however, in support of tiiis view. On the pathological side it has been shown that usually lesions of the pituitary body, particularly of the hypophysis, are associated with a peculiar disease known as acromegaly, the most prominent symptom of which is a marked hyper- trophy of the bones of the extremities and of the face. The conclusion some- times drawn from this fact that acromegaly is caused by a disturbance of the functions of the pituitary body is, however, very uncertain, and is not sup- ported by any definite clinical or experimental facts. Testis and Ovary. — Some of the earliest work upon the effect of the internal secretions of the glands was done upon the reproductive glands, especially the testis, by Brown-Se(juard.' According to this observer, extracts of the fresh testis "when injected under the skin or into the blood may have a remarkable influence upon the nervous system. The general mental and physical vigor, and especially the activity of the spinal centres, are greatly improved, not only in cases of general prostration and neurasthenia, but also in the case of the aged. Brown-Sequard maintained that this general dynamo- genie effect is due to some unknown substance formed in the testis and sub- sequently passed into the blood, although he admitted that some of the same substance may be found in the external secretion of the testis — i. e., the spermatic liquid. More recently Poehl ^ asserts that he has prepared a sub- stance, spermin, to which he gives the formula CJl^^^, which has a very beneficial effect upon the metabolism of the body. He believes that this spermin is the substance that gives to the testicular extracts prepared by Brown-Sequard their stimulating effect. He claims for this substance an extraordinary action as a physiological tonic. The precise scientific value of the results of experiments with the testicular extracts cannot be estimated at present, in spite of the large literature upon the subject ; wc must wait for more detailed and exact experiments, which doubtless will soon be made. Zoth ^ and also Pregel * seem to have obtained exact objective proof, by means ^Archives de Physiologic normale et pathologigue, 1889-92. ' Zeitschrifi fur klinische Medidn, 1894, Bd. xxvi. S. 133. 'Pfiiiger's Arckiv filr die gesammte Physiologic, 1896, Bd. Ixii. S. 335; also 1897, Bd. Ixix. S. 386. * Ibid., S.37Q. Vol. I.— 18 274 AN A3IEBICAX TEXT-BOOK OF PHYSIOLOGY. of et-gographic records, of the stimulating action of the testicular extracts upon the neuro-muscular apparatus in man. They find that injections of the testicular extracts cause not only a diminution in the muscular and nervous fatigue resulting from muscular work, but also lessen the subjective fatigue sensations. The fact that the internal secretion of the testis, if it exists at all, is not absolutely essential to the life of the body as a whole, as in the ease of the thyroids, adrenals, and pancreas, naturally makes the satisfactory determination of its existence and action a more difficult task. Similar ideas in general prevail as to the possibility of the ovaries furnish- ing an internal secretion that plays an important part in general nutrition. In gynecological practice it has been observed that complete ovariotomy witli its resulting premature menopause is often followed by distressing symptoms, mental and physical. In such cases many observers have reported that tliese symptoms may be alleviated by the use of ovarian extracts. So alsci in the natural, as well as in the premature menopause following opera- tions, it is a frequent, though not invariable, result for the individual to gain noticeably in weight. The probability of an eifect of the ovaries on general nutrition is indicated also by the interesting fact that in cases of osteomalacia, a disease characterized by softening of the bones, removal of the ovaries may exert a very favorable influence upon the course of the disease. These indi- cations have found some experimental verification recently in a research by Loewy and Richter' made upon dogs. These observers found that complete removal of the ovaries, although at first apparently without effect, resulted in the course of two to three months in a marked diminution in the consump- tion of oxygen by the animal, measured per kilo, of body-weight. If now the animal in this condition was given ovarian extracts (oophorin tablets) the amount of oxygen consumed was not only brought to its former normal, but considerably increased beyond it. A similar result was obtained when the extracts were used upon castrated males. The authors believe that their experiments show that the ovaries form a specific substance which is capable of increasing the oxidation of tlie body. ■ Kidney. — Tiegerstedt and Bergman^ state that a substance may be extracted from the kidneys of rabbits which when injected into the body of a living animal causes a rise of blood-pressure. They get the same effect from the blood of the renal vein. They conclude, therefore, that a substance, for wliich they suggest the name "rennin," is normally secreted l>y the kidney into the renal blood, and that tliis substance causes a vaso-constriction. KArchivfUr Physiologic, 1899, Suppl. Bd. S. 174. ' Skandinavisches Archiv fiir Physiologie, 1898, Bd. viii. S. 223 ; see also Bradford : Proceedings of the Royal Society, 1892. y. CHEMISTRY OF DIGESTIOI^ AND I^UTRITIOK A. Definition and Composition of Foods ; Nature of Enzymes. Speaking broadly, what we eat and drink for the purpose of nourish- ing the body constitutes our food. A person in adult life who has reached his maximum growth, and whose weight remains practically constant from year to year, must eat and digest a certain average quantity of food daily to keep himself in a condition of health and to prevent loss of weight. In such a case we may say that the food is utilized to repair the wastes of the body — that is, the destruction of body-material which goes on at all times, even during sleep, but which is increased by the physical and psychical activities of the waking hours — and in addition it serves as the source of heat, mechanical work, and other forms of energy liberated in the body. In a person who is growing — one who is, as we say, laying on flesh or increasing in stature — a certain portion of the food is used to furnish the energy and to cover the wastes of the body, while a part is converted into the new tissues formed during growth. The material that we eat or drink as food is for the most part in an insoluble form, or has a composition differing very widely from that of the tissues which it is intended to form or to rejiair. The object of the processes of digestion carried on in the alimentary tract is to change this food so that it may be absorbed into the blood, and at the same time so to alter its com- position that it can be utilized by the tissues of the body. For we shall iind, later on, that certain foods — eggs, for example — which are very nutritious when taken into the alimentary canal and digested cannot be used at all by the tissues if injected at once, unchanged, into the blood. The food of man- kind is most varied in character. At different times of the year and in different parts of the world the diet is changed to suit the necessities of the environment. When, however, we come to analyze the various animal and vegetable foods made use of by mankind it is found that they are all com- posed of one or more of five or six different classes of substances to which the name food-stuffs or alimentary principles has been given. To ascertain the nutritive value of any food, it must be analyzed and the percentage amounts of the different food-stuffs contained in it must be determined. The classi- fication of food-stuffs usually given is as follows : 275 276 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Water ; Inorganic salts ; Proteids (or proteid-containing bodies) ; Food-stuiFs. { Albuminoids (a groujj of bodies resembling proteids, but having in some respects a diiFerent nutritive value) ; Carbohydrates ; Fats. The main facts with regard to the specific nutritive value of each of these substances will be given later on, after the processes of digestion have been described. A few general remarks, however, at this place will serve to give the proper standpoint from which to begin the study of the chemistry of digestion and nutrition. Wetter and Salts. — Water and salts we do not commonly consider as foods, but the results of scientific investigation, as well as the experience of life, show that these substances are absolutely necessary to the body. The tissues must maintain a certain composition iu water and salts in order to function normally, and, since there is a continual loss of these substances in the various excreta, they must continually be replaced in some way in the food. It is to be borne in mind in this connection that water and salts constitute a part of all our solid foods, so that the body gets a partial supply at least of these substances in everything we eat. Proteids. — The composition and diiferent classes of proteids are described from a chemical standpoint in the section on The Chemistry of the Body. Different varieties of proteids are found in animal as well as in vegetable foods. The chemical composition in all cases, however, is approximately the same. Physiologically, they are supposed to have equal nutritive values out- side of differences in digestibility, a detail that will be given later. The essential use of the proteids to the body is that they supply the material from which the new proteid tissue is made or the old proteid tissue is repaired, although, as we shall find when we come to discuss the subject more thor- oughly (p. 345), proteids are also extremely valuable as sources of energy to the body. Inasmuch as the most important constituent of living matter is the proteid part of its molecule, it will be seen at once that proteid food is an absolute necessity. Proteids contain nitrogen, and they are frequently spoken of as the nitrogenous foods; carbohydrates and fats, on the contrary, do not contain nitrogen. It follows immediately from this fact that fats and carbo- hydrates alone could not suffice to make new protoplasm. If our diet con- tained no proteids, the tissues of the body would gradually waste away and death from starvation would result. All the food-stuffs are necessary in one way or another to the preservation of perfect health, but proteids, together with a certain proportion of water and inorganic salts, are absolutely necessary for the bare maintenance of animal life — that is, for the formation and preservation of living protoplasm. Whatever else is contained in our food, proteid of some kind must form a part of our diet. The use of CHEMISTRY OF DIGESTION AND NUTRITION. 277 the other food-stuffs is, as we shall see, more or less accessory. It may be worth while to recall here the familiar fact that in respect to the nutritive importance of proteids there is a wide difference between animal and vegetable life. What is said above applies, of course, only to animals. Plants can and for the most part do, build up their living protoplasm upon diets con- taining no proteid. With some exceptions that need not be mentioned here the food-stuffs of the great group of chlorophyll-containing plants, outside of oxygen, consist of water, COj, and salts, the nitrogen being found in the last- mentioned constituent. Albuminoids. — Gelatin, such as is found in soups or is used in the form of table-gelatin, is a familiar example of the albuminoids. They are not found to any important extent in our raw foods, and they do not therefore usually appear in the analyses given of the composition of foods. An examination of the composition and properties of these bodies (see section on The Chemistry of the Body) shows that they resemble closely the proteids. Unlike the fats and carbohydrates, tliey contain nitrogen, and they are evidently of complex structure. Nevertheless, they cannot be used in place of proteids to build protoplasm. They are important foods without doubt, but their value is similar in a general way to that of the non-nitrogenous foods, fats and carbohydrates, rather than to the so-called " nitrogenous foods," the proteids. Carbohydrates. — We include among carbohydrates the starches, sugars, gums, and the like (see Chemical section) ; they contain no nitrogen. Their physiological value lies in the fact that they are destroyed in the body and a certain amount of energy is thereby liberated. The energy of muscular work and of the heat of the body comes largely from the destruction or oxidation of carbohydrates. Inasmuch as we are continually giving off energy from the body, chiefly in the form of muscular work and heat, it follows that material for the production of this energy must be taken in the food. Carbo- hydrates form perhajjs the easiest and cheapest source of this energy. They constitute the bulk of our ordinary diet. FaU. — In the group of fats we include not only what is ordinarily under- stood by the term, but also the oils, animal and vegetable, that form such a common part of our food. Fats contain no nitrogen (see Chemical section). Their use in the body is substantially the same as that of the carbohydrates. Weight for weight, they are more valuable than the carbohydrates as sources of energy, but the latter are cheaper, more completely digested when fed in quantity, and more easily destroyed in the body. For these reasons we find that under most conditions fats are a subsidiary article of food as compared with the carbohydrates. From the standpoint of the physiologist, fats arc of special interest because the animal body stores up its reserve of food material mainly in that form. The history of the origin of the fats of the body is one of the most interesting parts of the subject of nutrition, and it will be discussed at some length in its proper place. As has been said, our ordinary foods are mixtures of some or all of the food-stuffs, together with such things as flavors or condiments, whose nutriti\-e !78 AN A2IEIIICAN TEXT-BOOK OF PHYSIOLOGY. value is of a special character. Careful analyses have been made of the different articles of food, mostly of the raw or uncooked foods. As might be expected, the analyses on record differ more or less in the percentages assigned to the various constituents, but almost any of the tables published give a just idea of the fundamental nutritive value of the common foods. For details of separate analyses reference may be made to some of the larger works upon the composition of foods.' The subjoined table is one compiled by Munk from the analyses given by Konig : Composition of Foods. In 100 parts. Meat . . Cheese . . . Cow's milk Human milk Wheat flour Wheat bread Rye flour Kye bread Kice Corn Macaroni Peas, beans, lentils Potatoes . . . Carrots Cabbages Mushrooms . . . Fruit Water. 76.7 73.7 36-60 87.7 89.7 13.3 35.6 13.7 42.3 13.1 13.1 10.1 12-15 75.5 87.1 90 73-91 84 Proteld. 20.8 12.6 25-33 3.4 2.0 10.2 7.1 11.5 6.1 7.0 9.9 9.0 23-26 2.0 1.0 2-3 4-8 0.5 1.5 12.1 7-30 3.2 3.1 0.9 0.2 2.1 0.4 0.9 4.6 0.3 li-2 0.2 0.2 0.5 0.5 Carbohydrate. Digestible. Cellulose. 0.3 3-7 4.8 5.0 74.8 0.3 55.5 0.3 69.7 1.6 49.2 0.5 77.4 0.6 68.4 2.5 79.0 0.3 49-54 4-7 20.6 0.7 9.3 1.4 4-6 1-2 3-12 1-5 10 4 Ash. 1.3 1.1 3-4 0.7 0.2 0.5 1.1 1.4 1.5 1.0 1.5 0.5 2-3 1.0 0.9 1.3 1.2 0.5 An examination of this table will show that the animal foods, particularly the meats, are characterized by their small percentage in carbohydrate and by a relatively large amount of proteid or of proteid and fat. With regard to the last t^vo food-stuffs, meats differ very much among themselves. Some idea of the limits of variation may be obtained from the following table, taken chiefly from Konig's analyses ; Water. 73.03 72.31 75.99 72.57 62.58 10.00 71.6 Proteid. Fat. Carbohydrate. Ash. Beef, moderately fat Veal, fat Mutton, moderately fat Pork, lean ... ..... Ham, salted Pork (bacon), very fat ^ Mackerel ^ 20.96 18.88 17.11 20.05 22.32 3.00 18.8 .5.41 7.41 5.77 6.81 8.68 80.50 8.2 0.46 0.07 1.14 1.33 1.33 1.10 6.42 6.5 1.4 The vegetable foods are distinguished, as a rule, by their large percentage in carbohydrates and the relatively small amounts of proteids and fats, as seen, for example, in the composition of rice, corn, wheat, and potatoes. Neverthe- ' Konig, Die Jtcn.ichlichen Nahrungs und Genussmittel, 3d ed., 1889 ; Parke's Manual of Prac- tical Hygiene, section on Food. ^ Atwater: The Chemistry of Foods and Nutrition, 1887. CHEMISTRY OF DIGESTION AND NUTRITION. 279 less, it will be noticed that the proportion of proteid in some of the vegetables is not at all insignificant. They are characterized by their excess in carbohy- drates rather than by a deficiency in proteids. The composition of peas and other leguminous foods is remarkable for the large percentage of proteid, which exceeds that found in meats. Analyses such as are given here are indispensable in determining the true nutritive value of foods. Nevertheless, it must be borne in mind that the chemical composition of a food is not alone sufficient to determine its precise value in nutrition. It is obviously true that it is not what we eat, but what we digest and absorb, that is nutritious to the body, so that, in addition to determining the proportion of food-stuffs in any given food, it is necessary to determine to what extent the several constitu- ents are digested. This factor can be obtained only by actual experi- ments. It may be said here, ho^vever, that in general the proteids of animal foods are more completely digested than are those of vegetables, and with them, therefore, chemical analysis comes nearer to expressing directly the nutritive value. The physiology of digestion consists chiefly in the study of the chemical changes that the food undergoes during its passage through the alimentary canal. It happens that these chemical changes are of a peculiar character. The peculiarity is due to the fact that the changes of digestion are effected through the agency of a group of bodies known as enzymes, or unorganized ferments, whose chemical action is more obscure than that of the ordinary reagents -with which we have to deal. It will save useless repetition to gwe here certain general facts that are known with reference to these bodies, reserving for future treatment the details of the action of the specific enzymes found in the difierent digestive secretions. Enzymes. — Enzymes, or unorganized ferments, or unformed ferments, is the name given to a group of bodies produced in animals and plants, but not themselves endowed with the structure of living matter. The term imorganized or unformed ferment was formerly used to emphasize the distinction between these bodies and living ferments, such as the yeast-plant or the bacteria. " Enzyme," however, is a better name, and is coming into general use. Enzymes are to be regarded as dead matter, although produced in living protoplasm. Chemically, they are defined as complex organic compounds con- taining nitrogen. Their exact composition is unknown, as it has not been found possible heretofore to obtain them in pure enough condition for analysis. Although several elementary analyses are recorded, they cannot be considered reliable. It is not known whether or not the enzymes belong to the group of proteids. Solutions of most of the enzymes give some or all of the general reactions for proteids, but there is always an uncertainty as to the purity of the solutions. With reference to the fibrin ferment of blood, one of the enzymes, observations have recently been made which seem to show that it belongs to the group of combined proteids, nucleo-albumins (for details see the section on Blood). But even should this be true, we are not justified in making any general application of this fact to the whole group. 280 AN AMERICAN TENT-BOOK OF PHYSIOLOGY. Classification of Mizymes. — Enzymes are classified according to the kind of reaction they produce — namely : 1. Proteolytic enzymes, or those acting upon proteids, converting them to a soluble modification, peptone or proteose. As examples of this group we have in the animal body pepsin of the gastric juice and trypsin of the pancreatic juice. In plants a similar enzyme is fouud in the pineapple family (bromelin) and in the jjapaw (papain). 2. Amylolytic enzymes, or those acting upon the starches, converting them to a soluble form, sugar, or sugar and dextrin. As examples of this group we have in the animal body ptyalin, found in saliva, amyhpjsin, found in pancreatic juice, and in the liver an enzyme capable of converting glycogen to sugar. In the plants the best-known example is diastase, found in germinating seeds. This particular enzyme has been known for a long time from the use made of it in the manufacture of beer. In fact, the name " dias- tase " is frequently used in a generic sense, " the diastatic enzymes," to cha- racterize the entire group of starch-destroying ferments. 3. Fat-splitting enzymes, or those acting upon the neutral fats, breaking them up into glycerin and the corresponding fatty acid. The best-known example in the animal body is found in the pancreatic secretion ; it is known usually as steapsin, although it has been given several names. Similar enzymes are known to occur in a number of seeds. 4. Sugar-spUftinf) enzymes, or those having the property of converting the double into the single sugars— the di-saccharides, such as cane-sugar and maltose, into the mono-saccharides, such as dextrose and lemdose. Two enzymes of this character are found in the small intestine of the animal body, one acting upon cane-sugar and one on maltose. The one acting on cane-sugar is known as invertine or invertase, while that acting on maltose is designated as maltase. 5. Coagulating enzymes, or those acting upon soluble proteids, precipitating them in an insoluble form. As examples of this class we have fibrin ferment (thrombin), formed in shed blood, and reiinin, the milk-curdling ferment of the gastric juice. An enzyme similar to rennin has been found in pineapple-juice. These five classes comprise the chief groups of enzymes that are known to occur in the animal body. One or more examples of each group take part in the digestion of food at some time during its passage through the alimentary canal. From time to time other enzymes have been recognized in the liquids or tissues of the body.^ Thus in shed blood and indeed in other tissues an enzyme (glycolytic enzyme) that is capable of destroying sugar seems to be present. When sugar is added to shed blood it disappears as such, although the products formed have not been recognized. Similarly from many tissues of the body oxidizing enzymes have been extracted that are capable of caus- ing energetic oxidation of organic bodies ; for instance, they can convert salicylaldehyde to salicylic acid. It is possible that these oxidizing enzymes, ' For a recent summary of facts and literature upon enzymes see Green : The Soluble Ferments and Fermentation, J897. CHEMISTRY OF DIGESTION AND NUTRITION. 281 or oxidases, form a group that plays an important part in the functional metabolism of the tissues, but at present our knowledge of their existence and functional value in the living organism is very uncertain. A great number of general reactions have been discovered, applicable, with an exception here and there, to the whole group of enzymes. Among these reactions the following are the most useful or significant : 1. Solubility.— The enzymes are soluble in water. Thev are also solu- ble in glycerin, this being the most generally useful solvent for obtaining extracts of the enzymes from the organs in which tlic}- are formed. 2. Effect of Temperature. — In a moist condition they are destroyed by temperatures below the boiling-point ; 60^ to 80° C. are the limits actually observed. Very low temperatures I'etard or even suspend entirely (0° C.) their action, without, however, destroying the enzyme. For each enzyme there is a temperature at which its action is greatest. 3. Incompleteness of Action. — With the exception perhaps of the coagulat- ing enzymes, they are characterized by the fact that in any given solution they never completely destroy the substance upon which they act. It seems that the products of their activity, as they accumulate, finally prevent the enzymes from acting further ; when these products are removed the action of the enzyme begins again. The most familiar example of this very striking peculiarity is found in the action of pepsin on proteids. The products of digestion in this case are peptones and proteoses, and when they have reached a certain concen- tration they prevent any further proteolysis on the part of the pepsin. 4. Relation of the Amount of Enzyme to the Effect it Produces. — With most substances the extent of the chemical change produced is proportional to the amount of the substance entering into the reaction. With the enzymes this is not so. Except for very small quantities, it may be said that the amount of change caused is independent of the amount of enzyme present, or, to state the matter more accurately, " with increasing amounts of enzymes the extent of action also increases, reaching a maximum with a certain percentage of enzyme ; increase of enzyme beyond this has no eifect." ' This fact was formerly inter- preted to mean that the enzyme is not used up — that is, not permanently altered — by the reaction that it causes. This belief, indeed, must be true substan- tially, but it has been found practically that a given solution of enzyme cannot be used over and over again indefinitely. It is generally believed now that, although an enzyme causes an amount of change in the substance it acts upon altogether out of proportion to the amount of its own substance, neverthe- less it is eventually destroyed ; its action is not unlimited. Whether this using up of the enzyme is a necessary result of its activity, or is, as it were, an acci- dental effect from spontaneous changes in its own molecule, remains unde- termined. Theories of the Manner of Action of the Enzymes. — It is now believed that the action of many of the body enzymes, especially tlie digestive enzymes, is that of hydrating agents ; they produce their effect by M'hat is ^Tammann : Zeitschrift fur physiologische Chemie, 1892, Bd. xvi. S. 271. 282 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. known as hydrolysis ; that is, they cause the molecules of the substance upon which they act to take up one or more molecules of water ; the resulting molecule then sjilits or is dissociated, with the formation of two or more sim- pler bodies. This is one of the most significant facts in connection with the action of the euzymes ; it is well illustrated by the action of invertin on cane- sugar, as follows : Ci2H220ii+H20 = CgHijOg + C5H12O5 Cane-sugar. Dextrose. Levulose. In what way enzymes cause the substances they act upon to take up water is unknown. The fact that they are not themselves used up in the reaction pro- portionally to the change they cause formerly influenced physiologists and chem- ists to explain their effect as due to catalysis, or contact action. In its original sense this designation meant that the molecules of enzyme act by their mere presence or contiguity, but it need scarcely be said that a statement of this kind does not amount to an explanation of their manner of action ; to say they "act by catalysis " means nothing in itself. Efforts to explain their action have resulted in a number of hypotheses, a detailed account of which would hardly be ajipropriate here. It may be mentioned that two ideas have found most general acceptance : one, that the enzyme acts by virtue of some peculiar physical property, such as the physical state of its molecules, or by setting up vibrations in the molecules of the suljstance acted upon ; the other idea is that the enzyme enters into a definite chemical reaction, in which, however, it plays the part of a carrier or go-between, so that, altliough the enzyme is directly concerned in producing a chemical change, the final outcome is that it remains in its original condition. A number of chemical reactions of this general character are known, in which some one substance passes through a cycle of changes, aiding in tiie production of new compounds, but itself returning always to its first condition ; for example, the part taken by HjSO^ in the manufacture of ether from alcohol, or the successive changes of lieenio- globin to oxyhfemoglobin and back again to haemoglobin after giving up its oxygen to the tissues. Perhaps the most suggestive reaction of this character is the one quoted by Chittenden ^ to illustrate this very hypothesis as to the manner of action of enzymes, as follows : Oxygen and carbon monoxide gas, if perfectly dry, will not react upon the passage of an electric spark. If, however, a little aqueous vapor is present, they may be made to unite readily, with the formation of COj. The water in this case, without doubt, enters into the reaction, but in the end it is re-formed, and the final result is as though the water had not directly participated in the process. The reactions supposed to take place are explained by the following equations : CO + 2H2O + O2 = CO (0H)2 + H2O2. H2O2 + CO = COfOH)^. 2CO(OH)2 = 2CO2 + 2Hp. ' Cartwright Lectures, Medical Record, New York, April 7, 1894. CHEMISTRY OF DIGESTION AND NUTRITION. 283 B. Salivary Digestion. The first of the digestive secretions with which the food comes in contact is saliva. This liquid is a mixed secretion from the six large salivary glands (parotids, submaxillaries, and sublinguals) and the smaller mucous and serous glands that open into the mouth. The physiological anatomy of these glands and the mechanism by which the secretions are produced and regulated will be found described fully in the section on Secretion ; we are concerned here only with the composition of the secretion after it is formed, and with its action upon foods. Properties and Composition of the Mixed Saliva. — Filtered saliva is a clear, viscid, transparent liquid. As obtained usually from the mouth, it is more or less turbid, owing to the presence in it, in suspension, of particles of food or of detached cells from the epithelium of the mouth. A some- what characteristic cell contained in it in small numbers is the so-called " salivary corpuscle." These bodies are probably leucocytes, altered in struc- ture, that have escaped into the secretion. So far as is known, they have no physiological value. The specific gravity of the mixed secretion is on an aver- age 1003, and its reaction is normally alkaline. The total amount of secretion during twenty-four hours varies naturally with the individual and the condi- tions of life; the estimat&s made vary from 300 to 1500 grams. Chemically, in addition to the water, the saliva contains mucin, ptyalin, albumin, and inor- ganic salts. The proportions of these constituents are given in the following analysis (Hammerbacher) : In 1000 parts. Water .... 994.203 Solids : /• Mucin (and epithelial cells) . . . . 2.202 -v ■I Ptyalin and albumin . 1.390 \ ,5797 >. Inorganic salts 2.205 ) Potassium sulphocyanide . , . . 0.041 The inorganic salts, in addition to the sulphocyanide, which occurs only in traces, consist of the chlorides of potassium and sodium, the sulphate of potassium, and the phosphates of potassium, sodium, calcium, and magnesium ; the earthy phosphates form about 9.6 jDcr cent, of the total ash. Mucin is an important constituent of saliva ; it gives to the secretion its ropy, viscid cha- racter, which is of so much value in the mechanical function it fulfils in swallowing. This substance is formed in the salivary glands. Its formation in the protoplasm of the cells may be followed microscopically (see the section on Secretion). Chemically, it is now known to be a combination of a proteid with a carbohydrate group (see section on The Chemistry of the Body). So far as known, mucin has no function other than its mechanical use. The pres- ence of potassium sulphocyanide (KCNS) among the salts of saliva has always been considered interesting, since, although it occurs normally in urine as well as in saliva, it is not a salt found commonly in the secretions of the body, and its occurrence in saliva seemed to indicate some special activity on the part of the salivary gland, the possible value of which has been a subject of specula- 284 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tion. In the saliva, however, the sulphocyanide is found in such minute traces and its presence is so inconstant that no special functional importance can be attributed to it. It is supposed to be derived from the decomposition of proteids, and it repi-esents, therefore, one of the end-products of proteid metab- olism. Potassium sulphocyanide may be detected in saliva by adding to the latter a dilute acidulated solution of ferric chloride, a reddish color being produced. Ptyalin and its Action. — From a physiological standpoint the most important constituent of saliva is jAyalin. It is an unorganized ferment or enzyme belonging to the amylolytic or diastatic group (p. 280) and possessing the general properties of enzymes already enumerated. It is found in human saliva and in that of many of the lower animals — for example, the pig and the herbivora — but it is said to be absent in the carnivora. Ptyalin has not been isolated in a sufficiently pure condition for satisfactory analysis, so that its chemical nature is undetermined ; we depend for its detection upon its specific action — that is, its effect upon starch. Speaking roughly, we say that ptyalin converts starch into sugar, but when we come to consider the details of its action we find that it is complicated and that it consists in a series of hydrolytic splittings of the starcli molecule, the exact jjroducts of the reaction depending upon the stage at which the action is interrupted. To demonstrate the action of ptyalin on starch it is only necessary to make a suitable starch paste by boiling some powdered starch in water, and then to add a little fresh • saliva. If the mixture is kept at a proper temperature (30° to 40° C), the presence of sugar may be detected within a few minutes. The sugar that is formed was for a time supposed to be ordinary grape-sugar (dextrose, C^H^fi^), but later experiments have shown conclusively that it is maltose (C12H22O11,- HjO), a form of sugar more closely related in formula to cane-sugar (see Chemical section). In experiments of the kind just described two facts may easily be noticed : first, that the conversion of starch to sugar is not direct, but occurs through a number of intermediate stages; second, that the starch is not entirely converted to sugar under the conditions of such experiments — namely, when the digestion is carried on in a vessel, digestion in vitro. The second fact is an illustration of the incomplete- ness of action of the enzymes, a general property that has already been noticed. We may suppose, in this as in other cases, that the products of digestion, as they accumulate in the vessel, tend to retard and finally to sus- pend the amylolytic action of the ptyalin. In normal digestion, however, it is usually the case that the products of digestion, as they are formed, are removed by absorption, and if the above explanation of the cause of the incompleteness of action is correct, then under normal conditions we should expect a complete conversion of starch to sugar. Lea^ states that if the products of ptyalin action are partially removed by dialysis during digestion Ml vitro, a much larger percentage of maltose is formed. His experiments would seem to indicate that in the body the action of the amylolytic ferments ' Journal of Physiology, 1890, vol. xi. p. 227. CHEMISTRY OF DIGESTION AKD NUTRITION. 285 may be complete, and that the final product of their action may be maltose alone. It will be found that this statement applies practically not to the ptyalin, but to the similar aniylolytic enzyme in the pancreatic secretion, o\ving to the fact that, normally, food is held in the mouth for a short time only, and that ptyalin digestion is soon interrupted after the food reaches the stomach. With reference to the intermediate stages or products in the conversion of starch to sugar it is difficult to give a perfectly clear account. It was formerly thought that the starch was first converted to dextrin, and this in turn was converted to sugar. It is now believed that the starch molecule, which is quite complex, consisting of some multiple of CgHigOj — possibly (051111,05)20 — first takes up water, thereby becoming soluble (soluble starch, amylodextrin), and then splits, with the formation of dextrin and maltose, and that the dextrin again undergoes the same hydrolytic process, with the formation of a second dextrin and more maltose; this process may continue under favorable con- ditions until only maltose is present. The difficulty at present is in isolating the different forms of dextrin that are produced. It is usually said that at least two forms occur, one of which gives a red color with iodine, and is there- fore known as erythrodextrin, while the other gives no color reaction with iodine, and is termed adiroodextrin. It is pretty certain, however, that there are several forms of achroodextrin, and, according to some observers, erythro- dextrin also is really a mixture of dextrins with maltose in varying propor- tions. In accordance with the general outline of the process given above, Neumeister ^ proposes the following schema, which is useful because it gives a clear representation of one theory, but which must not be considered as satis- factorily demonstrated (see also the section on Chemistry of the Body). /Maltose. Starch— soluble starch j (amylodextrin), i /Maltose. Erythrodextrin. < /Maltose. Achroodextrin a. < /Maltose. Achroodextrin )S. / /Maltose. Achroodextrin -y f (maltodextrin). 1 XMaltose. This schema represents the possibility of an ultimate conversion of all the starch into maltose, and it shows at the same time that maltose may be pres- ent very early in the reaction, and that it may occur together with one or more dextrins, according to the stage of the digestion. It should be said in conclu- sion that this description of the manner of action of the ptyalin is supposed to apply equally well to the amylolytic enzyme of the pancreatic secretion, the two being, so far as known, identical in their properties. From the stand- point of relative physiological importance the description of the details of aniylolytic digestion should have been left until the functions of the pancre- atic juice were considered. It is introduced here because, in the natural order ' Lehrbuch der physiologischen Chemie, 1893, p. 232. 286 AN A3TERICAN TEXT-BOOK OF PHYSIOLOGY. of treatment, ptyalin is the first of this group of ferments to be encountered. It is interesting also to remember in this connection that starch can be con- verted into sugar by a process of hydrolytic cleavage by boiling with dilute mineral acids. Although the general action of dilute acids and of amylolytic enzymes is similar, the two processes are not identical, since in the first proceas dextrose is the sugar formed, while in the second it is maltose. Moreover, variations in temperature affect the two reactions differently. Conditions Influencing the Action of Ptyalin. — Temperature. — As in the case of the other enzymes, ptyalin is very susceptible to changes of temper- ature. At 0° C. its activity is said to be suspended entirely. The intensity of its action increases with increase of temperature from this point, and reaches its maximum at about 40° C. If the temperature is raised much beyond this point, the action of the ptyalin decreases, and at from 65° to 70° C. tile enzyme is destroyed. In these latter points ptyalin differs from diastase, the enzyme of malt. Diastase shows a maximum action at 50° C. and is destroyed at 80° C. Effect of Reaction. — The normal reaction of saliva is slightly alkaline. Chittenden has shown, however, that ptyalin acts as well, or even better, in a perfectly neutral medium. A strong alkaline reaction retards or prevents its action. The' most marked influence is exerted by acids. Free hydrochloric acid to the extent of only 0.003 per cent. (Chittenden) is sufficient to prac- tically stop the amylolytic action of enzyme, and a slight increase in acidity not only stops the action, but also destroys the enzyme. The latter fact is of practical importance because it indicates that the action of ptyalin on starch must be suspended after the food reaches the stomach. Condition of the Starch. — It is a well-known fact that the conversion of starch to sugar by enzymes takes place much more rapidly with cooked starch — for example, starch paste. In the latter condition sugar begins to appear in a few minutes (one to four), provided a good enzyme solution is used. With starch in a raw condition, on the contrary, it may be many minutes, or even several hours, before sugar can be detected. The longer time required for raw starch is partly explained by the well-known fact that the starch-grains are surrounded by a layer of cellulose or cellulose-like material that resists the action of ptyalin. When boiled, this layer breaks and the starch in the interior becomes exposed. In addition, the starch itself is changed during the boiling ; it takes up water, and in this hydrated condition is acted upon more rapidly by the ptyalin, The practical value of cooking vegetable foods is evident from these statements without further comment. Physiological Value of Saliva. — Although human saliva contains ptyalin, and this enzyme is known to possess very energetic am3-lolytic properties, yet it is probable that it has an insignificant action in normal digestion. The time that food remains in the mouth is altogether too short to sup]30se that the starch is profoundly affected by the ptyalin. Indeed, the saliva of dogs and cats is said to contain no ptyalin, while horse's saliva is free from ptyalin, although it contains a zymogen that may give rise to ptyalin. It would seem that what- AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. 2S7 ever change takes place must be confined to the initial stages. After the mixed saliva and food are swallowed it is usually supposed that the acid reaction of the gastric juice soon stops completely all further amylolytic action, although this point is often disputed.' The complete digestion of the carbohydrates takes place after the food (chyme) has reached the small" intestine, under the influence of the amylopsin of the pancreatic secretion. For these reasons it is usually believed that the main value of the saliva, to the human being and to the carnivora at least, is that it facilitates the swallowing of food. It is impos- sible to swallow perfectly dry food. The saliva, by moistening the food, not only enables the swallowing act to take place, but its viscous consistency must aid also in the easy passage of the food along the oesophagus. In addition the solution of parts of the food in the saliva gives occasion for the stimula- tion of the taste nerves, and, as we shall see in studying the mechanism of gastric secretion, the conscious sensations thus produced are very important for gastric digestion. C. Gastric Digestion. After the food reaches the stomach it is exposed to the action of the secre- tion of the gastric mucous membrane, known usually as the gastric juice. The physiological mechanisms involved in the production and regulation of this secretion, and the important part played in gastric digestion by the movements of the stomach, will be found described in other sections (Secretion, Move- ments of Alimentary Canal). It is sufficient here to say that the secretion of gastric juice begins with the entrance of food into the stomach. By means of the muscles of the stomach the contained food is kept in motion for several hours and is thoroughly mixed with the gastric secretion, which during this time is exerting its digestive action upon certain of the food-stuffs. From time to time portions of the liquefied contents, known as chyme, are forced into the duodenum, and their digestion is completed in the small intestine. Gastric digestion and intestinal digestion go more or less hand in hand, and usually it is impossible to tell in any given case just how much of the food will undergo digestion in the stomach and how much will be left to the action of the intestinal secretions. It is possible, however, to collect the gastric secre- tion or to make an artificial juice and to test its action upon food-stuffs by digestions in vitro. Much of our fundamental knowledge of the digestive action of the gastric juice has been obtained in this way, although this has been supplemented, of course, by numerous experiments upon lower animals and human beings. Methods of Obtaining- Normal Gastric Juice. — The older methods used for obtaining normal gastric juice were very unsatisfactory. For instance, an animal Avas made to swallow a clean sponge to which a string was attached so that the sponge could afterward be removed and its contents be squeezed out ; or there was given the animal to eat some indigestible material, to start the secretion of juice by mechanical stimulation, the animal being killed at the ' Austin : Boston Medical and Surgical Journal; 1899. 288 A^' AMEBICAX TEXT-BOOK OF PHYSIOLOGY. proper time and the contents of its stomach being collected. A better method of obtaining normal juice was suggested by the famous observations of Beau- mont^ upon Alexis St. IMartin. St. Martin, by the premature discharge of his gun, was wounded in the abdomen and stomach. On healing, a fistulous opening remained in the abdominal wall, leading into the stomach, ^ that the contents of the latter could be inspected. Beaumont made numerous interest- ing and most valuable observations upon his patient. Since that time it has become customary to make fistulous openings into the stomachs of dogs when- ever it is necessary to have the normal juice for examination. A silver canula is placed in the fistula, and at any time the plug closing the canula may be removed and gastric juice be obtained. In some cases the oesophagus has been occluded or excised so as to prevent the mixture of saliva with the gastric juice. Gastric juice may be obtained from human beings also in cases of vom- iting or by means of the stomach-pump, but in such cases it is necessarily more or less diluted or mixed with food and cannot be used for exact analyses,. although specimens of gastric juice obtained by these methods are valuable in the diagnosis and treatment of gastric troubles. Properties and Composition of Gastric Juice. — The normal gastric secre- tion is a thin, colorless or nearly colorless liquid with a strong acid reaction and a characteristic odor. Its specific gravity varies, but it is never great, the average being about 1002 to 1003. Upon analysis the gastric juice is found to contain a trace of proteid, probably a peptone, some mucin, and inorganic salts, but the essential constituents are an acid (HCl) and two enzymes, pepsin and rennin. A satisfactory analysis of the human juice has not been reported, owing to the difficulty of getting proper specimens. According to Schmidt,^ the gastric juice of dogs, free from saliva, has the following composition, given in 1000 parts : Water . ... ... .... 973.0 Solids . 27.0 Organic substances 17.1 Free HCl 3.1 NaCl . . . 2.5 CaCl^ 0.6 KCl 1.1 NH4CI 0.5 Ca,(PO,), 1.7 Mg3(PO,)2 .... 0.2 FePOi 0.1 Gastric juice does not give a coagulum upon boiling, but the digestive enzymes are thereby destroyed. One of the interesting facts about this secretion is the way in which it withstands putrefaction. It may be kept for a long time, for months even, without becoming putrid and with very little change, if any, in its digestive action or in its total acidity. This fact shows that the juice possesses antiseptic properties, and it is usually supposed that the presence of the free acid accounts for this quality. ' The Physiology of Digestion, 1833. '' Hammarsten: Tert-book of Physiological Chumistry (translated by Mandel), 1893, p. 177. CHEMISTRY OF DIOESTION AND NUTRITION. 289 The Acid of Gastric Juice. — The nature of the free acid in gastric juice was formerly the subject of dispute, some claiming that the acidity is due to HCl, since this acid can be distilled ofp from the gastric juice, others contend- ing that an organic acid, lactic acid, is present in the secretion. All recent experiments tend to prove that the acidity is due to HCl. This fact was first demonstrated satisfactorily by the analyses of Schmidt, who showed that if, in a given specimen of gastric juice, the chlorides were all precipitated by eilver nitrate and the total amount of chlorine was determined, more was found than could be held in combination by the bases present in the secretion. Evidently, some of the chlorine must have been present in combination with hydrogen as hydrochloric acid. Confirmatory evidence of one kind or another has since been obtained. Thus it has been shown that a number of color teste for free mineral acids react with the gastric juice : methyl-violet solutions are turned blue, congo-red solutions and test-paper are changed from red to blue, 00 tropasolin from a yellowish to a pink-red, and so on. A number of additional tests of the same general character will be found described in the laboratory handbooks of physiology.^ It must be added, however, that lactic acid undoubtedly occurs, or may occur, in the stomach during digestion. Its pres- ence is usually explained as being due to the fermentation of the carbohydrates, and it is therefore more constantly present in the stomach of the herbivora. The amount of free acid varies according to the duration of digestion ; that is, the secretion does not possess its full acidity in the beginning, owing probably to the fact (Heidenhain) that in the first periods of digestion, while the secre- tion is still scanty in amount, a portion of its acid is neutralized by the swallowed saliva and the alkaline secretion of the pyloric end of the stomach (see the section on Secretion). Estimates of the maximum acidity in the human stomach are usually given as between 0.2 and 0.3 per cent. The acidity of the dog's gastric juice is greater — 0.46 to 0.56 per cent. (Pawlow). Origin of the HCl. — The gastric juice is the only secretion of the body con- taining a free acid. The fact that the acid is a mineral acid makes this circum- stance more remarkable, although other instances of a similar kind are known; for example, Dolium galea, a mollusc, secretes a salivary juice containing free HjSO^ and free HCl. When and how the HCl is formed in the stomach is still a subject of investigation. Histologically, attempts have been made to show that it is produced in the border cells of the peptic glands in the fundic end of the stomach (see Secretion). It cannot be said, however, that the evidence for this theory is at all convincing ; it can be accepted only provisionally. Ingenious efforts have been made to determine the place of production of the acid by micro-chemical methods. Substance that give color reactions with acids have been injected into the blood, and sections of the mucous membrane of the stomach have then been made to determine microscopically the part of the gastric glands in which the acid is produced ; but beyond proving that the acid is formed in the mucous membrane these experimente have given negative results, the color reaction for acid occurring throughout the thickness of the ' Stirling : Outlines of Practical Physiology. Vol. I.— 19 290 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. membrane.^ The chemistry of the production of free HCl also remains unde- termined. No free acid occurs in the blood or the lymph, and it follows, there- fore, that it is manufactured in the secreting cells. It is quite evident, too, that the source of the acid is the neutral chlorides of the blood ; these are in some way decomposed, the chlorine uniting with hydrogen to form HCl which is turned out upon the free surface of the stomach, while the base remains behind and probably passes back into the blood. The latter part of the pro- cess, the passage of the base into the blood-current, enables us to explain in part the facts, noticed by a number of observers, that the alkalinity of the blood is increased and the acidity of the urine is decreased after meals. Attempts to express the reaction that takes place in the decomposition of the chlorides are still too theoretical to merit more than a brief mention in a book of this character. According to Heidenhain, the cells secrete a free organic acid, wliich then acts upon and decomposes the chlorides. According to Maly, the HCl is the result of a reaction between the phosphates and the chlorides of the blood, as expressed in the two following equations : NaH^PO, + NaCl = Na^HPO, 4- HCl ; or, SCaClj + 2Xa2HPO, = Ca3(PO,)2 + 4NaCl -|- 2HC1. A recent theory by Liebermann supposes that the mass action of the COj formed in the tissues of the gastric mucous membrane upon the chlorides, with the aid of a nucleo-albumin of acid properties that can be isolated from the gastric glands, may account for the production of the HCl. Although it is customary to speak of the HCl as existing in a free state in the gastric juice, certain diiferences in reaction between this secretion and aqueous solu- tions of the same acidity have led to the suggestion that the HCl, or a part of it at least, is held in some sort of combination with the organic (proteid) con- stituents of the secretion, so that its properties are modified in some minor points just as the properties of hsemoglobiu are modified by the combination in which it is held in the corpuscles. The differences usually described are that in the gastric juice or in mixtures of HCl and proteid the acid does not dialyze nor distil off so readily as in simple aqueous solutions. The peptones and proteoses formed during digestion seem to combine with the acid very readily — so much so, in fact, that in certain cases specimens of gastric juice taken from the stomach, although they give an acid reaction with litmus-paper, may not give the special color reactions for free mineral acids. In such cases, how- ever, the acid may still be able to fulfil its part in the digestion of proteids. Nature and Properties of Pepsin. — Pepsin is a typical proteolytic enzyme that exhibits the striking peculiarity of acting only in acid media; hence peptic digestion in the stomach is the result of the combined action of pepsin and HCl. Pepsin is influenced in its action by temperature, as is the case with the other enzymes ; low temperatures retard, and may even suspend, its activity, while high temperatures increase it. The optimum temperature is stated to be from 37° to 40° C, while exposure for some time to 80° C. results, when the ' Friinkel : PJliigei's Archivfiir die gesammtePhysiologie, 1891, Bil. 48, S. 63. CHEMISTRY OF DIGESTION AND NUTBITION. 291 pepsin is in a moist condition, in the total destruction of the enzyme. Pepsin has never been isolated in sufficient purity for satisfactory analysis. It may be extracted, however, from the gastric mucous membrane by a variety of methods and in diiferent degrees of purity and strength. The commercial preparations of pepsin consist usually of some form of extract of the gastric mucous membrane to which starch or sugar of milk has been added. Laboratory preparations are usually made by mincing thoroughly the mucous membrane and then extract- ing for a long time with glycerin. Glycerin extracts, if not too much diluted with water or blood, keep for an indefinite time. Purer preparations of pepsin have been made by what is known as "Brucke's method," in which the mucous membrane is minced and is then self-digested with a 5 per cent, solution of phosphoric acid. The phosphoric acid is precipitated by the addition of lime- water, and the pepsin is carried down in the floccnlent precipitate. This pre- cipitate, after being washed, is carried into solution by dilute hydrochloric acid, and a solution of cholesterin in alcohol and ether is added. The choles- terin is precipitated, and, as before, carries down with it the pepsin. This precipitate is collected, carefully washed, and then treated repeatedly with ether, which dissolves and removes the cholesteriu, leaving the pepsin in aqueous solution. This method is interesting not only because it gives the purest form of pepsin, but also in that it illustrates one of the properties of this enzyme — namely, the readiness with which it adheres to precipitates occur- ring in its solutions. Pepsin illustrates very well two of the general properties of enzymes that have been described (p. 281): first, its action is incomplete, the accumulation of the products of digestion inhibiting further activity at a certain stage ; and, secondly, a small amount of the pepsin, if given sufficient time and the proper conditions, will digest a very large amount of proteid. Artificial Gastric Juice. — In studying peptic digestion it is not necessary for all purposes to establish a gastric fistula to get the normal secretion. The active agents of the normal juice are pepsin and acid of a proper strength ; and, as the pepsin can be extracted and preserved in various ways, and the HCl can easily be made of the proper strength, an artificial juice can be obtained at any time which may be used in place of the normal secretion for many purposes. In laboratory experiments it is customary to employ a glycerin extract of the gastric mucous membrane, and to add a small portion of this extract to a large bulk of 0.2 per cent. HCl. The artificial juice thus made, when kept at a temperature of from 37° to 40° C, will digest proteids rapidly if the preparation of pepsin is a good one. While the strength of the acid employed is generally from 0.2 to 0.3 per cent., digestion will take place in solutions of greater or less acidity. Too great or too small an acidity, however, will retard the process ; that is, there is for the action of the pepsin an optimum acidity which lies somewhere between 0.2 and 0.5 per cent. Other acids may be used in place of the HCl — for example, nitric, phosphoric, or lactic — although they are not so effective, and the opti- mum acidity is diiferent for each ; for phosphoric acid it is given as 2 per cent. Action of Pepsin-Hydrochloric Acid on Proteids. — It has been known for a long time that solid proteids, such as boiled eggs, when exposed to the 292 AX AMERICAN TEXT-BOOK OF PHYSIOLOGY. action of a normal or an artificial gastric juice, swell up and eventually pass into solution. The soluble proteid thus formed was known not to be coagu- lated by heat ; it was remarkable also for being more diifusible than other forms of soluble proteids, and was further ehai-acterized by certain positive and negative reactions that will be described more explicitly farther on. This end-product of digestion was formerly described as a soluble proteid with properties fitting it for rapid absorption, and the name of peptone was given to it. It was quickly found, however, that the process was complicated — that in the conversion to so-called "peptone" the proteid under digestion passed through a number of intermediate stages. The intermediate products were partiallj^ isolated and were given specific names, such as acid-albumin, parapeptone, and pi'opeptone. The two latter names, unfortunately, have not always been used with the same meaning by authors, and latterly they have fallen somewhat into disuse, although they are still frequently employed to indicate some one or other of the intermediate stages in the formation of pep- tones. The most complete investigation of the products of peptic digestion, and of proteolytic digestion in general, we owe to Kiihne and to those who have followed along the lines he laid down, among whom may be mentioned Chittenden and Neumeister. Their work has thrown new light upon the- whole subject and has developed a new nomenclature. In our account of the process we shall adhere to the views and terminology of this school, as they seem to be generally adopted in most of the recent literature. It is well,, however, to add, by way of caution, that investigations of this character are still going on, and the views at present accepted are liable, therefore, to. changes in detail as our experimental knowledge increases. Without giving the historical development of Kiihne's theory, it may be said that at present the following steps in peptic digestion have been described : The proteid: acted upon, whether soluble or insoluble, is converted first to an acid-alburaiu (see Chemical section) to which the name syntonin is usually given. In arti- ficial digestions the solid proteid usually swells first from tlie action of the acid, and then slowly dissolves. Syntonin has tlie general properties of acid- albumins, of which properties the most characteristic is that the albumin is j)recipitated upon neutralizing the solution with dilute alkali. If, in the begin- ning of a peptic digestion, the liquid is neutralized, a more or less abundant precipitate of syntonin will form, the quantity depending upon the stage of digestion. Syntonin in turn, under the influence of the pepsin, takes up water and undergoes hydrolytic cleavage, with the formation of several solu- ble proteids known together as primary albumoHes or proteoses} Each of these proteids again takes up M'ater and undergoes cleavage, with the formation of a second set of soluble proteids known as secondary proteoses, in contradis- tinction to the primary proteoses, but to wliich the specific name of deutero- ' The term proteose is used by some authors in place of the older name albumose, as it has a more general significance. According to this usage the name albumose is given to the proteoses formed from albumin, globniose to those formed from globulin, etc., while proteose is a general term applying to ihe intermediate products from any proteid. CHEMISTRY OF DIGESTION AND NUTRITION. 1'93 proteoses is given. Finally, the deutero-proteose, or more properly the deutero-proteoses, again undergo hydrolytic cleavage, with the formation of what are known as peptones. Peptic digestion can go no farther than the formation of peptones, but we shall find later that other proteolytic enzymes (trypsin, for example) are capable of splitting up a part of the peptones still further. The fact that trypsin can act upon only a part of the peptone shows that this latter substance is either a mixture of at least two separate although closely-related peptones, to which the names of anti-'peptone and hemi-peptone ^ have been given, or it is a compound containing such hemi- and anti- groups, and capable, under the action of trypsin, of splitting, with the formation of hemi-peptone and anti-peptone (Neumeister). If we consider peptic digestion alone, this distinction is unnecessary. The final products of peptic digestion are therefore spoken of usually simply as peptones, although the name ampho- peptone is also frequently used to emphasize the fact that two distinct varieties of peptone are possibly present. This description of the steps in peptic digestion may be made more intelligible by the following schema, which is modified somewhat from that given by Xeumeister : " This comparatively simple schema must not be regarded as final. It seems quite probable that further study Avill show that the process of splitting is more complicated than is here represented,^ but provisionally, at least, it ' Kiihne's full theory of proteolytic digestion assumes that the original proteid molecule contains two atomic groups, the hemi- and the .anti- group. Proteolytic enzymes split the mole- cule so as to give a hemi- and an anti- compound, each of which passes through a proteose stage into its own peptone. A condensed schema of the hypothetical changes would be as follows : Proteid. \ Anti-albumose. Hemi-albumose. I I Anti-peptone. Hemi-peptone. Ampho-peptoue. In the detailed description of proteolysis given above, primary and secondary proteoses are pre- sumably, according to this schema, mixtures in varying proportions of hemi- and anti- com- pounds, or, in other words, they are ampho-proteoses. No good way of separating the anti- from the hemi- compounds has been discovered except to digest them with trypsin. By this means each compound is converted to its proper peptone, and by the continued action of the trypsin the hemi-peptone is split into much simpler bodies (p. 303), only anti-peptone being left in solution. The conception of a proteid molecule with hemi- and anti- groups and the splitting into hemi- and anti-albumose is mainly an inference backward from the fact that there are two distinct peptones, one of which, hemi-peptone, is acted npon by trypsin, while the other is not so acted upon. The details of the splitting of the proteid under the influence of pepsin are still further complicated by the fact that in .some cases a part of the proteid remains undissolved, form- ing a highly resistant substance to which the name antalbumid has been given. It has been shown that if this substance is dissolved in sodium carbonate and then submitted to the action of trypsin, only anti-peptone is formed, indicating that it contains none of the hemi- group. In fact, the prop- erties of antalbumid show that it is a peculiar modification of the anti- group which may arise dur- ing the cleavage of the proteid molecule, and may vary greatly in quantity in different digestions. ^ Lehrbuch der physiologischen Chemie, 1 893, p. 187. " Consult Zunz : Zeitschrifi fur physiohgische Chemie, Bd. 28, S. 132 ; and Pick, Ibid., S. 219. 294 A^X AMERICAN TEXT- BOOK OF PHYSIOLOGY. may be used to indicate the general nature of the process and to show some of the important details that seem to be determined. Proteid. I Syntonin. (Primary proteoses) = Proto-proteose. Hetero-proteose. I 1 (Secondary proteoses) = Deutero-proteose. Deutero-proteose. (Ampho-peptones) = Peptone. Peptone. According to this schema, peptic digestion, after the syutoniu stage, consists in a succession of hydrolytic cleavages whereby soluble proteids (proteoses and peptones) are produced of smaller and smaller molecular weights. It is possi- ble, of course, that the steps in this process may be more numerous than those represented in the schema, but the general nature of the changes seems to be established beyond question. Moreover, it is easy to understand that the products of digestion in any given case will vary with the stage at which the examination is made. Sufficiently early in the process one may iind mainly svntonin, or syntonin and primary proteoses ; later the secondary proteoses and peptones may occur alone or with traces of the first products. It is worth emphasizing also that in artificial digestions with pepsin, no matter how long the action is allowed to go on, the final product is always a mixture of peptones and proteoses (deutero-proteose). Even when provision is made to dialyze off the peptone as it forms, thus simulating natural diges- tion, tlie final result, according to Chittenden and Amerman,^ is still a mixture of proteose and peptone. The extent of peptic digestion in the body will be spoken of presently iu connection with a r&um^ of the physiology of gastric digestion. In general, it may be said that from a physiological standpoint the object of the whole process is to get the proteids into a form in which they can be absoi'bed more easily. The properties and reactions of peptones and proteoses will be found stated in the Chemical section. It may serve a useful end, however, to give here some of their properties, in order to emphasize the nature of the changes caused by the pepsin. Peptones. — The name " peptones " was formerly given to all the products of peptic digestion after it had passed the syntonin stage — that is, to the pro- teoses as well as the true peptones. Commercially, the word is still used in this sense, the preparations sold as peptones being generally mixtures of proteoses and peptones. True peptones, in the sense used by Kiihne, are distinguished chem- ically by certain reactions. I^ike the proteoses, they are very soluble, they are not precipitated by heating, and they give a red biuret reaction (see Reactions of Proteids, Chemical section). They are distinguished from the primary pro- teoses by not giving a precipitate with acetic acid and potassium ferrocyanide, and from the whole group of proteoses by the fact that they are not thrown down from their solutions by the most thorough saturation of the liquid with ammonium sulphate. This last reaction gives the only means for the complete ' Jom-nal of Physiolor/y, 1893, vol. xiv. p. 483. CHEMISTRY OF DIGESTION AND NUTRITION. 295 separation of the peptones from the proteoses. The peptones, indeed, may be defined as being the products of proteolytic digestion which are not precipitated by saturation of the liquid with ammonium sulphate. The validity of this reaction has been called in question. It has been pointed out that, although the primary proteoses are readily precipitated by this salt, the deutero-pro- teoses, under certain circumstances at least, are not precipitated, and cannot therefore be distinguished or separated from the so-called " true peptones." We must await further investigations before attempting to come to any conclusion upon this point. It is well to bear in mind that the change from ordinary proteid to peptone evidently t&kes place through a number of intermediate steps, and the word peptone is meant to designate the final product. Whether this final product is a chemical individual with properties separating it from all the intermediate stages is perhaps not yet fully known, but, provisionally at least, we may adopt Kiihne's definition, outlined above, of what constitutes peptone, as it seems to be generally accepted in current literature. Peptones are characterized by their diffusibility, and this property is also possessed, although to a less marked extent, by the proteoses. Eecent work by Cliittenden,' in which he corroborates results published simultaneously by Kiihne, shows the following relative diffusibility of peptones and proteoses. The solutions used were approx- imately 1 per cent. ; they were dialyzed in parchment tubes against running water for from six to eight hours, and the loss of substance was determined and expressed in .'percentages of the original amount. Proto-proteose gave a loss of 5.09 per cent.; deutero-proteose, 2.21 per cent.; peptone, 11 per cent. Renriin. — In addition to pepsin the gastric secretion contains an enzyme that is charactei'ized by its coagulating action upon milk. It has long been known that milk is curdled by coming into contact with the mucous membrane of the stomach. Dried mucous membrane of the calf's stomach, when stirred in with fresh milk, will curdle the latter with astonishing rapidity, and this propertyhas been utilized in the manufacture of cheese. Hammarsten discovered that this action is due to the presence of a specific enzyme that exists ready formed in the membrane of the sucking-calf's stomach, and which is present in a preparatory form (rennin-zymogen) in stomachs of all mammals. This enzyme has been given several names; rennin seems preferable to any other, and is the term most commonly employed. Rennin may be obtained from the stomach by self-digestion of the mucous membrane or by extracting it with glycerin. Such extracts usually contain both pepsin and rennin, but the two have been separated successfully, most easily by the prolonged action of a temperature of 40° C in acid solutions, which destroys the rennin, but not the pepsin. Good extracts of rennin cause clotting of milk with great rapidity at a temperature of 40° C, the milk (cow's milk), if undisturbed, setting first into a solid clot, which afterward shrinks and presses out a clear yellowish liquid, the whey; with human milk, however, the curd is much less firm, being deposited in the form of loose flocculi. The whole process resembles the clotting of blood not only in the superficial phenomena, but also in the character of the chemical changes. Briefly, what happens is that the rennin ' Journal of Physiology, 1893, vol. xiv. p. 502. 296 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. acts upon a soluble proteid in the milk known usually as casein, but by some called " caseinogen," and changes this proteid to an insoluble modification which is precipitated as the curd. The chemistry of the change is not completely understood, and there is an unfortunate want of agreement in the terminology used to designate the products of the action. It has been shown that, as in the case of blood, curdling cannot take place unless lime salts are present. What seems to occur is as follows : Casein is a complex substance belonging to the group of nucleo-proteids, and when acted upon by renniu it undergoes hydro- lytio cleavage, with the formation of two proteid bodies, paracasein and whey proteid. The first of these bodies forms with calcium salts an insoluble com- pound which is precipitated as the curd ; the second remains liehind in solu- tion in the whey. It should be added that casein is also precipitated from milk by the addition of an excess of acid. The curdling of sour milk in the formation of bonnyclabber is a well-known illustration of this fact. When milk stands for some time the action of bacteria upon the milk-sugar leads to the formation of lactic acid, and when this acid reaches a certain concentration it causes the precipitation of the casein. One might suppose that the curdling of milk in the stomach is caused by the acid present in the gastric secretion, but it has been shown that perfectly neutral extracts of the gastric mucous membrane will curdle milk quite readily. So far as our positive knowledge goes, the action of rennin is confined to milk. Casein constitutes the chief proteid constituent of milk, and has there- fore an important nutritive value. It is interesting to find that before its peptic digestion begins the casein is acted upon by an altogether different enzyme. The value of the curdling action is not at once apparent, but we may suppose that casein is more easily digested by the proteolytic enzymes after it has been brought into a solid form. The action of rennin goes no further than the curdling ; the digestion of the curd is carried on by the pep- sin, and later, in the intestines, by the trypsin, with the formation of j^roteoses and peptones as in the case of other proteids. Action of Gastric Juice on Carbodydrates and Pats. — Human gastric juice itself has no direct action upon carbohydrates ; that is, it does not con- tain an amylolytic enzyme. It is possible, nevertheless, that some digestion of carbohydrates goes on in the stomach, for, as has been seen, the masticated food is thoroughly mixed with saliva before it is swallowed. The portion that enters the stomach in the beginning of digestion, when the acidity of the total contents is small (see p. 289), may continue to be acted upon by the ptyalin. According to a recent author,^ the gastric juice of the dog contains an amylolytic enzyme capable of acting on starch even in the presence of free HCl (0.5 per cent.). This statement needs confirmation, perhaps, and there is at present no evidence of the existence of a similar enzyme in the human gastric secretion. It should be added, however, that Lusk ^ has shown that cane-sugar can be inverted to dextrose and levulose in the stomach. The importance of this process of inversion, and the means by which it is accomplished, will be ' Friedenthal : Archivfur Physiologic, 3899; Suppl. Bd. 383. ^ Voit: Zeitschnft fur Biohgie, 1891, Bd. xxviii. S. 2G9. CHEMISTRY OF DIGESTION AND XUTRITION 297 described more in detail when speaking of the digestion of sugars in the small intestine (p. 308). Upon the fats also gastric juice has no direct digestive action. According to the best evidence at hand, neutral fats are not split in the stomach, nor are they emulsified or absorbed. Without doubt, the heat of the stomach is sufficient to liquefy most of the fats eaten, and the move- ments of the stomach, together with the digestive action of its juice on the proteids and albuminoids with which the fats are often mixed, bring about such a mechanical mixture of the fats and oils with the other elements of the chyme as facilitates the more rapid digestion of these substances in the intestine. Action of Gastric Juice on the Albuminoids. — Gelatin is, from a nutritive standpoint, the most important of the albuminoids. Its nutritive value is stated briefly on page 277. It has been shown that this substance is acted upon by pepsin in a way practically identical with that described for the proteids. Intermediate products are formed similar to the albnmoses, which products have been named gelatoses or glutoses; these in turn may be con- verted to gelatin peptones. It is stated that the action of pepsin is confined almost, if not entirely, to changing gelatin to the gelatose stage. The pro- teolytic enzyme of the pancreatic secretion, however carries the change to the peptone stage much more readily. "WTiy does the Stomach not Digest Itself? — The gastric secretion will readily digest a stomach taken from some other animal, or under certain con- ditions it may digest the stomach in which it is secreted. If, for instance, an animal is killed while in full digestion, the stomach may undergo self-diges- tion, especially if the body is kept warm. This phenomenon has been observed in human cadavers. It has been shown also that if a portion of the stomach is deprived of its circulation by an embolism or a ligature, it may be attacked by the secretion and a perforation of the stomach-wall may result. How, then, under normal conditions, is the stomach protected from corrosion by its own secretion? The question has given rise to much discussion, and in reality it deals with one of the fundamental properties of living matter, for the same question must be extended to take in the non-digestion of the small intestine by the alkaline pancreatic secretion, the non-digestion of the digestive tracts of the invertebrates, and the case of the unicellular animals in which there is formed within the animal's protoplasm a digestive secretion that digests foreign material, but does not aifect the living substance of the cell. In the particular case under consideration — namely, the protection of the mammalian stomach from its own secretion — explanations of the following character have been offered : It was suggested (Hunter) that the " principle of life" in living things protected them from digestion. This suggestion cannot be considered seriously at the present day, since it implies that living matter is the seat of a special force, the so-called " vital principle," diii'erent from the forms of energy acting upon matter in general. Appeals of this kind to an unknown force in explanation of the properties of living matter are not now permissible in the science of physiology. Moreover, it was shown by Bernard that the hind leg of a living frog introduced into a dog's stomach through a fistula undergoes digestion. The same thing will 298 AX AMERICAN TEXT-BOOK OF PHYSIOLOGY. happen, it may be added, if the leg is put into a vessel containing an artificial gastric juice at the proper temperature. Bernard's theory was that the epithe- lium of the stomach acts as a protection to the organ, preventing the absorp- tion of the juice. Othei-s believe that the mucus formed by the gastric mem- brane acts as a protective covering ; while still another theory holds that the alkaline blood circulating through the organ saves it from digestion, since it neutralizes the acid of the secretion as fast as it is absorbed, atid it is known that pepsin can digest only in an acid medium. None of these explanations is sufficient. The last explanation is unsatisfactory because it does not explain the immunity of the small intestine from digestion by the alkaline pancreatic juice, or the protection of the infusoria from their own digestive secretion. The mucous theory is inadequate, as we cannot believe that by this means tlie protection could be as complete as it is; and, moreover, this theory does not admit of a general application to other cases. The epithelium theory simply changL's the problem a little, as it involves an explanation of the immunity of the living epithelial cells. It is Avell known that in the dead stomach the epithelial lining is no longer a protection against digestion, so that we are led to believe that there is nothing peculiar in the composition of epithelial cells, as compared with other tissues, to account for their exemption under normal conditions. When we come to consider all the evidence, nothing seems clearer than that the protection of the living tissue is in every case due to the proper- ties of its living structure. So long as the tissue is alive, it is protected from the action of the digesting secretion, but the ultimate physical or chem- ical reason for this jn-operty is yet to be discovered. In the case of the mannnalian stomach it is quite probable that the lining epithelial cells are especially modified to resist the action of the digestive secretion, but, as has just been said, they lose this property as soon as they undergo the change from living to dead structure. The digestion of the living frog's leg in gastric juice, and similar instances, do not affect this general idea, since, as Bernard himself pointed out, what happens in this case is that the tissue is first killed by the acid and then undergoes digestion. On the other hand, Neumeister has shown that a living frog's leg is not digested by strong pan- creatic extracts of weak alkaline reaction, since under these conditions the tissues are not injured by the slightly alkaline liquid. When it is said that the exemption of living tissues from self-digestion is due to the peculiarities of their structure, it must not be supposed that this is equivalent to referring the whole matter to the action of a mysterious vital force. On the contrary, all that is meant is that the structure of living protoplasmic material is such that the action of the digestive secretion is prevented, possibly because it is not absorbed, this result being the outcome of the physical and chemical forces exhibited by matter with this peculiar structure. While a statement of this kind is not an explanation of the facts in question, and indeed amounts to a confession that an explanation is not at present possible, it at least refers the phenomenon to the action of known properties of matter. General Remarks upon Gastric Digestion. — From the foregoing CHEMISTRY OF DIGESTION AND NUTRITION. 299 account it will be seen that, speaking generally, the digestive functions of the stomach are in part to act cheniically upon the proteids, and in part, by the combined action of its secretion and its muscular movements, to get the food into a physical condition suitable for subsequent digestion in the intestine. The material sent out from the stomach (chyme) must be quite variable in composition, but physically the action of the stomach has been such as to reduce it to a liquid or semi-liquid consistency. The extent of the true digestive action of gastric juice on proteids is not now believed to be so complete as it was formerly thought to be. Examination of the chyme shows that it may contain quantities of undigested or only partially digested proteid, complete digestion being eifected in the intestines. Moreover, arti- ficial peptic digestion of proteids under the most favorable conditions shows that only a portion is ever converted to peptone, most of it remaining in the proteose stage. It has been suggested, therefore, that gastric digestion of proteids is largely preparatory to the more complete action of the pancreatic juice, whose enzyme (tripsin) has more jDowerful proteolytic properties. In accordance with this idea, it has been shown that an animal can live and thrive without a stomach. Several cases ' are on record in which the stomach was practically removed by surgical operations, the oesophagus being stitched to the duodenum. The animals did well and seemed perfectly normal. Exper- iments of this character do not, of course, show that the stomach is useless in digestion ; they demonstrate only that in the animals used it is not absolutely essential. The reason for this will better be appreciated after the digestive properties of pancreatic secretion have been studied. D. Intestinal Digestion. After the food has passed through the pyloric orifice of the stomach and has entered the small intestine it undergoes its most profound digestive changes. Intestinal digestion is carried out mainly while the food is passing through the small intestine, although, as we shall see, the process is completed during the slower passage through the large intestine. Intestinal digestion is effected through the combined action of three secretions — namely, the pancreatic juice, the bile, and the intestinal juice. The three secretions act together upon the food, but for the sake of clearness it is advisable to consider each one separately as to its properties and its digestive action. Composition of Pancreatic Juice. — Pancreatic juice is the secretion of the pancreatic gland. In man the main duct of the gland opens into the duodenum, in common with the bile-duct, about 8 to 10 cm. below the opening of the pylorus. In some of the other mammals the arrangement is different : in dogs, for example, there are two ducts, one opening into the duodenum, together with the bile-duct, about 3 to 5 cm. below the opening of the pylorus, and one some 3 to 5 cm. farther down. In rabbits the principal duct opens separately into the duodenum about 35 cm. below the opening of the bile-duct. For details as to the act of secretion, its time-relations to ' Ludwig and Ogata.- Archiv fur Anatomie und Phi/dologie, 1883, S. 89; and Cai-vallo and Pachon : Archives de Physiologie normale et palhologiqiie, 1894, p. 106. 300 A^- AMURICAX TEXT-BOOK OF PHYSIOLOGY. the ingestion of food, its quantity, etc., the reader is referred to the section on Secretion. Most of our exact knowledge of the properties of the pancreatic secretion has been obtained either from experiments upon lower animals, especially the dog and the rabbit, in which it is possible to establish a pan- creatic fistula and to collect the normal juice, or from experiments with arti- ficial pancreatic juice prepared from extracts of the gland. Various methods have been used in making pancreatic fistulse : usually the main duct of the gland, which in the two animals named is separate from the bile-duct, is exposed and a canula is inserted. A better method, devised by Heidenhain, consists in cutting out the piece of duodenum into which the main duct opens and sewing this isolated piece to the abdominal wall so as to make a permanent fistula, the continuity of the intestinal tract in this case being re-established, of course, by sutures. A simple method of obtaining normal pancreatic juice from the rabbit is described by Eatchford.' In his method the portion of the duodenum into which the main duct opens is resected and cut open along the border opposite to the mesenteric attachment. The mouth of the duct is seen as a small papilla projecting from the surface of the mucous membrane. Through the papilla a small glass canula may be passed into the duct, and the secretion, which flows slo\\'ly, may be collected for several hours. The total quantity obtainable by this means from a rabbit is small, but it is sufficient for the demonstration of some of the important properties of pancreatic juice, especially its action upon fats. As obtained by these methods, the secretion is found to be a clear, colorless, alkaline liquid. The secretion obtained from dogs is thick and glairy, and forms a coagulum upon standing, while that from rabbits is a thin, perfectly colorless liquid which does not form a cl(it. In dogs the secretion from a permanent fistula soon becomes thinner than it was when the fistula was first established, and this change in its con- sistency is accompanied by a corresponding variation in specific gravity. The specific gravity (dog) of the juice from a temporary fistula is given at 1030 ; from a permanent fistula, at 1010 to 1011. The secretion coagulates upon being heated, owing to the proteids held in solution, and it undergoes putre- faction very quickly, so that it cannot be kept for any length of time. The analysis of the secretion most frequently quoted is that given by C. Schmidt, as follows : Pancreatic Juice (Dog). Constituents. Immediately after From permanent establishing fistula. fistula. 900.76 980.45 99.24 19.55 90.44 12.71 8.80 6.84 0.58 3.31 7.35 2.50 0.53 0.08 j Water / t>olids . . ... ... Organic substances Ash . . Sodium carbonate Sodium chloride Calcium, magnesium, and sodium phosphates The composition of normal human pancreatic juice has not been determined completely, owing to the rarity of opportunities of obtaining the secretion. ' American Journal of Physiology, 1899, vol. ii. p. 483. CHEMmTRY OF DIGESTION AND NUTRITION. 301 Several partial analyses have been reported.. According: to Zawadsky,^ the composition of the secretion in a young woman was as follows : In 1000 parts. Water . . . . 864.05 Organic substances 132.51 Proteids . . . 92.05 ^ults ... . . . 3.44 The organic substances held in the secretion are in part of an albuminous nature, since they coagulate upon heating, but tiie exact nature of the proteid or proteids has not been determined satisfactorily. The most important of the organic substances — the essential constituents, indeed, of the whole secretion — are three enzymes acting respectively upon the proteids, the carbohydrates, and the fats. The proteolytic enzyme is called "trypsin;" the amylolytic enzyme is described under diiferent names : " amylopsin " is perhaps the best, and will be adopted in this section ; for the fat-splitting enzyme we shall use the term " steapsin." Owing to the presence of these enzymes the pancreatic secretion is capable of exerting a digestive action upon each of the three im- portant classes of food-stuifs. It is said that the pancreatic juice contains also a coagulating enzyme, similar to rennin, capable of curdling milk. Trypsin. — Trypsin is a more po\verful proteolytic enzyme than pepsin. Unlike the latter, trypsin acts best in alkaline media, but it is effective also in neutral liquids, or even in solutions not too strongly acid. Trypsin is aifected by changes in temperature like the other enzymes, its action being retarded by cooling and hastened by warming. There is, however, a temperature, that may be called the optimum temperature, at which the trypsin acts most powerfully ; if, however, the temperature is raised to as much as 70° to 80° C, the enzyme is destroyed entirely. Trypsin has never been isolated in a condi- tion sufficiently pure for analysis, so that its chemical composition is unknown. Extracts containing trypsin can be made from the gland veiy easily and bv a variety of methods. The usual laboratory method is to mince the gland and to cover it with glycerin for some time. In using this and other methods for preparing trypsin extracts it is best not to take the perfectly fresh gland, but to keep it for a number of hours before using. The reason for this is that the enzyme exists in the fresh gland in a preparatory stage, a zymogen (see sec- tion on Secretion), which in this case is called " trypsinogen." Upon standing, the latter is slowly converted to trypsin — a process that may be hastened by the action of dilute acids and by other means. An artificial pancreatic juice is prepared usually by adding a small quantity of the pancreatic extract to an alkaline liquid ; the liquid usually employed is a solution of sodium carbonate of from 0.2 to 0.5 per cent. To prevent putrefactive changes, which come on with such readiness in pancreatic digestions, a few drops of an alcoholic solution of thymol may be added. A mixture of this kind, if kept at the proper temperature, digests proteids very rapidly, and most of our knowledge of the action of trypsin has been obtained from a study of the products of such digestions. •■CenlrcdblaUfur Physiologic, 1891, Bd. v. S. 179. 302 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Products of Tryptic Digestion. — Tryptic digestion resembles peptic diges- tion in that proteoses and peptones are the chief products formed, but the two processes differ in a number of details. The naked-eye appearances, in the first place, are different in cases in which the proteid acted upon is in a solid form ; for while in the pepsin-hydrochloric digestion the proteid swells up and grad- ually dissolves, under the action of trypsin it does not swell, but suffers erosion, as it were, the solid mass of proteid being eaten out until finally only the indi- gestible part remains, retaining the shape of the original mass, but falling into fragments when shaken. In the second place, the hydrolytic cleavages seem to be of a more intense nature. In peptic digestion, after the syutonin stage is passed, there is a gradual change to peptone through the intermediate primary and secondary proteoses. Under the influence of trypsin, according to the most recent experiments, the solid proteid undergoes a transformation directly to secondary proteoses (deutero-proteoses), the intermediate stages being skipped. It was formerly thought that the solid proteid was converted first into a soluble proteid, and that if the solution was alkaline some alkali-albumin was formed, precipitable by neutralization, and comparable to the syntonin of pepsin-iiydro- chloric digestion. This soluble proteid was thought to be split into proteoses of the hemi- and anti- groups which were then converted to the corresponding peptones, according to Kiilme's schema (p. 293). There seems to be no doubt that with the proteid most frequently used in artificial digestion — namely^ fibrin from coagulated blood — the first effect is a conversion to a soluble globulin-like form of proteid ; but Neumeister finds that this does not happen with other proteids, and he thinks that in the case of fibrin it is not due to a true digestive action of tryjjsin, but to a partial solution of the fibrin by the inorganic salts in tlie liquid. In general, however, the preliminary stage of a soluble proteid is missed, as also is that of the primary proteoses. The proteid falls at once by hydrolytic cleavage into deutero-proteoses, and these in turn are transformed to peptones. Just at this point comes in one of the most characteristic differences between the action of pepsin and that of tryp- sin. Pepsin cannot affect the peptones further, but trypsin may act upon the supposed hemi-constituent and split it up, with the formation of a number of much simpler nitrogenous bodies, most of which are amido-acids. The final products of prolonged tryptic digestion are, first, a peptone which cannot further be decomposed by the enzyme and which constitutes wliat is known as anti-peptone^ and, second, a number of simpler organic substances, amido- ' In the account of tryptic digestion as in the case of pepsin the nomenclatnre of Kiihne is adhered to. It should be stated, however, that of late years some doubt has been thrown upon the existence of an anti-peptone. Siegfried (Archiv fiir Physiologie, 1894) identifies it with a body to which he gives the name carnic acid, while Kutscher {Zeltachrift fur physiologische Chetnie, Bd. 25) finds that anti-peptone prepared by Kiihne's method is at least a mixture, since it con- tains the bases lysin, arginin, and histidin. If it should be shown that what has been called anti-peptone is not a peptone at all, but a mixture of simpler bodies, then it would seem that the original basis of Kuhne's theory would Ijp destroyed. There would be no occasion for supposing the existence of hemi- and anti-groupings. The general schema of digestion that has been developed by this theory, with its stages of proteoses and peptones, would not, however, be interfered with. CHEMISTRY OF DIGESTION AND NUTRITION 303 acids and nitrogenous bases, that come from the splitting of that part of the peptone which can be acted upon by the trypsin, and which constitutes what is known as hemi-peptone. It may be remarked in passing that hemi-peptone has not been isolated. Ampho-peptones containing both anti- and hemi-pep- tones are formed in peptic digestion, and they may be obtained from tryptic digestion if it is not allowed to go too far ; anti-peptone, on the other hand, may be obtained from tryptic digestion which has been permitted to go on until the hemi-peptone has been completely destroyed, but no good method is known by which hemi-peptone can be isolated from solutions containing both it and the anti- form. The principal products formed by the breaking up of the hemi-peptone molecule under the influence of the trypsin can be formed in the laboratory by processes that are known to cause hydrolytic decomposi- tions. It is probable, therefore, that these substances may be looked upon as products of the hydrolytic cleavage of hemi-peptone. They are of smaller molecular weight and of simpler structure than the peptone molecule from which they are formed. A tabular list of these bodies, modified from Gam- g;ee,^ is given. The list includes only those substances that have actually been isolated ; it is possible that others exist : Final Products [other than Peptones) of the Action of Trypsin on Albuminous and Albuminoid Bodies. Bodies derived from the fatty acids. Bases. Organic body of unknown composition. Aromatic bodies. Iso-butyl amido-acetic Lvsin. Tryptophan (gives a Paroxyphenylamidopro- acid (leucin). Histidin. red color on the ad- pionic acid (tyrosin). Amido - valerianic acid Arginin. dition of chlorine- (biitalanin). Lvsatinin. water, and violet Amido-succinic acid (as- NH3. with bromine-water). partic acid). Amido-pyrotartaric acid (glutamic acid). (Diamido-acetic acid?) ' Of these substances, the ones longest known and most easily isolated are leucin (CjHjjNOj) and tyrosin (CgHuNOg). The chemical composition and proper- ties of these and the other products are described in the Chemical section. Leucin and tyrosin have been found in the contents of the intestines, and it is probable, therefore, that the splitting of the peptone that takes place so readily in artificial tryptic digestions occurs also, to some extent at least, within the body, although we have no accurate estimates of the amount of peptone destroyed in this way under normal conditions. On the supposition that tlie production of leucin, tvrosin, and the otlier simple nitrogenous bodies is a normal result of trvptic digestion within the body, it is interesting to inquire what physiological value, if any, is to be attributed to these, substances. At first sight, the formation of these simpler bodies from the valuable peptone would seem to be a waste. Peptone we know may be absorbed into the blood, and may then be used to form or repair proteid tissue, or to furnish energy to the ^ A Text-book of the Physiological Chemistry of the Animal Body, 1893, vol. ii. p. 230. 304 ^.V AMEBICAX TEXT-BOOK OF PHYSIOLOGY. body upon oxidation, but leucin and tyrosin and the other products of the breaking up of peptone are far less valuable as sources of energy, and so far as we know they cannot be used to form or repair proteid tissue. But we must be careful not to jump too hastily to the conclusion that the splitting of the peptone is useless. It remains possible that a wider knowledge of the subject may show that the process is of distinct value to the body, although it must be confessed that no plausible suggestion as to its importance has yet been made. In addition to any possible functional value which these amido- bodies and nitrogenous bases may possess, their occurrence in proteolysis is of immense interest to the physiologist. Some of them are of a constitution simple enough to be studied by exact chemical methods, and the hope is entertained that tlirough them a clearer knowledge may be obtained of tlie structure of the proteid molecule. It should be added that not only are these bodies found in the alimentary canal as products of tryptic digestion, but that they, or some of them, occur also in other parts of the body, especially under pathological conditions, and that, furthermore, they occur among the products of the destruction of the proteid molecule by laboratory methods or by the action of bacterial organisms. The different stages in a complete tryptic digestion as outlined above are represented in brief in the following scliema, modified from Neumeister : ' Proteid. I Deutero-albumoses. Peptone. \ Anli-peptone. Henii-peptone. I Leucm. Tyrosin. Aspartic acid. Nitrogenous bases. It may be said in conclusion that trj^psin produces peptone from proteids more readily than does pepsin. Under normal conditions it is probable that most of the proteid of the food receives its final preparation for absorption in the small intestine, under the influence of this enzyme. Albuminoids. — Gelatin and the other albuminoids are acted upon by trypsin, the products being similar in general to those formed from the pro- teids. As stated on page 297, pepsin carries the digestion of gelatin mainly to the gelatose stage; trypsin, however, produces gelatin peptones. It seems probable, therefore, that the final digestion of the albuminoids also is effected in the small intestine. Amylopsin. — The enzyme of the pancreatic secretion that acts upon starches is found in extracts of the gland, made according to the general methods already given, and its presence may be demonstrated, of course, in the secretion obtained by establishing a pancreatic fistula. The proof of the existence of this enzyme is found in the fact that if some of the pancreatic secretion or some of the extract of the gland is mixed with starch paste, the ' Lehrbmh der phyaiohghchen Ohemie, 1893, S. 200. CHEMISTRY OF DIGESTION AND NUTRITION. 305 starch quickly disappears and maltose or maltose and dextrin are found in its place. Amylopsin shows the general reactions of enzymes with rela- tion to temperature, incompleteness of action, etc. Its specific reaction is its efifect upon starches. Investigation has shown that the changes caused by it in the starches are apparently the same as those produced by ptyalin. In fact, the two enzymes ptyalin and amylopsin are identical in properties as far as our knowledge goes, so that it is not uncommon, in German liter- ature especially, to have them both described under the name of ptyalin. The term amylopsin is convenjent, however, in any case, to designate the special origin of the panci'eatic enzyme. As to the details of its action, it is unnecessary to repeat what has been said on page 285. The end-products of its action, as far as can be determined from artificial digestions, are a sugar, maltose (CijHjjOjuHjO), and more or less of the intermediate achrobdextrins, the relative amounts depending upon the completeness of digestion. As has previously been said, there are indications that under the favorable conditions of natural digestion all the starch may be changed to maltose, but possibly it is not necessary that the action should be so complete in order that the carbohydrate may be absorbed into the blood, as will be shown when we come to speak of the further action of the intestinal secretion upon maltose and the dextrins. The amylolytic action of the pancreatic juice is extremely import- ant. The starches constitute a large part of our ordinary diet. The action of the saliva upon them is probably, for reasons already given, of subordinate importance. Their digestion takes place, therefore, entirely or almost entirely in the small intestine, and mainly by virtue of the action of the amylopsin contained in the pancreatic secretion. The action of the amylopsin is supple- mented to some extent, apparently, by a similar enzyme formed in small quantities in the intestinal wall itself, the nature of which will be described presently in connection with intestinal secretion. Steapsin. — Steapsin, or lipase, is the name given to a fat-splitting enzyme occurring in the pancreatic juice. It is of the greatest importance in the digestion and absorption of fats. The peculiar power of the pancreatic juice to split neutral fats with the liberation of free fatty acid was first described by Bernard. His discovery has since been corroborated for different animals, including man, by the use of normal pancreatic juice obtained from a fistula, or by the aid of the tissue of the fresh gland, or, finally, by means of extracts of the gland. When neutral fats (see Chemical sw'tion for the composition of fats) are treated with an extract containing steapsin, they take up water and then undergo cleavage (hydrolysis), with the production of glycerin and the free fatty acid found in the particular fat used. This reaction is explained by the following equation, in which a general formula for fats is used : C3H,(G„H,„,,COO)3 + 3HP = C3H,(OH)3 -|- 3(C„H,„,,COOH). Fat. Glycerin. Free fatty acid. The reaction in the case of palmitin would be — C3H,(C„H3,COO)3 + 3H,0 = C3H,(OH)3 + 3(C,,H3,C»OH). Palmitin. Glycerin. Palmitic acid. Vol. I.— 20 306 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. While this action is undoubtedly caused by an enzyme, it has not been possible to isolate the so-called " steapsin " in a condition of even approximate purity. As a matter of fact also, ordinary extracts of pancreas, such as the laboratory extracts in glycerin, do not usually show the presence of this enzyme unless special precautions are taken in their preparation. It would seem that steapsin is easily destroyed. With fresh normal juice or with pieces of fresh pancreas the fat-splitting effect can be demonstrated easily. One striking method of making the demonstration is to use butter as the fat to be decomposed. If butter is mixed with normal pancreatic juice or with pieces of fresh pancreas, and the mixture is kept at the body-temperature, the several fats contained in butter will be decomposed and the corresponding fatty acids will be liberated, among them butyric acid, which is readily recognized by its familiar odor, that of rancid butter. The action of steapsin, as in the case of the other enzymes, is very much influenced by the temperature. At the body-temper- ature the action is very rapid. The nature of the fat also influences the rapidity of the reaction ; it may be said, in general, that fats with a high melting-point are less readily decomposed than those with a low melting- point. It has been shown, however, that even spermaceti, which is a body related to the fats and whose melting-point is 53° C, is decomposed, although slowly .and imperfectly, by steapsin. The fat-splitting action of the steapsin undoubtedly takes place normally in the intestines, but it is questionable whether all the fat eaten undergoes this process. In fact, it may be said that two views are taught at present regarding the digestion and absorption of fats. According to the older view, only a certain small proportion of the fat undergoes splitting, or saponification, as it is sometimes called. The remain- der of the fat becomes emulsified by the products (fatty acids) formed in the splitting, and are absorbed in an emulsified condition as neutral fats. Accord- ing to the more recent view,' all the fat is supposed to be acted upon by the steapsin, with or without previous emulsifieation, with the formation of glycerin and fatty acids. These two products, the latter perhaps in part as a soap formed by reaction with the alkaline salts of the intestine, are absorbed in solution, and subsequently are recombined, probably in the substance of the epithelial cells, to form a neutral fat again. On both theories one of the first results of the action of the steapsin is the formation of an emulsion, the value of Avhich on the first theory is that it brings the fat into a form in which it can be ingested by the epithelial cells of the villi, while on the second theory it consists in the fact that by subdividing the fat globules minutely the completion of the process of saponification is hastened. On either view, therefore, emulsifieation is an interesting pi'eliminary to the absorption of fat, and some discussion of the nature of the process seems to be demanded. Bmulsifloation of Pats. — An oil is emulsified when it is broken up into minute globules that do not coalesce, but remain separated and more or less uniformly distributed throughout the medium in which they exist. Artificial emulsions can be made by shaking oil vigorously in viscous solutions 'Moore and Eockwood: Journal of Physiology, 1897, vol. 21, p. 58. CHElMISTRY OF DIGESTION AND NUTRITION. 307 of soap, mucilage, etc. Milk is a natural emulsion that separates partially on standing, some of the oil rising to the top to form cream. Bernard made the important discovery that when oil and pancreatic juice are shaken together au emulsion of the oil takes place very rapidly, especially if the temperature is about that of the body. The main cause of the emulsification has been shown to be the formation of free fatty acids due to the action of steapsin, and the union of these acids with the alkaline salts present to form soaps. This fact has been demonstrated by experiments of the following character : If a perfectly neutral oil is shaken with an alkaline solution (J per cent, sodium-carbonate solution), no emulsion occurs and the two liquids soon sepa- rate. If to the same neutral oil one adds a little free fatty acid, or if one uses rancid oil to begin with and shakes it with \ per cent, sodium-carbonate solution, an emulsion forms rapidly and remains for a long time. Oil con- taining fatty acids when shaken with distilled water alone will not give an emulsion. It has been shown, moreover, by Gad and Ratchford that with a certain percentage of free fatty acids (5J per cent.) rancid oil and a sodium- carbonate solution will form a fine emulsion spontaneously — that is, without shaking. Shaking, however, facilitates the emulsification when the amount of free acid varies from this optimum percentage. In what way the formation of soaps in an oily liquid causes the oil to become emulsified is still a matter of speculation. The splitting of the oil into small drops seems to be caused, in cases of spontaneous emulsification, by the act of formation of the soap — that is, the union of the alkali with the fatty acid — in other cases by the mechanical shaking, or by these two causes combined. The application of these facts to the action of the pancreatic juice in the small intestine is easily made. When the chyme, containing more or less of liquid fat, comes into contact with the pancreatic juice, a part of the oil is quickly split by the steapsin, with the formation of free fatty acids. These acids unite with the alkalies and the alkaline salts present in the secretions of the small intestine (pancreatic juice, bile, intestinal juice) to form soaps. The formation of the soaps, aided, perhaps, by the peristaltic movements of the intestine, emulsifies the remainder of the fats and thus prepares them for absorption or further saponification. It has been suggested that the proteids in solution in the pancreatic juice aid in the emulsification, but there is no experimental evi- dence to show that this is the case. A factor of much more importance is the influence of the bile. In man the pancreatic juice and the bile are poured into the duodenum together, and in all mammals the two secretions are mixed with the food at some part of the duodenum. Now, it has been shown beyond question that a mixture of bile and pancreatic juice will cause a splitting of fats into fatty acids and glycerin much more rapidly than will the pancreatic juice alone.^ This effect of the bile is not due to the presence in it of a fat-splitting enzyme of its own : the bile seems merely to favor in some way the action of the steapsin contained in the pancreatic secretion. ' Xencki : Archiv fur experimentelk Pathnlogie u. Pharmakologie, 1886, Bd. 20, S. 367 ; Eatch- ford: Journal of Physiology, 1891, vol. 12, p. 27. 308 ^l.V AMERICAN TEXT-BOOK OF PHYSIOLOGY. Intestinal Secretion. — The small intestine is lined with tubular glands, the crypts of Lieberkiihu, that are supposed to form a secretion of consid- erable importance in digestion. To obtain the intestinal secretion, or mcms entericus, as it is often called, recourse has been had to an ingenious operation for establishing a permanent intestinal fistula. This operation, which usually goes under the name of the " Thiry-Yella fistula," consists in cutting out a small portion of the intestine without injuring its supply of blood-vessels or nerves, and then sewing the two open ends of this piece into the abdominal wall so as to form a double fistula. The continuity of the intestines is estab- lished by suture, while the isolated loop with its two openings to the exterior can be used for collecting the intestinal secretion uncontaminated by partially- digested food. The secretion is always small in quantity, and it must be started by a stimulus of some kind. According to Rohmann,^ it varies in quantity in different parts of the small intestine, being very scanty in the upper part and more abundant in the lower. The intestinal secretion is a yellowish liquid with a strong alkaline reaction. The reaction is due to the presence of sodium carbonate, the quantity of which is about 0.25 to 0.50 per cent. The chemical composition of the secretion has not been satisfactorily determined, but its digestive action has been investigated with success. Uj)on proteids and fats it is said to have no specific action — that is, it contains neither a proteolytic nor a fat-splitting enzyme. The possible value of its sodium carbonate in aiding the emulsification of fats has been referred to in the preceding paragraph. Upon carbohydrates the secretion has an important action. In the first place, it has been shown that it contains an amylolytic enzyme that is more abun- dant in the upper than in the lower part of the intestine. This enzyme doubt- less aids the amylopsin of the pancreatic secretion in converting starches to sugar (maltose) or sugar and dextrin. What is still more important, however, is the presence of inverting enzymes (invertase) capable of converting cane- sugar (sacciiarose) into dextrose and levulose, and of a similar enzyme (nial- tase) capable of changing maltose to dextrose. Both of these effects are examples of the conversion of di-saccharides to mono-saccharides. The di-saccharides of importance in digestion are cane-sugar, milk-sugar, and maltose. The first of these forms a common constituent of our daily diet; the second occurs always in milk ; and the third, as we have seen, is the main end-product of the digestion of starches. These substances are all readily soluble, and we might expect that they would be absorbed directly into the blood without undergoing further change. As a matter of fact, however, it seems that they are first dissociated under the influence of the sugar-splitting enzymes into simpler mono-saccharide compounds, although in the ca.sc of lactose this statement is perhaps not en'tirely justified, our knowledge of the fate of this sugar during absorption being as yet incomplete. According to some authors, lactose is absorbed unchanged (see Chemical section). The general nature of this change is expressed in the three following reactions : ' PUmer's Archivfur die gesammte Physiologie, 1887, Bd. 41, S. 411. CHE3ITSTRY OF DIGESTION AND NUTRITION. 309 Maltose. Dextrose. Dextrose. Cane-sugar. Dextrose. Levulose. CuH,Ai + H,0 = C,H„0, + C,H,A- Lactose. Dextrose. Galactose. For the reactions by means of which these diiferent isomeric forms of sugar are distinguished reference must be made to the Chemical section. The final stage in the artificial digestion of starches is the formation of maltose or of a mixture of maltose and dextrins. In the intestines, however, the process is carried a step farther by the aid of the sugar-splitting enzymes, and the maltose, and ap- parently the dextrins also, are converted into dextrose. According to this descrij)- tion, all of the starch is finally absorbed into the blood in the form of dextrose; and this conclusion falls in with the fact that the sugar found normally in the blood exists always in the form of dextrose. With reference to the sugar-splitting enzymes found in the small intestine, it should be added that they occur more abundantly in the mucous membrane than in the secretion itself. Indeed, the secretion is normally so scanty, especially in the upper part of the intestine, that it cannot be supposed to do more than moisten the free surface, and it is probable that the action of these enzymes takes place upon or in the mucous membrane, as the last step in the series of digestive changes of the carbohydrates immediately preceding their absorption. Digestion in the Large Intestine. — Observations upon the secretions of the large intestine have been made upon human beings in cases of anus prseter- naturalis in which the lower portion of the intestine (rectum) was practically isolated. These observations, together with those made upon lower animals, unite in showing that the secretion of the large intestine is mainly composed of mucus, as the histology of the mucous memljrane would indicate, and that it is very alkaline, and probably contains no digestive enzymes of its own. When the contents of the small intestine pass through the ileo-caecal valve into the colon they .still contain a quantity of incompletely digested material mixed with the enzymes of the small intestine. It is likely, therefore, that some at least of the digestive processes described above may keep on for a time in the large intestine ; but the changes here of most interest are the absorption that takes place and the bacterial decompositions. The latter are described briefly below. Bacterial Decompositions in the Intestines. — Bacteria of different kinds have been found throughout the alimentary canal from the mouth to the rectum. In the stomach, however, under normal conditions, the strong acid reaction prevents the action of those putrefactive bacteria that decom- pose proteids, and prevents or greatly retards the action of those that set up fermentation in the carbohydrates. Under certain abnormal conditions known to us under the general term of di/xpepsia, bacterial fermentation of the carbohydrates may be pronounced, but this must be considered as path- ological. 310 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. In the small intestine the secretions are all alkaline, and it was formerly taken for granted that the intestinal contents are normally alkaline. If this were so, the bacteria would find a favorable environment. It was supposed that putrefaction of the proteids might occur, especially during the act of tryptic digestion, and this supposition was borne out by the exti-aordinary readiness of ar- tificial pancreatic digestions to undergo putrefaction when not protected in some way. Two recent cases ' of fistula of the ileum at its junction with the colon in human beings have given opportunity for exact study of the contents of the small intestine. The results are interesting, and to a certain extent are opposed to the preconceived notions as to reaction and proteid putrefaction which have just been stated. They show that the contents of the intestine at the point where they are about to pass into the large intestine are acid, provided a mixed diet is used, the acidity being due to organic acids (acetic) and being equal to 0.1 per cent, acetic acid. These acids must have come from the bacterial fer- mentation of the carbohydrates, and a number of bacteria capable of producing such fermentation were isolated. The products of bacterial putrefaction of the proteids, on the contrary, were absent, and it has been suggested that the acid reaction produced by the fermentation of the carbohydrates serves the nseful purpose, under normal conditions, of preventing the putrefaction of the pro- teids. With reference, therefore, to the point we are discussing — namely, the bacterial decomposition of the contents of the intestines — we may conclude, upon the evidence furnished by these two cases, that in the human being, when living on a mixed diet, some of the carbohydrates undergo bacterial decompo- sition in the small intestine, but that the proteids are protected. We may further suppose that in the case of the proteids the limits of protection are easily overstepped, and that such a condition as a large excess'^of proteid in the diet or a deficient absorption from the small intestine may easily lead to exten- sive intestinal putrefaction involving the proteids as well as the carbohydrates. In the large intestine, on the contrary, the alkaline reaction of the secretion is more than sufficient to neutralize the organic acids arising from fermentation of the carbohydrates, and the reaction of the contents is therefore alkaline. Here, then, what remains of the proteids undergoes, or may undergo, putrefac- tion, and this process must be looked upon as a normal occurrence in the large intestine. The extent of the bacterial action upon the proteids as well as the carbohydrates may vary widely even within the limits of health, and if excessive may lead to intestinal troubles. Among the products formed in this way, the following are known to occur : Leucin, tyrosin, and other amido-acids ; indol ; skatol ; phenols ; various members of the fatty-acid series, such as lactic, butyric, and caproic acids ; sulphuretted hydrogen ; methane ; hydrogen ; methyl mercaptan, etc. Some of these products will be described more fully in treating of the composition of the feces. To what (extent these products are of value to the body it is difficult, with our imperfect knowledge, to say. It has been pointed out, on the one hand, that some of them (skatol, fatty •Macfayden, Nencki, and Sieber: Archivfiir experimentelie Patlwlogie u. Pharmakologie, 1891' Bd. 28, .S. 311 ; Jakowski : Archives des Sciences biologigues, St. Petersburg, 1892, t. 1. CHEMISTRY OF DIGESTION AND NUTRITION 311 acids, CO2, CH^, and HjS) promote the movements of the intestine, and may be of value from this standpoint ; on the other hand, some of them are absorbed into the blood, to be eliminated again in different form in the urine (indol and phenols), and it may be that they are of importance in the metab- olism of the body ; but concerning this our knowledge is deficient. On the whole, we must believe that the food in its passage through the alimentary canal is acted upon mainly by the digestive enzymes, the so-called " unorgan- ized " ferments, but that the action of the bacteria, or organized ferments, is responsible for a part of the changes that the food undergoes before its final elimination in the form of feces. These two kinds of action vary greatly within normal limits, and to a certain extent they seem to 'be in inverse relationship to each other. When the digestive enzymes and secretions are deficient or ineffective the field of action for the bacteria is increased, and this seems to be the case in some pathological conditions, the result being intes- tinal troubles of various kinds. The limits of normal bacterial action have not been worked out satisfactorily, but it is evident that our knowledge of digestion will not be complete until this is accomplished. It should be stated in conclusion that, however constant and important the occurrence of bacterial fermentation may be in the alimentary canal, it cannot be regarded as essential to the life of the animal, since Nuttall and Theirfelder,^ in a series of ingenious experiments made upon newly-born guinea-pigs, have shown that these animals may thrive, for a time at least, when the entire alimentary canal is free from bacteria. E. Absorption ; Summary op Digestion and Absorption op THE FoOD-STUPPS; FbCES. In the preceding sections we have followed the action of the various digestive secretions upon the food-stuffs as far as the formation of the supposed end-products. In order that these products may be of actual nutritive value to the body, it is necessary, of course, that they shall be absorbed into the circulation and thus be distributed to the tissues. There are two possible routes for the absorbed products to take : they may pass immediately into the blood, or they may enter the lymphatic system, the so-called " lacteals " of the alimentary canal. In the latter case they reach the blood finally before being distributed to the tissues, since the thoracic duct, into which the lym- phatics of the alimentary canal all empty, opens into the blood-vascular system at the junction of the left internal jugular and subclavian veins. The sub- stances that take this route are distributed to the tissues by the blood, but it is to be noticed that, owing to the sluggish flow of the lymph-circulation (see section on Circulation), a relatively long time elapses after digestion before they enter the blood -current. The products that enter the blood directly from the alimentary canal are distributed rapidly ; but in this case we must remember that they first pass through the liver, owing to the existence of 1 Zeitschriftfiir physiologische Chemie, 1895, Bd. 21; 1896, Bd. 22, and 1897, Bd. 23. 312 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the portal circulation, before they reach the general circulation. During this passage through the liver, as we shall find, changes of the greatest importance take place. The physiology of absorption is concerned with the physical and chemical means by which the end-products of digestion are taken up by the blood or the lymph, and the relative importance of the stomach, the small intestine, and the large intestine in this process. Leaving aside the fats, whose absorption is a special case, the absorption of the other products of digestion was formerly thought to be a simple physical process. The processes of diffusion and osmosis, as they are known to occur outside the body, were supposed to account for the absorption of all the soluble products. This belief is still held by many, but the facts known ^\\i\\ regard to the absorp- tion of the carbohydrates, proteids, and fats after the changes undergone during digestion are not wholly accounted for l)y the laws of diifusion and osmosis as they are known to us (see p. 65 for a discussion of the nature of these processes). For the present at least it seems to be necessary to refer many of the phenomena of physiological absorption to the peculiar properties of the living epithelial cells lining the alimentary canal. iSome of tlie important facts regarding absorption are as follows : Absorption in the Stomach. — In the stomach it is possible that there might be absorption of the following substances : water ; salts ; sugars and dextrins that may have been formed in salivary digestion from starch, or that may have been eaten as such ; the proteoses and peptones formed in the peptic digestion of proteids or albuminoids. In addition, absorption of soluble or liquid substances — drugs, alcohol, etc. — that have been swallowed may occur. It was formerly assumed without definite proof that the absorp- tion in the stomach of such things as water, salts, sugars, and peptones was very important. Of late years a number of actual experiments have been made, under conditions as nearly normal as possible, to determine the extent of absorption in this organ. These experiments have given unexpected results, showing, upon the whole, that absorption does not take place readily in the stomach — certainly nothing like so easily as in the intestine. The methods made use of in these experiments have varied, but the most interesting results have been obtained by establishing a fistula of the duodenum just beyond the pylorus.' Through a fistula in this position substances can be introduced into the stomach, and if the cardiac orifice is at the same time shut off by a ligature or a small balloon, they can be kept in the stomach a given time, then be removed, and the changes, if any, be noted. After establishing the fistula in the duodenum food may be given to the animal, and the contents of the stomach as they pass out through the fistula may be caught and examined. The older methods of introducing the substance to be observed into the stomach through the oesophagus or through a gastric fistula were of little use, since, if the substance disappeared, there was no way of deciding whether it was absorbed or was simply passed on into the intestine. ' Compare von Mering: Verhandl. des Congresses f. innere Med., 12, 471, 189.S; Edkins: Jdiirnal of Physiology, 1892, vol. 13, p. 445; Brandl : Zeitschrifl fiir Biologie, 1892, Bd. 29, S. 277. CHEMISTRY OF DIGESTION AND NUTRITION. 313 Water. — Experiments of the character just described show that water when taken alone is practically not absorbed at all in the stomach. Von Mering's experiments especially show that as soon as water is introduced into the stomach it begins to pass out into the intestine, being forced out in a series of spirts by the contractions of the stomach. Within a comparatively short time practically all the water can be recovered iu this way, none or very little having been absorbed in the stomach. For example, in a large dog with a fistula in the duodenum, 500 cubic centimeters of water were given through the mouth. Within twenty-five minutes 495 cubic centimeters had been forced out of the stomach through the duodenal fistula. The result was not true for all liquids ; alcohol, for example, was absorbed readily. Salts. — The absorption of salts from the stomach has not been investigated thoroughly. According to Brandl, sodium iodide is absorbed very slowly or not at all in dilute solutions. Not until its solutions reach a concentration of 3 per cent, or more does its absorption become important. This result, if applicable to all the soluble inorganic salts, would indicate that under ordi- nary conditions they are practically not absorbed in the stomach, since it can- not be supposed that they are normally swallowed in solutions so concentrated as 3 per cent. It was found that the absorption of sodium iodide was very much facilitated by the use of condiments, such as mustard and pepper, or alcohol, which act either by causing a greater congestion of the mucous mem- brane or perhaps by directly stimulating the epithelial cells. Sugars and Peptones. — Experiments by the newer methods leave no doubt that sugars and peptones can be absorbed from the stomach. In Von Mering's work diiferent forms of sugar — dextrose, lactose, saccharose (cane-sugar), maltose, and also dextrin — were tested. They were all absorbed, but it was found that absorption was more marked the more concentrated were the solutions. Brandl, however, reports that sugar (dextrose) and peptone were not sensibly absorbed until the concentration had reached 5 per cent. With these sub- stances also the ingestion of condiments or of alcohol increased distinctly the absorptive processes in the stomach. On the whole it would seem that sugars and peptones are absorbed with some difficulty from the stomach. Fats. — As we have seen, fats undergo no digestive changes in the stomach. The processes of saponification and emulsification are supposed to be pre- liminary steps to absorption, and, as these processes take place only after the fats have reached the small intestine, there seems to be no doubt that in the stomach fats escape absorption entirely. Absorption in the Small Intestine. — The soluble products of digestion — sugars and peptones or proteoses, as well as the saponified and emulsified fats — are mainly absorbed in the small intestine. This we should ex- pect from a mere a priori consideration of the conditions prevailing in this part of the alimentary canal. The partially-digested food sent out from the stomach meets the digestive secretions in the beginning of the small intestine. As we have seen, the diiferent enzymes of the pan- creatic secretion act powerfully upon the three important classes of food- stuffs and we have every reason to believe that their digestion makes 314 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. rapid progress. The passage of the food along the small intestine, although rapid compared with its passage through the large intestine, requires a number of hours for its completion. According to the observations made upon a patient with a fistula at the end of the small intestine,' food begins to pass into the large intestine in from two to five and a quarter hours after it has been eaten, and it requires from nine to twenty-three hours before the last portions reach the end of the small intestine ; this estimate includes, of course,, the time in the stomach. During this progress it has been converted for the most part into a condition suitable for absorption, and the mucous membrane with which it is in contact is one peculiarly adapted for absorption, since its- epithelial surface is greatly increased in extent by the vast number of villi as well as by the numerous large folds known as the " valvules conniventes."^ In addition to these considerations, however, we have abundant experimental proof that absorption takes place actively in the small intestine. The absorp- tion of fats can be demonstrated microscopically, as will be described presently. Experiments made by Rohmann ^ and others with isolated loops of intestine have shown that sugars and peptones are absorbed readily and in much more dilute solutions than in the stomach. Moreover, in the case just referred to,, of an intestinal fistula at the end of the small intestine, a determination of the proteid present in the discharge from the fistula, after a test-meal contain- ing a known amount of proteid, showed that about 85 per cent, had disappeared — that is, had been absorbed before reaching the large intestine. With refer- ence to water and salts, it has been shown that they also are readily absorbed ; some very interesting experiments demonstrating this fact have been reported bv Heidenhain.^ It must be remembered, however, that under normal con- ditions the absorption of water and salts is more or less compensated by the secretion formed along the length of the intestine, so that when the contents reach the ileo-csecal valve they are still of a fluid consistency similar to that of the chyme when it left the stomach to enter the intestine. A consideration of the mechanism of the absorption of fats, sugars, peptones, and water will be taken up presently, after a few words have been said of absorption in the large intestine. Absorption in the Large Intestine. — There can be no doubt that absorp- tion forms an important part of the function of the large intestine. The contents pass through it with great slowness, the average duration being given usually as twelve hours, and while they enter through the ileo-csecal valve in a thin fluid condition, they leave the rectum in the form of nearly solid feces. This fact alone demonstrates the extent of the absorption of water. As for the sugar and peptones, examination of the intestinal contents as they entered the large intestine in the case of fistula cited in the preceding paragraph showed that there may still be present an important percentage of proteid (14 per cent.) and a variable amount of sugars and fats — more than is ' Macfadyen, Nencki, and Sieber : Archivfur experimentelle Pathologie u. Pharmakologie, 1891,., Bd. 28, S. 311. ' Pjliiger's Archiv fur die gesammte Phyaiologie, 1887, Bd. 41, S. 411. ' Ibid., 1894, Bd. 56, S. 637. CHEMISTRY OF DIGESTION AND NUTBITION 315 found normally in the feces. Some of this carbohydrate and proteid under- goes destruction by bacterial action, as has already been explained (p. 310), but some of it is absorbed, or may be absorbed, before decomposition occurs. The power of absorption in the large intestine has been strikingly demon- strated by the fact that various substances injected into the rectum are absorbed and suffice to nourish the animal. Enemata of this character are frequently used in medical practice with satisfactory results, and careful experimental work on lowei' animals and on men under conditions capable of being properly controlled has corroborated the results of medical experience and shown that even in the rectum absorption takes place. Without giving the details of this work, it may be said that it is now known that proteids in solution, or even such things as eggs beaten to a fluid mass with a little salt, are absorbed from the rectum, and this notwithstanding the fact that no proteolytic enzyme is found in this part of the alimentary canal. Fats also (such as milk-fat) and sugars can be absorbed in the same way. Some of these facts have been corroborated in a striking way by Harley ' in experi- ments upon dogs from whicli he had removed the whole of the large intes- tine. It was found that in these animals there was an increase in the quan- tity of water in the feces, the total quantity being nearly five times as much as in the normal dog. Absorption of Proteids. — As we have seen in the preceding paragraphs, absorption of proteids takes place in the stomach and the small and large intestines, but in all probability mainly in the small intestine. The end- products of the digestion of proteids by the proteolytic enzymes are proteoses and peptones. Tryptic digestion produces also leucin, tyrosin, and the related amido- bodies, but so far as proteid has undergone decomposition to this stage it is no longer proteid, and does not have the nutritive value of proteid. The logical conclusion from our knowledge of proteid digestion should be that all proteid is reduced to the form of proteoses or peptones before absorption, and that the great advantage of proteolysis is that proteids are more readily absorbed in this form than in any other. In the main we must accept this conclusion. The process of ^^roteid digestion would seem to be without mean- ing otherwise. But we must not shut our eyes to the fact that proteid may be absorbed in other forms than peptones or proteoses. This has been demon- strated most clearly for the rectum and the lower part of the colon, as was stated in the preceding paragraph. Enemata of dissolved muscle-proteid (myosin), egg-albumin, etc. are absorbed from this part of the alimentary canal without, so far as can be determined, previous conversion to peptones and proteoses, and we must admit that the same power is possessed by otlier parts of the intestinal tract. It is probable, for instance, that the very first product of pepsin-hydrochloric digestion, syntonin, is capable of absorption directly. This fact, however, does not weaken the conclusion that peptones and proteoses are absorbed more easily than other forms of proteids, and that they constitute the form in which the bulk of our proteid is absorbed. ' Proceedings of the Eoyal Society, London, 1899, vol. Ixiv. No. 408. 316 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Opinions as to why these forms of proteids are more easily absorbed than any other must vary with the theory held as to the nature of absorption. Ex- periments have shoAvn that proteoses and peptones are more easily diifusible than other forms of proteids, and this fact tends to support the view that their absorption is due to physical diffusion. The object of digestion, on this view, is to convert the insoluble and non-dialyzable proteids into soluble, diffusible peptones. But a study of the details of proteid absorption has shown that the process cannot be explained entirely by the la\\s of simple dialysis that govern the process of diffusion through dead membranes. Pro- teids, like egg-albumin, M'hich are practically non-dialyzable are absorbed readily from the intestine. ^Moreover, when one considers the rate of absorp- tion of peptone from the alimeutary tract, it seems to be much too rapid and complete to be accounted for entirely by the diflFusibility of this substance as determined by experiments with parchment dialyzers. It is believed, there- fore, that the initial act in the absorption of proteids is dependent in some way upon the peculiar properties of the layer of living epithelial cells lining the mucous membrane. Whether the peculiarity is a physical one depending on some special structure of the cells that makes them permeable to the pro- teid molecules, or whether it is a more obscure and complicated process con- nected with the living activity of the cells, remains undetermined for the present. After the proteids have passed through the epithelium it is a matter of importance to determine whether they enter the blood or the lymph circulation. Experiments have shown conclusively tliat they are transmitted directly to the blood-capillaries : ligature of the thoracic duct, for example, which shuts off tlie entire lymph-flow coming from the intes- tine, does not interfere with the absorption of proteids. There is one other fact of great significance in connection with this subject : the proteids are absorbed mainly, if not entirely, as proteoses and jieptones, and they pass immediately into the blood ; nevertheless, examination of the blood directly after eating, while the process of absorption is in full activity, fails to show any peptones or proteoses in the blood. In fact, if these substances are injected directly into the blood, they behave as foreign, and even as toxic, bodies. In certain doses they produce insensibility with lowered blood- pressure, and they may bring on a condition of coma ending in death. jNIoreover, when present in the blood, even in small quantities, they are eliminated by the kidneys and are evidently unfit for the use of the tissues. It follows from these facts that while the peptones and proteoses are being absorbed by the epithelial cells they are at the same time changed into some other form of j^roteid. What this change is has not been determined. Ex- periments have shown that peptones disappear when brought into contact with fresh pieces of the lining mucous membrane of the intestine which are still in a living condition. The statement has been made that the pejitoues and proteoses are converted to serum-albumin, or at least to a native albumin of some kind, but we have no definite knowledge beyond the fact that the peptones and proteoses, as such, disa])pear. It is well to call attention to the CHEMISTRY OF DIGESTION AND NUTRITION. 317 fact that the digestion of proteids is supposed, according to the schema already described, to consist in a process of hydration and splitting, with the forma- tion, probably, of smaller molecules. The reverse act of conversion of pep- tones back to albumin implies, therefore, a process of dehydration and poly- merization that presumably takes place in the epithelial cells. It is at this point in the act of absorption of proteids that our knowledge is most deficient. Absorption of Sugars. — The carbohydrates are absorbed mainly in the form of sugar or of sugar and dextrin. Starches are converted in the intes- tine into maltt)se or maltose and dextrin, and then by the sugar-splitting enzymes of the mucous membrane are changed to dextrose. Ordinary cane- sugar is hydrolyzed into dextrose and levulose before absorption, and milk- sugar possibly undergoes a similar change to dextrose and galactose, though less is known of this. So far as our knowledge goes, then, we may say that the carbohydrates of our food are eventually absorbed in the form mainly of dextrose or of dextrose and levulose, leaving out of consideration, of course, the small part that normally undergoes bacterial fermentation. In accordance ^vith this statement, we find that the sugar of the blood exists in the form of dextrose. It is apparently a form of sugar that can be oxidized very readily by the tissues. In fact, it has been shown that if cane-sugar is in- jected directly into the blood, it cannot be utilized, at least not readily, by the tissues, since it is eliminated in the urine ; whereas if dextrose is intro- duced directly into the circulation, it is all consumed, provided it is not injected too rapidly. The sugars are soluble and dialyzable, but, as in the case of peptones, exact study of their absorption shows that it does not follow in detail the known laM's of osmosis through dead membranes. Experiments indicate, however, that in a general way the behavior of solutions of sugar placed in isolated loops of the intestine may be understood by assuming that a diffusion takes place, and it may be therefore that the peculiarities observed are connected with the structure of the living epithelium. We have to deal here in fact, with the same difficulty as was encountered in the case of the- proteids. A special vital activity of the epithelial cells cannot be excluded, and we must be content to await a fuller development of experimental inves- tigation before attempting to come to a final conclusion. As in the case of the proteids, the absorbed sugars — dextrose or dextrose and levulose — pass directly into the blood, and do not under normal conditions enter the lymph- vessels. This has been demonstrated In' direct examination of the blood of the portal vein during digestion (von Mering'), a distinct increase in its sugar-contents being found. Examination of the lymph shows no increase in sugar unless excessive amounts of carbohydrates have been eaten (Heiden- hain). Absorption of Pats. — As has been stated, fats are absorbed either in solid form, as emulsified droplets, or as fatty acids or soaps. In the latter case the fatty acids are again recombined to particles of neutral fiit, pre- sumably within the substance of the epithelial cells. So far as the emulsified fat 1 Dii Bois-Keymond's Archivfur Anatomic und Fhysiologie, 1877, S. 413. 318 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. is concerned, the process of absorption must be of a mechanical nature. The details of the process have been worked out microscopicall_y and have given rise to numerous researches. It is unnecessary to speak of the various theories that have been held, as it has been shown by nearly all the recent work that the immediate agent in the absorption of fats is again the epi- thelial cells of the villi of the small intestine. The fat-droplets may Ije seen within these cells, and can be studied microscopically after digestion in the act of passing, or rather of being passed, through the cell-substance. Reference to the histology of the villi will show that each villus possesses a comparatively large lymphatic capillary lying in its middle and ending blindly, apparently, near the apex of the villus. Between this central lym- phatic — or lacteal, as it is called here — and the epithelium lies the stroma, or main substance of the villus, which, in addition to its blood-capillaries and plain muscle-fibres, consists mainly of lymphoid or adenoid tissue containing numerous leucocytes. The fat-droplets have to pass from the epithelium to the central lymphatic, for it is one of the most certain facts in absorption, and one which has been long known, that the fat absorbed gets eventually into the lacteals in an emulsified condition and thence is conveyed through the system of lymphatic vessels to the thoracic duct and finally to the blood. The name " lacteal," in fact, is given to the lymphatic capillaries of the villus on account of the raiiky appearance of their contents, after meals, caused by the emulsified fat. It should be added, however, that it has not been jjossible to demonstrate experimentally that all the absorbed fat passes into the thoracic duet. Attempts have been made to collect all the fat passing thi'ough the thoracic duct after a meal containing a Icnown quantity of fat, but even after making allowance for the unabsorbed fat in the feces there is a considerable percentage of the fat absorbed that cannot be recovered from the lymph of the thoracic duct. While this result does not invalidate the conclusion stated above that the fat passes chiefly, perhaps entirely, into the lacteals, it does indicate that there are some factors concerned in the process of fat- absorption that are at j^reseut unknown to us. The passage of the fat- droplets to the central lacteal is not difficult to understand. The adenoid tissue of the stroma is penetrated by minute unformed lymph-channels that are doubtless connected with the central lacteal. In each villus lymph is continually formed from the circulating blood, so that there must be a slow stream of lymph through the stroma to the lacteal. When the fat-droplets have passed through the epithelial cells (and basement membrane) they drop into the interstices of the adenoid tissue and are carried in this stream into the lacteal. The lacteals were formerly designated as the " absorbents," under the false impression that they attended to all the absorption going on in the intestines, including that of peptones, sugars, and fats. It is now known that their action under ordinary conditions is limited to the absorption of fats. Absorption of Water and Salts. — From what has been said (p. 312) it is evident that absorption of water takes place very slightly, if at all, in the stomach. Whenever soluble substances, such as peptones, sugars, or salts, are CHEMISTRY OF DIGESTION AND NUTRITION. 319 absorbed in this organ, a certain amount of \vater must go with them, but the bulk of the water passes out of the pylorus. In the small intestine absorp- tion of water and of inorganic salts evidently takes place readily, and accord- ing to the experiments of Rohmann and Heidenhain, already referred to, the laws governing their absorption are different from what we should expect at first sight if the process were simply one of diffusion. The differences as regards the absorption of salts are especially emphasized by the experiments of Heidenhain.^ flaking use of an interesting method, for which reference must be made to the original paper, Heidenhain has shown that not only dilute solutions, but solutions of nearly the same osmotic pressure as the blood were readily absorbed. Indeed, specimens of the animal's own serum introduced into a loop of the intestine were completely absorbed, although in this case there was practically no difference in composition between the liquid in the intestine and the blood of the animal. In another paper by Heiden- hain ^ he has proved that the absorption of water in the small intestine, when ordinary amounts are ingested, takes place entirely through the blood-vessels of the villus, and not through the lacteals ; when larger quantities of water are swallowed, a small part may be absorbed through the lacteals, as shown by the increased lymph-flow, but by far the larger quantity is taken up directly l^y the blood. In the large intestine the contents become progressively more solid as they approach the rectum ; the absorption of water is such that the stream is mainly from the intestinal contents to the blood, giving us a phenomenon somewhat similar to the absorption of water by the roots of a plant. This process is difficult to understand upon the supposition that it is caused by osmosis, using that term in its ordinary sense, unless we assume that it is due entirely to the osmotic pressure of the indiffusible proteids of the blood as explained on p. 69. Composition of the Feces. — The feces differ widely in amount and in composition with the character of the food. Upon a diet composed exclu- sively of meats they are small in amount and dark in color ; with an ordinary mixed diet the amount is increased, and it is largest with an exclusively vege- table diet, especially with vegetables containing a large amount of indigest- ible material. The average weight of the feces in twenty-four hours upon a mixed diet is given as 170 grams, while with a vegetable diet it may amount to as much as 400 or 500 grams. The quantitative composition, therefore, will vary greatly with the diet. Qualitatively, we find in the feces the following things': (1) Indigestible material, such as ligaments of meat or cellulose from vegetables. (2) Undigested material, such as fragments of meat, starch, or fats which have in some way escaped digestion. Naturally, the quantity of this material present is slight under normal conditions. Some fats, however, are almost always found in feces, either as neutral fats or as fatty acids, and to a small extent as calcium or magnesium soaps. The quantity of fat found is '■ Pfliiger's Arehivfur die gesammte Physiologie, 1894, Bd. 50, S. 579. ^ Ibid., 1888, Bd. 43, supplement. 320 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. increased by an increase of the fats in the food. (3) Products of the intes- tinal secretions. Evidence has accumulated in recent years ^ to show that the feces in man on an average diet are composed mainly of the material of the intestinal secretions. The nitrogen of the feces, formerly supposed to represent undigested food, seems rather to have its origin in these secretions, and, therefore, like the nitrogen of the urine represents so much metabolism in the body. (4) Products of bacterial decomposition. The most character- istic of these products are indol and skatol. These two substances are formed normally in the large intestine from the putrefaction of proteid material. They occur always together. Indol has the formula C^HyN, and skatol, which is a methyl indol, the formula CgH.jN. They are crystal- line bodies possessing a disagreeable fecal odor ; this is epecially true of skatol, to which the odor of the feces is mainly due. Indol and skatol are eliminated from the body only in part in the feces ; a certain propor- tion of each is absorbed into the blood and is eliminated in a modified form through the urine — indol as indican (indoxyl-sulphuric acid), from which indigo was formerly made, and skatol as skatoxyl-sulphuric acid (see Chemical section for further information as to the chemistry of these bodies). (5) Cholesterin, which is found always in small amounts and is probably derived from the bile. (6) Excretin, a crystallizable, non-nitrogenous substance to which the formula CygHjsgSOj has been assigned, is found in minute quantities. (7) Mucus and epithelial cells thrown off from the intestinal wall. (8) Pigment. In addition to the color due to the undigested food or to the metallic compounds contained in it, there is normally present in the feces a pigment, hydrobilirubin, derived from the pigments (bilirubin) of the bile. Hydrobilirubin is formed from the bilirubin by reduction in the large intestine. (9) Inorganic salts — salts of sodium, potassium, calcium, magnesium, and iron. The importance of the calcium and iron salts will be referred to in a subsequent chapter, when speaking of their nutritive importance. (10) Micro-organisms. Great quantities of bacteria of different kinds are found in the feces. In addition to the feces, there is found often in the large intestine a quantity of gas that may also be eliminated through the rectum. This gas varies in composition. The following constituents have been determined to occur at one time or another: CH^, COj, H, N, HjS. They arise mainly from the bacterial fermentation of the proteids, although some of the N may be derived from air swallowed with the food. F. Physiology of the Livee and the Spleen. The liver plays an important part in the general nutrition of the body ; its functions are manifold, but in the long run they depend upon the properties of the liver-cell, which constitutes the anatomical and physiological unit of the organ. These cells are seemingly uniform in structure throughout the whole substance of the liver, but to understand clearly the different functions they fulfil one must have a clear idea of their anatomical relations to one another ' See Prausnitz: Zeitschrift fiir Bioloyle, 1897, .Bd. 35, S. 335 ; and Tsuboi : Ibid., S. C8. CHEMISTRY OF BIQESTIOK AND KUTIIITION. 321 and to the blood-vessels, the lymphatics, and the bile-duots. The histology of the liver lobule, and the relationship of the portal vein, the hepatic artery, and the bile-duct to the lobule, must be obtained from the text-books upon histol- ogy and anatomy. It is sufficient here to recall the fact that each lobule is supplied with blood coming in part from the portal vein and in part from the hepatic artery. The blood from the former source contains the soluble prod- ucts absorbed from the alimentary canal, such as sugar and proteid, and these absjrbed products are submitted to the metabolic activity of the liver-cells before reaching the general circulation. The hepatic artery brings to the liver- cells the arterialized blood sent out into the systemic circulation from the left ventricle. In addition, each lobule gives origin to the bile-capillaries which arise between the separate cells and which carry off the bile formed within the cells. In accordance with these facts, the physiology of the liver-cell falls naturally into two parts — one treating of the formation, composition, and physi- ological significance of bile, and the other dealing with the metabolic changes produced in the mixed blood of the portal vein and the hepatic artery as it flows through the lobules. In this latter division the main phenomena to be studied are the formation of urea and the formation and significance of glycogen. Bile. — From a physiological standpoint, bile is partly an excretion carrying off certain waste products, and partly a digestive secretion playing an import- ant r6le in the absorption of fats, and possibly in other ways. Bile is a con- tinuous secretion, but in animals possessing a gall-bladder its ejection into the duodenum is intermittent. For the details of the mechanism of its secretion, its dependence on nerve- and blood-supply, etc., the reader is referred to the section on Secretion. Bile is easily obtained from living animals by establishing a fistula of the bile-duct or, as seems preferable, of the gall-bladder. The latter operation has been performed a number of times on human beings. In some cases the entire supply of bile has been diverted in this way to the ex- terior, and it is an interesting physiological fact that such patients may con- tinue to enjoy fair health, showing that, whatever part the bile takes normally in digestion and absorption, its passage into the intestine is not absolutely necessary to the nutrition of the body. The quantity of bile secreted during the day has been estimated for human beings of average weight (43 to 73 kilo- grams) as varying between 500 and 800 cubic centimeters. This estimate is based upon observations on cases of biliary fistula.' Chemical analyses of the bile show that, in addition to the water and salts, it contains' bile- pigments, bile-acids, cholesterin, lecithin, neutral fats and soaps, sometimes a trace of urea, and a mucilaginous nucleo-albumin formerly designated improperly as muein. The last-mentioned substance is not formed in the liver-cells, but is added to the bile by the mucous membrane of the bile-ducts and gall-bladder. The quantity of these substances present in the bile must vary greatly in different animals and under different conditions. As an illustration of their relative ' Coperaan and Winston : Journal of Physiology, 3889, vol. x. p. 213 ; Kobson : Proceedings of the Royal Society, London, 1890, vol. 47, p. 499 ; PfaiF and Balch : Journal nf Experimental Medicine, 1897, vol. ii. p. 49. Vol. I.- 21 322 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. importance in human bile and of the limits of variation the two following analyses by Hammarsten ^ may be quoted : I. 11. Solids 2.520 2.840 Water 97.480 97.160 Mucin and pigment 0.529 0.910 Bile-salts 0.931 0.814 Taurocholate 0.3034 0.053 Glycocholate 0.6276 0.761 Fatty acids from soap 0.1230 0.024 Cholesterin 0.0630 0.096 Lecithin I QQ220 0.1286 Fat J Soluble salts 0.8070 0.8051 Insoluble salts 0.0250 0.0411 The color of bile varies in different animals according to the preponderance of one or the other of the main bile-pigments, bilirubin and biliverdin. The bile of carnivorous animals has usually a bright golden color, owing to the pres" ence of bilirubin, while that of the herbivora is a bright green from the biliverdin. The color of human bile seems to vary : according to some author- ities, it is yellow or brownish yellow, and this seems especially true of the bile as found in the gall-bladder of the cadaver ; according to others, it is of a dark- olive color with the greenish tint predominating. Its reaction is feebly alka- line, and its specific gravity varies in human l)ile from 1050 or 1040 to 1010. Human bile does not give a distinctive absorption spectrum, but the bile of some herbivora, after exposure to the air at least, gives a characteristic spectrum. The individual constituents of the bile will now be described more in detail, but with reference mainly to their origin, fate, and function in the body. For a description of their strictly chemical properties and reactions reference must be made to the Chemical section. Bile-pigments. — Bile, according to the animal from which it is obtained, contains one or the other, or a mixture, of the two pigments bilirubin and biliverdin. Biliverdin is supposed to stand to bilirubin in the relation of an oxidation product. Bilirubin is given the formula C,i;H;gN,03, and biliverdin CigH, 5X304, the latter being prepared readily from pure specimens of the former by oxidation. These pigments give a characteristic reaction, known as " Gmelin's reaction," with nitric acid containing some nitrous acid (nitric acid with a yellow color). If a drop of bile and a drop of nitric acid are brought into contact, the former undergoes a succession of color changes, the order being green, blue, violet, red, and reddish yellow. The play of colors is due to successive oxidations of the bile-pigments ; starting with bilirubin, the first stage (green) is due to the formation of biliverdin. The pigments formed in some of the other stages have been isolated and named. The reaction is very delicate, and it is often used to detect the presence of bile- pigments in other liquids — urine, for example. The bile-pigments originate 1 Eeported in Centralblatt fur Physiologic, 1894, No. 8. CHEMISTRY OF DIGESTION AND NVTRJTION. 323 from hsemoglobin. This origin was first indicated by the fact that in old blood-clots or in extravasations there was found a crystalline product, the so-called " hsematoidin," which was undoubtedly derived from haemoglobin, and which upon more careful examination was proved to be identical with bilirubin. This origin, which has since been made probable by other reac- tions, is DOW universally accepted. It is supposed that when the blood- corpuscles go to pieces in the circulation (p. 45) the hsemoglobin is brought to the liver, and then, under the influence of the liver-cells, is converted to an iron-free compound, bilirubin or biliverdin. It is very significant to find that the iron separated by this means from the hsemoglobin is for the most part retained in the liver, a small portion only being secreted in the bile. It seems probable that the iron held back in the liver is again used in some way to make new hsemoglobin in the hsematopoietic organs. The bile-pigments are carried in the bile to the duodenum and are mixed with the food in its long passage through the intestine. Under normal conditions neither bilirubin nor biliverdin is found in the feces, but in their place is found a reduction pro- duct, hydrobUirubin, formed in the large intestine. Moreover, it is believed that some of the bile-pigment is reabsorbed as it passes along the intestine, is carried to the liver in the portal blood, and is again eliminated. That this action occurs, or may occur, has been made probable by experiments of Wertheimer ' on dogs. It happens that sheep's bile contains a pigment (cholohsematin) that gives a characteristic spectrum. If some of this pig- ment is injected into the mesenteric veins of a dog, it is eliminated while passing through the liver, and can be recognized unchanged in the bile. The value of this " circulation of the bile," so far as tlie pigments are con- cerned, is not apparent. Bile-acids. — " Bile-acids " is the name given to two organic acids, glyco- cholic and taurocholic, which are always present in bile, and, indeed, form very important constituents of that secretion ; they occur in the form of their respective sodium salts. In human bile both acids are usually found, but the proportion of taurocholate is variable, and in some cases this latter acid may be absent altogether. Among herbivora the glycocholate predominates as a rule, although there are some exceptions ; among the carnivora, on the other hand, taurocholate occurs usually in greater quantities, and in the dog's bile it is present alone. Glycocholic acid has the formula C25Hj3NOe, and taurocholic acid has the formula C25H45NSO7. Each of them can be obtained in the form of crystals. When boiled with acids or alkalies these acids take up water and undergo hydrolytic cleavage, the reaction being represented by the following equations: C,,H,3N0, + H,0 = C,,H,A + CH,(NH,)COOH. Glycocholic acid. Cholic acid. GlycocoU (amido-acetic acid). raurocholic acid. Cholic acid. Taurin (amido-ethyl- sulphonic acid). ' Archives de Phydologie normale et pathulogigue, 1892, p. 577. 324 AN A2IEIUCAX TEXT-BOOK OF PHYSIOLOGY. These reactions are interesting not only in that they throw light on the structure of the acids, but also because similar reactions doubtless take place in the intes- tine, cholic acid having been detected in the intestinal contents. As the for- mulas show, cholic acid is formed in the decomposition of each acid, and we may regard the bile-acids as compounds produced by the synthetic union of cholic acid with glycocoll in the one case and with taurin in the other. Cholic acid or its compounds, the bile-acids, are usually detected in suspected liquids by the well-known Pettenkofer reaction. As usually performed, the test is made by adding to the liquid a few drops of a 10 per cent, solution of cane-sugar and then strong sulphuric acid. The latter must be added carefully and the temperature be kept below 70° C. If bile-acids are present, the liquid assumes a beautiful red-violet color. It is now known that the reaction con- sists in the formation of a substance (furfurol) by the action of the acid on sugar, which then reacts with the bile-acids. The bile-acids are formed directly in the liver-cells. This fact, which was for a long time the subject of discussion, has been demonstrated in recent years by an important series of researches made upon birds. It has been shown that if the bile-duct is ligated in these animals, the bile formed is reabsorbed and bile-acids and pigments may be detected in the urine and the blood. If, however, the liver is com- pletely e;stirpated, then no trace of either bile-acids or bile-pigments can be found in the blood or the urine, showing that these substances are not formed elsewhere in the body than in the liver. It is more difficult to ascer- tain from what substances they are formed. The fact that glycocoll and taurin contain nitrogen, and that the latter contains sulphur, indicates that some proteid or albuminoid constituent is broken down during their pro- duction. A circumstance of considerable physiological significance is that these acids or their decomposition products are absorbed in part from the intestine and are again secreted by the liver : as in the case of the pigments, there is an intestinal-hepatic circulation. The value of this reabsorption may lie in the fact that the bile-acids constitute a very efficient stimulus to the bile-secreting activity of the cells, being one of the best of cholagogues, or it may be that it economizes material. From what we know of the history of the bile-acids it is evident that they are not to be considered as excreta : they have some important function to fulfil. The following suggestions as to their value have been made : In the first place, they serve as a menstruum for dissolving the cholesterin which is constantly present in the bile and which is an excretion to be removed; secondly, they facilitate the absorption of fats from the intes- tine. The value of bile in fat-absorption will presently be referred to more in detail. It is an undoubted fact that when bile is shut off from the intes- tine the absorption of fats is very much diminished, and it has been shown that this action of the bile in fat absorption is owing to tJie presence of the bile-acids. Cholesterin. — Cholesterin is a non-nitrogenous substance of the formula CjoHj/ ) or C27H^5(OH). It is a constant constituent of the bile, although it CHEMISTRY OF DIGESTION AND NUTBITION. 325 occurs in variable quantities. Cliolesterin is vitv widely distributed in the body, being found especially in the white matter (medullary substance) of nerve-fibres. It seems, moreover, to be a constant constituent of all animal and plant cells. It is assumed that cholesterin is not formed in the liver, but that it is eliminated by the liver-cells from the blood, which collects it from the various tissues of the body. That it is an excretion is indicated by the fact that it is eliminated unclianged in the feces. Cholesterin is insoluble in water or in dilute saline liquids, and is held in solution in the bile by means of the bile-acids. We must regard it as a waste product of cell-life, formed probably in minute quantities, and excreted mainly thi-ough the liver. It is partly eliminated through the skin, in the sebaceous and sweat secretions, and in the milk. Lecithin, Pats, and Nucleo-albumin. — Lecithin also seems to be present, generally in small quantities, in the cells of the various tissues, but it occurs especially in the white matter of nerve-fibres. It is probable, therefore, that, so far as it is found in the bile, it represents a waste product formed in different parts of the body and eliminated through the bile. The special importance, if any, of the small proportion of fats and fatty acids in the bile is unknown. The ropy, mucilaginous character of bile is due to tiie presence of a body formed in the bile-ducts and gall-bladder. This substance was formerly designated as mucin, but it is now known that in ox-bile at least it is not a true mucin, but is a nucleo-albumin (see Chemical section). Ham- marsten reports that in human bile some true mucin is found. Outside the fact that it makes the bile viscous, this constituent is not known to possess any especial physiological significance. General Physiological Importance of Bile. — -The physiological value of bile has been referred to in speaking of its several constituents, but it will be convenient here to restate these facts and to add a few remai'ks of general interest. Bile is of importance as an excretion in that it removes from the body waste products of metabolism, such as cholesterin, lecithin, and bile- pigments. With reference to the pigments, there is evidence to show that a part at least may be reabsorbed while passing through the intestine, and be used again in some way in the body. The bile-acids represent end-products of metabolism involving the proteids of the liver-cells, but they are undoubt- edly reabsorbed in part, and cannot be regarded merely as excreta. As a digestive secretion the most important function attributed to the bile is the part it takes in the digestion of fats. In the first place, it aids in the splitting of a part of the neutral fats and the subsequent emulsification of the re- mainder (p. 307). More than this, bile aids materially in the absorption of the digested fats. A number of observers have sliown that when a permanent biliary fistula is made, and the bile is thus prevented from reaching the intes- tinal canal, a large proportion of the fat of the food escapes absorption and is found in the feces. This property of the bile is known to depend upon the bile-acids it contains, but how they act is not clearly understood. It was formerly believed, on the basis of some experiments by von Westinghausen, 326 AN AMEBICAK TEXT-BOOK OF PHYSIOLOGY. that the bile-acids dissolve or mix with the fats and at the same time moisten the mneons membrane, and for these reasons aid in bringing the fat into immediate contact with the epithelial cells. It was stated, for instance, that oil rises higher in capillary tubes moistened with bile than in similar tubes moistened with water, and that oil will filter more readily through paper moistened with bile than through paper wet with water. Groper,' wlio repeated these experiments, finds that they are erroneous. It seems certain, however, that the bile-acids enable the bile to hold in solution a considerable quantity of fatty acids, and possibly this fact explains its connection with fat absorption. It was formerly believed that bile is also of great importance in restraining the processes of putrefaction in the intestine. It was asserted that bile is an efficient antiseptic, and that this property comes into use normally in preventing excessive putre- faction. Bacteriological experiments made by a number of observers have shown, however, that bile itself has very feeble antiseptic properties, as is indicated by the fact that it putrefies readily. The free bile-acids and cholalic acid do have a direct retarding effect upon putrefactions outside the body; but this action is not very pronounced, and has not been demonstrated satis- factorily for bile itself. It seems to be generally true that in cases of biliary fistula the feces have a very fetid odor when meat and fat are taken in the food. But the increased putrefaction in these cases may possibly be due to some indirect result of the withdrawal of bile. It has been suggested, for instance, that the deficient absorption of fat that follows upon the removal of the bile results in the proteid and carbohydrate material becoming coated with an insoluble layer of fat, so that the penetration of the digestive enzymes is retarded and greater opportunity is given for the action of bacteria. We may conclude, therefore, that while there does not seem to be sufficient warrant at present for believing that the bile exerts a direct antiseptic action upon the intestinal contents, nevertheless its presence limits in some way the extent of jintrefaction. Lastly, bile takes, a direct part in suspending or destroying peptic digestion in the acid chyme forced from the stomach into the duodenum. The chyme meeting with bile and pancreatic juice is neutralized or is made alkaline, which alone would j^revent further peptonization. Moreover, when chyme and bile are mixed a precipitate occurs, consisting partly of proteids (proteoses and syntonin) and partly of bile-acids. It is probable that pepsin, according to its well-known property, is thrown down in this flocculent pre- cipitate and, as it were, prepared for its destruction. Glycogen. — One of the most important functions of the liver is the for- mation oi glycogen. This .substance was found in the liver in 1857 by Claude Bernard, and is one of several brilliant discoveries made by him. Glycogen has the formula (CgHj^Oj),,, which is also the general formula given to vegetable starch ; glycogen is therefore frequently spoken of as " animal starch." It gives, however, a port-wine-red color with iodine solutions, instead of the familiar deep blue of vegetable starch, and this reaction serves to detect glyco- ' Archiv fur Analomie und Physiologic ("Physiol. Abtlieilung"), 1889, S. 505. CHEMISTRY OF DIGESTION AND NUTRITION. 327 gen not only in its solutions, but also in the liver-cells. Glycogen is readily soluble in water, and the solutions have a characteristic opalescent appearance. Like starch, glycogen is acted upon by ptyalin and amylopsin, and the end- products are apparently the same — namely, maltose, or maltose and some dextrin. For a more complete account of the chemical relations of glycogen reference must be made to the Chemical section. Occurrence of Glycogen in the Liver. — Glycogen can be detected in the liver-cells microscopically. If the liver of a dog is removed twelve or fourteen hours after a hearty meal, hardened in alcohol, and sectioned, the liver-cells will be found to contain clumps of clear material which give the iodine reaction for glycogen. Even when distinct aggregations of the glycogen cannot be made out, its presence in the cells is shown by the red reaction with iodine. By this simple method one can demonstrate the important fact that the amount of glycogen in the liver increases after meals and decreases again during the fasting hours, and if the fast is sufficiently prolonged it may dis- appear altogether. This fact is, however, shown more satisfactorily by quanti- tative determinations, by chemical means, of the total glycogen present. The amount of glycogen present in the liver is quite variable, being influenced by such conditions as the character and amount of the food, muscular exercise, body-temperature, drugs, etc. From determinations made upon various animals it may be said that the average amount lies between 1.5 and 4 per cent, of the weight of the liver. But this amount may be increased greatly by feeding upon a diet largely made up of carbohydrates. It is said that in the dog the total amount of liver-glycogen may be raised to 17 per cent., and in the rabbit to 27 per cent., by this means, while it is estimated for man (Neumeister) that the quantity may be increased to at least 10 per cent. It is usually believed that glycogen exists as such in the liver-cells, being depos- ited in the substance of the cytoplasm. Reasons have been brought forward recently to show that possibly this is not strictly true, but that the glycogen is held in some sort of weak chemical combination. It has been shown, for instance, that although glycogen is easily soluble in cold water, it cannot be extracted readily from the liver-cells by this agent. One must use hot water, salts of the heavy metals, and other similar means that may be supposed to break up the combination in which the glycogen exists. For practical purposes, however, we may speak of the glycogen as lying free in the liver-cells, just as we speak of haemoglobin existing as such in the red corpuscles, although it is probably held in some sort of combination. Origin of Glycog-en. — To understand clearly the views held as to the origin of liver glycogen, it will be necessary to describe briefly the effect of the different food-stuffs upon its formation. Effect of Carbohydrates on the Amount of Glycogen.— The amount of glycogen in the liver is affected very quickly by the quantity of carbohydrates in the food. If the carbohydrates are given in excess, the supply of glycogen may be increased largely beyond the average amount present, as has been stated ■above. Investigation of the different sugars has shown that dextrose, levulose, 328 A.V A^^ERICAX TEXT-BOOK OF PHYSIOLOGY. saccharose (cane-sugar), and maltose are unquestionably direct glycogen-formers, that is, that glycogen is formed directly from them or from the products into which they are converted during digestion. Now, our studies in digestion have shown that the starches are converted into maltose, or maltose and dextrin, during digestion, and, further, that these substances are changed or inverted to the simpler sugar dextrose during absorption. Cane-sugar, which forms such an important part of our diet, is inverted in the intestine into dextrose and levulose, and is absorbed in these forms. It is evident, therefore, that the bulk of our carbohydrate food reaches the liver as dextrose, or as dextrose and levulose, and these forms of sugar must be converted into glycogen in the liver-cells by a process of dehydration such as may be represented in substance by the formula CjHjPe - H,0 = CgHioO^. There is no doubt that both dextrose and levulose increase markedly the amount of glycogen in the liver; and, since cane-sugar is inverted in the intestine before absorption, it also must be a good glycogen-former — a fact that has been abundantly demonstrated by direct experiment. Lusk ^ has shown, however, that if cane-sugar is in- jected under the skin, it has a very feeble effect in the way of increasing the amount of glycogen in the liver, since under these conditions it is probably absorbed into the blood without undergoing inversion. Experiments with sub- cutaneous injection of lactose gave similar results, and it is generally believed that the liver-cells cannot convert the double sugars to glycogen, at least not readily ; hence the value of the h}(lrol_ysis of these sugars in the alimentary canal before absorption. The relations of lactose to glycogen-formation have not been determined satisfactorily. If it contributes at all to the direct forma- tion of glycogen, it is certainly less efficient than dextrose, levulose, or cane- sugar. When the proportion of lactose in the diet is much increased, it quickly begins to appear in the urine, showing that the limit of its consumption in the body is soon reached. This latter fact is somewhat singular, since in infancy especially milk-sugar forms a constant and important item of our diet, and one would suppose that it is especially adapted to the needs of the body. Effed of Froteids on Glycogen-formation. — It was pointed out by Bernard, in his first studies upon glycogen-formation, that the liver can produce glycogen from proteid food. This conclusion has since been verified by more exact investigations. When an animal is fed upon a diet of proteid alone, or on proteid and gelatin, the carbohydrates being entirely excluded, glycogen is still formed in the liver, although in smaller amounts than in the case of carbohy- drate foods. This is an important fact to remember in studying the metabo- lism of the proteids in the body, for, as glycogen is a carbohydrate and con- tains no nitrogen, it implies that the proteid molecule is dissociated into a nitrogenous and a non-nitrogenous part, the latter being converted to glycogen hy the liver-cells. The possibility of the production of glycogen from proteids accords witli a well-known fact in medical ])ractice with reference to the path- ological condition known as diabetes. In this disease sugar is excreted in the urine, sometimes in large quantities. As the sugar of the blood is believed ' Voit: Zeitschriji fiir Biologic, 1891, xxviii. S. 285. CHEMISTRY OF DIGESTION AND NUTRITION. 329 to be formed ordinarily from the carbohydrates in the food, it was thought that by excluding this food-stuff from the diet the excretion of sugar might be prevented. It has been found, however, that in severe cases at least sugar continues to be present in the urine even upon a pure proteid diet. If we suppose that some of the proteid goes to form glycogen, the result ob- served is explained, for the glycogen, as will be explained presently, is finally converted to sugar and is given off to the blood. An interesting additional fact that points to the same conclusion is that the percentage of sugar in the blood remains practically constant after prolonged starvation, at a time when the animal is living at the expense of the proteids and fats of its own body. Effect of Fats and other Substances upon Gly cog en-formation. — It has been found that fats take no part in the formation of liver glycogen. Some attempts have been made to prove that fat in the body, and particularly in the liver, may be converted to sugar, but the evidence at present seems to be against this possibility.^ The Function of Glycogen : Glycog-enic Theory. — The meaning of the formation of glycogen in the liver has been, and still is, the subject of discus- sion. The view advanced first by Bernard is perhaps most generally accepted. According to Bernard, glycogen forms a temporary reserve supply of carbo- hydrate material that is laid up in the liver during digestion and is gradually made use of in the intervals between 'meals. During digestion the carbohy- drate food is absorbed into the blood of the portal system as dextrose or as dextrose and levulose. If these passed through the liver unchanged, the con- tents of the systemic blood in sugar would be increased perceptibly. It is now known that when the percentage of sugar in the blood rises above a certain low limit, the excess will be excreted through the kidney and will be lost. But as the blood from the digestive organs passes through the liver the ex- 2 (p. 436) is fatal within two or three minutes, but an atmosphere containing as much as 25 to 30 per cent, may be respired for a few minutes without ill effect (p. 436), Nitrogen, hydrogen, and carburotted hydrogen (CH,) may be inhaled with impunity if they contain not less than 13 volumes per cent, of O. The respiration of nitrous oxide or of air containing much ozone rapidly produces anaesthesia, unconsciousness, and death. Carbon monoxide (CO) and cyanogen are decid- edly toxic, combining with haemoglobin and displacing oxygen. Sulphuretted hydrogen, phosphoretted hydrogen, arseniuretted hydrogen, and antimoniu- retted hydrogen are all poisonous and are all destructive to haemoglobin. An atmosphere containing 0.4 volume per cent, of sulphuretted hydrogen is said to be toxic. Air containing 2 volumes per cent, of CO (carbon monoxide) is quickly fatal. Certain gases and vajjors — as, for instance, ammonia, chlorine, bromine, ozone, etc. — produce serious irritation of the respiratory passages, and may in this way cause death. G. Effects of the Gaseous Composition of the Blood on the Respiratory Movements. Certain terms are employed to express peculiarities in the respiratory phe- nomena : Eupnosa is normal, quiet, and easy breathing. Apnaea is a suspen- sion of the respiratory movements. Hyperpnwa is a condition of increased ' Journal of Physiology, 1899, vol. -24, p. 19. Ii£SPIIiA TION. 441 respiratory activity. Polypncea, thermopolypnoea, and heat-dyspncea are forms of hyperpnoea due to heating the blood or the skin. Dyspnoea is distinguished by deep and labored breathing ; the respiratory rate is usually less than the normal, but in some forms it may be higher. Asphyxia (suffocation) is cha- racterized by convulsive respirations which are followed in the final stage by infrequent, feeble, and shallow respirations. Eupjiwa is the condition of respiration observed during bodily and mental quiet, the quantities of O and COj in the blood being within the normal mean limits. Apnaa may be produced by rapidly repeated respirations of atmospheric air, under which circumstances the respiratory movements may be arrested for a period varying from a few seconds to a minute or more. This condition is produced most easily upon animals which have been tracheotomized and con- nected with an artificial respiration apparatus. If under these conditions the lungs are repeatedly inflated with sufficient frequency, and the blasts are then suspended, the animal will lie quietly for a certain period in a condition of apnoea. The respirations after a time begin, usually with very feeble move- ments which quickly increase in strength and depth to the normal type. The ultimate cause of apncea is still a mooted question, and the heretofore prevalent belief that it is due to hyperoxygenation of the blood is almost entirely dis- carded. The connection between the quantity of O in the blood and apncea is, however, suggested by several facts : thus, apncea is more marked after the respiration of pure O than after that of atmospheric air, and less marked if the air is deficient in O ; moreover, Ewald states that the arterial blood of apnoeic animals is saturated with O. These facts naturally lead to the inference that the blood is surcharged with O, and that the respiratory movements are arrested until the excess of O is consumed or until sufficient COj accumulates in the blood to excite respiratory movements. But Head ' has shown that apncea can be caused by the inflation of the lungs with pure hydrogen as well as by infla- tion with air or with pure O, although the'apnceic pause after the cessation of the inflations is not so long or may be absent altogether ; while Ewald's asser- tion as to the saturation of the blood with O is contradicted by Hoppe-Seyler, Gad, and others. The fact that the apnoeic pause exists for a longer period "when O is respired lends confirmation to Gad's theory that it is due in part to the large amount of O carried into and stored up, as it were, in the alveoli — an amount sufficient to supply the blood for a certain period and thus to dis- pense with respiratory movements. Gad found that even when apncea follows the inflation of the lungs with air, the air in the lungs contains enough O to supply the blood during the period occupied by the blood in making a com- plete circuit of the system. The fact, however, that apncea can be caused by the inflation of the lungs by an indifferent gas such as hydrogen, by -which every particle of O may be driven from the lungs, certainly shows that there exists some important factor apart from the O ; and this assump- tion receives support in the observation that after section of the pnenmo- ' Journal of Physiology, 1889, vol. 10, pp. 1, 279. 442 AK AMERICAN TEXT-BOOK OF PHYSIOLOGY. gastric nerves (the channels for the conveyance of sensory impulses from the lungs to the respiratory centre) it is very difficult to cause apncea by in- flation of the lungs with air, while if pure hydrogen is used violent dyspnoea results. It seems, then, that apnoea cannot be produced after division of the vagi unless there be an accumulation of O in the lungs. These facts suggest that the frequent forced inflations of the lungs excite the pulmonic peripheries of the pneumogastric nerves, thus generating impulses which inhibit the inspi- ratory discharges from the respiratory centre. This view receives further sup- port in several facts : first, that the same number of inflations, whether of pure O, of air, or of H, causes apnoea, the only difference being the length of the apnoeic pause after the cessation of artificial respiration, which pause lasts for the longest period when O is used, and for the shortest period, or not at all, when H is employed ; second, that apnoea cannot be caused by inflation of the lungs with H if the pneumogastric nerves be previously divided ; third, that the arrest of respiration which occurs during swallowing (" deglutition-apnoea ") is due to an inhibition of the respiratory centre by impulses generated in the terminations of the glosso-pharyngeal nerves (p. 462). It therefore seems evi- dent that apnoea may be due to either gaseous or mechanical factors, or to both, the former being effective, not because of the blood being saturated with 0, but because of the increased amount of O in the alveoli — a quantity sufficient for a time to aerate the blood ; while the mechanical factors give rise to inhibi- tory impulses which suspend for a longer or shorter period the rhythmical inspiratory discharges from the respiratory centre, doubtless by depressing the irritability of this centre (p. 455). From the experiment quoted it seems that the first of these factors may alone be sufficient to cause apnoea, but that apnoea is more easily produced, and lasts longer, when both factors act together, as is usually the case. The form of hyperpncea due to muscular activity is owing to the action upon the respiratory centre of certain substances which are formed in the muscles during contraction and are given to the blood. Muscular activity, as is well known, is accompanied by an increase in the rate and depth of the respiratory movements, and when the exercise is violent more or less marked dyspnoea may occur. Some physiologists have been led to the belief that the respiratory centre is connected directly or indirectly with the muscles by means of afferent nerve-fibres which convey impulses to the centre and thus excite it to activity ; while others have regarded a diminution of O and an increase of COj in the blood as the cause, the active muscles rapidly consum- ing the O in the blood and giving ofl" COj in great abundance. But Mathieu and Urbain, and Geppert and Zuntz,' have found that the volumes per cent, in the blood of O may be increased, and the volume per cent, of COj decreased, during muscular activity. It is probable that the hyperpnoea is due to prod- ucts of muscular activity M'hich are given to the blood and which act as powerful excitants to the respiratory centre. The precise nature of the bodies is unknown, but it is probable that they are of an acid character, for '■ Archivfiir die gesummle Physioloyic, 1888, Bd. 42, S. 189. RESPIRA TION. 443 Lehmaiin ' found that there was a distinct lessening of the alkalinity of the blood after muscular exercise. It is likely that the bodies are broken up in the system, because the results of Loewy's ^ investigations indicate that they are not removed by the kidneys. Polypncea, thermopoh/pncea, and heat-dyspnoea are due to a direct excitation of the respiratory centres through an increase of the temperature of the blood, or reflexly by excitation of the cutaneous nerves by external heat. TJiis con- dition may be produced, as was done by Goldstein, by exposing the carotids and placing them in warm tubes, thus heating the blood ; or, as was done by Richet and others, by subjecting the body to high external heat. Richet in employing this latter method found that dogs so exposed may have a respira- tory rate as high as 400 per minute. Ott records marked polypnoea as a result of direct irritation of the tuber cinereum. This form of hyperpnoea is entirely independent of the gaseous composition of the blood ; moreover, an animal in heat-dyspnoea cannot be rendered apnoeic, even though the blood be so thor- oughly oxygenated that the venous blood is of a bright arterial hue. Dyspnoea is generally characterized by slow, deep, and labored respiratory movements, although in some instances the rate may be increased. Several distinct forms are observed : " O-dyspnoea," due to a deficiency of O ; " COj-dyspnoea," due to an excess of COj in the blood ; and cardiac and hemorrhagic dyspnoeas, belonging to the O category. Dyspnceas due to the gaseous composition of the blood may be caused either by a deficiency of O or by an excess of COj, but are generally due to both. Dyspnoea from a deficit of O is observed when an animal is placed within a small closed chamber, or when an indifferent gas, such as pure hydrogen or nitrogen, is respired. Under the latter circumstances dyspnoea occurs even though the quantity of COj in the blood be below the normal. If, on the contrary, the animal be compelled to breathe an atmosphere containing 10 vol- umes per cent, of COj, dyspnoea occurs, notwithstanding an abundance of O (p. 436) both in the air and in the blood ; indeed, the quantity of O in the blood may be above the normal. Fredericq^ in ingenious experiments has directly demonstrated the influence of the quantity of COj in the blood upon the respiratory movements. He took two rabbits or dogs, A and B, ligated the vertebral arteries in each, exposed the carotids, and ligated one in each animal. The other carotid in each was cut, and the peripheral end of the vessel of one was connected by means of a cannula with the central end of the vessel of the other, so that the blood of animal A supplied the head (respiratory centre) of animal B, and vice versd. When the trachea of animal A was ligated or com- pressed the animal B showed signs of dyspnoea, because its respiratory centre was now supplied with the venous blood from A. On the contrary, animal A exhibited quiet respirations, almost apnoeic, because its centre received the thoroughly arterialized blood from B, in which the respiratory movements were augmented. In a second series of experiments blood was transfused through ' Archivfur die gesammte Physiologic, 1888, Bd. 42, S. 284. ^ Ibid., S. 281. ^Buli. Acad. ray. Med. Belgique, t. 13, pp. in-i.21. 444 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. the head : when the blood was laden with COj marked dyspnoea resulted ; when arterial blood was transfused the normal respirations were restored. While dyspnoea may be caused by the respiration of an atmosphere either deficient in O (" 0-dyspnoea ") or containing an excess of COj (" COj-dysp- ncea "), the phenomena in the two cases are in certain respects different : When an animal breathes pure N, thus causing O-dyspnoea, the dyspnoea is character- ized especially by frequent respiratory movements with vigorous inspirations, whereas if the atmosphere be rich in O and contain an excess of COj the respirations are especially marked by a slower rate and by the depth and vigor of the expirations ; O-dyspnoea continues for a long time before death ensues, and is more severe; in O-dyspnoea the absorption of O is diminished, but the excretion of COj is practically unaffected ; in O-dyspnoea the attendant rise of blood-pressure (p. 447) is more marked and lasting ; in O-dyspuoea death is preceded by violent motor disturbances which are absent in COj-dyspnoea. Blood poor in O (O-dyspnoja) affects chiefly the inspiratory portion of the respiratory centre (p. 457), while blood rich in COj (COj-dyspnoea) affects chiefly the expiratory portion ; hence in the former the dyspnoea is manifest especially in an increase in the frequency of the respirations (hyperpnoea) and in the vigor of the inspirations, while in the latter it is manifest in a lessened rate, strong expirations, and expiratory pauses. The marked increase in the depth of the respiratoiy movements in CO2- dyspnoea is not solely due to the direct action of COj upon the respiratory centre, for Gad and Zagari ' have shown that CO2 in abundance in inspired air acts upon the terminations of the sensory nerves of the larger bronchi and thus reflexly excites the respiratory centre. In a research on dogs these ob- servers opened the trachea and pa.ssed glass tubes through the trachea and tlie larger bronchi to the smaller bronchi. Before the tubes were inserted the inhalation of COj caused a considerable deepening of the respiratory move- ments, but after the insertion of the tubes, by means of which the gas was carried directly to the smaller bronchi, the characteristic action of the COj was no longer observed. From the results of these experiments we may con- clude that the marked increase in the depth of the respiratory movements in COg-dyspnoea is due in part to the irritation of the sensory nerve-fibres of the mucous membrane of the larger bronchi. Cardiac and hemorrhagic dyspnoeas are chiefly due to the deficiency in the supply of O — the former, to the poor supply of blood due to the enfeebled action of the heart ; and the latter, both to this and to the reduced quantity of blood (haemoglobin). All circumstances which enfeeble the circulation or lessen the quantity of hsemoglobin therefore tend to cause dyspnoea ; hence individuals with heart troubles or weakened by disease or with certain forms of ansemia are apt to suffer from dyspnoea upon the least exertion. All circumstances which interfere with the interchange of O and the elimination of COj in the lungs are favorable to the production of dyspnoea, ' Du Bois-Eeymond's Archie fur Physiologic, 1890, S. 588. RESPIRATION. 445 as in pneumonia, pulmonary tuberculosis, growths of the larnyx, abdominal tumors, etc., especially so upon exertion. Asphyxia is literally a state of pulselessness, but the term is now used to express a series of phenomena caused by the deprivation of air, as by placing an animal in a closed chamber of moderate size. These phenomena may be divided into three stages: the first is one of hyperpnoea; the second, of developing dyspnoea, and finally of convulsions ; and the third, of collapse. During the first stage the inspiratory portion of the respiratory centre especially is excited, the respirations being increased in frequency and depth. During the second stage the excitation of the expiratory portion of the respiratory centre is more intense than that of' the inspiratory portion, so that the respira- tions become slow and deep, prolonged and convulsive, and the movements of inspiration are feeble and in striking contrast to the violent spasmodic expira- tory efforts. During the third stage the dyspnoea is followed by general exhaustion ; the respirations are shallow and occur at longer and longer inter- vals, the pupils become dilated, the motor reflexes disappear, consciousness is lost, the inspiratory muscles contract spasmodically with each inspiratory act, convulsive twitciies are observed in the muscles of the extremities and else- where, gasping and snapping respiratory movements may be present, the legs are rigidly outstretched and the head and body are arched backward, feces and urine are usually voided, respiratory movements cease, and finally the heart stops beating. During these stages the circulation has undergone considerable disturbances. During the first and second stages the blood has been robbed of nearly all its O, the gums, lips, and skin become cyanosed, and, owing to the venous condition of the blood, the cardio-inhibitory centre has been decidedly excited, so that the heart's contractions are rendered less frequent ; the vaso- constrictor centre for the same reason has also been excited, causing a con- striction of the capillaries and an increase of blood-pressure. During the third stage these centres are depressed and finally are paralyzed. If asphyxia be caused by ligating the trachea, the whole series of events covers a period of four to five minutes, the first stage lasting for about one minute, the second a little longer, and the third from two to three minutes. If asphyxia be produced gradually, as by placing an animal within a relatively large confined air-space, death may occur without the appearance of any motor disturbances (p. 436). The heart usually continues beating feebly for several minutes after the cessation of respiration, so that by means of artificial respiration it is possible to restore the respiratory movements and other suspended functions. After death the blood is very dark, almost black. The arteries are almost if not entirely empty, while the veins and lungs are engorged. Death from drowning occurs generally from the failure of respiration, occasionally from a cessation of the heart's contractions. It is more difficult to revive an animal asphyxiated in this way than one which, out of water, has simply been deprived of air for the same length of time. Dogs submerged for one and a half minutes can rarely be revived, but recovery can usually be 446 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. accomplished after deprivation of air, out of water, for a period four to five times longer. After a person has been submerged for five minutes it is extremely difficult to effect resuscitation. H. Artificial Respiration. Effective methods for maintaining ventilation of the lungs are important alike to the experimenter and to the clinician. In the laboratory the usual method is to expose the trachea, insert a cannula (Fig. 77), and then period- ically force air into the lungs by means of a pair of bellows or a pump. Some of the forms of apparatus are very simple, while others are complicated. An ordinary pair of bellows does very well for short experiments, but for longer study, especially when it is necessary that the supply of air should be uniform, _ _ the bellows are operated by power. B Some of these instruments are so con- structed that air is alternately forced into and withdrawn from the lungs. \ J Periodical inflation of the lungs is f ~ "\ termed positive ventilation ; the period- FiG. 77— cannuiiB for dogs (a) and for cats ical withdrawal of air from the lungs and rabbits (6). ^^ suctiou is negative ventilation; and alternate inflation and suction is compound ventilation. In practising artificial respiration we should imitate the normal rate and depth of the respiratory movements. Long-continued positive ventilation causes cerebral anaemia, a fall of blood-pressure, and decrease of bodily tem- perature. In human beings it is not practicable, except under extraordinary circum- stances, to inflate the lungs by the above methods, so that we are dependent upon such means as will enable us to expand and contract the thoracic cavity without resorting to the knife. One method is to place the individual on his back, the operator taking a position on his knees at the head, facing the feet. The lower ribs are grasped by both hands and the lower antero-lateral portions of the thorax are elevated, thus increasing the thoracic capacity, with a conse- quent drawing of air into the lungs ; the ribs and the abdominal muscles are then pressed upon in imitation of expiration. These alternate movements are kept up as long as necessary. The following is Sylvester's method : " Place the patient on the back, on a flat surface inclined a little upward from the feet ; raise and support the head and shoulders on a small firm cushion or folded article of dress placed under the shoulder-blades. Draw forward the patient's tongue, and keep it project- ing beyond the lips ; an elastic band over the tongue and under the chin will answer this purpose, or a piece of string or tape may be tied around them, or by raising the lower jaw the teeth may be made to retain the tongue in that position. Remove all tight clothing from about the neck and chest, especially the braces "...." To imitate the movements of breathing : Standing at the RESPIliA TION. 447 patient's head, grasp the arms just above the elbows, and draw the arms gently and steadily upward above the head, and keep them stretched upward for two seconds. By this means air is drawn into the lungs. Then turn down the patient's arms, and press them gently and firmly for two seconds against the sides of the chest. By this means air is pressed out of the lungs. Eepeat these measures alternately, deliberately, and perseveringly about fifteen times in a minute, until a spontaneous effort to respire is perceived, immediately upon which cease to imitate the movements of breathing, and proceed to induce circulation and warmth." A new and effective method has been reported by Galliano : The patient is placed in Sylvester's position ; the arms are drawn up above and behind the head, and the Avrists tied. This causes the thorax to be expanded. Respiration is accomplished by pressing concentrically with the open hands upon the sides of the thorax and the epigastric region about twenty times a minute. This method is even more effective if in addition the jaw be wedged open, and short, sharp tractions of the tongue be practised immedi- ately preceding each pressure upon the thorax. These operations should be continued for at least one and a half hours, if necessary, and aided by fric- tion, external heat, etc. The periodical traction of the tongue acts as a strong excitant to the respiratory centre. I. The Effects of the Respiratory Movements on the Circulation. The respiratory movements are accompanied by marked changes in the cir- culation. If a tracing be made of the blood-pressure and the pulse (Fig. 78), and at the same time the inspiratory and expiratory movements be noted, it Fig. 78. — Blood-pressure and pulse tracing showing the changes during inspiration (in.) and expi- ration (EX.). will be seen that the blood-pressure begins to rise shortly after the onset of inspiration, commonly after a period occupied by one to three heart-beats, and reaches a maximum after the lapse of a similar brief interval after the begin- ning of expiration, when it begins to fall, reaching a minimum after the beginning of the next inspiration. During inspiration the pulse-rate is more frequent than during expiration and the character of the pulse-curve is some- what different. The Effects on Blood-pressure. — The changes in blood-pressure are mechanical effects due to the actions of the respiratory movements. When it 448 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. is remembered that the lungs and the heart with their great blood-vessels are placed within an air-tight cavity, that the lungs become inflated through the aspiratory action of the muscles of inspiration, and that during inspiration intrathoracic negative pressure is increased, it is easy to understand how the action which causes inflation of the lungs must affect in like manner such hollow elastic structures as the heart and the great blood-vessels, aud thus influence the circulation. It is obvious, however, that this influence must make itself felt to a more marked degree upon the vessels than upon the heart, and upon the flaccid walls of the veins than upon the comparatively rigid walls of the arteries. Moreover, the effects upon the flow of blood through the vessels entering and leaving the thoracic cavity must be different : the inflow through the veins must be favored, and the outflow through the arteries hindered ; but it is upon the flaccid veins chiefly that the mechanical influences of inspiration are exerted. If the thoracic cavity be freely opened, movements of inspiration no longer cause an expansion of the lungs, nor is there a tendency to distend the heart and the large blood-vessels ; if, however, in an intact animal the out- let of the thorax be restricted, as by pressure upon the trachea, the force of the inspiratory movement would make itself felt chiefly upon the heart and the vessels, and it is under such circumstances that the maximal influences of in- spiration upon the circulation are observed. The lungs on the one hand and the heart and its large vessels on the other may be regarded as two sacs placed within a closed expansible cavity, the former having an outlet communicating with the external air, and the latter having inlets and outlets communicating with the extrathoracic blood-vessels, both being dilated when the thorax ex- pands and constricted when it contracts. Moreover, the blood-vessels in the lungs may be compared to a system of delicate tubes placed within a closed distensible bag and communicating with tubes outside of the bag, simulating the communication of the venae cavm and the aorta with the extrathoracic vessels. When such a bag is distended the tubes undergo elongation and narrowing, aud their capacity is increased. The narrowed vessels also tend to be expanded, owing to the negative pressure present ; and thus have their capacity further increased. The lungs in the same way, when expanded by the act of inspiration, exhibit a simultaneous elongation and narrowing of the intrapulmonary vessels, which results, however, in an increase in their total capacity. During expiration negative intrathoracic pressure becomes less, so that there is a gradual return of the elongated and narrowed intrathoracic vessels to that condition which existed at the beginning of inspiration ; at the same time the intrapulmonary vessels are not only subjected to the passive influ- ence of the declining intrathoracic pressure, but are actively squeezed, as it were, between the air in the lungs on one side and the expiratory forces expelling the air on the other. Thus we have during expiration passive and active agents combining to bring about changes in the capacity of the intra- pulmonary vessels. The mechanical effects of the movements of respiration upon blood-press- RESPIRA TION. 449 ure may be crudely demonstrated by Hering's device (Fig. 79). The chamber A represents the thorax ; the rubber bottom b the diaphragm ; c, the opening of the trachea ; E D, a tube leading from the thoracic cavity to the manometer I, by means of which intrathoracic pressure is measured ; G is a vessel contain- ing water, colored blue in imitation of venous blood, communicating by means of a tube with an oblong flaccid bag F, in imitation of the heart and the intra- thoracic vessels, and finally with the vessel h ; v' and v are valves in imitation of valves in the heart and pulmonary vein and aorta. If now the knob K wliich is fastened to the centre of the diaphragm be pulled down, rarefaction of tlie air within the chamber occurs, so that the greater external pressure forces air through the tube C into the two rubber bags (lungs) ; at the same time and for the same reason water is forced from the vessel G into F, which is distended. The diaphragm upon being released is drawn up iu part by virtue of its own elasticity and in part by the negative pressure within the chamber. The rubber bags are emptied by their own natural elastic reaction. At the Fig. 79.— Hering's device to illustrate the influence of respiratory movements upon the circulation. same time the distended bag F contracts on its contained fluid, forcing it into the vessel H, the valve V preventing a back-flow into G. The degree of force exerted by the traction on the diaphragm is read from the scale on the man- ometer. This simple contrivance teaches us that during the entire phase of inspira- tion there is a condition of progressively increasing negative pressure within the thorax, and that not only is air aspirated into the lungs, but that blood is Vol. I.— 29 450 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. drawn into the large, flaccid venae cavse; and that during expiration there is a gradual diminution of negative pressure during which air is expelled from the lungs and blood from the expanded venae cavae. The increased flow into the thoracic cavity during inspiration is favored in its progress through the pulmonary vessels by the increased capacity of the lung-capillaries and by the fact that the increased negative pressure affects the thin-walled and slightly distended pulmonary veins more than the thick-walled and more distended pulmonary artei-ies, so that the "driving force " of the lung circulation, which is essentially tlie difference in pressure between the blood in the pulmonary arteries and that in the veins, is thereby increased during inspi- ration and the blood-current is driven with greater velocity. More blood thus being brought into the chest, and consequently to the heart, during inspiration, and less resistance being offered to the flow of the blood through the lungs, more blood must ultimately find its way to the left side of the lieart, and con- sequently into the general circulation. If, therefore, the general capillary resistance in the systemic circulation remains the same, it is evident that an increased blood-supply to the left ventricle must cause the general blood-pres- sure to rise. That this rise does not become manifest immediately at the beginning of inspiration is doubtless owing to the filling of the flaccid and partially collapsed large veins and to the increased capacity of the intrapul- monary vessels. The continuance of the rise for a short time after the ces- sation of inspiration is due apparently to the partial emptying of the lung- vessels, whereby, owing to the arrangement of the heart-valves, the excess of blood is forced toward the left side of the heart. Besides the above factors, the flow of blood to the right side of the heart is favored by the pressure transmitted from the conjoint actions of the diaphragm and the abdominal walls through the abdominal viscera to the abdominal vessels. The pressure upon the arteries tends to drive the blood toward the lower extremities and to hinder the flow from the heart ; in the veins, however, the flow toward the heart is encouraged, while that from the extremities is hindered. The rigid walls of the arteries protect them from being materially affected, but the flaccid veins are influenced to a marked degree ; while, there- fore, the flow from the left side of the heart is not materially interfered with, that through tlie veins toward the right side is appreciably facilitated, and thus the supply of blood to the heart is increased. The effects of these movements may be seen after section of the phrenic nerves, which causes paralysis of the diaphragm, when it will be noted that the blood-pressure curves are much re- duced. This diminution is attributed to two causes — the enfeebled respiratory movements, which are now confined to the ribs and the sternum, and the absence of the pressure transmitted from the diaphragm through the abdominal organs to the veins. If in such an animal the abdomen be periodically com- pressed, in imitation of the effects produced by the contraction of the dia- phragm, the respiratory curves may be restored to tlieir normal height. During expiration, since the conditions are reversed the effects also must be reversed. The increased negative intratlioracic pressure occasioned by inspira- BESPIRA TION. 451 tion now gives place to a gradual diminution, and with this a lessening of the aspiratory action due to the sub-atmospheric intrathoracic pressure ; the blood- supply is further reduced because of the lessened amount of blood coming through the inferior vena cava ; the abdominal veins, instead of being com- pressed and their contents forced chiefly toward the heart, are now being filled ; finally, during the shrinkage of the lungs the intrapulmonary vessels become lessened in capacity, and thus temporarily force more blood into the left side of the heart and cause the brief rise of arterial pressure observed at the beginning of expiration. Another factor believed by some to be involved in the respiratory undula- tions in blood-pressure is a rhythmical excitation of the vaso-constrictor centre in the medulla oblongata, asserted to occur coincidently with the inspiratory discharge from the respiratory centre. This has, however, been disproved. Others have held that the blood-pressure changes are due to the pressure ex- erted by the expanding lungs upon the heart; -while others contend that rhythmical alterations in the heart-beats are important. This latter factor is of importance in man and in the dog, in which there is a distinct increase in the rate of the heart-beat during inspiration, and co-operates in producing the general rise of pressure during inspiration. The BflEects on the Pulse. — During inspiration the pulse-rate is more rapid than during expiration. If we cut the pneumogastric nerves, it will be seen that, while the rate is increased as the result of the section, the diiference during inspiration and expiration is abolished ; on the other hand, if the thorax be widely opened, but the pneumogastric nerves are left intact, the inspiratory increase in the rate still occurs. This indicates that the cardio-inhibitory centre is either less active during inspiration or more active during expiration, and that there is an associated activity of the respiratory and cardio-inhibitory centres. Why this sympathy should exist between the respiratory and cardio- inhibitory centres we do not know, but it has been suggested that during expi- ration the blood reaching the centres is less highly arterialized than during the inspiratory phase, and that the cardiac centre is so sensitive to the difference as to be affected, and thus its activity is somewhat increased during the expira- tory phase, with the consequent decrease in the pulse-rate. During inspiration the pulse-rate is not only higher than during expiration, but the form of the pulse-wave is affected. The systolic, dicrotic, and sec- ondary waves are smaller and the dicrotic notch is more pronounced, so that the dicrotic character of the curves is better marked. The BflFects of Obstruction of the Air-passages and of the Respira- tion of Rarefied and Compressed Air on the Circulation. — The blood- pressure undulations produced during quiet breathing become marked in pro- portion to the depth of the respiratory movements. Inspiration or expiration against extraordinary resistance — as after closing the mouth and nostrils, or respiring rarefied or compressed air — may materially modify the circulatory phe- nomena. When we make the most forcible inspiratory effort, the air passages being fully open, not only is there a full expansion of the lungs, but great 452 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. diastolic distention of the heart and dilatation of the intrathoracic vessels ; yet, notwithstanding that this powerful aspiratory action encourages the flow of an extraordinarily large amount of blood into the thoracic vessels, the heart-beats may be very small, because intrathoracic negative pressure is so great that the thin-walled auricles meet with great resistance while contracting ; in conse- quence, then, of this forced inspiratory effort little blood is driven through the lungs to the left auricle and by the left ventricle into the general circulation. If we make the greatest possible expiratory effort, and maintain the expira- tory phase with air-passages open, the heart-beats are small, owing to the small amount of blood which flows through the venae cav£e to the right auri- cle, and to the resistance offered by the compressed intrapulmonary vessels. If, after a most powerful expiration, we close the mouth and nostrils and make a powerful inspiratory effort, the aspiratory effect of inspiration on the heart and the blood-vessels is manifest to its utmost degree : the heart and the vessels tend to undergo great dilatation, the blood-flow to the right auricle and ventricle is increased, the intrapulmonary vessels and the heart become en- gorged, and, owing to the powerful traction of the negative pressure upon the heart, especially upon the right auricle, very little blood is forced through the lungs to the left auricle and ventricle and subsequently into the general circu- lation, thus causing a fall of blood-pressure ; indeed, the heart-sounds and the pulse may disappear. If now we make the most forcible inspiratory effort, close the glottis, and make a powerful expiratory effort, not only is the air in the lungs subjected to high positive pressure, but the heart and the great vessels partake in the pressure-effects, the blood being forced from the pul- monic circulation into the left auricle, thence by the ventricle into the aorta, with the result of a temporary rise of blood-pressure. The pressure upon the intrathoracic veins is so great that the flow of blood into the chest is almost shut off, hence the veins outside the thorax become very much distended, as seen in the superficial veins of the neck, and the heart is pressed upon to such an extent that, together with the lessened supply of blood, the heart-sounds and the radial pulse may disappear and the blood-pressure falls. The respiration into or from a spirometer (p. 427) containing rarefied or compressed air modifies the blood -pressure curves. Inspiration of rarefied air causes a greater rise of blood-pressure than when respiration occurs at normal pressure, while during expiration, although the blood-pressure falls, it may remain somewhat above the normal. The increase of pressure is due to the aspiratory effort required to draw the air into the lungs, which effort also makes itself felt to a more marked degree upon the heart and the intrathoracic and intrapulmonary vessels, thus increasing the blood-flow through the pulmonary circulation. During expiration air is aspirated from the lungs into the spi- rometer, tending to dilate the intrathoracic and intrapulmonary vessels and the heart and thus to aid the pulmonary circulation. After a time, however, there is a. fall of blood-pressure on account both of the engorgement of the thoracic vessels and the accompanying depletion of the general circulation, and of the distention of the heart and interference with its contractions. Inspiration of compressed air lessens the extent of, and may prevent, the BESPIBATION. 453 inspiratory rise, or it may cause a fall. If, upon the respiration of compressed air, the pressure of the air be above that exerted by the elastic tension of the lungs, no effort of the inspiratory muscles is required, the chest being expanded by the pressure of the air. Therefore, instead of an increase of negative intra- thoracic pressure, as in normal inspiration, there is a decrease, and negative intrathoracic pressure is replaced by positive pressure. As a result, the blood- vessels and the heart, instead of being dilated by an aspiratory action, are pressed upon, forcing the blood into the general circulation, and thus causing a transient rise of pressure, which is, however, succeeded by a fall due to obstruc- tion to the flow of blood through the heart and the pulmonary vessels. Ex- piration into compressed air causes at first a transient increase of blood-pressure followed by a fall, the former being due to the forcing of some of the blood from the intrathoracic and intrapulmonary vessels into the general circulation, and the latter to obstruction to the blood-flow through the heart and the pul- monary circulation. When individuals are exposed to compressed air, as in a pneumatic cabinet, or to rarefied air, as in ballooning, the effects on the circulation become of a very complex character, owing chiefly to the additional influences of the abnormal pressure upon the peripheral circulation ; moreover, the effects of breathing against obstructions or of respiring rarefied or compressed air may be materially influenced by secondary effects resulting from excitation of the cardiac and vaso-motor mechanisms. In artificial respiration, as ordinarily performed in the laboratory, air is periodically forced into the lungs by a pair of bellows or a pump, and is ex- pelled from the lungs by the normal elastic and mechanical factors of expira- tion. When the lungs are inflated the pulmonary capillaries are subjected to opposing forces — the positive pressure of the air within the lungs on one hand, and the resistance of the thoracic walls on the other — so that the blood is squeezed out, thus momentarily increasing the blood-pressure, but subsequently retarding the current and consequently lowering the pressure. During expira- tion the pressure is removed and the blood-flow is encouraged ; there is, there- fore, a temporary fall during the filling of the pulmonary vessels, followed by a rise due to the removal of the obstruction. If the air is aspirated from the lungs, the rise of the pressure is augmented, owing to the further dilatation of the intrapulmonary capillaries ; hence, in artificial respiration, during the in- spiratory phase the blood-pressure curves are reversed, there being a primary transient rise followed by a fall, and during the expiratory phase a transient fall followed by a rise. In normal respiration the oscillations are due essen- tially to the changes in capacity of the intrapulmonary vessels caused essen- tially by the alterations in their length, while in artificial respiration the effects of these alterations are opposed and superseded by those due directly to positive intrapulmonary pressure. J. Special Rbspiratoby Movements. The rhythmical expansions and contractions of the thorax which we under- stand as respiratory movements have for their object the ventilation of the 454 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. lungs. There are, however, other movements which possess certain respiratory characters, but wliich are for entirely different purposes, hence they are spol Blum : Pfiiiger's Archiv, 1899, Bd. 77, S. 70. " Zeitschrift fUr physiologische Chemie, 1899, Bd. 27, S. 14. " Boss, E. : Ibid., 1899, Bd. 28, S. 40. 510 AJV AMERICAN TEXT-BOOK OF PHYSIOLOGY. Fluorine, F = 19. Fluorine is found in the bones and teeth, in muscle, brain, blood, and in all investigated tissues of the body, though in minute quantities. In one liter of milk 0.0003 gram of fluorine have been detected.' Fluorine is found in plants, and in soil without fluorine plants do not flourish. It seems to be a necessary constituent of protoplasm. Free fluorine is a gas which cannot be preserved, as it unites with any vessel in which it is prepared. Hydrofluoric Acid, HF, is prepared by heating a fluoride with concentrated sul- phuric acid, in a platinum or lead dish, CaP, + H,SO.i = CaSOi + 2HR Properties. — Hydrofluoric acid is a colorless gas, so powerfully corrosive that breathing its fumes results fatally. Its aqueous solutions are stable, but can be kept only in vessels of platinum, gold, lead, or india-rubber. It etches glass, uniting to form volatile silicon fluoride, SiO^-f 4HP = SiF, + aH,0. Circulation in the Body. — Tappeiner and BrandP have shown, on feeding sodium fluoride (NaF) to a dog in doses varying between 0.1 and 1 gram daily, that the fluorine fed was not all recoverable in the urine and feces, but was partially stored in the body. On subsequently killing the dog, fluorine was found in all the organs investigated, and was especially found in the dry skeletal ash to the extent of 5.19 per cent, reckoned as sodium fluoride. From the microscopic appearance of the crystals seen deposited in the bone, the presence of calcium fluoride was concluded. In this form it normally occurs in bones and teeth. Nitrogen, N = 1 4. Free nitrogen constitutes 79 per cent, of the volume of atmospheric air. It is found dissolved in the fluids and tissues of the body to about the same extent as distilled water would dissolve it. It is swallowed with the food, may par- tially diffuse through the mucous membrane of the intestinal tract, but forms a considerable constituent of any final intestinal gas. It is found in the atmos- phere combined as ammonium nitrate and nitrite, which are useful in furnish- ing the roots of the plant with material from which to build up proteid. Bacteria upon the roots of certain vegetables combine and assimilate the free nitrogen of the air (Hellriegel and Willforth). Cultures of algte do the same.' Preparation. — (1) By abstraction of oxygen from air through burning phosphorus in a bell jar over water, pentoside of phosphorus being formed, which dissolves in the water and almost pure nitrogen remains. (2) By heating nitrite of ammonium, NH4NO., = 2N 4- 2H,0. Properties. — Nitrogen is especially distinguished by the absence of chemical afiinity for other elements. It does not support combustion, and in it both a ' G. Tammann : Zeitxchrift fiir physiologische Chemie, 1888, Bd. 12, S. 322. * Zeitschrift fur Biologie, 1892, Bd. 28, S. 518. ' P. Kossowitch : Botanisdm Zeitung, 1894, Jahrg. 50, S. 97. THE CHEMISTRY OF THE ANIMAL BODY. 511 flame and animal life are extinguished, owing to lack of oxygen. It acts as a diluent of atmospheric oxygen, thereby retarding combustion, but on higher animal life it is certainly without direct influence. Ammonia, NH3, is found in the atmosphere as nitrate and nitrite to the extent of one part in one million. It is found in the urine in small quantities, is a constant product of the putrefaction of animal matter, and is a product of trypsin proteolysis. Preparation. — (1) Through the action of nascent hydrogen on nascent nitrogen. This may be brought about by dissolving zinc in nitric acid, 3Zn + 6HNO3 = 3Zn(]Sr03)2 + 6H. lOH + 2HNO3 = 6H2O + 2N. N + 3H = NH3. Ammonia is produced in a similar way in the dry distillation of nitro- genous organic substances in absence of oxygen, being therefore a by-product in the manufacture of coal-gas. In putrefaction nascent hydrogen acts on nascent nitrogen, producing ammonia, which in the presence of oxygen becomes oxidized to nitrate and nitrite, or in the presence of carbonic oxide is con- verted into ammonium carbonate. Ammonium nitrite is likewise formed on burning a nitrogenous body in the air, in the evaporation of water, and on the discharge of electricity in moist air, 2N 4- 2H2O = NH.NO,. At the same time a small amount of nitrate is formed in the above three processes, 2N + 2H2O + O = NH.NOj. Hence these substances find their way into every water and soil, and furnish nitrogen to the plant. The value of decaying organic matter as a fertilizer is likewise obvious. Properties. — Ammonia is a coloi-less gas of pungent odor. It readily dis- solves in water and in acids, entering into chemical combination, the radical NH^ appearing to act like a metal with properties like the alkalies, and its salts will be described with them. Very small amounts of ammonia instantly kill a nerve, but upon muscular substance it acts first as a stimulant, provok- ing contractions : 1 part of ammonia in 500 of water will kill an amoeba, and 1 part in 10,000 will slow and finally arrest ciliary motion.^ Ammonia in the Body. — If it be agreed with Hoppe-Seyler that normal decomposition in the tissues is analogous to putrefaction, then nascent hydrogen acting on nascent nitrogen in the cell produces ammonia, which in the presence of carbonic acid becomes ammonium carbonate, and in turn may be converted into urea by the liver. If acids (HCl) be fed to carnivora (dogs) the amount of ammonia present in the urine is increased, which indicates that an amount of ammonia usually converted into urea has been taken for the neutralization ' Bokorny : PJliiger's Archiv, 1895, Bd. 59, S. 557. 512 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. of the acid.' In a similar manner acids formed from decomposing proteid may be neutralized (see pp. 506 and 550). The ammoniacal fermentation, of the urine consists in the decomposition of urea into ammonium carbonate by the micrococcus urince, the urine becoming alkaline. Compounds of Nitrogen with Oxygen. — There are various oxides of nitrogen, the higher ones being powerfully corrosive, and some of these unite with water to form acids, of which nitric acid (HNO3) is the strongest. Only nitrous and nitric oxides are of physi- ological interest. Nitrous Oxide, NjO, likewise called "laughing-gas," is prepared by heating ammo- nium nitrate, NH,N03 = N,0 + 2HA It supports ordinary combustion almost as well as pure oxygen, but it will not sustain life. Mixed with oxygen it may be respired, producing a state of unconsciousness preceded by hysterical laughter. Nitric Oxide, NO, is prepared by dissolving copper in nitric acid, 3Cu + 8HNO3 = aCulNOa)^ + 4H2O -I- 2N0. Contact with oxygen converts it into peroxide of nitrogen (NO2), which is an irritating irrespirable gas of reddish color. Nitric oxide in blood first unites with the oxygen of oxyhsemoglobin, forming the peroxide (NO2), and then the nitric oxide combines with haemoglobin, forming a highly stable compound, nitric-oxide haemoglobin (Hb-NO). Nitrogen in the Body. — Nitrogen is taken into the body coml:)ined in the great group of proteid substances, which are normally completely absorbed by the intestinal tract. It passes from the body in the form of simple decom- position-products, in larger part through the urine, but likewise through the juices which pour into the intestinal canal. The unabsorbed residues of these latter juices, mixed with intestinal epithelia constitute in greater part the feces.'' An almost insignificant amount of nitrogen is further lost to the body through the hair, nails, and epidermis, but, generally speaking, the sum of the nitrogen in the urine and feces corresponds to the proteid decomposition for the same time (1 gram N = 6.25 grams proteid). When the nitrogen of the proteid eaten is equal in quantity to the sum of that in the urine and feces, the body is said to be in nitrogenous equilibrium. When the ingested nitrogen has been larger than that given off, proteid has been added to the substance of the body ; when smaller, proteid has been lost. These propositions were established by Carl Voit. A small amount of urea and other nitrogenous substances may be excreted in profuse sweating. Proteid nitrogen never leaves the body in the form of free nitrogen or of ammonia. That ammonia is not given oiF by the lungs may be demonstrated by perform- ing tracheotomy on a rabbit, and passing the expired air first through pure potassium hydrate (to absorb CO2) and then through Nessler's reagent. The experiment may be continued for hours with negative result.' ' Fr. Walther: Archiv fiir exper. Palhologie und Pharmakohgie, 1877, Bd. 7, S. 164. ^ Menichanti and Praiisnitz : Zeitschrifl fiir Biologic, 1894, Bd. 30, S. 353. ' Bachl : Zeitschrifl fur Biologie, 1869, Bd. 5, S. 61. THE CHEMISTRY OF THE ANIMAL BODY. 513 Phosphorus, P =-32. Phosphorus is fouud combined as phosphate in the soil ; it is necessary to the development of plants. As phosphate it is present in large quantity in the bones, and is found also in all the cells, tissues, and fluids of the body, probably in loose chemical combination with the proteid molecule. It is pres- ent in nuclein, protagon, and lecithin. J5-eparaft.ore.— Phosphorus was first prepared by igniting evaporated urine, SNaH.POi + 5C = 3H,0 + 5C0 + 2P + NajPO^. In a similar way it may be obtained by chemical treatment of bones. The vapors of phosphorus may be condensed by passing them under water, where at a temperature of 44.4° the phosphorus melts and may be cast into sticks. Properties. — Phosphorus is a yellow, crystaUine substance, soluble in oils and carbon disulphide. It is insoluble in water, in which it is kept, since in moist air it gives off a feeble glowing hght, accompanied by white fumes of phosphorous acid (H3PO3) and small amounts of ammonium nitrate, peroxide of hydrogen, and ozone, to which latter the peculiar odor is ascribed. Phosphorus ignites spontaneously at a temperature of 60°, and this may be produced by mere handling, the resulting burns being severe and dangerous. This form of phosphorus is poisonous, but if it be heated to 250° in a neutral gas (nitrogen) it is changed into red phosphorus, which has different properties and is not poisonous. Phospharus-poisoniiig. — On injecting phosphorus dissolved in oil into the jugular vein, embolisms are produced by the oil in the capillaries of the lungs, the expired air contains fumes of phosphorous acid, and the lungs glow when cut out (Magendie). If the phosphorus oil be injected in the form of a fine emulsion, embolism is avoided,' and the fine particles of phosphorus are generally distributed throughout the circulation. On autopsy of a rabbit after such injec- tion in the femoral vein, all the organs and blood-vessels glow on exposure to the air.^ If two portions of arterial blood be taken, and one of them be mixed with phosphorus oil, and they be let stand, both portions' become venous in the same time.* Hence phosphorus in blood, as in water, is not readily oxidized. Persons breathing vapor of phosphorus acquire phosphorus-poisoning. What the direct action of phosphorus is, is unknown, but the results are most inter- esting. To understand the results it may be supposed that proteid in decompos- ing in the body splits up into a nitrogenous portion, the nitrogen of which finds its exit through the urine and feces, and a non-nitrogenous portion, which is re- solved into carbonic oxide and water, just as are the sugars and the fats. This carbonic acid is given off, for the most part, through the lungs. Now if a starv- ing dog, which lives on his own flesh and fat, be poisoned with phosphorus, the proteid decomposition as indicated by the nitrogen in the urine is largely increased, while the amounts of carbonic acid given off and oxygen absorbed are largely decreased ; on post-mortem examination the organs are found to contain excessive quantities of fat. We have here presumptive evidence that a part of the proteid molecule usually completely oxidized has not been burned, 'L. Hermann: Pfluger's Archiv, 1870, Bd. 3, S. 1. ' H. Meyer : Archiv fiir exper. Pathologie und Pharmakologie, 1881, Bd. 14, S. 327. 'Meyer, Op. cit.,S. 329. Vol. I.— 33 514 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. but has been converted into fat.^ Similar results are characteristic of arsenic and antimony poisoning, and of yellow atrophy of the liver. Rosenfeld has recently shown that much of the fat found in the liver of a dog poisoned with phosphorus is fat transported from the fat repositories of the body (fatty infiltration). The high proteid metabolism, however, of itself would indicate the retention of an unburned part of the proteid molecule, which in this case probably appears as fat^ (fatty degeneration, see p. 559). A parallel case of high proteid metabolism is seen in diabetes, where sugar from proteid remains unburned. Compounds of Phosphorus with Oxygen. — Of these compounds three oxides and several acids exist, but only meta- and orthophosphoric acid need attention here. Phosphorus Peroxide, PjOj, is a white powder, which rapidly absorbs moisture ; it is produced by burning phosphorus in dry air. Metaphosphoric Acid, HPO3, is said to occur combined in nuclein. Preparation. — (1) By dissolving Vfi^ in cold water, P2O5 + H^O = 2HPO3. (2) By fusing phosphoric acid, H3PO, = HPO3 + HjO. It is converted slowly in the cold, rapidly on heating, into phosphoric acid. Crystalline it forms ordinary glacial phosphoric acid. Metaphosphoric acid precipitates proteid from solution, yielding a body said to be pseudonuclein,^ but this seems to be untrue ' (see p. 579). Orthophosphoric Acid, H3PO4. — Salts of this acid constitute all the in- organic compounds of phosphorus in the body, and are called phosphates. Preparation. — (1) By heating solutions of metaphosphoric acid, HPO3 + HP = H3PO,. (2) By treating bone-ash with sulphuric acid, Ca3(P04)2 + SH^SO, = 3CaSO, + 2H3PO,. Properties. — On evaporation of the liquors obtained above, the acid separates in color- less hygroscopic crystals. Phosphoric acid forms different salts according as one, two, or three atoms of hydrogen are supplanted by a metal. Thus there exist primary sodium or calcium phosphates, NaHjPOi and Ca^ + ^^° + ^'^^*" Methyl ether. (2) Alcohols oxidized give first aldehyde and then acid : CH30H-fO = HC^, Acids.— These are found as glycerin esters in milk-fat. They are likewise present in sweat and in cheese. Palmitic, CigHj^O^, and Stearic, CigHg^Oj, Acids.— As glycerin esters these two acids are found in the ordinary fat of adipose tissue, and in the fat of milk. The acids may occur in the feces, and are found combined with calcium in adipocere (p. 560). "Wool-fat consists of the cholesterin esters of these acids. The bile contains palmitic, stearic, and oleic acids,' and to these have been attributed its very slight acid reaction.* Compounds of the Alcohol Radicals with Nitrogen. Amines. — These are bodies in which either one, two, or three of the hydrogen atoms in ammonia are replaced by an alcohol radical, and are termed respectively primary, second- ary, and tertiary amines. Metliyl, ethj'l, and propyl amine bases are the products of pro- teid putrefaction. They resemble ammonia in their basic properties. Methylamine, NHjlCHj).— This is found in herring-brine. It has the fishy smell noted in decaying fish. It is a product of the distillation of wood and of animal matter. Feeding methylamine hydrochloride is said to cause the appearance of methylated urea in a rabbit's urine ^ (analogous to the formation of urea from ammonia salts) : 2HC1.NH,(CH3) + CO, = OCCNHCHs)^ -f 2HC1 + H^O. According to Schiff"er,* the body, probably through intestinal putrefaction, has the power of partially converting creatin into oxalic acid, ammonia, carbonic acid, and methylamine, which last is finally excreted as methylated urea in the urine. Ethylamine, C2II5NH2, when fed as carbonate appears in part as ethylated urea in the urine.' Trimetliylamilie, N(CH3)3. — Like ethylamine, this is found in herring-brine and among the products of proteid putrefaction and distillation. In the putrefaction of meat the first ptomaine appearing is chohn, which certainly is derived from lecithin,; the cholin (see p. 543) gradually disappears, and in its place trimethylamine may be detected.* Compounds with Cyanogen. The radicle NC — forms a series of bodies not unlike the halogen com- pounds. Owing to the mobility of the cyanogen group, Pfliiger^ has sought to attribute the properties of living proteid to its presence in the molecule, whereas in the dead proteid of the blood-plasma, for example, he imagines that the nitrogen is contained in an amido- group. When the cyanogen radical occurs in a compound in the form of N:=C — the body is called a nitril, when in the form of C^N — an iso-nitril. Cyanogen Gas, NC — CN. — A very poisonous gas. ' Gmelin: Zeitschrift fiir phyMogisehe Ohemie, 1893, Bd. 18, S. 28. 2 Ibid., 1895, Bd. 20, S. 203. ' Lassar-Cohn : Ibid., 1894, Bd. 19, S. 571. * Jolles : Pfliiger's Archiv, 1894, Bd. 57, S. 13. * Schiifer : Zeitschrift fiir physiologische Ohemie, 1880, Bd. 4, S. 245. ' Loc. cit. ' Schmiedeberg : Archiv fiir exper. Pathologic und Pharmakologie, 1877, Bd. 8, S. 5. ' Brieger: Abstract in Jahresberieht iiber Thierchemie, 1885, S. 101. » Pfliiga^s Archiv, 1875, Bd. 10, S. 251. 542 AN AMEBICAN TEXT-BOOK OF PHYSIOLOGY. Hydrocyanic Acid, HCN. — This is likewise a strong poison. Amj'gdalin is a glucoside occurring in cherry-pits, in bitter almonds, etc. , together with a ferment called emulsin, which latter has the power of transforming amj'gdalin into dextrose, benzaldehyde, and hydro- cyanic acid. Hydrocyanic acid, therefore, gives its taste to oil of hitter almonds, and it may likewise be detected in cherry brandy. Fotassium Cyanide, KCN. — This and all other soluble cyanides are fatal poisons. Acetonitril, or Methyl Cyanide, CH3CX. — This and its higher homologous nitrils are violent poisons. After feeding acetonitril in small doses, formic acid (see p. 534) and thiocyanic acid (see below) appear in the urine, the thiocyanic acid being a sjTithetio prod- uct of the ingested cyanogen radical, and the HS — group of decomposing proteid.' After feeding higher homologues of acetonitril or hydrocyanic acid, thiocyanide likewise appears in the urine. Since the amount of thiocyanide in the urine is normally very small, there is no reason for believing that cyanogen radicals similar to those described above are ever, to any great extent, cleavage-products of proteid.^ Through intravenous injections of sodium sulphide, and especially of sodium thiosulphate, poisonous cyanogen compounds may be administered much beyond the dose ordinarily fatal •} NaCN + SO, < ^^ + = NCSNa + Na.,S04. Cyanamide, NC.NHj. — ^This is a laboratory decomposition-product of creatin, but does not occur in the body. It is poisonous when administered. When boiled with dilute sulphuric or nitric acids it is converted into urea : NCNH, + H^O = ILNCONH,. It is to be remembered that creatin in the body is not converted into urea. Ammonium Cyanate, 0CN(NH4). — Boiling ammonium cyanate converts it into urea. This was shown by Wohler in 1828, and was the first authoritative laboratory production of a body characteristic of living organisms : OCN(NH,)=OC(NH2)2. This reaction illustrates Pfliiger's idea of the transformation of the unstable cyanogen radical in living proteid into the amido- compound in the dead substance. According to Hoppe- Seyler, the urea-formation in the body is as indicated in the above reaction, but that no cyanic acid or ammonium cyanate is to be detected on account of their extreme instability. Fotassium Thiocyanide, NC'SK. — This substance is usually found in human saliva to the extent of about 0.01 per cent., and in the urine. Since it contains nitrogen and sul- phur its original source must be from proteid. The amount in the urine is probably wholly and quantitatively derived from that in the saliva.* If thiocyanides be fed, they appear quickly in the urine without change. Thiocyanides are less poisonous than the simple cyanides (see discussion under Acetonitril above). Thiocyanides give a red color with ferric chloride in acid solution. Diatomic Alcohol, Radicals. Thus far only derivatives of monatomic radicals have been discussed ; next in order follow diatomic alcohol radicals, represented by the formula CnHj,,, and including the bodies ethylene, H2C=^CH2, propylene, CH3 — HC = CH2, etc. This set of hydrocarbons is called the olefines. The first series of compounds which are of physiological interest are the amines of the olefines. Amines of the Olefines. These include the group of ptomaines — basic substances which are formed from proteid through bacterial putrefaction. Those which are poisonous are ' Lang : Archiv fiir ezper. Palhologie und Pharmakologie, 1894, Bd. 34, S. 247, ^ Op. cit., S. 256. ^ Lang : Archiv fur exper. Pathologic und Pharmakologie, 1895, Bd. 36, S. 75. « Gscheidlen: Pfiiigei's Archiv, 1877, Bd. 14, S. 411. THE CHEMISTRY OF THE ANIMAL BODY. 543 called toxines. These bodies are diamines of the olefines, and have been investigated especially by Brieger.^ Tetramethylene-diamin, or Putresein, H2N.CH,.CH,,CH,.CH2.NH,.— This com- pound is found in putrefying proteid, and has been detected in the urine and feces in cystitis. Pentamethylene-diamin, or Cadaverin, H2N.C5H10.NHj.— This is found with putrescine wherever produced. They are both found in cultivations of Koch's cholera bacil- lus and in cholera feces. In cystitis they are a result of special infection of the intestinal tract, are principally excreted in the feces, but are partially absorbed, and prevent, perhaps through chemical union, the burning of oystein normally produced.^ Diamines are not normally present in the urine. Neuridin and Saprin. — These are isomers of cadaverin and are produced by the same putrefactive processes. Cholia. — This is trlmethyl oxyethyl ammonium hydroxide, and has its source in lecithin decomposition, and putrefaction (see p. 559). Cholin has been found in the cerebrospinal fluid in cases of general paralysis in the insane, and is regarded as the eifective poison.' Muscarin, or Oxycholin. — This is a violent heart-poison, and may be obtained by treating cholin with nitric acid. OH Nenrin. — This is trimethyl-vinyl ammonium hydroxide, (CH3)3 = N CO, the other of urea. The skeletal struc- ture of all alloxuric bodies may be written thus : N— C C / i >c N— C Alloxan. Urea. These bodies fall into three groups, that of hypoxanthin, of xanthin, and of uric acid. Bodies belonging to the first two groups are called alloxuric bases, or more commonly xanthin bases, or nudein bases, because they are derived from nuclein. The strong family analogy of the three groups is shown by the following reactions — results of heating with hydrochloric acid in sealed tubes at 180° to 200°:^ QH,N,0 + 7H2O = 3NH3 + C^H^NO^ + CO2 + 2CHA. Hypoxanthin. GlycocoU. Formic acid. CjH.N A + 6H3O = 3NH3 + C^H.NO^ + 2CO2 + CH A. Xanthin. C^H.NA + 5H2O = 3NH3 + C^H.NO^ + 3CO2. Uric acid. Reference to the formulae below will show that the molecules of COj given off correspond to the number of CO radicals in the alloxuric body, while the molecules of formic acid correspond to the number of CH groups. Emil Fisher * has discovered a body called purin, and has given another classification. The chemical series of the purin bodies may thus be presented : ' Drechsel : Archiv fur Physiologie, 1891, S. 248. ' Formula by Schulze and Winterstein : Zeitschrift fiir physiologiache Chemie, 1899, Bd. 26, S. 12. ' Kruger : Ibid., 1894, Bd., 18, S. 463. * Beriehte der deutschen chemischen Gesellschaft, 1899, Bd. 32, S. 435. THE CHEMISTRY OF THE ANIMAL BODY. 553 C,H,NP3 C,H,NA C,H,N,0 C,H,N,. Uric acid. Xanthin. Hypoxanthin. Purin. To purin is given the following formula : N = C — H IN — 6C :_c c— N H — C C — NH, 2C 5C — N7 \ II II >C-H II C8 N— C— N 3N_4C — N9/- Purin. Purin nucleus. For the convenience of chemical description the atoms of the purin nucleus are numbered as above, since the chemical constitution varies with the locality to which the atoms are attached to the nucleus. The purin deriv- atives number many hundreds, but only about a dozen are known at present to have physiological significance. Hypoxanthin is 6-oxypurin, xanthin is 2, 6-dioxypurin, uric acid is 2, 6, 8-trioxypurin, adenin is 6-amino-purin, while guanin is 2-amino- 6-oxypurin. Hypoxanthin, xanthin, adenin, and guanin are decomposition products of the nucleins, and from their oxidation uric acid is derived. (rt) PURINS. Purin, CjH^Nj. This, according to Emil Fisher, is a substance which may occur in the body, but which on account of its ready decomposition has not yet been discovered there. (6) MONOXYPUEINS. NH_C=0 Hypoxanthin, or Sarcin, H — C C — NH\ II II C — H.— This is found N _ C— N /' in small amount in the tissues and fluids of the body and in the urine. Hypoxanthin is derived from some nucleins, especially those contained in the sperm of salmon and carp, through the action of water or dilute acids. (o) DiOXYPURINS. NH — C=0 I I Xanthin, O = C C — NH \ I II C — H. — This substance, like hypoxan- NH — C— N -/ thin, is found in the tissues and fluids of the body and in the urine. It is a decomposition product of some nucleins and may be found in those of the pancreas, thymus, testicle, carp sperm, etc. Methyl Dioxypurins.— The alkaloids theophyllin, theobromin, and caffein occur in tea, coffee, cocoa, etc., and are habitually taken in the food. Theophyllin (1, 3-dimethyl- 554 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. xanthin) probably loses its labile 3-methyl in the body, and occurs in the urine as 1-methyl- xanthin. In like manner theobromin (3, 7-dimethylxanthin) is converted into heteroxan- thin (7-methylxanthin). CafFein (1, 3, 7-trimethylxanthin) also parts with its 3-methyl- radicle and appears in the urine as paraxanthin (1, 7-dimethylsanthin). Kriiger and Salomon' find 22. 3 grams of heteroxanthin, 31.3 grams of 1-methylxanthin, and 15.3grams of para-xanthin in 10,000 liters of urine, or much more in quantity than the true nuclein bases (xanthin, etc.). That theophyllin, theobropain, and cafFein may be demethylated in the tissue is an interesting commentary on the methylation of tellurium, selenium, and pj'ridin by the tissues. {d) MONOAMINOPDBINS. N = C — NH^ I I Adenin, or 6-Aminopurin, H — C C — NH\ II II C-H. N — C— N^ Adenin is found in the blood, the tissues, and the urine. It is especially a decomposition product of thymus nuclein, although other nucleins may con- tain it. Nitrous oxide converts it into hypoxanthin. (e) Aminoxypurins. NH — C=0 Guanin, or 2-Amino-6-Oxypurin, H.,X^C C — NH\ II II C-H N C— N ^ This also is found as a decomposition product of some nucleins, especially that of the pancreas. Combined with calcium it gives the brilliant irides- cence to fish-scales.^ It is found in the fresher layers of guano, and, accord- ing to Voit, is here very probably derived from the fish eaten by the water- fowl. Epiguanin, or 7-Methyl-guanin.— This has been found in the urine, and like the other methylated purins may very likely be derived from the food fed.' Episarcin is a purin base which has been found in the urine, but whose configura- tion has not yet been made out. Camin is said to occur in the urine. Its composition is unknown. (/) Trioxypurins. NH— C = O Uric Acid, O = C C— NH \ II >C0. — This acid is found in the nor- NH— C— NH mal urine in small amounts, and may be detected in the blood and tissues, ' Zeitschrifl fiir physiologische Chemie, 1898, Bd. 26, S. 350. ' Voit : Zeitschrifl fiir uisseTischaftiiche Zoologie, Bd. 15, H. 515. ' Kriiger and Salomon : Zeilschrift fiir physiologisehe Chemie, 1898, Bd. 26, S. 389. THE CHEMISTRY OF THE ANIMAL BODY. 555 especially in gout. It is the principal excrement of birds and snakes, that of the latter being almost pure ammonium urate. Preparation.— {I) By heating glycocoll with urea at 200° : C,H,NO, + 3CO(NH,), = C^H.N.O, + 3NH3 + 2H,0. (2) By heating the amide of trichlorlactic acid with urea : CCI3CHOH.CO.NH, + 2CO(NH,), = C,H,X/_)3 + 3HC1 + NH, + H,0. Properties. — Uric acid may be deposited in white hard crystals, which are tasteless, odorless, and almost insoluble in water, alcohol, or ether. (For its solution in the urine see p. 522.) Presence of urea adds to its solubility.' Its most soluble salts are those of lithium and piperazin. Uric acid is dibasic — that is, two of its hydrogen atoms may be replaced by monad elements. (1) Nitric acid in the cold converts uric acid into urea and alloxan . CsH.NA + + H,0 = OCCO + OC(NH,),. Alloxan. (2) Whereas, if the hot acid acts, it produces parahanic acid : /NH — C0\ /NH — CO 0C< >CO + = OC< J +C0.. \NH-CO/ NNH-io Parabanic acid. (3) Through water addition parabanic acid becomes oxaluric acid: /NH — C = /NHj 0C< I +H,0 = OC< \NH — C = \NH.CO.COOH Oxaluric acid. (4) And still another molecule of water added produces oxalic acid and urea : ^ /NH, COOH 0C< +H,0= I +OC(NH.,),. \NH.CO.COOH COOH Oxalic acid. The above reactions lead up to the constitutional formula of uric acid, and show its decomposition into urea and oxalic acid through oxidation and hydrolysis. It is known that uric acid when fed increases the amount of urea in the urine, and it is possible that the oxaUc acid in the urine may have the same source. Uric acid oxidized with permanganate of potassium is converted into allantoin, /NH — CII— NH\ 0C< I >C0, \NH2 CO-NH/ a substance which is found in the allantoic fluid, and in the urine of pregnant women and of newborn children, and in the urine of dogs after feeding thymus (see below). If uric acid be carefully evaporated with nitric acid on a small white porcelain cover, a reddish residue remains, which moistened with ammonia gives a brilliant purple color, due to the formation of murexid, C8H,(NH4)N506; subsequent addition of alkali gives a red coloration. This is known as the murexid test and is very delicate. The Purin Bases in the Body. — All true nucleins yield one or more of the purin bases. Nucleins are combinations of nucleic acid and proteid, ' G. Eiidel : Archiv fur exper. Pathologic und Pharmakotogie, 1893, Bd. 30, S. 469. ' See Bunge: Physiologiache Chemie, 1894, S. 312. 556 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. except the nuclein from spermatozoa in which the acid combines with pro- tamin. The simplest indication of the cleavage of nuclein (see Nuclein) on chemical treatment, may be written as follows : Nuclein. Proteid. Nucleic acid. Phosphoric acid. Adenin. Guanin. Xanthin. , Hypoxanthin. The idea that the purin bodies occurring in the urine of mammals are the metabolic products of nucleins, the uric acid being derived from the oxidation of the bases, was made especially clear by the experiments of Horbaczewski.^ His statement that feeding nucleins increases the purin bases and the uric acid in the urine has been frequently confirmed. He also showed that if fresh spleen pulp, which contains no purin bodies, be per- mitted to putrefy, the extract will contain xanthin and hypoxanthin, whereas if the spleen pulp be shaken with the air uric acid is produced, being oxi- dized from these bases. Spitzer^ finds, if air be passed through spleen and liver extracts digested at 40° with the exclusion of putrefaction, that uric acid is produced. The nuclein bases formed decrease with the increase of uric acid. Hypoxanthin and xanthin added to such digests are readily oxi- dized to uric acid, as are adenin and guanin, although with greater difficulty. Extracts of the kidney, pancreas, thymus, and blood have no such power. Feeding uric acid and nuclein bases increases the amount of urea in the urine. Minkowski' has proved that after feeding hypoxanthin uric acid increases in the urine, showing its oxidation. Minkowski also showed after feeding a man with thymus, the nuclein of which yields principally adenin with some guanin, that the amount of uric acid was increased in the urine ; the same food fed to a dog increased the uric acid, and allantoin, an oxidation product of uric acid, also appeared. Feeding adenin to a dog did not in- crease the uric acid or allantoin excretion, but on autopsy of the dog there was found a deposit of uric acid in the uriniferous tubules with indications of inflammatory processes. This is the first known artificial production of a deposition of uric acid. It would seem that the adenin in combination with nucleic acid in thymus may be readily burned to uric acid in such a way that it is readily excreted, whereas adenin itself behaves diffisrently. Loewi* finds that the same amount of nuclein food fed to difTerent people results in the same excretion of uric acid. He therefore concludes that all the purin bodies liberated in metabolism are quantitatively eliminated. The analysis of ' Sitzungsberichte der 'Wiener Akaelemie der Wissemchafi, 1891, Bd. 100, Abth. iii. S. 13. » PflUger's Archiv, 1899, Bd. 76, S. 192. ' Archiv fur exper. Pathologic und Pharmakologie, 1898, Bd. 41, S. 375. * Ibid., 1900,Bd. 44, S. 1. THE CHEMISTRY OF THE ANIMAL BODY. 557 10,000 liters of urine^ has shown the pi-esence of 10.11 grams of xanthin, 8.5 grains of hypoxanthin, and 3.54 grams of adenin. Xanthin fed to birds is converted into uric acid. In birds the formation of uric acid depends on a syntlietio union of ammonia and lactic acid in the liver, since on extirpation of the liver the last two substances appear in the urine in amounts proportional to the normally formed uric acid (see p. 546). The literature on the subject of gout is enormous. It is sufficient to re- mark here that it is not even known whether gout is due to an increased for- mation or an increased retention of uric acid. The amount of uric acid in the blood is certainly increased. The normal amount of uric acid in the daily urine is put at 0.7 gram, that of the purin bases at 0.1325,^ although this latter may be too high on account of the presence of the bases derived from tea and coffee. The amount of the bases may be quadrupled in leucocy- thsemia.' Diatomic Dibasic Acids, CoHjn-jO^. COOH Oxalic Acid, | . — This is found as calcium oxalate in the urine, and COOH is present in most plants. It is a product of boiling proteid with barium hydrate. It may be obtained synthetically by heating sodium formate : COONa 2HC00Na= | -F2H. COONa Oxalic acid and its alkaline salts are very soluble in water. Its calcium salts are insoluble in water and dilute acetic acid, but are soluble in the acid phos- phates of the urine. According to Lommel,* oxalic acid is a product of metabolism, and is not produced proportionally to proteid destroyed, but occurs in increased amounts in the urine when nucleins (thymus) and gelatin are fed. The occurrence of oxalic acid in the urine after feeding nucleins is significant in virtue of its possible origin from uric acid (see Uric Acid, p. 554). Stones in the bladder are sometimes composed of calcium oxalate, as are also urinary sediments wlien formed in consequence of ammoniacal fermentation. Succinic Acid, HOOC.C2H,.COOH.— This has been detected in the spleen, thymus, thyroid, in echinococcus fluid, and often in hydrocele fluid. It is a product of alcoholic fermentation, and of proteid putrefaction. It is often found in plants. Amido-succinic Acid, or Aspartic Acid, HOOC.CjHjNHj.COOH. This is a product of boiling proteid with acid or alkalies, and it is also formed under the influence of trypsin in proteid digestion. » Kriiger and Salomon: Zeilschrifi fiir physiolorjische CItemie, 1S98, Bd. 26, S.,350. ' Kruger and Wulff: IMd., 1895, Bd. 20, S. 184. ' Boudzynski and Gottlieb, Op. cit, S. 132. • Deutsehes Archivfilr klinische Medizin, 1899, Bd. 63, S. 599. 658 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. Monamide of Amido-succinic Acid, or Asparagin, H2XOC.C2H3NH2.COOH. — This is found widely distributed in plants, especially in the germinating seed. If a plant be placed in the dark its proteid nitrogen decreases, whereas the non-proteid nitrogen increases,^ the cause of this being attributed to proteid metabolism with the production of amide- acids, i. e. aspartic and glutamic acids, leucin, and tn-osin. In the sunlight, it is believed, these bodies are later reconverted into proteid. One view regarding the for- mation of asparagin is based theoretically on the production of succinic acid from carbo- hydrates (as in alcoholic fermentation) and the subsequent formation of oxysuccimc acid (or malic acid, HOOC.CjHaOH.COOH), which the inorganic nitrogenous salts change to asparagin.^ At any rate asparagin in the plant has the power of being constructed into proteid. Since proteid in the animal body may yield 60 per cent, of dextrose in its decomposition, as will be shown, it seems fair to surmise that the synthesis of proteid in the plant may in part depend upon the union of asparagin or similar amido- compounds with the carbohydrates present. Asparagin if fed is converted into urea. It forms no proteid synthesis in the animal, and has only a very small effect as a food-stuff.' Glutamic acid, HOOC.CIINH2.CH.2.CH,.COOH.— This is found as a cleavage- product of tryptic digestion in the intestinal canal. Glutamin, its amido- compound, is, like asparagin, widely distributed in the vegetable kingdom and in considerable amounts. It probably plays the same r61e as asparagin in the plant. Glutamin is more soluble than asparagin and is therefore less easily detected. Compounds of Triatomic Alcohol Radicals. Glycerin, or Propenyl Alcohol, CHjOH.CHOH.CHjOH. The glycerin esters of the fatty acids form the basis of all animal and vegetable fats. Glycerin is furthermore formed in small quantities in alcoholic fermentation. Preparation. — (1) Through the action of an alkali on a fat, glycerin and a soap are formed, a process called saponijioation : 2C3H,(C,3H3,0,)3 + 6NaOH = 2C3H,(OH)3 + 6NaC,3H3,0,. stearin. Sodium stearate. (2) Fats may be decomposed into glycerin and fatty acid by superheated steam, and likewise by the fat-splitting ferment in the pancreatic juice. Thus, if a thoroughly washed butter-ball, consisting of pure neutral fat, be colored with blue litmus, and a drop of pancreatic juice be placed upon it, the mass will gradually grow red in virtue of the fatty acid liberated from its glycerin combination. This reaction takes place in the intestine. If fatty acid be fed, the chyle in the thoracic duct is found to contain much neutral fat.* This synthesis indicates the presence of glycerin in the body — perhaps, in this case, in the villus of the intestine : the source of this glycerin, whether from proteid or carbohydrates, is problematical. If glycerin be fed, only little is absorbed (since diarrhoea ensues), and of that little some appears in the urine. It seems, therefore, to be oxidized with difficulty in the body. Glycerin Aldehyde, HOCHj.CHOH.CHO, and Dioxyacetone, HOCHj.CO.CH., OH. — These substances are formed by the careful oxidation of glycerin with nitric acid, and together are termed gJycerose. They have a, sweet taste and are the lowest known ' Schulze and Kisser : Landidrthschatfliche Versuchs-Siaiion, 1889, Bd. 36, S. 1. ' Miiller*: Ibid., 1886, Bd. 33, S. 326. ' See Voit : Zeitschn/i fiir Biologic, 1892, Bd. 29, S. 125. • Munk : Virchow's Archiv, 1880, Bd. 80, S. 17. THE CHEMISTRY OF THE ANIMAL BODY. 559 members of the glycose (sugar) series— i. e. substances which are characterized by the presence of either aldehyde-alcohol, — CHOH— CHO, or ketone-alcohol, — CO— CHjOH, radicals. ^ The constituents of glycerose, from the number of their carbon atoms, are called trioses. On boiling glycerose with barium hydrate the two constituents readily unite to form i-fructose (levulose). Glycerin Phosphoric Acid, (HO),C3H,.H2PO,.— This is the only ethe- real phosphoric acid in the urine. It is found in mere traces. Lecithin. CH/*^^"^'"-^*^'^^ %O.PO.(OH).O.C2H,.N(CH3)30H.— Lecithin is found in every cell, animal or vegetable, and especially in the brain and nerves. It is found in egg-yolk, in muscles, in blood-corpuscles, in lymph, pus-cells, in bile, and in milk. On boiling lecithin with acids or alkalies, or through putrefaction in the intestinal canal, it breaks up into its constituents, fatty acids, glycerin phosphoric acid, and cholin (see p. 543), substances which the intestine may absorb. The fatty acids may be stearic, palmitic, or oleic, two molecules of different fatty acids sometimes uniting in one molecule of lecithin : hence there are varieties of lecithins. Through further putrefaction cholin breaks up into carbonic oxide, methane, and ammonia.^ Lecithin treated with distilled water swells, furnishing the reason for the " myelin forms " of nervous tissue. Lecithin is readily soluble in alcohol and ether. It feels waxy to the touch. Protagon, which has been obtained especially from the brain, is a crystalline body containing lecithin and cerebrin — which is a glucoside (a body separable into proteid and a sugar). The chemical identity of protagon is shown in that ether and alcohol will not extract lecithin from it.^ Protagon readily breaks up into its constituents. While protagon seems to be regarded as the principal form in which lecithin occurs in the brain, simple lecithin is believed to be present in the nerves and other organs. This subject has not been properly worked out. Noll ^ states that the quantity of protagon in the spinal cord may amount to 25 per cent, of the dry solids, in the brain to 22 per cent., and in the sciatic nerve to 7.5 per cent. Regarding the synthesis of lecithin in the body, or the physiological importance of the substance, absolutely nothing is known. Fat in the Body. — Animal and vegetable fats consist principally of a mixture of the triglycerides of palmitic, stearic, and oleic acids. In the intestines the fat-splitting ferments convert a small portionof fat into glycerin and fatty acid ; the fatty acid unites with alkali to form a soap, in the presence of M'hich the fat breaks up into fine globules called an emulsion ; the fat-split- ting ferment then acts further on the fat, probably converting it all into fatty acid and glycerin.^ A fine emulsion of lanolin (fatty acid in combination with cholesterin, isocholesterin, etc.) is not absorbed, because the intestine does not break up the combination,^ and the melted particles themselves cannot ' Hasebroek : Zeitschrift fur physiologische Chemie, 1888, Bd. 12, S. 148. ^ Gamgee and Blankenhom : Journal of Physiology, 1881, vol. ii. p. 113. ^ Zeitschrift fiir physiologische Chemie, 1899, Ed. 27, S. 370. ' Frank, O. . Zeitschnft fur Biologic, 1898, Bd. 36, S. 568. ' Counstein : Archiv fur Physiologic, 1899, S. 30. 560 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. be absorbed. When the fatty acids are produced they unite with the alifali of the intestines to form soaps. The solution of these soaps is greatly aided by the bile.^ The tissue of the villus has the power to unite synthetically the absorbed soap and glycerin to form neutral fat. It should be remembered that the changes necessary for the absorption of fat may also take place in a cleansed isolated loop of the intestine.^ Fat may likewise be derived from ingested carbohydrates. The chemical derivation of fatty acid from carbohydrates has already been mentioned in the case of formic, acetic, propionic (see p. 537), and butyric acids. The fatty acids of fusel oils are likewise formed from carbohydrates in fermentation. The laboratory synthesis of sugar from glycerin has been already related. These reactions, however, furnish only the smallest indication of the large transformation of carbohydrates into fat possible in the body. If geese be fed with rice in large quantity, and the excreta and air respired be ana- lyzed, it may be shown that carbon is retained in large amount by the body, in amount too great to be entirely due to the formation of glycogen, and must therefore have been deposited in the form of fat.' Such fattening of geese produces the delicate p&U de foie gras. The principle has been established in the case of the dog as well.* The formation of fat from proteid (fatty degeneration) is believed to take place in some pathological cases (see p. 513). Recollection of the fact that proteid may yield 60 per cent, of sugar aids in the comprehension of this problem.^ Other usually cited proofs of the formation of fat from proteid include the conversion of casein into fat incident to the ripening of cheese ;_ and the transformation of muscle in a damp locality into a cheese-like mass called adipocere, which is probably effected by bacteria.* Adipocere contains double the original quantity of fatty acid, occurring as cal- cium, and sometimes as ammonium salts. Experiments of C. Voit show that on feeding large quantities of proteid, not all the carbonic acid is expired that belongs to the proteid destroyed as indicated by the nitrogen in the urine and feces. The conclusion follows that a non-nitrogenous substance has been stored in the body. Too much carbon is retained to be present only in the form of glyco- gen ; fat from proteid must therefore have been stored.' The formation of fat normally from proteid has been combated by Pfluger, it would seem without proper foundation. For behavior of fat in the cell see p. 558. Oleic Acid, CigHj^Oj. — This acid belongs to the series of fatty acids hav- ing the formula C„H2n_202. Its glyceride solidifies only as low as -f 4° C. It is the principal compound of liquid oils. Pure stearin is solid at the body's temperature, but mixed with olei'n the melting-point of the mixture is reduced below the temperature of the body and its absorption is thereby rendered possi- ble. The fat in the body is all in a fluid condition, due to the presence of olein. ' Moore and Kockwood : Journal of Physiology, 1897, vol. xxi. p. 58. 2 Cunningham : Ibid., 1898, vol. 23, p. 209. ' Voit: Abstract in Jahresberichi iiber Thierchemie, 1885, Bd. 15, S. 51. ' Eiibner : ZeUschrift fur Biologie, 1886, Bd. 22, S. 272. ' Kay, McDermott and Lusk : American Journal of Physiology, 1899, vol. 3, p. 139. * Bead Lehmann : Abstract in Jahresberichi iiber Thierchemie, 1889, Bd. 19, S. 516. ' Erwin Voit : Miinchener medicinische Wochenschrift, No. 26, 1892 ; abstract in Jahresberichi uber Thierchemie, 1892, S. 34 ; Cremer, M. : Zeilschrifl fur Biologie, 1899, Bd. 38, S. 309. THE CHEMISTRY OF THE ANIMAL BODY. 561 Gabbohydratbs. The important sugar of the blood and the tissues is dextrose. It is derived from the hydration of starcliy foods, and from proteid metabolism. From dextrose the lactic glands probably manufacture another carbohydrate, milk-sugar. Cane-sugar forms an article highly prized as a food. The study of the various sugars or carbohydrates is of especial interest, because their chemical nature is noAv well known. Carbohydrates were formerly defined as bodies which, like the sugars and substances of allied constitution, contain carbon, hydrogen, and oxygen, the carbon atoms being present to the number of six or multiples thereof, the hydrogen and oxygen being present in a proportion to form water. Glycoses include the monosaccharides like dextrose, C5H12O5 ; disaccharides include, for example, cane-sugar, CijECgjOji, which breaks up into dextrose and levu- lose, while polysaccharides comprise such bodies as starch and dextrins, which have the formula (CgH,„05)„. In recent years the term glycose has been extended to cover bodies having three to nine carbon atoms and possessing either the constitution of an aldehyde-alcohol, — CH(OH)CHO, called aldoses, or of a ketone-alcohol, — COCHjOH, called ketoses. These bodies also have hydrogen and oxygen present in a proportion to form water, and the number of carbon atoms always equals in number those of oxygen. According to their number of carbon atoms they are termed trioses, tetroses, pentoses, hexoses, heptoses, octoses, and nonoses. It has been shown (foot-note, p. 54.5) how from the asjonmetric carbon atom in lactic acid two configurations are derived. If a body (such as trioxybutyric acid) contains two asymmetric carbon atoms, four configurations are possible. CH,OH CH.OH CH.OH CH.OH [COH OHCH OHCH HCOH [COH OHCH HCOH OHCH COOH COOH COOH COOH Similarly among the glycose-aldoses, a triose has two modifications ; a tetrose, four ; a pen- tose, eight : a hexose, sixteen, etc. Thus in the following formula by the variations of H and OH on the four asymmetric carbon atoms, sixteen possible hexoses may be obtained. CH,OH -C— — c- — c- -C- CHO The carbohydrates have well-defined optical properties, rotating polarized light to the right or left, and were therefore originally designated as d- (dextro-) and I- (lasvo-) respec- tively. An inactive (i-) form consists in an equal mixture of the two others ; at present, however, the d- may signify a chemical relation to dextrose : thus levulose, which is ordinary fruit sugar and rotates polarized hght to the left, is called d- fructose, on account of its deriva- tion from dextrose. Where the OH group is attached on the right it may be indicated by the sign -|-, on the left by — , or the -|- OH may be written below, the — OH above. H H OH H or CH2OH C C C C CHO OH OH H OH OHO CHO HCOH c + OHCH c- , HCOH c+ ' HCOH c + CH2OH CH.OH d-Glucose. Vol. I.- -36 562 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. The Glycoses. The triose called glycerose has already been described. A tetrose called erythrose, which is the aldose of erythrite, C4H5(OH)^, a tetratomic alcohol, is known. Of the possible pentoses, arabinose, xylose, and rhamnose (methyl-arabinose) occur in the vegetable kingdoms in considerable quantity. They may be absorbed by the intestinal canal.^ Pentoses are found in the urine in rare cases.^ Some nueleins, especially those of the pancreas and thymus, yield pentoses on decomposition. Subcutaneous injection of arabinose, xylose, and rhamnose results in their excretion to the extent of more than 60 per cent, in the urine.^ The rest may be burned. Hexoses, or Glucoses. — Through the oxidation of hexatomic alcohols there may be obtained, first, glucoses, then monocarbonic acids, and lastly saccharic acid, or its isomer mucic acid : C,He(0H)5CH,0H. C,H5(OH),CHO. C,He(OH),COOH. Mannite. Mannose Maunonic acid, (and levulose). C,He(OH),(COOH),. Saccharic acid. Mannose and levulose are respectively the aldose and ketose of mannite, galactose is the aldose of dulcite, whereas glucose is probably the aldose of sorbite — dulcite and sorbite being, like mannite, hexatomic alcohols. Propeiiies. — (1) The hexoses are converted into their respective alcohols on reduction with sodium amalgam. (2) The hexoses act as reducing agents, converting alkaline solutions of cuprous oxide salts (obtained through presence of tartrate) into red cuprous oxide, which precipitates out (Trommer's test). Levulic acid is among the products formed (see p. 538). Of the higher saccharides only maltose and milk-sugar give this reaction. (3) Strongly characteristic are the insoluble crystalline compounds formed by all glycoses with phenylhydrazin, called osazones (see p. 534) : C,H,A + 2H,N.NH(C,H,) = CJIioO,(:N.NH.C,H,), + 2Bfi + H,. Levulose. Phenyiliydrazin, Glycosazone. Levulose, dextrose, and mannose give the same glycosazone. The glycos- azones are decomposed into osones by fuming hydrochloric acid : CeH,„0/:N.NH.CJ-I,), + 2H,0 = C,H,,0, + 2H,N.NH.QH,. Glycosone. Osones are converted into sugar by nascent hydrogen. The osone de- rived from levulose, dextrose, and mannose yields levulose by this treatment, and the transformation of dextrose and mannose into levulose is therefore demonstrated. • Weiske: Zeitschrift fiir physiologische Chemie, 1895, Bd. 20, S. 489. 2 Salkowski : Zeitschrift fur physiologische Chemie, 1899, Bd. 27, S. 507. ' Voit, F. : Deutsches Archiv fur klinische Medizin, Bd. 58, S. 523. THE CHEMISTRY OF THE ANIMAL BODY. 563 (4) Only trioses, hexoses, and nonoses are capable of alcoholic fermenta- tion. Synthesis of the Glucoses.— Formose (see p. 533) may be purified by means of phenylhydrazin as above, so that pure i-fructose is obtained ; this treated with sodium amalgam yields ?:-mannite, which on oxidation is converted into ^-man- nonic acid ; this last is separated by a strychnin salt into its two components ; the d-mannonic acid is divided and one part treated with hydrogen, with result- ing c?-mannose, which, as has been shown above, is convertible into d-fructose or ordinary fruit-sugar ; the second part of the d-mannonic acid treated with chinolin is transformed through change in configuration into its isomer, d-gluconic acid, which on reduction yields d-glucose, or ordinary dextrose. This shows the preparation of the common sugars from their elements. The transformation of levulose into dextrose is especially to be noted, since it takes place in the body. K H OHH rf-Glucose, Dextrose, Grape-sugar, CHjOH C C C C CHO.— OH OHH OH This is the sugar of the body. It is found in the blood and other fluids and in the tissues to the extent of 0.1 per cent, and more, even during starvation. The principal source of the dextrose of the blood is that derived from the digestion of starch, and also of cane-sugar, in the intestinal tract. Dextrose is likewise pro- duced from proteid, for a diabetic patient fed solely on proteid may still excrete sugar in the urine. Minkowski ^ finds that in starving dogs after extirpation of the pancreas the proportion of sugar to nitrogen is 2.8 : 1. The same ratio has been shown to exist in phlorhizin diabetes in fasting rabbits^ and goats' when the drug is frequently administered. After frequent dosage of phlorhizin to fasting, meat-fed, or gelatin-fed dogs, the ratio dextrose : nitrogen approxi- mates 3.75 : 1. Since 1 gram of N in the urine corresponds (neglecting the fsecal N) to 6.25 grams of proteid destroyed, therefore, 3.75 grams of sugar must have arisen from 6.25 grams of proteid (including gelatin). In other words, there has been a production from the proteid molecule of 60 per cent, of dextrose, which contains nearly 60 per cent, of the physiologically avail- able energy of the proteid consumed.* A similar large excretion of dextrose has been noted in cases of human diabetes mellitus." In pancreas diabetes the pancreas may perhaps manufacture a terment which, supplied from the lymph of the pancreas " to the tissues, becomes the first cause of the decomposition of dextrose, and in whose absence diabetes , ensues. Excess of dextrose in the body is stored up, especially in the liver- cells, as glycogen, which is the anhydride of dextrose ; the glycogen may be afterwards reconverted into dextrose. The presence of sugar in the body in starvation, even when little urea may be detected there, shows the readier excre- ' Archivfiir JExper. Pathologie und Pharmakologie, 1893, Bd. 31, S. 85. ' Lusk : Zeitschrift fiir Biohgie, 1898, Bd. 86, S. 82. ' Lusk: Unpublished. * Eeillv, Nolan, and Lusk : American Journal of Physiology, 1898, vol. i. p. 395. ■'' Bumpf : Berliner Hinischer Wochenschrift, 1898, Bd. 24, Heft 43. 8 Biedl : Centralbatt fiir Physiologic, 1898, Bd. 12, S. 624. 564 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. tion of the nitrogenous radical of proteid. Traces of dextrose are found in normal urine. Dextrose is a sweet-tasting crystalline substance ; its solutions rotate polar- ized light to the right. Jecorin, a substance found in the liver and the blood, yields dextrose on decomposition. It is said to be a glycose-lecithin.^ Grlucosamin, CgH„05XH2. — This is yielded as a decomposition product of some proteids. Egg albumin, for example, yields 8 per cent, of gluco- samin. It reduces copper solutions, and has been mistaken for dextrose. PI H OH d-Pructose, Levulose, Fruit-sugar, CHpH C C C COCHpH.— OHOHH This occurs in many fruits and in honey. It is sweeter than dextrose, and rotates polarized light to the left. It is a product of the decomposition of cane-sugar in the intestinal canal. If levulose be fed, any excess in the blood may be converted into glycogen, and through the glycogen into dextrose. It is possible thus to convert 50 per cent, of the levulose fed into dextrose.^ When levulose is fed to a diabetic patient, it may be burned, though power to burn dextrose has been lost.' H OHOHH d- Galactose, CH^OH C C C C CHO.— This is found combined OHH H OH with proteid in the brain, forming the glucoside cerebrin. It is produced together with dextrose in the hydrolytic decomposition of milk-sugar. It does not undergo alcoholic fermentation, at least not with Saccharomyces apiculatus. "NA'hen fed it may in part be directly burned or in part converted into glycogen. The Disacchaeides, CijHjjOu. These are di-multiple sugars in ether-like combination. To cane-sugar and milk-sugar, Fisher has ascribed the following formulae :* Cane-sugar. ^CH-~-__p. CHPH P,/CHOH ^C ^\CHOH /CHOH CH 0( CHOH CHOH ^CH CH,OH CH^OH Dextrose group. Levulose group. Cane-sug-ar, or Saccharose. — Cane-sugar, obtained from the sugar-cane and tlie beet-root, is largely used to flavor the food, and likewise assumes importance as a food-stuff. On boiling with dilute acids, cane-sugar is con- verted through hydrolysis into a mixture of levulose and dextrose. The same ' Bing : Cmlralblatt fur Physiologic, 1898, Bd. 12, S. 209. ^ Minkowski ; Archiv fur Palhologie und Pharmakologie, 1893, Bd. 31, S. 157. ' Loc. cit. * Berichte der deutschen chemischen Gesdlschaft, 1894, Bd. 26, S. 2400. MiLB :-SUGAB. CHjOH CHOH CH P./CHOH ^\CHOH CH - o- CHO CHOH CHOH CHOH CHOH -CH, Galactose group. Dextrose group. THE CHEMISTRY OF THE ANIMAL BODY. 565 result is obtained by warming with 0.05 to 0.2 per cent, hydrochloric acid at the temperature of the body.^ This inversion, therefore, takes place in the stomach. In the intestinal canal the inversion is accomplished through the action of a ferment present in the intestinal juice. Subcutaneous injection of cane-sugar results in its quantitative excretion through the urine ; ^ but fed per os, cane-sugar is converted into dextrose and levulose, which may be burned in the body. Milk-sugar, or Lactose. — This is found in the milk and in the amniotic fluid. It is probably manufactured from dextrose in the mammary glands, for the blood does not contain it. It is always present in the urine during the first days of lactation, but is not found there ante-partum? It readily undergoes lactic fermentation, producing lactic acid, which then causes clotting of the milk. This fermentation may take place in the intestinal tract. Boiling with dilute acids splits up milk-sugar into galactose and dextrose. This decom- position probably does not take place in the stomach. The intestinal juice causes this transformation, especially in suckling animals,* and lactase of the pancreatic juice will also split milk-sugar.' Milk-sugar injected subcutane- ously in man is quantitatively eliminated through the kidney.' It must, therefore, undergo inversion in the intestine into galactose and dextrose before it can be burned. Isomaltose. — This is the only disaccharide which has been synthetically obtained, having been produced by boiling dextrose with hydrochloric acid. It ferments with difficulty and forms an osazone which melts at 150°-153°. It, with dextrin, is a product of the action of diastase and of the diastatic enzymes found in saliva, pancreatic juice, intestinal juice, and blood upon starch and glycogen. Through further action of the same ferments isomaltose is converted into maltose. Maltose. — Maltose (and dextrin) are the end-products of the action of diastase on starch and glycogen, the process being one of hydrolysis : 3CeH,„0, + HP = C.,H,0„ + CeHioO,. Maltose. Dextrin. It is likewise a product of the diastatic action of ptyalin (saliva), amylopsin (pancreatic juice), and of ferments in the intestinal juice and in the blood. Maltose readily undergoes alcoholic fermentation and forms an osazone which melts at 206°. It is converted into dextrose by boiling with acids. Certain ferments convert maltose (and dextrin) into dextrose (see Starch). Cellulose Group, (CglTioOs)^. Cellulose. — This is a highly polymerized anhydride of dextrose, perhaps also of man- nose. It forms the cell-wall in the plant. It undergoes putrefaction in the intestinal 1 Ferris and Lusk : American Journal oj Physiology, 1898, vol. 1, p. 277. ' Voit, F. : Dewtsehes ArchivfUr klinische Medkin, 1897, Bd. 58, S. 523. ' Lemaire: Zeitschrift fUr physiologische Chemie, 1896, Bd. 10, S. 442. *Weinland : Zeitschrift fUr Biologic, 1899, Bd. 38, S. 16. 5 Ibid., 1899, Bd. 38, S. 607. " Voit, F. . Loc. cit. 566 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. canal, especially in herblvora (see p. 532), and owing to the production of fatty acids it may have value as a food. In man only young and tender cellulose is digested, such as occurs in lettuce and celery. The bulk of herbivorous fecal matter consists of cellulose. Cellulose is only with difficulty attacked by acids and alkalies. Tunicin, found among the tunicates, is identical with cellulose, so that the substance is not solely characteristic of the vegetable kingdom. Starch, (C5HiQ05)2g. — This substaace on boiling with dilute acids breaks down by hydrolysis principally to dextrose. It is found in plants, and may be manufactured by them from cane-sugar, dextrose, levulose, and from other sugars. It forms a reserve food-stuff, being converted into sugar as the plant requires it — in winter, for example. Starch gives a blue color with iodine. According to recent investigations^ starch is said to be broken up by diastase into five successive hydrolytic cleavage-products as follows : (1) Amylo- dextrin {Ci2ii2o^io)5i> ^ substance giving a deep-blue color with iodine. This is next changed to (2) Erythrodextrin, {C-^^^tf^^^if^ + H2O, or (CijHjoOiJjy. (C12H22O11), which is readily soluble in water and gives with iodine a reddish- brown color. Erythrodextrin is converted into (3) Aohroodextrin, (Ci2ll2„Oi|,)5 + H2O, or (Ci2H2„Oio)5.Ci2H220ij, which is likewise very soluble, tastes slightly sweet, but gives no coloration with iodine. Achroodextrin now breaks up into (4) IsomaUose, which through change in configuration is transformed to its isomere (5) Maltose. Products similar to these are formed by the various diastatic ferments in the body, and in addition also some dextrose. Ptyalin^ acts rapidly on starch, producing dextrin and maltose, but very little dextrose. Amylopsin, from the pancreas, acts still more rapidly than ptyalin, and with the production of con- siderable dextrose. The diastatic ferment of intestinal juice acts very slowly on starch, forming dextrin, maltose, and a little dextrose, while the ferment in blood-serum likewise acts slowly but with complete transformation of all the maltose and dextrin formed, into dextrose. The above facts lead Hamburger to suggest that the diastatic ferments of the body consist of mixtures, in different proportions, of diastase, which forms dextrin and maltose from starch, and of glucase, which converts these into dextrose. This, however, is merely an hypothesis, and glucase has never been prepared. The vegetable diastase is not iden- tical with that found in the body. Thus ptyalin, like emulsin, breaks up salicin into sali- cylic alcohol and dextrose, of which action vegetable diastase is incapable. But ptyalin, again, is not identical with emulsin, for it will not act on amj'gdalin. The subcutaneous injection of solutions of achroodextrin, erythrodextrin, and amylo- dextrin results in their partial elimination in the urine, the rest being burned.' Glycogen, or Animal Starch. — Recent investigations have shown that in all the particulars of diastatic decomposition glycogen is identical with vege- table starch.* Glycogen is soluble in water, giving an opalescent fluid. The blood has a normal composition which does not greatly vary. After a hearty meal excess of fat is deposited in fatty tissue, excess of proteid in the muscular ' Lintner und Diill : Berichte der dmtschen chemischen Gesdlsehaft, 1893, Bd. 26, S. 2533. ' See Hamburger : Pfliiger's Archiv, 1895, Bd. 60, S. 573. ' Voit, P. . Deutsches Archiv fur Idinische Medizin, Bd. 43, S. 523. * Kiilz and Vogel : Zeitschrift fur Biologic, 1895, Bd. 31, S. 108. ■-■'! ^ THE CHEMISTRY OF THE ANIMAL BODY. 567 tissue, while excess of sugar is stored in the muscles and especially in the liver- cells in the less combustible and less diffusible form of glycogen. About one- half of the total quantity of glycogen is found in the muscles, the remainder in the liver, where it may even amount to 40 per cent, of the dry solids. When the blood becomes poor in sugar, the store of glycogen is drawn upon to such an extent that in hunger the body loses the larger part of its glycogen. Muscular work likewise causes the rapid conversion of glycogen into sugar. The sources of glycogen are certain ingested carbohydrates, and also the dextrose derived from proteid. If large quantities of proteid be fed, glycogen may be stored. If dextrose, levulose, or galactose (or anything which produces these, e. g. cane-sugar, maltose, milk-sugar) be fed, there may be a direct conversion of these sugars into glycogen. Cremer maintains that the pentoses are burned in the body, but are only indirectly glycogen- producers in the sense of sparing other sugar from destruction, which may be used to form glycogen. Dextrins. — These have been described under starch. H H OHH d-Glucuronic Acid, or Glycuronic Acid, HOOC C C C C C HO. OH OHH OH — Obtained by reducing d-saccharic acid with nascent hydrogen. After feed- ing chloral hydrate, naphthalin, camphor, terpentine, phenol, ortho-nitrotoluol, and other bodies, they appear in the urine (usually having been first converted into alcohol) in combination with glycuronic acid. Urochloralic acid, naphthol- glycuronic acid, campho-glycuronic acid, terpene-glycuronic acid, etc., all rotate polarized light to the left. It seems that these ingested substances unite in the body with the aldehyde group of dextrose, at the same time protecting all but one group of the dextrose molecule from further oxidation (Fischer). Glycu- ronic acid, which is easily separated by hydrolysis from its aromatic combina- tion, itself rotates polarized light to the right, reduces alkaline copper solutions, and might be confounded with dextrose except that it does not ferment with yeast. Glycuronic acid is likewise found in the urine after administration of curare, morphine, and after chloroform-narcosis, perhaps paired with aromatic bodies formed in the organization. Combustion in the Cell in General. — Experiments' show that taking the proteid decomposition in the starving dog as 1, it is necessary to feed three to four times that amount of proteid taken alone in order to attain nitrogenous equilibrium, 1.6 to 2.1 times that amount of proteid when fed with fat, and 1 to 1.2 times that amount when fed with carbohydrates. The physiological proteid minimum is in these cases never less than the amount required in starvation. Only after feeding gelatin with proteid may the proteid fed be below the amount decomposed in starvation. The above shows what is well known, that sugar spares proteid from decomposition more than fat does. E. Voit^ states ' E. Volt and Korkunoff : Zeitschrift fiir Biologic, 1895, Bd. 32, S. 117. 2 Op. cit.,8. 128 and 135. 568 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. these two propositions : (1) The part played by these several food-stuifs in the total metabolism depends on the composition of the fluid feeding the cell. The greater the amount of one of these food-stuffs, the greater its decompo- sition and the less the decomposition of the others, so long as the total decom- position suffers no change. (2) The several food-stuffs do not act wholly on account of their quantity in the fluid surrounding the cell, but especially accord- ing to the chemical affinity of the cell-substance for them individually. First in this regard comes proteid, then carbohydrates, and lastly fat. The excessive proteid decomposition in diabetes is due to the non-combus- tion of the proteid protecting sugars,^ and the same is in part true in fever, where a small supply of carbohydrates reaches the blood.^ Dextrose and levulose weight for weight have equal value in protecting proteid metabolism.' For further discussion of carbohydrates in the body see under the indi- vidual sugars, and under Fat in the Body. Benzol Derivatives or Aromatic Compounds. The aromatic compounds are characterized by a configuration in which six atoms of carbon are linked together in a circle called the benzol ring. The type of this is benzol, a hydrocarbon found in coal-tar and having the formula, H C / -^ H— C C— H 1 H— C C— H \ // "\/' C 4 H The hydrogen atoms may be substituted by others, substitution of one OH group, for example, forming phenol, CgHj — OH. If, however, two OH groups are substituted, three different bodies, corresponding to the different arrangements on the ring, become possible. If the two OH groups occupy the positions 1 and 2 the substance is or^/io-dioxybenzol ; if 1 and 3, meta- dioxybenzol ; and if 1 and 4, ^ara-dioxybenzol. It is possible to -convert bodies of the fatty series into those of the aro- matic. Acetylene passed through red-hot tubes yields benzol. On the other hand, aromatic bodies may be converted into those of the fatty series. If phenol in aqueous solution be subjected to electrolysis by an alternating cur- rent under which circumstances hydrogen and oxygen are alternately liberated on the same pole, the effect of this intermittent oxidation and reduction is to break up the phenol into caproic acid, and finally, after passing through acids of lower carbon contents, into carbonic acid and water. The aromatic compounds found in the urine are normally exclusively ' Lusk : Zeitschriftfur Biologk, 1890, Bd. 27, S. 459. ' May; Ibid., 1894, Bd. 30, S. 1. ' De Kenzi und Eealis : VII. Congress fur innere Medizin, 1896. THE CHEMISTRY OF THE ANIMAL BODY. 569 derived from the products of proteid putrefaction in the intestines. It is admitted that neither fats nor carbohydrates play any part in their formation. Benzol, CsHg.— This body if fed is absorbed and afterward converted into oxybenzol or phenol, with subsequent behavior similar to phenol. Phenol (Carbolic Acid, Oxybenzol, Phenyl-hydroxide), CgH^OH. — This is an aromatic alcohol. A 5 per cent, solution precipitates proteid, and a much weaker solution produces irritation of the tissues, and especially those of the kidney, where its excretion takes place. It is strange that a strong antiseptic like phenol should be a normal product of proteid putrefaction. Phenol is obtainable from tyrosin, by processes of cleavage and oxidation (see Tyrosin), and in the intestinal canal is probably derived from tyrosin. A small amount of the phenol ordinarily absorbed is converted by the organism into pyrocatechin, a dioxybenzol. These two substances are found in normal urine in ethereal combination with sulphuric acid, CgHjO.SOj.OH (or as an alkaline ethereal sulphate). This synthesis, accomplished by the union of the phenol and sulphuric acid with loss of water, has been obtained by electrolysis, using alternating electric currents.^ If phenol be administered in more than a very small amount, hydroquinone likewise appears in the urine, paired like the others with sulphuric acid, and should the phenol administered exceed at any time the available sulphate, it forms to a certain extent a synthesis with glycuronic acid, and so combined appears in the urine. Phenol gives with 3Iillon's reagent (mercuric nitrate in nitric acid with some nitrous acid) a brilliant red coloration. This is given by all bodies having an hydroxyl group on the benzol ring, of which substance tyrosin may be mentioned as an example. It is likewise given by proteid, slowly in the cold, more rapidly on warming, and this fact together with the cleavage putrefactive products has given foundation to the belief that the oxy- benzol ring exists preformed in the proteid molecule. Pyrocatechin, CeH^(OH)2. — This is ortho-dioxybenzol. For its forma- tion see under Phenol. Hydroquinone, ^114(011)2. — Para-dioxybenzol. Found in the urine especially in cases of carbolic-acid poisoning (see Phenol). If such urine be shaken in the air, it is turned black, owing to the oxidation of hydroquinone to quinone, C^H^ | . jp-Cresol, CgH^.OH.CHg.— This is a product of intestinal putrefaction, and is derived from tyrosin (which see). It is found in the urine as an ethereal sulphate. Benzoic Acid, C5H5COOH.— Salts of this acid and analogous bodies are found especially in plants. In the urine of herbivora therefore is found a considerable amount of hippuric add, COOH.CH^.NH.CO.CjHj, the com- bination of benzoic acid and glycocoU (see Glycocoll, p. 537). On feeding phenyl-acetic acid, CeH.CH^COOH, phenaceturic acid, COOH.CH,.NH.- CO.CH2.C5H5, appears in the urine, while the higher benzyl acids, such as phenyl-propionic acid, suifer the oxidation of the side chain in the body, and ' Drechsel : Journal fiir praklische Chemie, Bd. 29, p. 229 ; abstr. Jahresbericht iiber Thierchemie, 1884, S. 77. 570 AN A3IERICAN TEXT-BOOK OF PHYSIOLOGY. ordinary hippuric acid is formed. After eating apple-parings and other vege- table substances, hippuric acid is found in human urine. It is further stated that phenyl-acetic acid and phenyl-propionic acids are normal products of proteid putrefaction, though in very small quantities ; hippuric acid and phen- aceturic acid must therefore be constantly present in traces in human urine. Hippuric acid is split into its constituents by hydrolysis through the action of the Micrococcus urece. p-Oxyphenyl-acetic Acid, C5H4.OH.CH2COOH. — This is a product of the intestinal putrefaction of proteid and of tyrosin (which see). It occurs in the urine either paired with sulphuric acid or as an alkaline salt of oxyphenyl- acetic acid.^ jo-Hydrocumaric Acid, C6H4.0H.C'2Fl4COOII. — This second oxy- acid is likewise derived from proteid and tyrosin (which see) putrefaction. Its occur- rence in the urine is similar to the above oxy- acid. Tyrosin, Amido-hydrocumaric Acid, p-Oxyphenyl-amido-propionic Acid, C5H4.OH.C2H3XH2COOH. — Tyrosin is a constant product of the putre- faction of all proteid bodies (except gelatin), and is therefore found in cheese. It may be formed in large quantities by boiling horn-shavings with sul- phuric acid. Leucin is always formed whenever tyrosin is. Tyrosin forms characteristic sheaf-shaped bundles of crystals. All the aromatic bodies thus far described have been eliminated in the urine with their benzol nucleus intact. Tyrosin, however, may be completely burned in the body. This seems to be because of the presence of the amido- group on the side chain, for phenyl-amido-propionic acid is likewise destroyed. Tyrosin is found in the urine in yellow atrophy of the liver, in phosphorus-poisoning, etc. (see Leucin, p. 540). Through cleavage, oxidation, or reduction, the following reactions take place, phenol being the final product.^ The substances not found in intes- tinal putrefaction are named in italics : CA.OH.C.HaNH^COOH + H, = CeH.,.OH.C,H,COOH -t- NH, p-TIydrocuinaric acid. CeH^.OH.C.H.COOH = C6H,.OH.C,H5 + CO, p-Ellii/l'phcnol. C'eH^.OH.CHj + 30 = C6H,.OH.CH2COOH + H,0 p-Oxyphenyl-acetic acid. CeH,.OH.CH,COOH = CeH,.0II.Cir3 + CO, p-Cresol. CeH^.OH.CH, + 30 = CeH.OH COOH + 11,0 p-Oxybenzoic acid. CeH,.0H.C00H = CeHjOH + CO, Phenol. It has never been shown that tyrosin is a normal product of proteid metabolism within the tissues. AYith leucin it is a normal product of pancreatic diges- tion (see p. 540). Homogentisic Acid, Dioxyphenyl-acetic Acid, Hydroquinoae-acetic Acid.— This is found in the urine in alcaptonuria. Feeding tyr(jsin in this disease increases the ^ Baumann : Zeiischrifl fiir physiologische Cliemie, 1886, Bd. 10, S. 125. ' Baumann : Berichte der deutsehen chemischen Qesellschaft, 1879, Bd. 12, S. 1450. THE CHEMISTRY OF THE ANIMAL BODY. 571 amount of homogentisic acid. It may arise from the reduction and oxidation of tyrosin according to the following reaction i^ OH + H, OH/ \ +NH3+CO, + 2H,0 + 5O2 = I •'OH CH,CHNH,COOH CH.COOH Pyridin.— This body has the accompanying formula, one of the OH groups in benzol H C HC CH being substituted by N : | || • When pyridin is fed, methyl-pyridin ammonium hydroxide, OH.CH3.NC3H5, is excreted in the urine.' This is another ease, besides those of selenium and tellurium, of methylation in the body. H H C C HC C CH Chinolin. — The accompanying formula I || | illustrates the composition HC C CH N C H of this body. Several of the methyl-chinolins burn readily in the body.' Cynurenic Acid, C9H5N.OH.COOH.— This is oxychinolin carbonic acid ; it is found normally in dog's urine, being derived from proteid in amounts proportional to proteid metabolism. It is, however, not derived from the metabolism of gelatin,* a body which does not yield the aromatic chain. Indol, or Benzopyrol, CgHjN. — The source of iudol is surely from proteid putrefaction ; it may also be obtained by melting proteid with potash. H H C C -^ \ /\ ^ \ /\ HC C CH HC C COH I II II I II II HC C CH HC C CH % /\/ % /\/ C N C N H H H H Indol. Indoxyl. After its absorption it receives an oxy- group just as benzol does, and like benzol pairs with sulphuric acid with the loss of a molecule of water, and appears as ethereal sulphate in the urine. In preparing indol from feces the fecal odor clings to it. Pure indol, however, has no smell. An alcoholic ' Embden: Zeitschrifl fiir physiologische Chemie, 1892, Bd. 17, S. 182. ' His: Arehivfdr exper. Paikologie und Pharmakologie, 1887, Bd. 22, S. 253. ' Cohn: Zeitschrifl fllr physiologisdie Chemie, 1894, Bd. 20, S. 210. * Mendel and Jackson : American Journal of Physiology, 1899, vol. ii. p. 1. 572 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. solution of indol mixed with hydrochloric acid colors fir-wood cherry-red. If urine be mixed with an equal volume of hydrochloric acid, chloroform added, and then gradually an oxidizing agent (chloride of lime), any indoxyl- sulphuric acid present will be oxidized to indigo-blue, which gives a blue color to the chloroform in which it dissolves. Skatol, or ;9-Methyl Indol, CsHjCHgNH.— The history of skatol, H C ^ \ /\ HC C CCH3 I II II , HC C CH ^ /\/ C N H H Skatol. is the same as that of indol. Its source is from proteid putrefaction ; after. ab- sorption it unites with an oxy- group, and the skatoxyl thus produced pairs with sulphuric acid, and appears in the urine as ethereal skatoxyl-sulphuric acid. CH3 I C Bpinephrin.— C5H, '^ C.CHOH.CO.C5H3(OH)2. The above is the formula for epinephrin, the active principle of the suprarenals, as proposed by Abel.' Abel has formed several distinct salts of this pyrrol base. Of the sulphate of epinephrin, only 0.000018 gram per kilogram of dog causes a sharp rise in blood-pressure. Aromatic Bodies in the Urine. — There have been named above as appearing in normal human urine the ethereal sulphates of phenol, j3-cresol, pyrocatechin, indoxyl, skatoxyl, hydroparacumaric acid, and oxyphenyl-acetic acid, of which, however, the last two appear likewise as their salts without being combined with sulphuric acid.^ These are derived from proteid putre- factive products formed almost entirely in the large intestine (see p. 545), which are partially absorbed and partially pass into the feces. The amount of ethereal sulphate in the urine gives an indication of the amount of intes- tinal putrefaction. It does not disappear in starvation, mucin and nucleo- proteid of bile and intestinal juice furnishing material.^ If the intestinal tract be treated so as to make it antiseptic, the ethereal sulphates disappear from the urine.'' Diarrhoea likewise decreases their amount, obviously from the short time given for putrefaction. The synthesis between the aromatic bodies and sulphuric acid probably occurs in the liver. The liver and the kidney both have the power of combining with a considerable amount of ' Zeitschrift fur physiohgische Chemie, 1899, Bd. 28, S. 318. ^ Baumann r Zeitschrift fiir physiologisclie Chemie, 1886, Bd. 10, S. 125. ' Von Noorden : Pathologic des Sloffwechseh, 1893, S. 163. * Baumann : Op. cit., S. 129. THE CHEMISTRY OF THE ANIMAL BODY. 573 indol and phenol, holding them until the requisite synthesis between them and sulphuric acid occurs, and thereby rendering them non-poisonous.' Inosit.— This is the hexatomic phenol of hexahydrobenzol, CeHg(OH),. It was long mistaken for a carbohydrate. It has been found in muscle, liver, spleen, suprarenals, lungs, brain, and testicles ; likewise in plants, in unripe peas and beans. After drinking much water it may be washed out in the urine, and perhaps for this reason is often found in the voluminous urine of the diabetic. When fed it is burned; also by the diabetic. Its origin is unknown. Substances of Unknown Composition. Coloring Matters in the Body. Haemoglobin, CiiaHusoNauFeSjOa^s (Zinoffsky's formula for haemoglobin in horse's blood). — Haemoglobin is found in the red blood-corpuscle, probably in chemical union with the stroma.^ United with oxygen it forms oxyhaemoglobin, which gives the scarlet color to arterial blood ; haemoglobin itself is darker, more bluish, and therefore venous blood is of a less brilliant red. Methods for preparing oxyhasmoglobin crystals are numerous, but all depend on getting the haemoglobin into solution. If the corpuscles in cruor be washed with physiological salt-solution, and then treated with distilled water, the HbO will be dissolved ; on shaking with a little ether the stroma will likewise dis- solve ; after decantation and evaporation of the ether, at the room's temperature, the solution is cooled to — 10° and a one-fourth volume of alcohol at the same temperature added; after a few days rhombic crystals of oxyhaemoglobin may be collected, redis- solved in water, and reprecipitated for purification. The crystals may be dried in vacuo over sulphuric acid. Once dry they may be heated to 100° without decomposition, but in aqueous solution they are decomposed at 70° into a globulin and haematin, the latter having a brown color. This difference in color gives the distinction between "rare " and "well-done" roast-beef Gastric and pancreatic digestion likewise converts oxyhsemo- globin into a globulin, which may be absorbed, and haematin, which passes into the feces. Haemoglobin is without doubt formed in the body from simple proteids by a synthetic process, (for further information see pp. 529 and 574, and likewise under the section on Blood.) CO-Hsemoglobin (see p. 517). NO-Haemog'lobin (see p. 512). Metlisemoglobiii. — This is found in blood-stains, and may be considered as oxyhaemo- globin which has undergone a chemical change whereby some of the loosely combined oxygen has been liberated.' Hsematin, CsjHjjNjOiFe. — This is a cleavage-product of haemoglobin in the presence of oxygen. (See above, under Haemoglobin). It is not itself a constituent of the bodj'. It is insoluble in dilute acids, alcohol, ether, or chloroform, but is soluble in alkalies or in acidified alcohol or ether, showing characteristic absorption-bands. If a little dry blood be placed on a microscope slide with NaCl and moistened with glacial acetic acid, and warmed, characteristic brown microscopic crystals ofJuBmin, CsjHgoNjFeOn.HCl, crystallize out. If these crystals and the spectroscopic test be obtained, one can be absolutely posi- tive of the presence of blood. HEemocliroinogen, CeiHeiNgFejO,.— This substance has the same composition as haematin, only it contains less oxygen.* If reduced haemoglobin be heated in sealed tubes with dilute acids or alkali in absence of oxygen, a purple-red compound is produced called ' Herter and Wakeman : Journal of Experimental Medicine, 1899, vol. iv. p. 307. ' Bead Stewart, G. N. : Journal of Physiology, 1899, vol. xxiv. p. 238. ' Zeynek: Archivfur Physiologie, 1899, S. 460. ♦ Zeynek : Zeil'sehrifl fiir physiologische Chemie, 1898, Bd. 25, S. 492. 574 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. hsemochromogen, which is a crystallizable cleavage-product of haemoglobin. According to Hoppe-Sej'ler the oxygen in oxyhemoglobin is bound to the hasmochromogen group. Hsemochromogen treated with a strong dehydrating agent is converted, with elimination of iron, into hcematoporpJiyri/i, CisHjaNoOa, an isomer of bilirubin. Haematoporphyrin is said to occur in normal urine.' Hasmatoporphyrin treated with nascent hydrogen is converted into a body believed to be identical with hydro- or urobilirubin. Analogous to this is the work of the liver in the body, manufacturing the biliary coloring matter from haemoglobin, and retaining the separated iron for the synthesis of fresh haemoglobin (see p. 529). Htematoidin, found in old blood-stains, is believed to be identical with bilirubin. The Bile-pigments. — The ordinarj' coloring matter of yellow human bile is Mlirubm, C32H38N4O6. The next higher oxidation-product is the green hiliverdin, C32H3eN406, which is the usual dominant color in the bile of herbivora. These coloring-matters and others derived from them have been found in gall-stones. Jolles* gives the following products of the oxidation of bilirubin: Bilirubin (red) CeHisX-.O,; Biliverdin (green) CieHis^aOj ; Bilicyanin (blue) ? (violet) ? (red) ? (brown) ? Bilixanthin (brownish-yellow) deHigNjOs. If nitric acid containing a little nitrous acid be added to a solution ol bilirubin, a play of colors is observed at the juncture of the two fluids, undoubtedly depending upon various stages of oxidation. Above is a ring of green (biliverdin), then blue and violet (bilicya- nin), red, yellowish-brown (bilixanthin). Bilixanthin (=choletelin) is the highest oxida- tion-product. The above is known as Gmelin's test.' If bilirubin or biliverdin is subjected to the action either of nascent hydrogen or of putrefaction it is reduced to hydrobilirubin, C32H44NjO,. This substance is therefore formed in the intestinal tract, is in part absorbed, and appears in the urine, where it is called urobilin, though the two are identical. Urobilin gives a yellowish coloration to the urine. Injection into the blood-vessels of distilled water, ether, chloroform, the biliary salts, or arsenuretted hydrogen, produces a solution of the red blood-corpuscles and conver- sion of haemoglobin into biliary coloring matters which are thrown out in the urine. Bili- rubin, biliverdin, and bilicyanin give characteristic spectra. Melanins. — Under this name are classed the pigments of the skin, of the retina, and of the iris. In melanosis and kindred diseases they are deposited in black granules. Abel and Davis ' prepared pure pigment from the skin of the negro and find that it con- tains no iron and 1.5 per cent, of sulphur. These pigments arise from proteid. On decomposition they yield two melaninic acids.* Tryptophan. — This is said to be a cleavage-product of hemipeptone in tryptic diges- tion ; ' it gives a red color with chlorine and a violet color with bromine, due to halogen- addition compounds. Lipochromes. — These include lutein, the yellow pigment of the corpus luteum, of ' Garrod: Journal of Physiology, 1894, vol. 17, p. 348. 2 Pjluger's Arehw, 1899, Ed. 75, S. 446. ' For a delicate modification of this test see JoUes: Zeitschrifl fiir physiologische Chemie, 1895, Ed. 20, S. 461. * Journal of Experimented Medicine, 1896, vol. i. p. 361. *■ Jones : Ainerican Journal of Physiology, 1899, vol. ii. p. 380. « Stadelmann : Zeitschrifl fiir Biologic, 1890, Bd. 26, S. 491. THE CHEMISTRY OF THE ANIMAL BODY. 575 Wood-plasma, butter, egg-yolk, and of fat ; likewise visual purple of the retina, which is Meaohed by light. Solutions of the pure visual purple from rabbits or dogs become clear as water on exposure to light. ' Oholesterin. Cholesterin, C27H45OH. — This is found in all animal and vegetable cells and in the milk.^ 'It is especially present in nervous tissue and in blood-corpuscles. It is excreted through the bile and through the intestinal wall.' In the blood-plasma it is present as an ester combined with oleic and palmitic acids, while in the corpuscle it occurs as simple cholesterin.* It may be prepared by dissolving gall-stones in hot alcohol, from which solution the cholesterin crystallizes on cooling in characteristic plates. It is insoluble in water or acids, but soluble in the biliary salts, ether, and hot alcohol. It is probably not absorbed by the intestinal canal. In human feces stercorin appears instead of choles- terin.^ This stercorin (the koprosterin of Bondzynski) is a dihydrocholesterin," CjvHjjOH, and is the result of putrefactive change.' Cholesterin feels like a fat to the touch, but is in reality a monatomic alcohol. With concentrated sulphuric acid it yields a hydrocarbon, cholesterilin, CieH^, coloring the sulphuric acid red (Salkowski's reaction). Iso-cholesterin, an isomere, is found combined as an ester with fatty acid in wool-fat or lanohn. The physiological importance of cholesterin is unknown. The Pboteids. Consideration of the proteids from a purely chemical standpoint is impos- sible, for their composition is unknown. There exist only the indices of com- position furnished by the products of cleavage and disintegration. Bodies at present classed as individuals may sometimes be shovs^n to be identical, with characterizing impurities. It remains for the chemist to do for the proteid group what Emil Fischer with phenyl-hydrazin has accomplished for the sugars. As a characteristic proteid, egg-albumin may be mentioned. Proteid forms (after water) the largest part of the organized cell, and is found in all the fluids of the body except in urine, sweat, and bile. Proteid contains carbon, hydrogen, nitrogen, oxygen, sulphur, sometimes phosphorus and iron. General Reactions. — A neutral solution of proteid (with the exception of the peptones and proteoses) is partially precipitated on boiling, and is quite completely precipitated on careful addition of an acid (acetic) to the boiling solution. Proteids are precipitated in the cold by nitric and the other com- mon mineral acids, by metaphosphoric but not by orthophosphoric acid. Metallic salts, such as lead acetate, copper sulphate, and mercuric chloride, precipitate proteid ; as do ferro- and ferricyanide of potassium in acetic-acid solution. Further, saturation of acid solutions of proteid with neutral salts (NaCl, Na^SO,, (NH,)2SO,) precipitates them, as does likewise alcohol in • Kuhne : Zeitschrift Jur Biologic, 1895, Bd. 32, S. 26. 2 Schmidt-Miihlheim : Pfiuger's Archiv, 1883, Bd. 30, S. 384. ' Moraczewski: Zeitschrift fur physiologische Ohemie, 1898, Bd. 25, S. 122. * Hepner: Pfiuger^s Archiv, 1898, Bd. 73, S. 595. 5 Flint : American Journal of Medical Sciences, 1 862. « Bondzynski and Hiimnicke: Zeitschrift fur physiologische Chemie, 1896, Bd. 22, S. 396. ' MiiUer, P. : Ibid., 1900, Bd. 29, S. 129. 576 AN AMERICAN TEXT-BOOK OF PHYSIOLOGY. neutral or acid solutions. Proteid is also precipitated by tannic acid in acetic- acid solutions, by phospho-tuugstic and phospho-molybdic acids in the presence of free mineral acids, by picric acid in solutions acidified by organic acids.' The precipitation of proteid is also accomplished by nucleic acid, taurocholic acid, and chondroitic sulphuric acid in acid solutions. Of the color-reactions the action of INIillon's reagent has been described (see p. 569). Soluble proteids give the biuret test (see p. 549). With concen- trated sulphuric acid and a little cane-sugar a pink color is given when proteid is present (see p. 544). Proteid heated with moderately concentrated nitric acid gives yellow flakes, changing to orange-yellow on addition of alkalies (xantho-proteid reaction). Proteid in a mixture of one part of concentrated sulphuric acid and two parts of glacial acetic acid gives a reddish-violet color (Adamkiewicz), a reaction accelerated by heating. Finally, proteid dissolves after heating with concentrated hydrochloric acid, forming a violet-colored solution (Liebermann). The following, taken in part from Chittenden,^ is submittfid as a general classification of the proteids : Simple Peoteids. {Serum-albumin ; Egg-albumin ; Lacto-albumin ; Myo-albumin. C Serum-globulin ; Fibrinogen ; jNIyosin ; Myo-globulin ; Paramyosinogen ; ^ Cell-globulin. Acid-albumin ; Alkali-albumin. Proteoses and Peptones. Coagulated Proteids Albumins Globulins Albuminates L Other coagulated proteids. Combined Proteids. Haemoglobin ; Histo-hsematins ; Chlorocruorin ; Haemerythrin ; Hsemocyanin. Mucins ; Mucoids. ' The above list is given by Hammarsten, Physiological Chemistry, translated by Mandel, p. 18. ^ "Digestive Proteolysis," CartorijAt Lectures, 1895, p. 30. Chromo-proteids Glyco-proteids < THE CHEMISTRY OF THE ANIMAL BODY. 577 f Casein ; Pyin ; - ^, „..™„ Vitellin. ^ 2. Those vieldinj^ true nuclein | ^ „ " . ' I. Cell-uuclem. Phospho-glyco-proteids. Helieo-proteid. Albuminoids. Collagen (gelatin). Elastin. Keratin and Neurokeratin. Albumins. — Bodies of this group are soluble in water and precipitated by boiling, or on standing with alcohol. Serum-albumin is the principal prot«id constituent of blood- plasma, while lacto-albumin and myo-albumin are similar bodies found respectively in milk and muscle. Globulins. — These are insoluble in water, but soluble in dilute salt-solutions. They are coagulated on heating. If blood-serum be dialyzed with distilled water to remove the salts present, serum-globulin formerly held in solution separates in flakes. Fibrinogen and serum-globulin are in blood-plasma and the lymph. JMyosin is the principal constituent of dead muscles ; in the living muscle myosin is said to be present in the form of niyosin- ogen. Myoglobulin in muscle is akin to serum-globulin in plasma. Paramyosinogen in muscle is characterized by the low temperature at which it coagulates (+47°). Cell- globulin is also found in the animal cell. The globulins of vegetable cells are interesting as having been obtained in well-defined crystalline form and in great purity of composition.^ These are not generally coagulable by heat, and indeed vegetable proteids show many points of divergence from those of the animal. Osborne ^ finds that solutions of pure crystalline edestine obtained from plants take up hydrochloric acid in exact chemical relations, forming the hydrochlorate or bihydrochlorate of edestine. The simplest formula for edestine (containing two atoms of sulphur) which can be calculated gives a molecular weight of 7,138, twice which is 14,276. This latter molec- ular weight exactly unites with one molecule of hydrochloric acid to form edestine hydrochlorate. Osborne regards the many variations in similar " native ' ' albumins as being fundamentally caused by the quantity and quality of the acid or alkali with which they unite. Albuminates. — If any of the above native animal proteids or any coagulated proteid be treated with an alkaline solution, alkali albuminate is formed. In this way the alkali of the intestine acts upon proteid. If hydrochloric acid acts on proteid, there is a gelatin- ization and slow conversion into acid albuminate, a process accelerated by the presence of pepsin. This takes place in the stomach. Both alkali and acid albuminates are in- soluble in water, but both are soluble in dilute acid or alkali, without loss of individual identity. Proteoses and Peptones. — These are bodies obtained from the digestion of proteids, through a process of hydrolysis. They are non-coagulable by heat. If a mixture of pro- teoses and peptones be saturated with ammonium sulphate the proteoses are said to be precipitated, while true peptone remains in solution. The chemical identity of this true peptone is still, however, to be established. In the gastric digestion of fibrin, proto- proteose, hetero-proteose, and deutero-proteose B, arise as primary cleavage products.' 1 Osborne : Journal of American Chemical Society, 1894, vol. xvi., Nos. 9, 10; and other arti- cles in the same journal by the same author. 2 Op. cit., 1899, vol. 21, p. 486. ' Zunz, E. : Zeitsekrifl fur physiologische Chemie, 1899, Bd. 28, S. 132. Vol. I.— 37 578 AN A3fEBICAN TEXT-BOOK OF PHYSIOLOGY. Fibrin yields a carbohydrate radicle which appears in deutero-proteose B and subse- quently in peptone A. ^ The primary proteoses are believed to break up into secondary proteoses, such as deutero-proteose A and deutero-proteoso C, and perhaps others, and these secondary proteoses may be converted into peptones, although gastric digestion will not convert some deutero-proteoses into peptone.' Egg albumin and other proteids yield similar products. The whole process of proteolytic cleavage has been compared with the hydrolytic cleavage of starch into dextrins and sugars. According to Kiihne, proteid consists of a herai- and an anti- group, which separate into distinct hemi- and anti- bodies in proteolysis. Of the final products, hemi- and anti-peptone, only the former yields leucin and tyrosin in tryptic proteolysis. This is the only radical difference between the two peptones, hence hemi-peptone has never been isolated. Kutscher' denies the existence of anti-peptone and shows that prolonged tryptic proteolysis almost completely transforms proteid into amido bodies. Coagulated Proteids. —These are insoluble in water, salt-solutions, alcohol, dilute acids and alkalies, but soluble in strong acids and alkalies, pepsin-hydrochloric acid, and alkaline solutions of trypsin. The chemical or physical change which is effected in coagulation of proteid is unknown. Combined Proteids. — These consist of proteid united to non-proteid bodies such as hsemochromogen, carbohydrates, and nucleic acid. Chromo-proteids. — These are compounds of proteid with an iron- or copper-contain- ing pigment, like haemoglobin, which has already been described. Histolicematins are iron-containing pigments found especially in muscle. That which is found in muscle is called myohsematin, and resembles haemochromogen somewhat in its spectroscopic appear- ance, and is believed to be present in two forms corresponding to haemoglobin and oxs'haemo- globin. It has been regarded as an oxygen-carrier to the tissues. Among the inverte- brates the blood often contains only white corpuscles with sometimes a colored plasma. Thus the blood-serum of the common earth-worm contains dissolved haemoglobin, that of some other invertebrates a green respiratory pigment, cMoroemorin, whose charac- terizing component seems similar to hsematin ; Tiosmerythnn occurs in the pinkish corpus- cles of Sipuiicuhis, while the blood of crabs, snails, and other animals (moUusks and arthropods) is colored blue by a pigment, hcemoq/anin, which contains copper instead of iron. Glyco-proteids. — These consist of proteids combined with a carbohydrate. They are insoluble in water, but soluble in very weak alkalies. On boiling with dilute mineral acids they yield a reducing substance. Mucins are found in mucous glands, goblet cells, in the cement substance of epithelium and in the connective tissues. Of the nearly related mucoids may be named colloid, a sub- stance appearing like a gelatinous glue in certain tumors ; pseiido-mucoid, the slimy body which gives its character to the liquid in ovarian cysts ; and chondro-mucoid, found as a constituent of cartilage. On boihng chondro-mucoid with dilute sulphuric acid it jdelds acid-albuminate, a peptone substance, and chondroitic acid. The last is a nitrogenous ■ethereal sulphuric acid, yielding a carbohydrate on decomposition, and found preformed in every cartilage * and in the amyloid liver. ^ It is, of course, not a proteid. Amyloid is similar to chondro-mucoid, and may be identical with it. It is said to consist of chondroitic sulphuric acid in combination with proteid,* and yields proteid and phosphoric acid on decomposition. ^ Pick: Zeitschrifl fiir physiologische Chemie, 1899, Bd. 28, S. 219. ' Folin : Ibid., 1898, Ed. 2.5, S. 152. ° Die Endprodukle der Trypsinverdauung, Strassburg, 1899. * Momer : Zeitschriftfur physiologische Chemie, 1 895, Bd. 20, S. 357. * Oddi: Archiv fur exper. Pathotogie und Pharmakologie, 1894^ Bd. 33, S. 376. 5 Krawkow : Ibid., 1897, Bd. 40, S. 195. THE CHEMISTRY OF THE ANIMAL BODY. 579 Nucleo-proteids, or Nucleo-albumins • and Nucleic Acids— These are compounds of proteid with nuclein, which latter yields phosphoric acid on decomposition. If nucleo- proteid, which is found in every cell, be digested with pepsin-hydrochloric acid, there remains a residue of insoluble nuclein, which is likewise insoluble in water but soluble in alkalies. If this nuclein yields xanthin bases on further decomposition, it is called true nuclein ; if it fails to yield these bases, it is called paranuclein or pseudonuclein. Nucleo-proteids yielding proteid and paranuclein on decomposition include the casein of milk, pyin of the pleural cavity, vitellin of the egg, Bunge's iron-containing hasmatogen of the egg, as well as nucleo-proteids found in all protoplasm. They all contain iron. Paranuclein is probably absorbable (see p. 514). Casein yields on peptic digestion phosphorized albumoses from which paranuclein is split: this cleavage is followed by the further digestion of the albumose and the gradual solution of the paranuclein.' Kobrak' slujws that woman's casein has two-thirds the acidity of cow's casein, but that the former dis- solved and reprecipitated six times has the same properties as the latter. He believes that woman's casein may consist of cow's casein united with another product of more basic properties. A second group of nucleo-proteids yields true nuclein on decomposition. This true nuclein is a modified form of the original nucleo-proteid, and consists of nucleic acid in combination with proteid. On decomposition the nuclein breaks up into its constituent proteid and nucleic acid, which latter always yields one or more of the xanthin bases, which are, therefore, called nuclein bases. The nucleic acid is similar to that derived from sperm, which is combined with protamin in the sperm nucleus. The nucleic acid of yeast nuclein yields guanin and adenin, that of a bull's testicle adenin, hypoxanthin, and xanthin, that of the thymus adenin and guanin, that of the pancreas guanin alone. The latter has been termed ' ' guanylic acid, ' ' and ' ' adenylic ' ' and ' ' xanthylic ' ' acids may also be considered individual nucleic acids. Each one of this family of acids has the power of combining with any soluble proteid to form nucleo-proteid, hence there may exist a large variety of nucleo-proteids. And the variety is further increased by the diversity of other decom- position products yielded by the various nucleic acids. Thus most nucleic acids yield thymic acid, which, however, cannot be found in pancreas nucleo-proteid. A crystalline base called cytosin has been discovered in thymus nucleic acid. Some nucleic acids, like that derived from yeast, readily yield carbohydrates (a hexose and a pentose) ; while others, like thymus nucleic acid, show the presence of the carbohydrate group only in the pro- duction of levulic acid after very thorough decomposition ; and still others (salmon sperm) fail to indicate the presence of any carbohydrate radicle. According to Kossel, nuclei may at times contain free nucleic acid. According to Bang,* nucleic acid may unite in three ways : with protamin, as in sperm nucleic acid ; loosely with proteid, as in most nucleo-proteids ; and strongly with proteid, as in pancreas nucleo-proteid. The last-named pancreas nucleic acid yields guanin on decomposition, and has been termed " guanylic acid." Bang gives the following analysis ; guanin, 36 per cent, (containing nine-tenths of all the nitrogen present) ; a little ammonia ; a pentose, 30 per cent., and I'^Oo, 17.6 per cent. The rest unaccounted for is 17.5 per cent. Phospho-glyco-proteids. — This class is represented by Hammarsten's helico-protdd, which yields paranuclein, and, unlike other nucleo-proteids of the paranuclein class, it yields a reducing carbohydrate on boiling with acids. The Albuminoids.— These are bodies derived from true proteid in the body, but not themselves convertible into proteid. They are resistant to the ordinary proteid solvents, and as a rule exist in the solid state when in the body. 1 These two terms are used here as synonymous, though Hammarsten would confine the terra nucleo-albumin to those proteids which yield paranuclein. 2 Salkowski: Zeitschrift filr physiologische Chemie, 1899, Bd. 27, S. 297. '' Pfluger's Arckw, 1900, Bd. 80, S. 69. * Zeitschrift fiir physiologische Chemie, 1898, Bd. 26, S. 133. 580 .i:\^ AJ/EBICAX TEXT-BOOK OF PHYSIOLOGY. Collagen. — This is the chief constituent of the fibres of connective tissue, of the organic matter of bone (ossein) and is lil^ewise one of the constituents of cartilage. Col- lagen is insoluble in water, dilute acids and alkalies. On boiling with water it forms gelatin through hydration, which is soluble in hot water, but gelatinizes on cooling (as in bouillon). Dry gelatin swells when brought into cold water. By continuous boiling or by gastric or tryptic digestion further hydration takes place with the formation of soluble gelatin peptone. Gelatin fed will not take the place of proteid, but, like sugar, only more effectively, it may prevent proteid waste by being burned in its stead.' Gelatin yields leucin and glycocoll on decomposition, but no tyrosin. It therefore gives the biuret reaction, but none with jMillon's reagent. It contains but little sulphur. It yields about the same amido- acids as ordinary proteid. Elastin. — This is very insoluble in almost all reagents and in boiling water. On decomposition it yields leucin, tyrosin, glycocoll, and lysatin. It is slowly hydrated by boiling with dilute acids, and by pepsin hydrochloric acid. It contains very little sulphur, and gives Millon's test. It is found in various connective tissues, and especially in the cervical ligament. Keratin and Neuro-keratin. — These are insoluble in water, dilute acids and alkalies ; insoluble in pepsin hydrochloric acid, and alkaline solutions of trypsin. Keratin is found in all horny structures, in epidermis, hair, wool, nails, hoofs, horn, feathers, tortoise-shell, whalebone, etc. Ne-uro-keratin has been discovered in the brain, and in the medullary sheath of nerve-fibres.' On decomposition with hydrochloric acid keratin yields all the products given by simple proteids. It contains more sulphur than simple proteid and yields more tyrosin. Dreohsel ' believes that it is transformed from simple proteid by the substitution of sulphur for some of the oxygen and of tyrosin for leucin or other amido- acid. Part of the sulphur is loosely combined, and a lead comb turns hair black, due to the formation of lead sulphide. There are different keratins, and their sulphur content varies greatly. Histon. — Histon is a proteid split off from yeast nuclein and the nuolein of the white blood-corpuscles and blood plates. Kossel has suggested that it is a combination of pro- teid and protamin, which the investigations of Bang * tend to confirm. Protamins and Remarks on the Theoretical Composition of the Proteid Molecule. — The protamins have been discovered in fish-sperm united with nucleic acid. According to Kossel, protamins are the simplest proteids. They all give the biuret test. On heating with dilute acid or in tryptic digestion they are converted into protone (protamin peptone), and then they break up into amido acids. Several protamins have been dis- covered. That obtained from sturgeon-sperm is called sturin, from the herring, clupein, from the salmon, salmin, and from the mackerel, scombrin. iSturin, according to Kossel,^ breaks up as follows : CaeHeoN^gO, + 5H,0 = C,H,N,0, + 3C,H,,N,0, + C,H,,Np^ Kossel's investigations show that salmin and clupein are identical and yield on decomposition arginin and amido valerianic acid, while scombrin also yields arginin, without any histidin or lysin.^ ' Voit : Zeitschrififw Biologle, 1872, Bd. 8, S. 297. ^ Kiihne and Chittenden: Ibid., 1890, Bd. 26, S. 291. ' Ladenburg's Handworterbuch der Chemie, 1885, Bd. 3. S. 571. ' Zeitschrifi fiir physiologische Chemie, 1899, Bd. 27, S. 463. * Deutsche medicinische Wochenschri/l, 1898, No. 37. * Zeitschrifi fiir phydologischo Chemie, 1899, Bd. 26, S. 588. THE CHEMISTRY OF THE ANIMAL BODY. 581 All proteids yield histidin, arginin, and lysin on decomposition. As regards the composition of the proteid molecule, Kossel pictures a protamin nucleus like sturin, to which may be attached lencin, tyrosin, glucosamin, or glycocoll, and to these again sulphur, iodine, or iron. Treatnient of proteid with 20 per cent, hydrochloric acid or tryptic digestion may break it up into leucin, tyrosin, histidin, argenin, lysin, etc. Kossel speaks of histidin, arginin, and lysin as hexon-bases, since they (and leucin also) contain six atoms of carbon, and he calls attention to the fact that in this respect they are similar to the carboydrates. Just as carbohydrates exist as poly-hexoses, so prota- mins and proteids may be built up as poly-hexon-bases. Cohn has found that proteid may yield as much as 50 per cent, of leucin. The products derived from proteid in metabolism are different from the above. Thus it has been found that the body's proteid, the proteid from meat, and gelatin, may all yield about 60 per cent, of dextrose in diabetes.^ It has been further sho^\ n ° that the metabolism of the body's proteid, of casein, and of gelatin yields between 3 and 4 per cent, of glycocoll, which may be eliminated as hippuric acid. It is possible to conceive of a carbo- hydrate portion united to a protamin nucleus and to amido bodies such as glycocoll ^ (see p. 558). Miiller and Seeman * have declared that the source of the sugar in diabetes must be the hexon-bases and leucin, but Halsey^ has shown that feeding leucin will not increase the sugar in diabetes. Halsey suggests a synthetic formation of sugar from lower proteid decomposition-products, but a synthetic formation of sugar in the animal has never been shown. It must be admitted that we are still in the dark regarding even the simplest expres- sion of the constitution of proteid. It has been impossible within the limits set to do more than to glance at the proteid bodies. Many facts concerning the behavior of proteids have been mentioned throughout the text, and cannot be classified here. The size of the proteid molecule must be very great, and one computation shows the following figures ^ (see also p. 577) : Egg-albumin. Proteid from hsemoglobin (dog). It is well, perhaps, finally, to speak of experiments which, however incom- plete, at least throw some light on the possibilities of the problem of the syn- thesis of proteid. Lilienfeld^ through the condensation of the ethyl-ester of ' Keilly, Nolan, and Liisk : American Journal of Physiology, 1898, vol. i. p. 395. 2 Parker and Lusk : Ibid., 1900, vol. iii. p. 472. ' Bay, McDermott, and Lusk : Ibid., 1899, vol. iii. p. 153. ' Deutsche medicinische Woehensehrift, 1899, S. 209. 5 Silzungsberichte der Oesellsehaft zur Beforderung der gesammten Naturwissenschaften, zu Marburg, 1899, S. 102. ^ Bnnge : Physiologische Chemie, 3d ed., 1893, S. 56. ' Verhandlungen der Berliner physiologischen Gesellsohaft, Archiv fur Physiologic, 1894, S. 383. 582 AX AMERICAN TEXT-BOOK OF PHYSIOLOGY. glycocoU has obtained a body insoluble in water, but swelling in it, forming a gelatinous mass. The substance gives the biuret reaction, is insoluble in alcohol and dilute hydrochloric acid, but dissolves in pepsin-hydrochloric acid. These reactions show its kinship to gelatin. Lilienfeld likewise de- scribes a synthetically formed peptone and a coagulable proteid,^ the peptone formed principally through condensation of the above-described product ^\•ith the ethyl-esters of the amido- bodies, leucin and tyrosin, the proteid from the same with addition of formic aldehyde. Grimaux likewise has produced, with other reagents, colloids whicli resemble proteids. Probably none of these substances are native proteids, but they furnish indications of lines of attack for the future mastery which in time is sure. ' Verhandlungen der Berliner physiologischen Gesellschaft, Arehiv fiir Physiologic, 1894, S. 555. INDEX. Abdominal muscles, action of, in vomitin? 387 respiratory action of, 407 respiration, definition of, 398 Absorbents, 318 Absorption, effect of alcohol on, 535 in the small intestine, 313 in the stomach, 312 mechanism of, 312 nature of process, 27 of fats, 317 of gases by liquids, 414 of proteids, 316 of sugars, 317 of water and salts, 318 part played bv leucocytes in, 48 paths of, 311 spectrum of oxyhsemoglobin, 41 Accelerator centre, cardiac, 177 respiratory, 457 nerves of the heart, 167, 168, 169 Accessory articles of the diet, 357 thyroids, 268 Acetic acid, 536 Acetone, relation of, to fat metabolism, 539 Acetonitril, 542 Acetonuria, 537 Acetyl-acetic acid, 537 Acetyl-propionic acid, 538 Achroodextrin, 285, 566 Acid, acetic, 536 acetyl-acetic, 537 acetyl-propionic, 538 amido-acetic, 537 amido-ethyl-sulphonic, 543 a-amido-a-thiopropionic, 546 aspartic, 557 benzoic, 569 butyric, 539 capric, 541 caproic, 540 caprylic, 541 carbamic, 548 carbolic, 569 carbonic, chemical structure of, 545 choleic, 543 cholic, 543 chondroitic, 578 cyuurenic, 571 diamido-acetic, 551 a-e-diamido-caproic, 552 diamido-valeric, 552 dithio-diamido-ethidene lactic, 547 fellic, 543 formic, 534 glutamic, 558 glycerin phosphoric, 559 glycuronic, 567 hippuric, 339, 569 homogentisic, 570 hydriodic, 509 hydrobromic, 509 hydrochloric, 507 hydrocumaric, 570 Acid, hydrocyanic, 542 hydrofluoric, 510 iso-butyl amido-acetic, 540 iso-valerianic, 539 lactic, 545 levulic, 538 malic, 558 mercapturic, 547 metaphosphoric, 514 methyl amido-acetic, 538 monobasic fatty, 532 nucleic, 579 oleic, 560 orthophosphoric, 514 oxalic, 557 oxaluric, 555 oxybutyric, 548 oxyphenyl-acetic, 570 oxyphenyl-amido-propionic, 570 palmitic, 541 parabanic, 555 phenaceturic, 569 phenyl-acetic, 569 propionic, 538 sarco-lactic, 546 silicic, 519 stearic, 541 succinic, 557 sulphuric, 506 sulphurous, 506 thiolactic, 547 thymic, 579 uric, 322, 338, 554, 557 Acids, efi'ect of, on pancreas, 236 Acinus, definition of, 212 Acromegaly, 273 Adamkiewicz reaction for proteids, 576 Addison's disease, 271 Adenin, 339, 554 Adipocere, 541, 560 Adrenal bodies, internal secretion of, 272 removal of, 271 secretory nerves of, 272 Adrenal extracts, physiolegieal ac tion of, 271 Afferent respiratory nerves, 460 Age, influence of, on heat production, 482 on pulse rate, 121 on respiration, 425 relation of body-temperature to, 469 Air, alveolar, composition of, 413 atmosjjheric, composition of, 410, 413 complemental, 427 expired, composition of, 410 inspired, composition of, 410 in the lungs, renewal of, 413 passages, obstruction of, 452 residual, 427 respiratory changes in, 410 stationary, 427 suction of, iuto veins, 97 supplemental, 427 tidal, volume of, 426 variations in the composition of, 435 Albuminates, 577 683 584 INDEX. Albuminoids, digestion of, in the stomach, 297 enumeration of, 577 nutritive value of, 277, 349 properties of, 579 protection of proteids by, 349 tryptic digestion of, 304 Albuminous glands, 216 Albumins, properties of, 577 Albumose injections, efTect of, on blood, coagu- lation, 62 Alcaptonuria, 570 Alcohol, absorption of, in the stomach, 313 amyl, 539 cerotyl, 540 eetyl, 540 ethyl, 535 melicyl, 540 nutritive value of, 358 physiological action of, 357, 535 propyl, 536, 538 toxic effects of, 359 Alcoholic fermentation, 535 Alcohols, monatomic, 531 Aldehydes, general properties of, 534 Aldoses, 561 Alimentary canal, movements of, 369 principles, 276 Allantoin, 555 Alloxuric bases, 338, 339, 552 Altitude, effect of, on the number of red cor- puscles, 46 Alveolar air, composition of, 413 capacity, 427 tension of carbon-dioxide, 413 of oxygen, 413 Alveolus, glandular, definition of, 212 Amido-acetic acid, 537 Amido-acids, properties of, 538 Amines, definition of, 541 Ammonia, inhalation of, 440 occurrence of, 511 origin of, in the body, 511 properties of, 511 Ammoniacal fermentation of urine, 512 Ammonium carbamate, 548 carbonate, 523 cyanate, 542 magnesium phosphate, 527 Amniotic fluid, inhibitory efiect of, on respira- tion, 464 Amoeboid movement of leucocytes, 48 Ampho-peptone, definition of, 293 Amygdahn, fermentative decomposition of, 542 Amyl alcohol, 539 Amylodextrin, 566 Amyloid, 578 Amylolytic enzyme of gastric juice in the dog, -'96 of succus entericus, 308 of the liver, 330 enzymes, definition of, 280 action of, in the body, 285 Amylopsin, 232, 280 action of. on starch, 566 digestive action of, 305 occurrence of, 304 properties of. 305 Anabolism, definition of, 19 Aniesthetics, effect of, on body-temperature, 472 Animal foods, composition of, 278 heat, 467 source of, 474 Annulus Vieussens, 159 Antalbumid, 293 Autilytic secretion, 230 Antimony poisoning, 514 Anti-peptone, definition of, 293 Anti-peptone, nature of, 302 Antiperistalsis, intestinal, 383 of the stomach, 379 Antrum pylori, 377 Apex beat, 117 preparation of the frog's heart, 188 ventricular, rhythmicity of, 151 Apncea, definition of, 440 foetal, 464 phenomena of, 441 relation of vagi to, 442 Apomorphia, action of, 389 Arabinose, 562 Arginin, 552 Argon of the blood, 417 Aromatic compounds in urine, 572 metabolism of, 568, 569 Arsenic poisoning, 514 Arterial blood-pressure, explanation of, 92 pulse, cause of, 93 definition, 139 extinction of, 94 Arteries, coronary, 179 elongation of, 140 rate of fiow in, 101 Artificial respiration, circulatory efiiects of, 453 methods of maintaining, 446 Asparagin, 558 Aspartic acid, 557 Asphyxia, 441 circulatory changes in, 445 effects of, on the blood-vessels, 202 on the respiratory rhythm, 425 stages of, 445 Aspiration of the thorax, influence of, on the circulation, 77, 95 on the lymph-flow, 147 on venous circulation, 77, 95 Assimilation, general characteristics of, 19 Associated respiratory movements, 408 Asymmetrical carbon atom, definition of, 545 Atelectasis, 396 Atmospheric air, composition of, 410, 413 Atrophy of the heart after section of the vagi, 167 Atropin. action of, on salivary glands, 222, 229 on sweat glands, 260 efl'ect of, on body-temperature, 472 Augmentor centre of the heart, 177 nerves of the heart, 161, 167 Auricles, connection of, 135 degree of emptying, in systole, 138 functions of, 135 influence of, on venous blood-flow, 136 negative pressure in the, 137, 138 systolic changes in the, 115 Auricular pressure, 135. 137 systole, duration of, 124, 136 effect of, on venous blood-flow, 138 on ventricular fllling, 137 Auriculo-ventricular valves, 108 Auscultation, 118 Axilla, temperature in the, 468 Bacterial decomposition in the intestines, 309 Banting diet, 353 Barometric pressures, effect of, on respiration, 434 Bartholin, duct of, 217 Basophiles, 47 Baths, influence of, on body-temperature, 471 Beckmann's apparatus, 68 Beef-tea, physiological action of, 359 Beer, 535 Beeswax, 540 Benzoic acid, 340, 569 INDEX. 585 Benzol, molecular constitution of, 568 Beuzopyrol, 571 Bidder's ganglion, 148 Bile, amount secreted, 246, 321 ■ antiseptic property of, 326 composition of, 245, 321 discharge of, from the gall-bladder, 248, 249 fatty acids of the, 541 influence of, on emulsification of fats, 307 mineral, constituents of, 530 pigments of, 245, 322 physiological value of, 325 relation of, to fat absorption, 325 secretion of, 246 sulphur of, 507 Bile-acids, 245 detection of, 324 Neukomm*s test for, 545 occurrence of, 323 origin of, 324 Pettenkofer's test for, 324, 544 relation of, to fat absorption, 326 Bile-capillaries, 244 Bile-ducts, occlusion of, 249 Bile-pigments, 322 chemical properties of, 574 Gmelin's test for, 322, 574 origin of, 45, 530 Bile-salts, 245 chemistry of, 543 circulation of, 544 Bile-secretion, normal mechanism of, 248 relation of, to blood-flow in the liver, 247 Bile-vessels, motor nerves of, 248 Biliary flstulse, 321 Bilicyanin, 574 Bilirubin, 245, 574 Biliverdin, 245, 574 Bilixanthin, 574 Biuret, 549 Bladder, urinary, movements of, 369, 390 vaso-motor nerves of, 209 Blood, 33 chemical composition of, 50 circulation of, 76 coagulation of, 54 defibrinated, 34 distribution of, in the body, 63 foreign, action of, on the heart, 192 gaseous exchanges of the, 411 general function of the, 33 histological structure of, 33 identification of, 573 oxidations in the, 423 reaction of the, 34,290 regeneration of, after hemorrhage, 63 specific gravity of, 34 total quantity of, in the body, 63 transfusion, 64 31ood-corpuscles, inorganic salts of, 50, 530 varieties of, 33 JBlood-gases, analyses of, 411 extraction of, 420 tension of, 415 Blood-leucocytes, 47 JJlood-plasma, color of, 33 composition of, 51 inorganic salts of, 50 Blood-plates, 49 Blood-pressure, aortic, 91 capillary, 84, 93 efiect of the accelerator nerves on, 170 effect of the depressor nerve on, 173 effect of, on renal secretion, 253, 256 mean, definition of, 90 methods of measuring, 84, 85 origin of the, 91, 92 Blood-pressure, pulmonary, 91 respiratory changes iu, 447 venous, 91, 94 Blood-serum, composition of, 51 deflnitioij, 34 mineral constituents of, ,530 osmotic pressure of, 68 Bodily metabolism, estimation of, 343 movements, effect of, on lymph-flow, 147 temperature, eflect of, on respiratory ex- cljanges, 432 Body-weight, influence of, on heat-production, 482 loss of, from starvation, 362 Border-cells of the gastric glands, 237, 238 Brain, vaso-motor nerves of the, 203 Bromelin, 280 Bromine, 508 Bronchial capacity, 427 Broncho-constrictor nerves, 465 Broncho-dilator nerves, 465 Brunner's glands, 243 Buffy coat, 55 Butyric acid, 539 Cadaverin, 543 Caffeiu, 553 action of, on tlie kidneys, 254 on body-tempej'ature, 472 Calcium, absorption of, 525 excretion of, 526 physiological value of, 524 relation of, to heart muscle, 151 carbonates, 524 chloride, 523 fluoride, 510, 523 phosphates, 523 salts, action of, on the heart, 190 amount of, in fibrin, 58 excretion of, 356 nutritive value of, 356 relation of, to blood-coagulation, 57, 524 sulphate, 523 Calorie, definition of, 504 Calorimetric equivalent, 478 Calorimetry, direct and indirect, 365, 475, 478 Cane sugar, injection of, 317 inversion of, 565 Capacity of the heart-ventricles, 105 Capillaries, biliary, 244 blood, length of, 79 permeability of, 70 pressure in the, 84 rate of flow in, 101 resistance in the, 81 structure of, 80 time spent by the blood in, 103 secretion of the fundic glands, 238 Capillary circulation, microscopic characters of, 80 pressure, origin of, 93 relation of, to lymph formation, 72, 75 Capric acid, 541 Caproic acid, 540 Caprylic acid, 541 Capsules, suprarenal, extirpation of, 271 Carbamic acid, 548 relation of, to urea formation, 336 Carbamide, 548 Carbo-haemoglobin, nature of, 39 Carbohydrates, absorption of, 317 affinity of cell-substance for, 568 chemistry of, 561 combustion equivalent of, 365 definition of, .561 digestion of, in the stomach, 296 586 IXDEX. Caiboh yd rates, dynamic value of, 475 ferrueutation of, in tlie intestines, 310 molecular constitution of, 561 nutritive value of, 277, 353 origin of fat from, 352 proteid-protection by, 508 synthesis of, 26 Carbon, metabolism of, 518 occurrence of, 516 properties of, 516 Carbon-dioxide, action of, on the heart, 191 dyspnoea, 444 elimination, conditions affecting, 429 cutaneous, 422 estimation of, 428 inhalation, effects of, 440 occurrence of, 517 of the blood, extraction of, 517 properties of, 518 tension of, in the alveoli, 413 in the blood, 416 Carbon equilibrium, definition of, 345 Carbonic acid, chemical constitution of, 545 Carbon monoxide, absorption spectrum of, 44 composition of, 38 properties of, 517 Carbon-monoxide haimoglobin, 517 inhalation, 440 Carburetted hydrogen inhalation, 440 Cardiac centre, augmentor, 177 inhibitory, 176 cycle, analysis of, 122 definition of, 104 duration of, 123 dyspnoea, 444 excitation, propagation of, during vagus stim- ulation, 163 impulse, 117 nerves, anatomy of, 159 classification of, 171 extrinsic, 159 of frogs, 160 of mammals, 160 Cardio-inhibitory centre, respiratory variations in, 451 Cardiopneumatic movements, 412 Cardiogram, 117 Cardiometer, 106 Cam in, 7CA Casein, 261 composition of, 579 curdling of, by acids, 296 by rennin, 295 Catalysis, 282, 503 Cell-difl'erentiation, 22 Cell-division, 20 Cell-granules of glandular epithelium, 216 Cellulose, 565 Centre, augmentor of the heart, 177 cardio-inhibitory, 176 defecation, 387 deglutition, 377 expiratory, 457 inspiratory, 457 micturition, 391, 393 peripheral reflex, 178 respiratory, 455 salivary secretory, 230 sweat, 260 thermogenic, 491 vaso-motor, 198 vomiting, 389 Centripetal nerves of the heart, 171 Centrosome, 22 Cerebral circulation, 203 crossed, 443 Cerebral cortex, relation of, to the vaso-motor centre, 202 Cerebrin, 559 Cerotyl alcohol, 540 Cerumen, 257 Cervical sympathetic, vaso-motor function of, 193 Cetyl alcohol, .540 Chest, effects of opening the, 115 Cheyne-Stokes respiration, 424 Chief cells of the gastric glands, 237 Chinese wax, 1340 Chinoliu, 571 Chloral, effect of, on the respiratory rhythm, 425 hydrate, 536 Chlorine, inhalation of, 440 occurrence of, .507 Chlorocruorin, 578 Chloroform, fate of, in the body, 533 Chocolate, nutritive value of, 357 Cholagogues, 246 Cholesterin, 575 amount of, in the blood, 51 distribution of, 325 excretion of, 325 of the bile, 245 of milk, 261 of sebaceous secretion, 257 Choletelin, 574 Cholin, 541, .543 Cholo-hEematiii, 323 Cbondroitic acid, 578 Cbondro-miicoid. 578 Chorda tympani nerve, vaso-dilator function of^ 194 Chordae tendiueie, 109 Chromatin, 22, 28 Chromo-proteids, .576 Chromosomes, 22, 28 Chyme, 287, 381 Circulating proteid, definition of, 346 Circulation, capillary, velocity of, 83 cerebral, 203 of hydriodic acid, 509 of hydrofluoric acid, 510 of the bile, 32.3, 324 of the blood, causes of, 77 definition, 76 discovery of, 76 microsci>pK- appearances of, 80 portal, 77 pulmonary, 78, 103 rate of, 79, 98 pulmonary, 103 renal, 255 Circulation-time, 79 Climate, influence of, on body-temperature, 469- Clothing, influence of, ou heat-loss, 486 Clotting of the blood, 55 of milk, 295 Clupein, 580 CO2 elimination, cutaneous, 2.58, 342 during muscular work, 361 sleep, 361 Coagulated proteids, properties of, 578 Coagulating enzymes, definition of, 280 Coagulation of the blood, accelerating agents of the, 61 conditions necessary for, 57 description of the, 54 nature of, 60 intravascular, 60 retarding influences affecting, 61, 62 theories of the, 55, 56 time taken by the, 55 uses of, 55 INDEX. 587 Coagulation of milk, 295 Cocaiue, effect of, on intestinal movements, 384 Coefficient of absorption of liciuids for gases, 414 Coffee, nutritive value of, :!57 Cold, effect of, on coagulation of tlie blood, 61 Collagen, 580 Colloid, 578 substance of the thyroid, secretion of, 268 Colostrum corpuscles, origin of, 263 definition of, 264 Combined proteids, 579 Combustion, 501 equivalent of foods, 365 Comedones, 257 Complemental air, 427 Compressed air, respiration of, 452 Condiments, nutritive value of, 359 Conductivity of living matter, 21 Conduction in the heart of the contraction wave, 154 Congo-red test for mineral acids, 289 Conjugated sulphates, nutritive history of, 340 Consciousness, 29 Contractility of living matter, 21 of plain muscle, 370 Coutraction volume of the heart, 105 wave of the heart, rate of propagation of, 153 Coronary arteries, anatomy of, 179, 180 ligation of, 181, 183 circulation, effect of ventricular systole on, 185 volume of, 184 veins, closure of, 184 Corpora Arantii, 112 Corpuscles, colostrum, 263 of the blood, 45 salivary, 283 Cortex cerebri, connection of, with the respira- tory centre, 463 Cortical stimulation, vascular effects of, 202 Costal respiration, definition of, 398 Coughing, 454 Coughs, sympathetic, 455 Crab-extract, lymphagogic action of, 73 Creatin, chemical constitution of, 550 nutritive history of, 339, 551 Creatiniu, 551 nutritive history of, 339 Cresol, 569 elimination, 340 Crossed cerebral circulation, 443 Crying, 454 Crystalloids, diffusion of, 69 Crystals of CO-ha;moglobin, 40 of hsemin, 44, 573 of haemoglobin, 39 Cutaneous nerves, influence of, on respiration, 463 respiration, 422 secretion, 257 Cyanamide, 542 Cyanogen gas, 541 inhalation, 440 Cynurenic acid, 571 Cystein, 546 Cystin, 547 Cytology, definition of, 31 Cytosin, 579 " Dangerous region," 97 Decomposition, bacterial, in the intestines, 309 Defecation, 386 Defibrinated blood, definition of, 34 preparation of, 55 Deglutition, 372 analysis of, 376 Deglutition, apncea, 442 centre for, 377 explanation of, 375 nervous regulation of, 376 Demilunes, 219 Depressor nerve, 172, 203 Deutero-proteose, definition of, 293 Dextrose, action of, on the heart, 191 amount of, in the blood, 51, 317 origin of, 563 oxidation of, in the tissues, 317 storage of, 563 Diabetes mellitus, dextrose excreted in, 354, 563 fatty acids in, 536 on proteid diet, 329 phosphorus excretion in, 515 relation of the pancreas to, 266 Dialysis, definition of, 65 of soluble substances, 69 Diaphoretics, effect of, on heat dissipation, 489 Diaphragm, movements of, 398 Diastase, 280 Diastatic enzymes, 280, 566 Dicrotic pulse, 144 wave of the pulse-curve, 143 Diet, accessory articles of, 357 average, for man, 366 Dietetics. 366 Differential manometer, 131 Diffusion, definition of, 65 of proteids, 70 through membranes, 66 Digastric mu.scle, 372 Digestion, action of alcohol on, 535 gastric, 287 in the large intestine, 309 influence of, on respiratory exchanges, 431 intestinal, 299 of fats, 305 of proteids, 292, 301 of starch, 284 pancreatic, 301, 308 purpose of, 275 salivary, 283 Digitalis, effect of, on the respiratory rhythm. 425 Dioxyacetone, 5.58 Dioxyphenyl-acetic acid, 570 Disaccharides, 564 digestion of, 308 Disassiniilation, definition of, 19 Dissociation of electrolytes, 67 Diuretics, action of, 254 Drinking-water, 504 Dropsy, 147 Drowning, phenomena of, 445 resuscitation from, 445 Drugs, action of, on body-temperature, 472 on salivary glands, 222, 229 on sweat-glands. 260 on therraogenesis, 484 on thermolysis, 48(1 Duct of Bartholin, 217 of Riviuus, 217 of Stenson, 217 of Wharton, 217 of Wirsuug, 231 Dyslysin, 544 Dyspepsia, cause of, 309 Dyspnoea, definition of, 441 effect of, on inte-stinal movements, 386 phenomena of, 444 varieties of, 443, 444 ECK fistiil.i, 336 Edestine, .577 Efferent respiratory nerves, 463 588 INDEX. Egg albumin, absorption of, 315 Elastin, 580 Electrical changes in active glands, 231 in the heating heart, 152, 153 in the heart, during vagus stimulation, 164 Electrolytes, definition of, 67 Emigration of leucocytes, 83 Emphysema, influence of, on the respiratory rhythm, 424 Emulsification of fats, 306 influence of the bile on, 307 Emulsions, preparation of, 307, -359 Endocardiac pressure (see Intracardiac press- ure). Encmata, nutritive, 315 Energy, potential, of foods, 364 Enzyme action, theories of, 282 glycolytic, 354 Enzymes, classification of, 280 composition of, 279 definition of, 279 effect of, on blood coagulation, 63 general properties of, 281 mode of action of, 282 of pancreatic juice, 332, 235, 301 solubility of, 281 Eosinophiles, 47 Epiguanin, 554 Epinephnn. 272, 572 Episarcin, 554 " Erection " of the heart, 114 Erectores spinse muscles, respiratory action of, 405 Erythroblasts, 45 Erythrodextrin, 285, 566 Erythrose, 562 Escape of the heart from Vagus inhibition, 163 Ether, ethyl. 536 Ethereal sulphates, .506 of the urine, 572 Ethers, properties of, 536 Ethyl alcohol, 535 Etbylamine, 541 Eudiometer, 421 Eupncea, definition of, 440 Excitation, cardiac, electrical variation in, 153 propagation of, 153, 154 wave, cardiac, 152 Excretin, occurrence of, in feces, 320 Excretions, definition of, 213 Exercise, effect of, on metabolism, 359 on pulse-rate, 121 Expiration, forced, muscles of, 407 movements of, 406 Expiratory centre, 457 Extirpation of the liver, 336 of the pancreas, 266 of the thyroids, 268 Extractives of the blood, 50, 51 Extracts, adrenal, 271 ovarian, 274 testicular, 273 thyroid, 269 Exudations, secretion of, 215 F.4T, affinity of cell-substance for, 568 nutritive history of, ,559 origin of, from carbohydrates, 352 from proteid, :i51, 560 Fat-absorption, influence of bile on, 325 mechanism of, 318 Fat-combustion, equivalent of, 365 Fat-formation in the body, .351, 560 Fat-metabolism, acetone formation in, .537 Fats, absorption of, in the stomach, 313 action of, on gastric secretion, 241 digestion of, 305 Fats, dynamic value of, 475 emulsification of, 306 gastric digestion of, 297 nutritive value of, 277, 350 of feces, 319 origin of, in the body, 351, .560 relation of, to glycogen formation, 329 synthesis of, from fatty acids, 558 Fatty acids, monobasic, 532 degeneration in phosphorus-poisoning, 514 Feces, composition of, 319 Fellic acid, 543 Fermentation, alcoholic, 535 lactic, 545 Ferments, unorganized, 279 Ferratin, 528, .529 Ferric phosphates, 528 Ferrosulphide, 528 Fever, body-temperature in, 472 cause of, 473 effect of, on blood coagulation, 55 on the respiratory centre, 458 heat dissipation in, 489 Fibrillar contraction of the heart, 181, 183 Fibrin ferment, 56 absence of, in circulating blood, 61 nature of, 57 origin of, 59 preparation of, 59 mode of deposition of, 54, 55 Fibrin-globulin, .56 Fibrinogen, 53, 54 Fibrinoplastin, .56 Fictitious meal, effect of, on gastric secretion, 239 Filtration processes in .secretion, 213, 215 Flavors, nutritive value of, 359 Fluorine, occurrence of, 510 Food, combustion equivalent of, 365 definition of, 275 dynamic value of, 364 effect of, on respiratory activity, 431 energy liberated by, 474 influence of, on thermogenesis, 484 rate of movement of, in the intestines, 314 Food -stuffs, classification of, 276 composition of, 278 Liebig's classification of, 346 Force of ventricular systole during vagus stimulation, 163 Formic acid, .534 aldehyde, 533 Formose, synthesis of, .533 Frequenc.y of respiration, conditions affecting, 425 relation of, to the pulse-rate, 426 Galactose, 562, 564 Gall-bladder, motor nerves of, 248 Galvanic current, effect of, on the heart apex, 150 Ganglion-cells of the heart, 148 Ganglion, submaxillary, 219 Gas analysis, 421 (las-pump, description of, 420 Gaseous interchanges in the lungs, 410, 417 in the tissues, 419 Gases, absorption of, 414 in the large intestine, 320 in the blood, respiratory changes in, 411 of the saliva, 221 law of partial pressure of, 413 poisonous, inhalation of, 440 solutions of, 415 Gastric digestion of proteids, 292 value of, 299 fistulce, 288 glands, histology of, 237 lyDEX. 589 Gastric glands, secretory changes in, 242 juice, acidity of, 289 action of, on carbohydrates, 296 on mills, 296 antiseptic property of, 288 artificial, preparation of, 291 composition of, 238, 288 methods of obtaining, 287 mineral constituents of, 530 secretion, inhibition of, 241 nervous regulation of, 239 normal mechanism of, 240 relation of, to the character of the diet, 241 stimulants for, 241 Gelatin, digestion of, in the stomach, 297 nutritive value of, 349 proteid, protecting power of, 567 Gelatoses, 297 Geuio-hyoid muscle, function of, in mastication 372 Gerhardt's reaction, 537 Gland, adrenal, 271 '• mammary, 262 pancreatic, 231. 266 parathyroid, 268 parotid, 217 sublingual, 217 submaxillary. 217 thyroid, 267 ' Gland-cells, selective activity of, 27 Glands, albuminous, histology of, 216 Brunner's, 243 cutaneous, 257 gastric, 237 intestinal, 243 Lieberkiihn's, 243 mucous, histology of, 216 salivary, 215 sebaceous, 257 serous, definition of, 216 structure of, 211 sweat, 259 Glauber's salt, 522 Globin, .37 Globulicidal action of serum, 36 Globulins, 577 Glomeruli, renal, secretory function of, 253 Glossopharyngeal nerves, influence of, on resjii- ration, 462 Glottis, respiratory movements of, 408 Glucosamin, 564 Glucoses, 562 synthesis of, 563 Glutamic acid, 558 Glutamin, 558 Glutolin, 53 Glutoses, 297 Glycerin, 558 aldehj'de, 558 phosphoric acid, 559 Glycerose, 558 Glycocoll, 537, 543 nutritive history of, 538 Glycogen, 566 amount of, in the liver, 327 demonstration of, in the liver, 327 distribution of, 330 , efi'ect of exercise on, 361 of starvation on, 362 of sugars on, 328 function of, 329 in the muscles, 330 origin of, 326, 327 properties of, 327, 566 Glycogen-elimination of the liver, 265 Glycogen-formation, effect of proteid diet on, 328 Glycogen-formers, 328 Glycogenic theory, 329 Glycolysis, 354 Glycolytic enzyme, 280, 354 origin of, 267 Glyco-proteids, 576, 578 Glycosazones, 562 Glyco-secretory nerves, 248 Glycoses, 562 Glycosuria after pancreas extirpation, 266, 563 Glycuronic acid, 567 Gmelin's test for bile-pigments, 322, 574 Goblet cells, 216 Goitre, 269 Gout, 557 Grammeter, 477 Gram-molecular solution, 67 Guaniu, 339, 554 Guanidin, 550 Gtinzburg's reagent, 508 H^MATis, 37, 44, 573 Haematogen, 356 composition of, 579 nutritive value of, 528 Hfematoidin, 44, 323, 574 Hsematopoiesis, deiinition of, 45 Haematopoietic tissues, embryonic, 46 H«matoporphyrin, 44, 574 Hiemerythrin, 578 Hsemin, 44, 573 Haemochromogen, 37, 44, 573 Haemocyanin, 578 Haemoglobin, 573 absorption spectra of, 43 action of, on carbonates, 517 affinity of, for CO2, 417 amount of, 38 compounds of, with gases, 38 condition of, in the corpuscles, 35 crystals of, 39 decomposition products of, 37 derivatives of, 44 distribution of, in animals, 37 elementary composition of, 37 molecular formula of, 37, 38 nature of, 37 oxygen capacityof, 416 Hawking, 454 Head, vaso-motor nerves of, 204 Heart, ansemia of, 183 artificial stimulation of, 156 augmentor nerves of, 167 cause of rhythmic beat of, 148 centripetal nerves of, 171 changes in form of, 113 in 'position of, 114 in size of, 112 compensatory pause of, 156 electrical currents of, 152 erection of, 114 fibrillar contraction of, 181 heat produced by, 108 human, output of the, 106 intrinsic nerves of, 148 isolation of, 148, 187 lymphatics of the, 186 muscle, atrophy of, after section of the vagi. 167 conduction of the contraction wave by, 154 rhythmicity of, 151 normal stimulus of, 151 nutrition of, 179 Heartbeat, abnormal sequence of, 152 conduction of, from auricles to ventricles, 155 effect of blood-supply on, 186 590 INDEX. Heart-beat, genesis of, 149, 150 • heat produced by, 108 rate of, 121 Heart-ijause, 122 position of, 117 pumping action of, 7S refractory period of, 156 Heart-sounds, 118 suction-pump action of, 134 tetanus of, 105 vaso-motor nerves of, 206 worli done by the, 107 Heat-dissipation, conditions affecting, 485 estimation of, 480 Heat-dyspnoea, 441, 443 expenditure of, 476 income of, 475 Heat-production, amount of, 364 by the heart, 108 conditions affecting, 482 estimation of, 481 relation of, to respiratory activity, 483 Heat-regulation, 495 source of, 474 Helico-proteid, composition of, 5711 Hemi-peptone, decomposition of, by trypsin, 303 definition of, 293 Hemorrhage, eflect of, on hematopoiesis, 46 fatal limits of, 63 regeneration of the blood after, 63 relation of, to blood-pressure, 91 saline injections after, 64 Hemorrhagic dyspnoea, 444 Hepatin, 528 Heredity, physical basis of, 28 Hexon-bases, origin of, 580 Hexoses, 562 Hibernation, effect of, on the respiratory quotient, 438 Hiccough, 455 Higher lirain centres for the heart, 178 Hippuric acid, nutritive history of, 339 Histidin, 552 Histohfematin, 44, 578 Histon, ,580 effect of, on intravascular clotting, 61 Homogentisic acid, 570 Homothermous animals, 467 Hiifner's method of urea determination, 549 Hydrfemia from saline injections, 69 Hydrsemic plethora, effect of, on lymph secre- tion, 74 Hydration, nature of the process of, 503 Hydriodic acid, 509 Hydrobilirubin, 320 Hydrobromic acid, 509 Hydrocarbons, saturated, 531 Hydrochloric acid, occurrence of, 507 of the gastric juice, 238 preparation of, 507 properties of, 508 secretion of, 2S9 tests for, 508 Hydrocumaric acid, .570 Hj'drocyanic acid, 542 Hydrofluoric acid, circulation of, in tho body, 510 Hydrogen, inhalation of, 440 occurrence of, 499 peroxide, 505 preparation of, 500 properties of, 500 Hydrolysis by enzyme action, 282 definition of, 504 of fats, 305 of proteids. 292 Hydroquinone, 569 Hypertonic solutions, physiological definition of, 69 Hypertonicity, definition of, 37 Hyperpncea, 440 from muscular activity, 442 Hypophysis cerebri, function of, 273 Hypotonicity, definition of, 37 Hyposanthin, 553 relation of, to uric acid formation, 338 Ice calorimeter, principle of, 504 Icterus, 249, 544 Idio-ventricular rhythm, 152 Imbibition of water, 504 Iiidol, 571 elimination of, 340 occurrence of, in feces, 320 Inferior larvngeal nerve, respiratory function of, 464 mesenteric ganglion, reflex activity of, 392 Inflammation, emigration of leucocytes in, 83 lufra-hyoidei muscles, 405 Infundibular body, function of, 272 Inhibition of the heart, reflex, 172 Inhibitory centre, cardiac, localization of, 176 tonus of, 176 centres, respiratory, 457 nerves of the heart, 161 of the intestines, 385 of the pancreas, 233 of tlie spleen, 333 of the stomach, 382 Innervation of the blood-vessels, 192 of the heart, 148 Inorganic salts of the blood, 50 of urine, 341 relation of, to blood coagulation, 56, 57 to the heart beat, 151, 189 Inosit, 573 Inspiration, enlargement of the thorax in, 398 muscles of, 398, 404 Inspiratory centre, 4,57 Intercostales muscles, respiratory action of, 402, 407 Intermittent pulse, 141 Internal secretion, definition of, 265 of the adrenal bodies, 272 of the kidneys, 274 of the liver, 265 of the ovaries, 274 of the pancreas, 266 of the pituitary body, 273 of the testis, 273 of the thyroids, 270 Intestinal contents, reaction of, 310 digestion, 299 juice, 243 movements, 382-385 Intestines, innervation of, 384 intrinsic nervous mechanism of, 384 largo, absorption in the, 314 pendular movements of, 384 peristiilsis of, 382 putrefactive changes in the, 310 small, absorption in the, 313 vaso-niotor nerves of, 206 Intracardiac pressure, 107, 125, 126 methods of measuring, 129, 130 Intrapulmonary pressure, 408 Intrathoracic pressure, 397, 409 Intravascular clotting, 60, 61 Intrinsic nerves of the heart, 148 Invertase, occurrence of, 308 Invertine, definition of, 280 Iodine, 509 lodothyrin, properties of, 270 Ionic theory of solutions, 67 INDEX. 591 Iron, amount of, in haemoglobin, 39 excretion of, 530 inorganic, absorption of, 529 nutritive history of, 528 occurrence of, 528 synthesis of, into haemoglobin, 529 salts, excretion of, 356 nutritive value of, 356 Irradiation of medullary centres, 201 Irrigating fluids for the isolated heart, 189, 191 Irritability of living matter, 18 Ischaemia of heart muscle, 181 Iso-butyl alcohol, 539 Iso-butyric acid, 539 Iso-dynamic equivalence of foods, 365 Isolated apex of frog's heart, 188 Isolation of the heart, 148, 191 Isomaltose, 565 Iso-pentyl alcohol, 539 Isotonic solutions, 36, 69 Isotouicity, 36, 68 Iso-valerianic acid, 539 Jaundice, 249, 544 Jecorin, 564 Kakyokinesis, 20 Katabolism, definition of, 19 Keratin, 580 Ketoses, definition of, 561 Kidneys, blood-flow through the, 255 histology of, 249 internal secretion of, 274 nerve-endings in, 251 vaso-motor nerves of, 207, 256 ^'Klopf-versuch" of Goltz, 175 Kymograph, 89 Lactalbumin, 261 Lacteal vessels, 318 Lacteals, absorption through the, 311 Lactic acid, 545 fermentation, 545 occnrrence of in the stomach, 289 Lacto-globulin, 261 Lactose, 262, 565 Laky blood, 35 Langerhans, bodies of, 232 Lanolin, 257, 575 Large intestine, digestion in the, 309 Latent heat, definition of, 504 period of cardiac accelerator nerves, 170 of heart muscle, 153 of vagus-stimulation, 162 Latham's hypothesis of the structure of pro- toplasm, 24 Laughing, 454 Lecithin, 559 amount of, in the blood, 51 occurrence of, 325 of bile, 245 of milk, 261 Leech extract, effect of, on blood coagulation, 62 lymphagogic action of, 73 Leucin, chemical properties, 540 formation of, in tryptic digestion, 303 nutritive history of 540 occurrence of, 540 Leucocytes, behavior of, in blood capillaries, 82 classification of, 47, 48 emigration of, 83 from the thymus gland, composition of, 51 functions of, 48 influence of. on blood-plasma, 49 origin of, 49 Leucocythaemia, fatty acids in, 530 purin' bases excreted in, 557 Leuconuclein, effect of, on intravascular clot- ting, 61 Levatores ani muscles, expiratory action of, 407 costarum breves, inspiratory action of, 402 Levulic acid, 538 Levulose, 562 fate of in pancreatic diabetes, 267 occurrence of, 564 oxidation of, in diabetes, 564 Lieberkiihn's crypts, histology of, 243 Liebig's method of urea determination, 549 Life, general hypothesis of, 25 Ligatures of Stannius, 178 Limbs, vaso-motor nerves of, 209 Lipase, 305 Lipochromes, 574 Liqueurs, 535 Living matter, elementary constituents of, 499 general properties of, 18 molecular structure of, 23 Liver, defensive action of, against intravascular clotting, 61 extirpation of the, 336 functions of, 320 histology of, 244, 321 internal secretion of, 265 lymph formation in, 73 nerve-endings in, 245 secretory function of, 244 nerves of, 247 urea formation in, 331 vaso-motor nerves of, 206 Loew's hypothesis of the structure of pro- toplasm, 23 Loop of Henle, 2,50 Lungs, capacity of 427 nerve-supply of 465 structure of 396 vaso-motor nerves of, 205 Lunulae of the semilunar valves. 111 Lutein, 574 Luxus consumption, 348 Lymph, 33 amount of, 146 definition of, 70 formation of, 71 gases of, 419 mechanical theory of the origin of the, 75 movement of 71, 146 pressure of, 146 secretion of, 214 Lymphagogues, action of, 73, 74 Lymphatics of the heart, 186 Lymphatic s.ystem, nature of, 145 Lymph glands, 146 Lymphoc.vtes, 48 Lysatin, .551 Lvsatinin, relation of, to urea formation, .337, .551 Lysin, ,552 Magnesium carbonate, .527 nutritive histor.v of, 527 occurrence of, .527 phosphates, .527 Jlalic acid, 558 Malpighian corpuscle of the kidney, structure of 249 Maltase, 280, 565 in starch digestion, 285 occurrence of, 308 Mammary glands, histological changes in, 262 normal secretion of, 264 secretory nerves of, 263 structure of, 261 Mauuose, 562 592 INDEX. Manometer, differential, 131 elastic, 127 maximum, 107 mercurial, 87 Marsh gas, 532 Masseter muscle, 372 Mastication, 372 " Mastzellen," relation of, to colostrum corpus- cles, 263 Meat extracts, physiological action of, 359 Meats, composition of, 278 Meconium, biliary salts in, 544 Melanins, 574 Melicyl alcohol, 540 Mercapturic acids, 547 Mercury manometer, description of, 87 Metabolism, conditions influencing, 359 definition of, 20 during sleep, 361 during starvation, 362 effect of temperature on, 362 influence of the cell-nucleus on, 22 methods of estimating, 343 Metaphosphoric acid, 514 Methane, origin of, 532 Methsemoglobin, 44, 573 Methods, physiological. 31 Methyl amido-acetic acid, 538 Methylamine, 511 Methyl mercaptan, 534 selenide, 534 tellurido, 534 violet, in testing for mineral acids, 289 Micellae, definition of, 25 Micturition, 389 centre for, 391. 393 nervous mechanism of, 392 Milk, composition of, 261 mineral constituents of, 530 normal secretion of, 264 Milk-sugar, 565 Millon's reaction for proteids, 576 nature of, 569 with phenol, 569 Mineral acids, tests for, 289 constituents, amount of, in the tissues, 530 Mitosis, 20 Molecules, physical and physiological, 25 Mononuclear leucocytes, 48 Morphin, effect of, on body-temperature, 472 Mouth, temperature in the, 469 Mucin of bile, 325 of gastric .juice, 288 of saliva, 283 physiological value of, 221 properties of, 578 secretion of, 217 Mucous glands, histology of, 216 Miiller's experiment, 452 Murexid, .555 Muscarin, 543 action of, on the h^art, 150 Muscle, digastric, 372 genio-h.yoid, 372 glycogenic function of, 330 involuntary, properties of, 370 masseter, 372 mineral constituents of, 530 mylo-hyoid, 372 obliquus externus, 407 internus, 407 pterygoid, externa], 372 internal, 372 pyramidalis, 407 temporalis, 372 transversalis abdominis, 407 trapezius, 405 Muscles, abdominales, action of, in vomitings 387 respiratory function of, 407 erectores spinae, 405 expiratory, 407 glycogen of the, 330 infrahyoidei, 405 inspiratorv, 399, 405 intercostal, 402, 407 levatores ani, 407 costarum, 402 of mastication, 372 pectorales, 405 quadrati lumborum, 399 rhomboidei, 405 scalei, 401 serrati postici, 399, 402 sterno-cleido-mastoid, 404 thermogenic function of, 490 triangulares sterni, 407 vaso-motor nerves of, 210 Muscular exercise, effect of, on metabolism, 359' on the pulse rate, 121 on the rate of respiration, 426 on the respiratory exchanges, 433 on the respiratory quotient, 438 on the sweat glands, 260 on the venous circulation, 95 Mycoderma aceti, 537 Mylo-hyoid muscle, 372 Myogenic theory oi the causation of the heart- beat, 150 Myohsematiu, 57'8 Myosin, absorption of, 315 Myxcedema, 269 Native albumins, 577 Negative pressure in the auricles, 137 in the heart, 98 in the thorax, 95 in the veins, 94 variation of the beating heart, 153 Nerve, auriculo-temporal, 218 chorda tympani, 194, 219 coronary, of the tortoise, 164 depressor, 172, 203 facial, secretory fibres of, 219 glosso-pharyngeal, secretory fibres of. 218 Jacobson's, 218 lingual, secretory fibres of, 219 small superficial petrosal, 218 vagus, cardiac branches of, 159 gastric branches of, .381 intestinal branches of, 385 pulmonary branches of, 465 respiratory functions of, 459 secretory fibres of, 232, 239 trophic influence of, on the heart, 166 Nerve-endings in the liver, 245 in the salivary glands, 220 Nerves, augmentor, of the heart, 167 cardiac, 1^8 cervical sympathetic, 193 depressor, of the heart, 172 of the bile vessels, 248 phrenic, 463 septal, of the frog's heart, 166 splanchnic, 173 trigeminal, 463 Nervi erigentes, intestinal branches of, 385 Neukomm's test for bile acids, 545 Neuridin, 543 Neurin, 543 Neurogenic theory of the causation of the heart- beat, 149 Neuro-keratin, 580 Neutral salts, effect of, on blood coagulation, 62' INDEX. 593 Neutrophiles, 47 Nicotin, action of, on intestinal movements, 384 on secretory nerves, 229 Nitric oxide, 512 hsemoglobin, 39, 512 Nitrogen equilibrium, definition of, 344, 512 history of, in the body, 512 inhalation, 440 occurrence of, 510 of the feces, 320 preparation of, 510 tension of the blood, 417 Nitrogenous equilibrium, definition of, 344, 512 excreta of milk, 262 of sweat, 259 extractives of the spleen, 333 metabolism, estimation of, 343 Nitrous oxide, inhalation of, 440 properties of, 512 Noeud vital, 456 Nucleic acid, 579 Nuclein bases, 552 composition, 55fi, 579 Nucleo-histon of the blood-plates, 49 relation of, to intravascular clotting, 61 Nueleo-proteids, classification of, 577 properties of, 579 Nucleus, functions of, 22 relation of, to oxidation, 503 Nutrition of living matter, 18 Nutritive value of albuminoids, 349 of carbohydrates, 353 of fats, 350 of proteids, 276, 345 of salts, 354 of water, 354 Obliquus externus, respiratory action of, 407 internus, respiratory action of, 407 Occlusion of the bile-duct, efiect of, 249 (Edema, 148 (Esophagus, deglutition in the, 374 Oils, effect of, on gastric secretion, 241 on pancreatic secretion, 236 Oleflnes, 542 Oleic acid, 541-560 Oncometer, 255 Oophorin tablets, action of, 274 Opening of the chest, effect of, on heart, 115 Opium, effect of, on respiratory rhythm, 425 " Organeiweiss," 346 Ornithin, 552 Ortbophosphoric acid, 514 Osazones of glycoses, 562 Osmosis, definition of, 65 relation of, to secretion, 213 Osmotic pressure, definition of, 65 method of determining, 67, 68 relation of, to concentration, 66 Osones, preparation of, 562 Osteomalacia, 524, .525 ovariotomy in, 274 Osteoporosis, 525 Ovariotomy, effects of, 274 Ovaries, internal secretion of, 274 Oxalate solutions, effect of, on blood coagula- tion, 63 Oxalic acid, 557 Oxaluric acid, 555 Oxidases, 281 Oxidation, 501 physiological, Hoppe-Seyler's theory of, 505 Traube's tlieory of 502 Oxidizing enzymes, 280 Oxy butyric acid, 548 Oxycholin, 543 Oxygen, alveolar tension of, 413 38 Oxygen, occurrence of, 500 preparation of, 501 properties of, 501 tension in the blood, 415 respiratory effects of, varying, 440 Oxygen-absorption, coeflicien't of, 415 conditions affecting, 429 cutaneous, 422 estimation of, 428 Oxygen-dyspnoea, 444 Oxyhaemoglobin, composition of, 38 dissociation of, 415, 501 Oxyntic cells of gastric glands, 237 Oxyphenyl-acetic acid, 570 Oxyphenyl-amido-propionic acid, 570 Oxypliiles, 47 Ozone inhalation, 440 preparation of, 502 properties of, 502 Palmitic acid, 541 Pancreas, anatomy of, 231 extirpation of, 266 grafting of, 267 histology of, 231 innervation of, 232 internal secretion of, 266 mineral constituents of, 530 secretory changes in, 233 vaso-motor nerves of, 207 Pancreatic diabetes, 267, 353, 563 fistulse, preparation of, 300 juice, amylolytic action of, 305 artificial, 301 collection of, 300 composition of, 232, 299 fat-splitting power of, 305 secretion, composition of, 232, 299 histological changes during, 233 nervous mechanism of, 232 normal mechanism of, 235 reflex character of, 236 relation of, to the character of the food, 237 Papain, 280 Papillary muscles, 110 Parabamic acid, 555 Paracasein, 296 Paraffins, 531 Paraformic aldehyde, 533 Paraglobulin, amount of, in the blood, 53 composition of, 53 functions of, 53 origin of, 53 properties of, 53 Paralytic secretion, 229 Parapeptone, definition of, 292 Paranuclein, 579 Parathyroids, anatomy of, 268 function of, 269 Parotid gland, anatomy of, 217 innervation of, 218 P^te de foie gras, 560 Pause, compensatory, of the heart, 156 Pauses, respiratory, 424 Pectoral muscles, respiratory action of, 405 Pendular movements of the intestines, 384 Pentamethylene-diamin, 543 Pentoses, 562 Pepsin, 237, 238 effect of, on blood coagulation, 63 preparation of, 291 properties of, 290 Pepsin-hydrochloric acid, action of, 292 Pepsinogen granules, 242 Peptic digestion, 292, 294 Pepton-injection, efiect of, on lymph formation, 73 594 INDEX. Pepton-injection, toxicity of, 316 Peptones, absorption of, in the stomach, .313 definition of, 292, 295 effect of, on blood coagulation, 62 properties of, 294, 577 Perfusion cannula, 187 Peripheral reflex centres, 178 Peristalsis, definition of, 372 intestinal, 382 of the stomach, 379 of the ureters, 389 Permeability of the capillary walls, 70 Peroxide of hydrogen, 505 Pettenliofer's reaction for bile acids, 324, 544 Pexinogen granules, 242 Pfliiger's hypothesis of the structure of proto- plasm, 23 Phagocytosis, 48 Pharynx, deglutition in the, 373 Phenaceturic acid, 569 Phenol, 569 elimination of, 340 Phenyl-acetic acid, 569 Phloridziu diabetes, 563 Phosphates, 514 Phosphoric acid, salts of, 514 Piiosphorus, nutritive history of, 515 occurrence of, 513 peroxide, 514 poisoning, 513 preparation of, 513 properties of, 513 Phrenic nerves, 463 Physical molecules, definition of, 25 Physiological division of labor, 22 molecules, 25 salt solution in transfusions, 64 Physiology, definition of, 17 human, definition of, 30 methods employed in, 30 subdivisions of, 17, 29 Pigments, biliary, 45, 245, 322, 530, 574 blood-, .37, 44, 573 Pilocarpin, action of, on salivary glands, 229 on sweat-glands, 260 Pilomotor mechanism, relation of, to thermo- lysis, 494 Pituitary body, anatomy of, 272 functions of, 273 internal secretion of, 273 extracts, action of, 272 Plain muscle, histology of, 369 physiology of, 370 tone of, 371 Plant-cells, assimilation in, 18 Plasma of blood, 33, 50 oxygen absorption-coefficient of, 416 Plastic food-stufl's, definition of, 346 Plethysmograph, 196 Pneumatic cabinet, 453 Pneumogastric nerve (see Vagus), pulmonary branches of, 465 respiratory function of, 459, 460 Pneumograph, 423 Poikilothermous animals, 467 Polynucleated leucocytes, 48 Polypncea, 441 Portal vein, vaso-motor nerves of, 209 Positive variation of the heart during vagus stimulation, 164 Post-mortem rise of temperature, 497 Potassium carbonates, nutritive history of, 520 chlorides, nutritive history of, 519 cyanide, 542 occurrence of, 519 phosphates, nutritive liistory of, 520 relation of, to heart muscle, 151 Potassium salts, toxicity of, 520 sulphocyauide, detection of, 2.S4 occurrence of, 283, 542 of the urine, 507 thiocyanide, 542 Potential energy of food, 364 Pressor nerves, 202 Pressure, intracardiac, 107 intrathoracic, 396, 409 intraventricular, 125 of the lymph, 146 Propeptones, definition of, 292 Propionic acid, 538 Propyl alcohol, 536, 538 Protagon, 559 Protamine, nature and origin of, 24 Protamins, properties of, 580 Proteid, affinity of cell substance for, 568 circulating, definition of, 346 metabolism during starvation, 363 etTect of muscular work on, 360 end-products of, 337 Proteid-absorption, mechanism of, 316 Proteids, absorption of, 315 classification of, 576 color reactions of, 576 combined, classification of, 579 combustion equivalent of, 365 diffusion of, 70 dynamic value of, 475 effect of, on glycogen formation, 328 gastric digestion of, 292 general reactions of, 575 general significance of, 24 living, theoretical structure of, 23, 24 molecular structure of, 581 nutritive value of, 276, 345 of milk, 261 of the blood, 49, 50 origin of fat from, 351 osmotic pressure of, 69 putrefaction of, in the intestines, 310 rapidity of oxidation of, 347 simple, classification of, 576 substitutes for, in the diet, 348 synthesis of, 518, 582 tryptic digestion of, 303 vegetable, 577 Proteose injection, effects of, 316 Proteoses, definition of, 292 properties of, f>77 Proteolysis, 293 tryptic, 303 value of, 315 Proteolytic enzymes, definition of, 280 Protoplasm, 17, 499 Prothrombin, .58 Pseudo-mucoid, 578 Pterygoid muscles, 372 Ptomaines, chemical structure of, 542 Ptyalin, 221, 280 action of, 284, 286, 566 occurrence of, 284 Pulmonary circulation, 78, 103 innervation of, 205 ventilation, forces concerned in, 413 Pulse, arterial, cause of, 93 celerity of, 142 definition of, 139 dicrotic wave of, 143 extinction of, 94 frequency of, 121, 141 regularity of, 141 respiratory variations in the rate of, 451 size of, 141 tension of, 141 I transmission of, 140 INDEX. 595 Pulse, relation of, to body-temperature 471 respiratory, 96 ' Pulse-curve, 142 Pulse-rate, diurnal variations of, 121 Pulse-volume of the heart, definition of, 105 Purin, 553 bases, 552 in leucocythEBmia, 557 Putrefaction, intestinal, products of, 310 Putrescin, 543 Pyin, 579 Pyramidalis muscle, expiratory action of, 407 Pyridiu, 571 Pyrocatechin, 569 QuADRATi lumborum, respiratory action of, 399 Quinine hydrochlorate, action of, on salivary glands, 222 Eakbfied air, respiration of, 452 Eate of conduction in heart muscle, 154 of heart-beat, variations of, 121 of progress of the food in the intestines, 314 of respiratory movements, 425 of transmission of the pulse, 140 Reaction, iniluence of, on action of ptyalin, 286 of bile, 322 of blood, 34 of gastric juice, 288 of intestinal contents, 310 of pancreatic juice, 232, 300 of succus entericus, 308 of sweat, 342 of urine, 250, 334 Rectus abdominis, expiratory action of, 407 Red corpuscles, behavior of, in the capillaries, 81 color of, 35 composition of, 51 disintegration of, 45 form of, 35 function of, 35 number of, 35 origin of, 45, 46, 333 size of, 35 structure of, 35 variations in the number of, 46 Reduction, 502 processes in the animal body, 536 Reflex acceleration of the heart, 177 coughs, 455 discharge of bile, 248 inhibition of the heart, 172 secretion of gastric j nice, 239 of pancreatic juice, 236 of saliva, 230 vaso-motor changes, 202 Reflexes through sympathetic ganglia, vaso- motor, 200 Refractory period of the heart, 156, 158 Regeneration of blood after hemorrhage, 63 Eennin, 238 action of, on milk, 296 occurrence of, in gastric juice, 295 of the kidneys, 274 preparation of, 295 Reproduction of living matter, 18, 20 Reproductive organs, vaso-motor nerves of, 208 Residual air, definition of, 427 Respiration, artificial, 446 associated movements of, 408 cutaneous, 422 definition of, 395 heat dissipated in, 488 intensity of, 429 internal, 422 nervous mechanism of, 455 rhythm of, 423 Respiratory activity, conditions affecting, 429 centres, 455 aiferent nerves to, 459 conditions influencing the, 458 foetal, 464 rhythmicity of, 458 food-stufis, definition of, 346 movements, circulatory efi'ects of, 447 duration of, 424 efl'ect of, on blood-pressure, 448 on venous circulation, 95, 96 frequency of, 425 special, 453 nerves, afferent, 460 efferent, 463 pauses, 424 pressure, 408 quotient, 410 during hibernation, 434 relation of, to the diet, 353 variations of, 437 sounds, 409 Resuscitation from drowning, 445 Eete mirabile of the Malpighian corpuscles, 249 Ehamnose, 562 Eheometer, 99 Ehomhoideus muscles, respiratory action of, 405 Ehythm of the respiratory movements, 423 Ehythmic activity of the vaso-constrictor cen- tre, 201 Rhythmicity of the heart, abnormal, 152 cause of, 148 Ribs, respiratory movements of, 400 Rickets, 356, 525 Right lymphatic duct, 145 .Ringer's solution for the heart, 190 Eivinus, ducts of, 217 Roy's tonometer, 188 Saccharose, 564 Saliva, composition of, 220, 283 mineral constituents of, 530 properties of, 220, 283 uses of, 286 Salivary corpuscles, 283 glands, 215 anatomy of, 217 histology of, 219 histological changes in, 226 nerves of, 218, 221 vaso-motor nerves of, 222 secretion, action of drugs on, 229 normal mechanism of, 230 Salkowski's reaction for cholesterin, 575 Salmin, 580 Salt-licks, 355 Salt solution, physiological, injection of, 64 Salts, absorption of, 318 lymphagogic action of, 73 nutritive value of, 276, 354 Saponification of fats, 306, 558 Saprin, 543 Sarcin, 553 Sarco-lactic acid, 546 Sarcosin, 538 Scaleni muscles, inspiratory action of, 401 Scombrin, 580 Sebaceous glands, structure of, 257 secretion, composition of, 342 function of, 258 physiological value of 342 Sebum, composition of, 257 Secreting glands, electrical changes in, 231 histological changes in, 226 Secretion, antilytic, 230 biliary, 248 capillaries of the gastric glands, 238 596 INDEX. Secretion, defiuition of, 211 gastric, 240 histological changes during, 226 internal, definition of, 211 intestinal, 243 mammary, 264 mechanism of, 213 pancreatic, 235 paralytic, 229 psychical, of gastric juice, 239 relation of, to intensity of stimulus, 223 salivary, 230 sebaceous, 257, 342 sweat, 259 urinary, 251 Secretions, general characteristics of, 213 Secretogogues for the gastric glands, 359 Secretory centre, salivary, 230 fibres proper, definition of, 224 nerves, evidence for, 222 mode of action of, 225 of the adrenal bodies, 272 of the kidneys, 251 of the liver, 247 of the mammary glands, 263 of the pancreas, 232 of the stomach, 239 of the sweat glands, 259 salivary, endings of, 220 significance of, 214 stimulation of, 222 Semilunar valves, 110 Sensory nerves, influence of, on respiration, 463 of the heart, 172 relation of, to the respiratory centre, 459 reflex influence of, on the pulse-rate, 175 Septal nerves of the frog's heart, 166 Serous cavities, 146 Serrati postici inferiores, respiratory function of, 399 supenores, inspiratory action of, 402 Serum, bactericidal action of, 36 globulicidal action of, 36 osmotic pressure of, 68 toxicity of, 36 Serum-albumin, action of, on carbonates, 517 amount of, in the blood, 52 composition of, 52 functions of, 52 properties of, 52 Sex, influence of, on heat production, 482 on pulse-rate, 121 on respiration, 430 relation of body-temperature to, 470 Shivering, 362, 491 Silicic acid, properties of, 519 Silicon, 519 Simple proteids, .576 Sinuses of Valsalva, 111 Size, influence of, on pulse-rate, 121 Skatol, 572 elimination of, 340 occurrence of, in feces, 320 Skin, functions of, 341 glands of, 257 Sleep, effect of, on metabolism. 361 on the respiratory quotient, 438 on respiration, 424 Smegma prseputii, 257 Sneezing, 4.54 Snoring, 455 Sobbing, 454 Sodium ammonium phosphate, 523 carbonates, 522, 523 chloride, nutritive history of, 521 phosphates, 522 sulphate, 522 Special respiratory movements, 453 Specialization of function, 21 Specific gravity of blood, 34 of blood-corpuscles, 34, 35 of urine, 251 heat, definition of, 477 of the human bodj', 504 Spectroscope, 40 Spectrum, definition of 40 of CO-haemoglobin, 44 of haemoglobin, 42 of oxyhaemoglobin, 41 solar, 41 Spermaceti, 540 Spermin, physiological action of, 273 Sphincter antri pyloric!, 377 pylori, 377, 381 urethrse, 390 vesicae iuternus, 390 Sphincters ani, 386 Sphygmogram, 143 Sphygmograph, 142 Sphygmomanometer, 141 Sphygmometer, 141 Spinal centres for vaso-motor nerves, 199 Spirometer, 427 Splanchnic nerves, gastric fibres of, 3S2 influence of, on blood-pressure, 173 on respiration, 463 intestinal fibres of, 385 stimulation of, 173 Spleen, composition of, 333 function of, 322 innervation of, 333 movements of, .322 vaso-motor uerves of, 207 Staimius's ligatures, 178 Starch, 566 digestion of, 284, 305 hydrolysis of, by acids, 286 by amylolytic ferments, 285 Starvation, efl'ect of, on metabolism, 362 glycogen disappearance during, 331 nutrition during, 350 phosphorus excretion in, 516 potassium excretion in, 520 Steapsin, 232, 280 demonstration of, 306 occurrence of, 305 Stearic acid, 541 Stensoii's duet, 217 Stereo rin, .575 Sterno-cleido-mastoid muscles, respiratory ac- tion of, 404 Sternum, respiratory movements of, 401 Stethograph, 423 Stimulants of the sweat glands, 260 physiological action of, 357 Stimuli, artificial, effect of, on the heart, 156 Stokes's reagent, composition of, 43 Stomach, absorption in, 312 extirpation of, 299 glands of, 237 immunity of, to its own secretion, 297 innervation of, 381 movements of. 377, 378 musculature of, 377 Stromuhr of Ludwig, 99 Strontium, 526 Strychnine, effect of, on body-temperature, 472 Sturin, -580 Sublingual gland, anatomy of, 217 Submaxillary gland, anatomy of, 217 Succinic acid, .5.57 Succus eutericus, 243 action of, on carbohydrates, 309 collection of, 308 INDEX. 597 Succus entericus, digestive action of, 308 ferments of, 308 Suction action of the heart, 134 Sudorific drugs, 260 Sufibcation (see Asphyxia). Sugar injections, lymphagogic action of, 73 Sugars, absorption of, 313, 317 consumption of, by the tissues, 353 efi'ect of, on glycogen formation, 328 synthesis of, 533 Sulphates of the urine, estimation of, 506 origin of, 506 Sulph-haemoglobin, 506 Sulphur, elimination of, 340 metabolism of, 507 ' neutral, 506 occurrence of, 505 Sulphuretted hydrogen, inhalation of, 440 properties of, 506 Sulphuric acid, 506 Sulphurous acid, 506 Superior laryngeal nerves, influence of, on res- piration, 459, 462 Supplemental air, definition of, 427 Suprarenal capsules, extirpation of, 271 Swallowing, 375 Sweat, amount of, 258, 342 composition of, 259, 342 nitrogenous constituents of, 512 Sweat-centres, spinal, 261 Sweat-glands, secretory nerves of, 259 stimulation of. 260 structure of, 258 Sweat-nerves, 259 Sweat-secretion, action of drugs on, 260 Sympathetic nerves, cardiac, 168, 171 pulmonary, 466 reflex influence of, on the pulse-rate, 175 secretory fibres to the pancreas, 232 to the salivary glands, 218, 222 vaso-motor centres, 200 Synthesis of proteids, 518, 582 of sugars, 563 Synthetic processes of plants, 518 Syntonin, absorption of, 315 occurrence of, in peptic digestion, 292 Systole, auricular, 124, 136 ventricular, 123 Taetae, 524 Taurin, 507, 543 Tea, nutritive value of, 357 Temperature, axillary, 468 body-, efi'ect of, on respiratory activity, 432 influence of drugs on, 472 lowering of, 472 variations of, 469 effect of, on enzymes, 281 on heat dissipation, 487 on metabolism, 362 on sweat glands, 260 on the respiratory quotient, 438 on tryptic digestion, 301 external, effect of, on respiration, 426 on respiratory exchanges, 432 on thermotaxis, 496 influence of, on heat production, 483 on ptyalin, 286 of animals, 467 of respired air, 410 post-mortem rise of, 497 regulation of, 473 topography of, 468 Temporal muscle, 372 Tension of the blood-gases, 415 Testicular extracts, action of, 273 Testis, internal secretion of, 273 Tetanus of the heart, 165 Tetramethylene-diamin, 543 Theobromin, 553 Theophyllin, 553 Thermo-accelerator centres, 492 Tliermogenesis, 477 mechanism of, 489 Thermogenic centres, 491 nerves, 490 tissues, 490 Thermo-inhibitory centres, 492 Thermolysis, 485 mechanism of, 494 Thermotaxis, 489, 495, 496 Thiolactic acid, 547 Thiry-Vella fistula, 308 Thoracic duct, 145 Thorax, efiects of opening the, 115 movements of, in respiration, 397 negative pressure in the, 396 Thrombin, 58, 280 Thrombus, 60 Thymic acid, 579 Thyroglobulin, 509 Thyroidectomy, 269 Thyroid extract, injection of, 269, 270 Thyroids, anatomy of, 267 extirpation of, 268 functions of, 268 grafting of, 269 internal secretion of, 270 Thyroiodine, 509 Tidal air, volume of, 426 Time of a complete circulation, 79 Tinctures, definition of, 535 Tissue-proteid, definition of, 346 Tissue-respiration, 422 Tongue, vaso-motor nerves of, 204 Tonicity of involuntary muscle, 371 of vaso-constrictor centre, 199 Tonograph, definition of, 127 Tonometer, 188 Tonus, ventricular, during vagus stimulation, 163 Transfusion of blood, 64 Transversalis abdominis muscle, respiratory action of, 407 Trapezius muscle, respiratory action of, 405 Traube-Hering waves, 201 Triangulares sterni muscles, expiratory action of, 407 Trigeminal nerves, influence of, on respiration, 463 Trimethylamine, 541 Trioses, 559 Trommer's test for carbohydrates, 562 Tropaeolin 00 test for mineral acid, 289 Trophic influence of the vagi on the heart, 167 nerves of the salivary glands, 224 pulmonary, 466 Trypsin, 232 effect of, on blood coagulation, 63 extracts, preparation of, 301 /*♦. properties of, 301 Trypsinogen, 235 granules, 235 Tryptic digestion, products of, 302 value of, 304 Tryptophan, 574 Tubules, urmiferous, 250 Tunicin, 566 Tyrosin, 570 formation of, in tryptic digestion, 303 Units, calorimetric, 477 Unorganized ferments, definition of, 279 Urea, amount of, in sweat, 335 598 INDEX. Urea, amount of, in the blood, 51 in the urine, 335 antecedents of, 335 elimination of, 252 estimation of, 549 formation of, after removal of the liver. 337 in. the liver, 331 origin of, in the body, 550 in the liver, 266 preparation of, 548 from proteid, 337 presence of, in sweat, 342 properties of, 549 Ureters, movements of, 371, 389 Uric acid, formation of, 338 in the liver, 322 in the spleen, 333 molecular structure of, 554 occurrence of, 338 origin of, in birds, 5.jT in mammals, 338, 556 preparation of, 555 properties of, 555 Urinary bladder, innervation of, 392 movements of, 390 pigments, origin of, from haemoglobin, 45 secretion, normal stimulus for, 255 relation of, to the blood-flovr through the kidney, 253 Urine, aciditj' of, after meals, 290 composition of, 250, 334 ethereal sulphates of, 572 secretion of, 251 Uriniferous tubules, secretory function of, 252 structure of, 250 Urobilin, 574 Vagus, anabolic action of, on the heart, 166 anatomy of, in the dog, 159 cardiac branches of, 159 effect on the heart, nature of, 166 gastric branches of, 381 inhibition, dependence of, on the character of the stimulus, 165 intestinal branches of, 385 nerves, pulmonary branches of, 465 relation of, to apncea, 442 respiratory function of, 459 pneumonia, 466 secretory fibres of, to the pancreas, 232 to the stomach, 239 stimulation, auricular effects of, 164 effect of, on the heart, 152, 163 on the ventricle, 162 latent period of, 162 Valsalva's experiment, 452 sinuses, 111 Valves, auriculo-ventricular, 108 of lymphatic vessels, 146 semilunar, 110 Valvulas conuiventes, value of, in absorption, 314 Vaseline, 531 Vaso-constrictor centre, rhythmical activity of, 201, 451 nerves, discovery of, 193 Vasodilator nerves, discovery of, 194 Vaso-motor centre, medullary, 198 centres, spinal, 199 sympathetic, 200 nerves, anatomy of, 198 methods of investigating, 195 of the brain, 203 of the generative organs, 208 of the head, 204 of the heart, 206 of the intestines, 206 Vaso-motor nerves of the kidney, 207, 256 of the limbs, 209 of the liver, 206 of the lungs, 205, 466 of the muscles, 210 of the pancreas, 207 of the portal system, 209 of the salivary glands, 222 of the spleen, 207 of the tongue, 205 of the veins, 195 special properties of, 197 reflexes, 201 through the vagi, 172 Vegetable foods, composition of, 278 proteids, 577 Veins, effect of compression of, on lymph forma- tion. 72 entrance of air into, 97 rate of flow in, 101 vaso-motor nerves of, 209 A'elocity of blood-flow, 90, 100, 101 Vense Thebesii, 184 Veno-motor nerves of the limbs, 209 Venous blood-flow, effect of the auricles on, 137 circulation, 95, 96 pressure, 91, 94 . pulse, respiratory, 96 Ventilation, principles of, 439 Ventricles, independent rhythm of, 152 work done by, 106, 107 Ventricular cycle, analysis of, 133 diastole, duration of, 123 pressure-curves, analysis of, 128 pressures, 125 systole, duration of, 123 Vernix caseosa, 258 Vessels of Thebesins, 186 Villus, intestinal, structure of, 318 Viscero-motor nerves to the intestines, 385 Viscosity of irrigating media for the heart, 191 Visual purple, .575 Vital capacity of the lungs, 427 force, definition of, 25 Vitellin, composition of, 579 Voluntary control of the heart, 178 Vomiting, 387 causes of, 388 centre for, 389 nervous mechanism of, 388 Wandering cells, definition of, 48 Water, absorption of, 313, 318 amount lost through the lungs, 410 distribution of, 503 effect of, on pancreatic secretion, 236 elimination of, 340 imbibition of, 504 latent heat of, 504 nutritive value of, 276, 354 properties of, 503 Wharton's duct, 217 William's frog-heart apparatus,188 valve, 187 Wines, 535 Wirsung's duct, 231 Work done by the heart ventricles, 106, 107 Xanthin. .553 physiological significance of, 339 Xantho-proteid reaction, 576 Xylose, 562 Yawning, 454 Zymogen granules, definition of, 228 of the pancreas, 235 CATALOGUE OF THE MEDICAL PUBLICATIONS OF W. 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" If this text-book is a fair reflex of the present position of American surgery, we must admit it is of a very high order of merit, and that English surgeons will have to look very carefully to their laurels if they are to preserve a position in the van of surgical practice."— London Lancet. AN AMERICAN TEXT=BOOK OF THE THEORY AND PRACTICE OF MEDICINE. By 12 Distinguished American Practitioners. Edited by William Pepper, M.D., LL.D., Professor of the Theory and Practice of Medi- cine and of Clinical Medicine in the University of Pennsylvania. Two handsome imperial octavo volumes of about 1000 pages each. Illus- trated. Prices per volume : Cloth, ^5 . 00 net ; Sheep or Half Morocco, ^6.00 net. Sold by Subscription. " I am quite sure it will commend itself both to practitioners and students of medicine, and become one of our most popular text-books."-ALFRED LooMis M D. LL D., Pro- fessor of Pathology and Practice of Medicine, University 0/ the City of New york. '• We reviewed the first volume of this work, and said : < It is undoubtedly one of the best text-books on the practice of medicine which we possess.' A consideration of the second and last volume leads us to modify that verdict and to say that the cornpleted work U in our opinion the best of its kind it has ever been our fortune to see. "-iV«o York Medical Jmrnal. ., IDttstrated Catalogae of the "American Text-Boofcs" sent free upon applfcation. 8 Medical Publications of W. B. Saunders & Co. AN AMERICAN YEAR-BOOK OF MEDICINE AND SURGERY. A Yearly Digest of Scientific Progress and Authoritative Opinion in all branches of Medicine and Surgery, drawn from journals, monographs, and text-books of the leading American and Foreign authors and investigators. Arranged with critical editorial comments, by eminent American specialists, under the general editorial charge of George M. Gould, M.D. Volumes for 1896, '97, '98, and '99. One imperial octavo volume of about 1200 pages. Cloth, ^6.50 net; Half Morocco, ^7.50 net. Year-Book of 1900 in two volumes — Vol. I., including General Medicine; Vol. II., General Surgery. Prices per volume: Cloth, ^3.00 net; Half Morocco, I3.7S net. Sold by Subscription. " It is difficult to Icnow whicli to admire most — the researcli and industiy of the distin- guished band of experts whom Dr. Gould has enlisted in the service of the Year-Book, or the wealth and abundance of the contributions 10 every department of science that have been deemed worthy of analysis. ... It is much more than a mere compilation of abstracts, for, as each section is entrusted to experienced and able contributors, the reader has the advant- age of certain critical commentaries and expositions . . proceeding from writers fully qualified to perform these tasks. . It is emphatically a book which should find a place in every medical library, and is in several respects more nseful than the famous ' Jahrbiicher ' of Germany." — London Lancet. ABBOTT ON TRANSMISSIBLE DISEASES. The Hygiene of Transmissible Diseases ; their Causation, Modes of Dissemination, and Methods of Prevention. By A. C. Abbott, M.D., Professor of Hygiene and Bacteriology, University of Pennsylvania ; Director of the Laboratory of Hygiene. Octavo volume of 311 pages, containing a number of charts and maps, and numerous illustrations. Cloth, J2.00 net. THE AMERICAN POCKET MEDICAL DICTIONARY. [See Borland's Pocket Dictionary, page 12. J ANDERS* PRACTICE OF MEDICINE. Third Revised Edition. A Text-Book of the Practice of Medicine. By James M. Anders, M.D., Ph.D., LL.D., Professor of the Practice of Medicine and of Clinical Medicine, Medico-Chirurgical College, Philadelphia. In one handsome octavo volume of 1292 pages, fully illustrated. Cloth, ^^5.50 net; Sheep or Half Morocco, ^6.50 net. " It is an excellent book, — concise, comprehensive, thorough, and up to date. It is a credit to you ; but, more than that, it is a credit to the profession of Philadelphia— to us." James C. Wilson, Professor of the Practice of Medicine and Clinical Medicine, TefTerson Medical College, Philadelphia. "^ ^ ASHTON'S OBSTETRICS. Fourth Edition, Revised. Essentials of Obstetrics. By W. Easterly Ashton, M.D., Pro- fessor of Gynecology in the Medico-Chirurgical College, Philadelphia. Crown octavo, 252 pages; 75 illustrations. Cloth, gi.oo net; inter- leaved for notes, $1.25 net. [See Sounders' Question- Compends, page 23.] " Embodies the whole subject in a nut-shell. We cordially recommend it to our read- ers." — Chicago Medical Times. Medical Publications of W. B. Saunders & Co. 9 BALL'S BACTERIOLOGY. Third Edition, Revised. Essentials of Bacteriology ; a Concise and Systenaatic Introduction to the Study of Micro-organisms. By M. V. 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Fractures. By Carl Beck, M.D., Surgeon to St. Mark's Hospital and the New York German Poliklinik, etc. 225 pages, 170 illustrations. Cloth, $ net. BECK'S SURGICAL ASEPSIS. A Manual of Surgical Asepsis. By Carl Beck, M.D., Surgeon to St. Mark's Hospital and the New York German Poliklinik, etc. 306 pages; 65 text-illustrations, and 1 2 full- page plates. Cloth, ^1.25 net. " An excellent exposition of the ' very latest ' in the treatment of wounds as practised by leading German and American surgeons." — Birmingham (Eng.) Medical Review. " This little volume can be recommended to any who are desirous of learning the details of asepsis in surgery, for it will serve as a trustworthy guide." — London Lancet. BOISLINIERE'S OBSTETRIC ACCIDENTS, EMERGENCIES, AND OPERATIONS, Obstetric Accidents, Emergencies, and Operations. By L. Ch. BoiSLiNiERE, M.D., late Emeritus Professor of Obstetrics, St. Louis Medical College. 381 pages, handsomely illustrated. Cloth, ^2.00 net. 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A Text-Book of Materia Medica, Therapeutics, and Pharma- cology. By George F. Butler, Ph.G., M.D., Professor of Materia Medica and of Clinical Medicine in the College of Physicians and Surgeons, Chicago; Professor of Materia Medica and Therapeutics, Northwestern University, Woman's Medical School, etc. Octavo, 874 pages, illustrated. Cloth, ^^4. 00 net ; Sheep, ^5.00 net. " Taken as a whole, the book may fairly be considered as one of the most satisfactory of any single-volume works on materia medica in the market." — Journal of tJte American I Medical Association. CERNA ON THE NEWER REMEDIES. Second Edition, Revised- Notes on the Newer Remedies, their Therapeutic Applications and Modes of Administration. By David Cerna, M.D., Ph.D., formerly Demonstrator of and Lecturer on Experimental Therapeutics in the University of Pennsylvania ; Demonstrator of Physiology in the Medical Department of the University of Texas. Rewritten and greatly enlarged. Post-octavo, 253 pages. Cloth, gi. 00 net. " The appearance of this new edition of Dr. Cerna's very valuable work shows that it is properly appreciated. The book ought to be in the por.session of every practising physi- cian." — New York Medical Journal. CHAPIN ON INSANITY. A Compendium of Insanity. By John B. Chapin, M.D., LL.D., Physician-in-Chief, Pennsylvania Hospital for the Insane ; late Physi- cian-Superintendent of the Willard State Hospital, New York ; Hon- orary Member of the Medico-Psychological Society of Great Britain, of the Society of Mental Medicine of Belgium. 1 2mo, 234 pages, illustrated. Cloth, ^1.25 net. " The practical parts of Dr. Chapin's book are what constitute its distinctive merit. We desire especially to call attention to the fact that on the subject of therapeutics of insanity the work is exceedingly valuable. 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Y. ; Chief of Clinic, Nervous Dept., College of Physicians and Surgeons, N. Y. Handsome octavo volume of 843 pages, profusely illustrated. Cloth, I5.00 net; Half Morocco, ^6.00 net. Medical Publications of W. B. Saunders & Co. 11 CLARKSON'S HISTOLOGY. A Text-Book of Histology, Descriptive and Practical. By Arthur Clarkson, M.B., CM. Edin., formerly Demonstrator of Physiology in the Owen's College, Manchester; late Demonstrator of Physiology in Yorkshire College, Leeds. Large octavo, 554 pages; 22 engravings in the text, and 174 beautifully colored original illustra- tions. Cloth, strongly bound, ^4.00 net. " The work must be considered a valuable addition to the list of available text-books, and IS to be highly recommended." — New York Medical Journal. "This is one of the best viorks for students we have ever noticed. We predict that the book will attain a well-deserved popularity among our siaAents."— Chicago Medical Recorder. CLIMATOLOGY. Transactions of the Eighth Annual Meeting of the American Climatological Association, held in Washington, September 22-25, 1891. Forming a handsome octavo volume of 276 pages, uniform with remainder of series. (A limited quantity only.) Cloth, ^1.50. COHEN AND ESHNER'S DIAGNOSIS. Second Edition, Revised. Essentials of Diagnosis. By Solomon Solis-Cohen, M.D., Pro- fessor of Clinical Medicine and Applied Therapeutics in the Philadel- phia Polyclinic ; and Augustus A. Eshner, M.D., Professor of Clinical Medicine in the Philadelphia Polyclinic. Post-octavo, 417 pages; 55 illustrations. Cloth, ^i.oo net. [See Saunders' Question- Compends, page 23.] "We can heartily commend the book to all those who contemplate purchasing a 'com- pend.' It is modern and complete, and will give more satisfaction than many other works which are perhaps too prolix as well as behind the times." — Medical Review, St. Louis. CORWIN'S PHYSICAL DIAGNOSIS. Third Edition, Revised. Essentials of Physical Diagnosis of the Thorax. By Arthur M. CoRWiN, A.M., M.D., Demonstrator of Physical Diagnosis in Rush Medical College, Chicago ; Attending Physician to Central Free Dis- pensary, Department of Rhinology, Laryngology, and Diseases of the Chest, Chicago. 219 pages, illustrated. Cloth, flexible covers, 1 1 . 2 5 net. " It is excellent. The student who shall use it as his guide to the careful study of physical exploration upon normal and abnormal subjects can scarcely fail to acquire a good working knowledge of the subject." — Philadelphia Polyclinic. "A most excellent little work. It brightens the memory of the differential diagnostic signs, and it arranges orderly and in sequence the various objective phenomena to logical solution of a careful diagnosis. "—/o«r«a/ 0/ Nervous and Mental Diseases. CRAGIN'S GYNAECOLOGY. Fourth Edition, Revised. Essentials of Gynascology. By Edwin B. Cragin, M. D., Lecturer in Obstetrics, College of Physicians and Surgeons, New York. Crown octavo, 200 pages; 62 illustrations. Cloth, ;^i.oo net; interleaved for notes, $1.25 net. [See Saunders' Question- Compends, page 23.] « A handy volume, and a distinct improvement on students' compends in general. No author tho"^ not himself a practical gynecologist c6uld have consulted the student's needs so thoroughly as Dr. Cragin has ion^r -Medical Record, New York. 12 Meaical Publications of W. B. Saunders & Co. CROOKSHANK'S BACTERIOLOGY. Fourth Edition, Revised. A Text-Bool< of Bacteriology. By Edgar M. Crookshank, M.B., Professor of Comparative Pathology and Bacteriology, King's College, London. Octavo volume of 700 pages, with 273 engravings and 22 original colored plates. Cloth, ^6.50 net ; Half Morocco, I7. 50 net. " To the student who wishes to obtain a good resumi of what has been done in bacteri- ology, or who wishes an accurate account of the various methods of research, the book may be recommended with confidence that he will find there what he requires. " — London Lancet. Da COSTA'S SURGERY. Second Ed., Revised and Greatly Enlarged. Modern Surgery, General and Operative. By John Chalmers DaCosta, M. D. , Professor of Practice of Surgery and Clinical Surgery, Jefferson Medical College, Philadelphia ; Surgeon to the Philadelphia Hospital, etc. Handsome octavo volume of 911 pages, profusely illus- trated. Cloth, ^4.00 net; Half Morocco, ^5.00 net. "We know of no small work on surgery in the English language which so well fulfils the requirements of the modern student." — Medico-Chirurgical Journal^ Bristol, England. DE SCHWEINITZ ON DISEASES OF THE EYE. Third Edition, Revised. Diseases of the Eye. A Handbook of Ophthalmic Practice. By G. E. DE ScHWEiNiTZ, M.D., Professor of Ophthalmology in the Jefferson Medical College, Philadelphia, etc. Handsome royal octavo volume of 696 pages, with 256 fine illustrations and 2 chromo-litho- graphic plates. Cloth, ^4.00 net ; Sheep or Half Morocco, ^5.00 net. " A clearly written, comprehensive manual. One which we can commend to students as a reliable text-book, written with an evident knowledge of the wants of those entering upon the study of this special branch of medical science." — British Medical Journal. ** A work that will meet the requirements not only of the specialist, but of the general practitioner in a rare degree. I am satisfied that unusual success awaits it." — William Pepper, M.D., Professor of the Theory and Practice of Medicine and Clinical Medicine, University of Pennsylvania. DORLAND'S DICTIONARY. Third Edition, Revised. The American Pocket JVledical Dictionary. Containing the Pro- nunciation and Definition of all the principal words and phrases, and a large number of useful tables. Edited by W. A. Newman Borland, M. D., Assistant Demonstrator of Obstetrics, University of Pennsylvania; Fellow of the American Academy of Medicine. 518 pages ; handsomely bound in full leather, limp, with gilt edges and patent index. Price, ^i.oo net; with thumb index, ^1.25 net. DORLAND'S OBSTETRICS. A Manual of Obstetrics. By W. A. Newman Borland, M.D., Assistant Demonstrator of Obstetrics, University of Pennsylvania; Instructor in Gynecology in the Philadelphia Polyclinic. 760 pages; 163 illustrations in the text, and 6 full-page plates. Cloth, $2.50 net. " By far the best book on this subject that has ever come to our notice." — American Medical Review. " It has rarely been our duty to review a book which has given us more pleasure in its perusal and more satisfaction in its criticism. It is a veritable encyclopedia of knowledge, a gold mine of practical, concise thoughts." — American Medico- Surgical Bulletin. Medical Publications of W. B. Saunders & Co. 13 iPROTHINGHAM'S GUIDE FOR THE BACTERIOLOGIST. Laboratory Guide for the Bacteriologist. By Langdon Froth- INGHAM, M.D.V., Assistant in Bacteriology and Veterinary Science, Sheffield Scientific School, Yale University. Illustrated. Cloth, 75 cts. •' It is a convenient and useful little work, and will more than repay the outlay neces- sary for Its purchase in the saving of time which would otherwise be consumed in looking np the various points of technique so clearly and concisely laid down in its pages."— Ameri- can Medico- Surgical Bulletin. QARRIGUES' DISEASES OF WOMEN. Third Edition, Revised. Diseases of Women. By Henry J. Garrigues, A.M., M.D., Pro- fessor of Gynecology in the New York School of Clinical Medicine ; Gynecologist to St. Mark's Hospital and to the German Dispensary, New York City, etc. Handsome octavo volume of 783 pages, illus- trated by 367 engravings and colored plates. Cloth, $4.00 net; Sheep or Half Morocco, $5.00 net. ' ' One of the best text-books for students and practitioners which has been published in the English language ; it is condensed, clear, and comprehensive. The profound learning and great clinical experience of the distinguished author find expression in this book in a most attractive and instructive form. Young practitioners to whom experienced consultants may not be available will find in this book invaluable counsel and help." — ^Thad. A. Reamy, M.D. , LL. D. , Professor of Clinical Gynecology, Medical College of Ohio. GLEASON'S DISEASES OF THE EAR. Second Edition, Revised. Essentials of Diseases of the Ear. By E. B. Gleason, S.B., M.D., Clinical Professor of Otology, Medico-Chirurgical College, Philadelphia ; Surgeon-in-Charge of the Nose, Throat, and Ear Depart- ment of the Northern Dispensary, Philadelphia. 208 pages, with 114 illustrations. Cloth, ;gi.oo net; interleaved for notes, ^1.25 net. [See Saunders' Question- Compends, page 23. J " It is just the book to put into the hands of a student, and cannot fail to give him a useful introduction to ear-affections ; while the style of question and answer which is adopted throughout the book is, we believe, the best method of impressing facts permanently on the mind." — Liverpool Medico-Chirurgical Journal. GOULD AND PYLE'S CURIOSITIES OF MEDICINE. Anomalies and Curiosities of Medicine. By George M. Gould, M.D., and Walter L. Pyle, M.D. An encyclopedic collection of rare and extraordinary cases and of the most striking instances of abnormality in all branches of Medicine and Surgery, derived from an exhaustive research of medical literature from its origin to the present day, abstracted, classified, annotated, and indexed. Handsome im- perial octavo volume of 968 pages, with 295 engravings in the text, and 12 full-page plates. POPULAR EDITION: Cloth, $3.00 net; Half Morocco, $4.00 net. " One of the most valuable contributions ever made to medical literature. It is, so far as we know, absolutely unique, and every page is as fascinating as a novel. Not alone for the medical profession has this volume value : it will serve as a book of reference for all who are interested in general scientific, sociologic, or medico-legal \.q,^\q.s."— Brooklyn Medical Journal. "This is certainly a most remarkable and interesting volume. It stands alone among medical literature, an anomaly on anomalies, in that there is nothing like it elsewhere in medical literature. It is a book full of revelations from its first to its last page, and cannot but interest and sometimes almost horrify its xez.i.as."— American Medico- Surgical BulUHn. 14 Medical Pnblications of W. B. Saunders & Co. QRAFSTROM'S MECHANO-THERAPY. A Text=Book of Mechano-Therapy (Massage and Medical Gym- nastics). By Axel V. Grafstrom, B. Sc, M. D., late Lieutenant in the Royal Swedish Army ; late House Physician City Hospital, Black- well's Island, New York. i2mo, 139 pages, illustrated. Cloth, $1.00 net. GRIFFITH ON THE BABY. Second Edition, Revised. The Care of the Baby, By J. P. Crozer Griffith, M.D., Clini- cal Professor of Diseases of Children, University of Pennsylvania ; Physician to the Children's Hospital, Philadelphia, etc. i2mo, 404 pages, with 67 illustrations in the text, and 5 plates. Cloth, gi.sonet. " The best book for tbe use of the young mother with which we are acquainted. . . . There are very few general practitioners who could not read the book through with advan- tage. ' ' — Archives of Pediatrics. "The whole book is characterized by rare good sense, and is evidently written by a master hand. It can be read with benefit not only by mothers but by medical students and by any practitioners who have not had large opportunities for observing children." — Ameri- can Journal of Obstetrics, GRIFFITH'S WEIGHT CHART. Infant's Weight Chart. Designed by J. P. Crozer Griffith, M.D., Clinical Professor of Diseases of Children in the University of Penn- sylvania, etc. 25 charts in each pad. Per pad, 50 cents net. GROSS, SAMUEL D., AUTOBIOGRAPHY OF. Autobiography of Samuel D. Gross, M. D., Emeritus Professor of Surgery in the Jefferson Medical College, Philadelphia, with Remi- niscences of His Times and Contemporaries. Edited by his Sons, Samuel W. Gross, M.D., LL.D., and A. Haller Gross, A.M. Pre- ceded by a Memoir of Dr. Gross, by the late Austin Flint, M.D. Two handsome volumes, over 400 pages each, demy octavo, gilt tops, with Frontispiece on steel. Price pejr volume, ^2.50 net. HAMPTON'S NURSING. Second Edition, Revised and Enlarged. Nursing : Its Principles and Practice. By Isabel Adams Hamp- ton, Graduate of the New York Training School for Nurses attached to Bellevue Hospital ; late Superintendent of Nurses and Principal of the Training School for Nurses, Johns Hopkins Hospital, Baltimore, Md. 12 mo, 512 pages, illustrated. 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HEISLER'S EMBRYOLOGY. A Text-Book of Embryology. By John C. Heisler, M.D., Pro- fessor of Anatomy in the Medico-Chirurgical College, Philadelphia. Oc- tavo volume of 405 pages, handsomely illustrated. Cloth, ^2.50 net. HIRST'S OBSTETRICS. Second Editipn. A Text-Book of Obstetrics. By Barton Cooke Hirst, M. D., Professor of Obstetrics in the University of Pennsylvania. Handsome octavo volume of 848 pages, with 618 illustrations, and 7 colored plates. Cloth, ^5.00 net; Sheep or Half Morocco, ^6.00 net. " The illustrations are numerous and are works of art, many of them appearing for the first time. The arrangement of the subject-matter, the foot-notes, and index are beyond criticism. As a true model of what a modern text-book on obstetrics should be, we feel justified in affirming that Dr. Hirst's book is without a rival." — New York Medical Record. HYDE AND MONTGOMERY ON SYPHILIS AND THE VENEREAL DISEASES. Second Edition, Revised and Enlarged. Syphilis and the Venereal Diseases. By James Nevins Hyde, M. D., Professor of Skin and Venereal Diseases, and Frank H. Mont- gomery, M. D. , Lecturer on Dermatology and Genito-Urinary Diseases in Rush Medical College, Chicago, 111. Octavo, nearly 600 pages, with 14 beautiful lithographic plates and numerous illustrations. " We can commend this manual to the student as a help to him in his study of venereal diseases." — Liverpool Medico-Chirurgical Journal. "The best student's manual which has appeared on the subject." — St. Louis Medical and Surgical Journal. INTERNATIONAL TEXT-BOOK OF SURGERY. In two volumes. By American and British authors. Edited by J. Collins Warren, M.D., LL.D., Professor of Surgery, Harvard Medical School, Boston; and A. Pearce Gould, M.S., F.R.C.S., Lecturer on Practical Sur- gery and Teacher of Operative Surgery, Middlesex Hospital Medical School, London, Eng. Vol. I. General Surgery. — Handsome octavo, 947 pages, with 458 beautiful illustrations and 9 lithographic plates. Vol. II. Special or Regional ^w/y^/j.— Handsome octavo, 1072 pages, with 471 beautiful illustrations and 8 lithographic plates. Prices per volume: Cloth, 55.00 net; Half Morocco, 56.00 net. 16 Medical Publications of W. B. Saunders & Co. JACKSON'S DISEASES OF THE EYE. A Manual of Diseases ol the Eye. By Edward Jackson, A.M., M.D., sometime Professor of Diseases of the Eye in the Philadelphia Polyclinic and College for Graduates in Medicine. i2mo volume of 535 pages, with 178 beautiful illustrations, mostly from drawings by the author. Cloth, ^2.50 net. JACKSON AND QLEASON'S DISEASES OF THE EYE, NOSE, AND THROAT. Second Edition, Revised. Essentials of Refraction and Diseases of the Eye. By Edward Jackson, A.M., M.D., Professor of Diseases of the Eye in the Phila- delphia iPolyclinic and College for Graduates in Medicine ; and — Essentials of Diseases of the Nose and Throat. By E. 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" The book is certainly an admirable risumi of what every gynecological student and practitioner should know, and will prove of value not only to those who have the ' American Text-Book of Gynecology,' but to others as -vifLVL." —Brooklyn Medical Journal. 18 Medical Publications of W. B. Saunders & Co. MACDONALD'S SURGICAL DIAGNOSIS AND TREATMENT. Surgical Diagnosis and Treatment. By J. W. Macdonald, M.D. Edin., F.R.C.S., Edin., Professor of the Practice of Surgery and of Clinical Surgery in Hamline University; Visiting Surgeon to St. Barnabas' Hospital, Minneapolis, etc. Handsome octavo volume of 800 pages, profusely illustrated. Cloth, ^5.00 net; Half Morocco, J6.00 net. " A thorough and complete work on surgical diagnosis and treatment, free from pad- ding, full of valuable material, and in accord with the surgical teaching of the day." — The Medical News, New York. " The work is brimful of just the kind of Practical information that is useful alike to students and practitioners. It is a pleasure to commend the bock because of its intrinsic value to the medical practitioner." — Cincinnati Lancet-Clinic . MALLORY AND WRIGHT'S PATHOLOGICAL TECHNIQUE. Pathological Technique. A Practical Manual for Laboratory Work in Pathology, Bacteriology, and Morbid Anatomy, with chapters on Post-Mortem Technique and the Performance of Autopsies. By Frank B. Mallory, A.M., M.D., Assistant Professor of Pathology, Harvard University Medical School, Boston; and James H. Wright, A.M., M.D., Instructor in Pathology, Harvard University Medical School, Boston. Octavo volume of 396 pages, handsomely illustrated. Cloth, ;$2.so net. " I have been looking forward to the publication of this book, and I am glad to say that I find it to be a most useful laboratory and post-mortem guide, full of practical information, and well up to date." — William H. Welch, Professor of Pathology, Johns Hopkins Uni- versity, Baltimore, Aid. MARTIN'S MINOR SURGERY, BANDAGING, AND VENEREAL DISEASES. Second Edition, Revised. Essentials of Minor Surgery, Bandaging, and Venereal Diseases. By Edwvrd Martin, A.M., M.D., Chnical Professor of 'Genito-Urinary Diseases, University of Pennsylvania, etc. Crown octavo, 166 pages, with 78 illustrations. Cloth, $!i.oo net; interleaved for notes, §1.25 net. [See Saunders' Question- Compends, page 2 3. J "A very practical and systematic study of the subjects, and shows the author's famil- iarity with the needs of students." — Therapeutic Gazette. MARTIN'S SURGERY. Seventh Edition, Revised. Essentials of Surgery. Containing also Venereal Diseases, Surgi- cal Landmarks, Minor and Operative Surgery, and a complete de- scription, with illustrations, of the Handkerchief and Roller Bandages. By Edward Martin, A.M., M.D., Clinical Professor of Genito- Urinary Diseases, University of Pennsylvania, etc. Crown octavo, 342 pages, illustrated. With an Appendix on the preparation of the materials used in Antiseptic Surgery, etc., and a chapter on Appendicitis. Cloth, $i.oo net; interleaved for notes, ^1.25 net \^tt Saunders' Question- Compends, page 23.] " Contains all necessary essentials of modern surgery in a comparatively small space. Its style is interesting, and its illustrations are admirable." — Medical and Surgical Reporter. Medical Publications of W. B. Saunders & Co. 19 McFARLAND'S PATHOGENIC BACTERIA. Second Edition, Re- vised and Qreatly Enlarged. Text=Book upon the Pathogenic Bacteria. By Joseph McFar- LAND, M. D., Professor of Pathology and Bacteriology in the Medico- Chirurgical College of Philadelphia, etc. Octavo volume of 497 pages, finely illustrated. Cloth, ^2.50 net. " Dr. McFarland has treated the subject in a systematic manner, and has succeeded in presenting in a concise and readable form the essentials of bacteriology up to date. 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Third Edition, Revised. Essentials of the Practice of Medicine. By Henry Morris, M. D., late Demonstrator of Therapeutics, Jefferson Medical College, Phila- delphia ; with an Appendix on the Clinical and Microscopic Examina- tion of Urine, by Lawrence Wolff, M. D. , Demonstrator of Chemistry, Jefferson Medical College, Philadelphia. Enlarged by some 300 essen- tial formula collected and arranged by William M. Powell, M.D. Post-octavo, 488 pages. Cloth, ^1.50 net. [See Saunders' Question- Compends, page. 2 2.] " The teaching is sound, the presentation graphic ; matter full as can be desired, «i«l style attractive."— ^«^>-sVa« Practitioner and News. 20 Medical Publications of W. B. Saunders & Co. MORTEN'S NURSE'S DICTIONARY. Nurse's Dictionary of Medical Terms and Nursing Treat- ment. 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Lectures on the Principles of Surgery. By Chas. B. Nancrede, M.D., LL.D., Professor of Surgery and of Clinical Surgery, Univer- sity of Michigan, Ann Arbor. Octavo volume of 398 pages, illustrated. Cloth, $2.'^o net. NORRIS'S SYLLABUS OF OBSTETRICS. Third Edition, Revised. Syllabus of Obstetrical Lectures in the Medical Department of the University of Pennsylvania. By Richard C. Norris, A.M., M.D., Demonstrator of Obstetrics, University of Pennsylvania. Crown octavo, 222 pages. Cloth, interleaved for notes, $2.00 net. PENROSE'S DISEASES OF WOMEN. Third Edition, Revised. A Text-Book of Diseases of Women. By Charles B. Penrose, M. D., Ph.D., Formerly Professor of Gynecology in the University of Pennsylvania; Surgeon to the Gynecean Hospital, Philadelphia. Octavo volume of 531 pages, handsomely illustrated. Cloth, I3.7S net. «' I shall value very highly the copy of Penrose's ' Diseases of Women ' received. I have already recommended it to my class as THE BEST book." — Howard A. Kelly, Professor of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, Md. Medical Publications of W. B. Sau nders & Co. 21 POWELL'S DISEASES OF CHILDREN. Second Edition. Essentials of Diseases of Children. By William M. Powell, M.D., Attending Physician to the Mercer House for Invalid Women at Atlantic City, N. J. ; late Physician to the Clinic for the Diseases of Children in the Hospital of the University of Pennsylvania. Crown octavo, 222 pages. Cloth, ^i.oonet; interleaved fornotes, ^1.25 net. [See Saunders' Question- Commends, page 21. J " Contains the gist of all the best works in the department to which it relates."^ American Practitioner and News. PRINQLE'S SKIN DISEASES AND SYPHILITIC AFFECTIONS. Pictorial Atlas of Skin Diseases and Syphilitic Affections (American Edition). Translation from the French. Edited by J. J. Pringle, M.B., F.R.C.P., Assistant Physician to the Middlesex Hospital, London. Photo-lithochromes from the famous models in the Museum of the Saint-Louis Hospital, Paris, with explanatory wood- cuts and text. In 12 Parts. Price per Part, ^3.00. Complete in one volume, Half Morocco binding, ^40.00 net. "I strongly recommend this Atlas. The plates are exceedingly well executed, and will be of great value to all studying dermatology." — Stephen Mackenzie, M.D. "The introduction of explanatory wood-cuts in the text is a novel and most important feature which greatly furthers the easier understanding of the excellent plates, than which nothing, we venture to say, has been seen better in point of correctness, beauty, and general merit." — New York Medical Journal. PRYOR— PELVIC INFLAMMATIONS. The Treatment of Pelvic Inflammations through the Vagina. By W. R. Pryor, M.D., Professor of Gynecology in New York Poly- clinic. i2mo, 248 pages, handsomely illustrated. Cloth, ^2.00 net. " This subject, which has recently been so thoroughly canvassed in high gynecological circles, is made available in this volume to the general practitioner and student. Nothing is too minute for mention and nothing is taken for granted ; consequently the book is of the utmost value. The illustrations and the techniqueare beyond criticism." — Chicago Medical Recorder. PYE'S BANDAGING. Elementary Bandaging and Surgical Dressing. With Direc- tions concerning the Immediate Treatment of Cases of Emergency. For the use of Dressers and Nurses. By Walter Pye, F.R.C.S., late Surgeon to St. Mary's Hospital, London. Small 121110, with over 80 illustrations. Cloth, flexible covers, 75 cents net. " The directions are clear and the illustrations are good." — London Lancet. "The author writes well, the diagrams are clear, and the book itself is small and port- able, although the paper and type are good." — British Medical Journal. RAYMOND'S PHYSIOLOGY. A Manual of Physiology. By Joseph H. Raymond, A.M., M.D., Professor of Physiology and Hygiene and Lecturer on Gynecology in the Long Island College Hospital; Director of Physiology in the Hoagland Laboratory, etc. 382 pages, with 102 illustrations in the text, and 4 full-page colored plates. Cloth, ^1.25 net. " Extremely well gotten up, and the illustrations have been selected with care. The text is fully abreast with modern physiology." — British Medical Journal. .3^ m f m^k P" ^smm ^^SB^^^^"^ Saunders' Question Arranged in Question and Answer Form. qrHE MOST COMPLETE AND BEST r^rM^;rD"DMT^C illustrated series OF V-^L-'iVll XlINL/O COMPENDS EVER ISSUED. Now the Standard Authorities in Medical Literature .... with Students and Practitioners in every City of the United States and Canada. «■>>- OVER ^75,000 COPIES SOLD. THE REASON WHY. They are the advance guard of "Student's Helps" — that DO help. They are the leaders in their special line, well and authoritatively written by able men, who, as teachers in the large colleges, know exactly what is wanted by a student preparing for his examinations. The judgment exercised in the selection of authors is fully demonstrated by their professional standing. Chosen from the ranks of Demonstrators, Quiz-masters, and Assistants, most of them have become Professors and Lecturers in their respective colleges. Each book is of convenient size (5x7 inches) , containing on an average 250 pages, profusely illustrated, and elegsmtly printed in clear, readable type, on fine paper. The entire series, numbering twenty-three volumes, has been kept thoroughly revised and enlarged when necessary, many of the books being in their fifth and sixth editions. TO SUM UP. Although there are numerous other Quizzes, Manuals, Aids, etc. in the market, none of them approach the " Blue Series of Question Compends ; ' ' and the claim is made for the following points of excellence : 1. Professional distinction and reputation of authors. 2. Conciseness, clearness, and soundness of treatment. 3. Quality of illustrations, paper, printing, and binding. Any cf these Compends will be mailed on receipt of price (see next page for List). Saunders' Question-Compend Series. Price, Qoth, $J.OO net per copy, except when otherwise ordered. " Where the work of preparing students' manuals is to end we cannot say, but the Saunders Series, in our opinion, bears off the palm at present."— TVezf Tork Medical Record. 1. ESSENTIALS OF PHYSIOLOQY. By H. A. Hare, M.D. Fourth edition, revised and enlarged. 2. ESSENTIALS OF SURGERY. By Edward Martin, M. D, Seventh edition, revised, with an Appendix and a chapter on Appendicitis. 3. ESSENTIALS OF ANATOMY. By Chari.es B. Nancrede, IVI.D. Sixth edition, thoroughly revised and enlarged. 4. ESSENTIALS OF MEDICAL CHEMISTRY, ORGANIC AND INORGANIC. By Lawrence Wolff, M.D. Fifth edition, revised. 5. ESSENTIALS OF OBSTETRICS. By W. Easterly Ashton, M.D. Fourth edition, revised and enlarged. 6. ESSENTIALS OF PATHOLOGY AND MORBID ANATOMY. By C. E. Armand Semple, M.D. 7. ESSENTIALS OF MATERIA MEDICA, THERAPEUTICS, AND PRE- SCRIF»T10N=WRITINQ. By Henry Morris, M.D. Fifth edition, revised. 8. 9. ESSENTIALS OF PRACTICE OF MEDICINE. By Henry Morris, M.D. An Appendix on Urine Examination. By Lawrence Wolff, M.D. Third edition, enlarged by some 300 Essential Formulae, selected from eminent authorities, by Wm. M. Powell, M.D. (Double number, f 1.50 net.) 10. ESSENTIALS OF QYN/ECOLOGY. By Edwin B. Cragin, M.D. Fovirth edition, revised. 11. ESSENTIALS OF DISEASES OF THE SKIN. By Henry W. Stelwagon, M.D. Fourth edition, revised and enlarged. 12. ESSENTIALS OF MINOR SURGERY, BANDAGING, AND VENEREAL DISEASES. By Edward Martin, M.D. Second ed., revised and enlarged. 13. ESSENTIALS OF LEGAL MEDICINE, TOXICOLOGY, AND HYGIENE. By C. E. Armand Semple, M.D. 14. ESSENTIALS OF DISEASES OF THE EYE, NOSE, AND THROAT. By Edward Jackson, M.D., and E. B. Gleason, M.D. Second ed., revised. 15. ESSENTIALS OF DISEASES OF CHILDREN. By William M. Powell, M. D. Second edition. 16. ESSENTIALS OF EXAMINATION OF URINE. By Lawrence Wolff, M.D. Colored "VoGEL Scale." (75 cents net.) 17. ESSENTIALS OF DIAGNOSIS. By S. SolisCohen, M.D., and A. A. Eshnkr, M.D. Second edition, thoroughly revised. 18. ESSENTIALS OF PRACTICE OF PHARMACY. By Lucius E. Sayre. Second edition, revised and enlarged. 20. ESSENTIALS OF BACTERIOLOGY. By M. V. Ball, M.D. Third edidon, revised. 21. ESSENTIALS OF NERVOUS DISEASES AND INSANITY. By John C. Shaw, M.D. Third edition, revised. 22. ESSENTIALS OF MEDICAL PHYSICS. By Fred J. Brockway, M.D. Second edition, revised. 23. ESSENTIALS OF MEDICAL ELECTRICITY. By David D. Stewart, M.D., and Edward S. Lawrance, M.D. 24. ESSENTIALS OF DISEASES OF THE EAR. By E. B. Gleason, M.D. Second edition, revised and greatly enlarged. Pamphlet containing specimen pages, etc sent free upon application. Saunders' New Series of Manuals for Students and Practitioners. 'TTHAT there exists a need for thoroaghly reliable Iiand-books on the leading branches of Medicine and Surgery is a fact amply demonstrated fay the favor with which the SAUNDERS NEW SERIES OF MANUALS have been received fay medical sttidents and practitioners and fay the Medical Press. These manuals are not merely condensations from present literature, faut are afaly -written by well-known authors and practitioners, most of them faeing teachers in representative American colleges. Each volume is concisely and authoritatively written and exhaustive in detail, without being encumbered with the introduction of "cases," which so largely expand the ordinary text-book. These manuals will therefore form an admirable collection of advanced lectures, useful alike to the medical student and the practitioner: to the latter, too busy to search through page after page of elaborate treatises for w^hat he wants to know^, they will prove of inestimable value ; to the former they will afford safe guides to the essential points of study. The SAUNDERS NEW SERIES OF MANUALS are conceded to fae superior to any similar faooks now^ on the market. No other manuals afford so much infor- mation in such a concise and available form. A liberal expenditure has enabled the publisher to render the mechanical portion of the work worthy of the h^h literary standard attained by these books. Any of these Manuals will be mailed on receipt of price (see next page for List). Saunders' New Series of Manuals. VOLUMES PUBLISHED. PHYSIOLOGY. 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Newman Dorland, M.D., Assistant Demonstrator of Obstetrics, University of Pennsylvania ; Chief of Gynecological Dis- pensary, Pennsylvania Hospital, etc. Profusely illustrated. Cloth, ^2.50 net. DISEASES OF WOMEN. By J. Bland Sutton, F. R. C. S., Assistant Surgeon to Middlesex Hospital and Surgeon to Chelsea Hospital, London; and Arthur E. Giles, M.D., B. Sc. Lond., F.R.C.S. Edin., Assistant Surgeon to Chelsea Hospital, London. Handsomely illustrated. Cloth, S2.50 net. VOLUMES IN PREPARATION. NERVOUS DISEASES. By Charles W. Burr, M.D., Clinical Professor of Nervous Diseases, Medico-Chirurgical College, Philadelphia ; Pathologist to the Orthopaedic Hospital and Infirmary for Nervous Diseases ; Visiting Physician to the St. Joseph Hospital, etc. *#* There will be published in the same series, at short intervals, carefully-prepared workt on various subjects by prominent specialists. Pamphlet containing specimen pages, etc sent free upon application. 26 Medical Publications of W. B. Saunders & Co. SAUNDBY'S RENAL AND URINARY DISEASES. Lectures on Renal and Urinary Diseases. By Robert Saundby, M. D. Edin. , Fellow of the Royal College of Physicians, London, and of the Royal Medico-Chirurgical Society ; Physician to the General Hospital ; Consulting Physician to the Eye Hospitai and to the Hos- pital for Diseases of Women ; Professor of Medicine in Mason College, Birmingham, etc. Octavo volume of 434 pages, with numerous illus- trations and 4 colored plates. Cloth, ^2.50 net. " The volume makes a favorable impression at once. The style is clear and succinct. We cannot find any part of the subject in which the views expressed are not carefully thought out and fortified by evidence drawn from the most recent sources. The book may be cordially recommended.' ' — British Medical JournaL SAUNDERS' MEDICAL HAND-ATLASES. For full description of this series, with list of volumes and prices, see page 2. " Lehmann Medicinische Handatlanten belong to that class of books that are too good to be appropriated by any one nation." — Journal of Eye, Ear, and Throat Diseases. " The appearance of these works marks a new era in illustrated English medical works." — The Canadian Practitioner. SAUNDERS' POCKET MEDICAL FORMULARY. Sixth Edition, Revised. By William M. Powell, M.D., Attending Physician to the Mercer House for Invalid Women at Atlantic City, N. J. Containing 1800 formulae selected from the best-known authorities. With an Appen- dix containing Posological Table, Formulse and Doses for Hypo- dermic Medication, Poisons and their Antidotes, Diameters of the Female Pelvis and Foetal Head, Obstetrical Table, Diet List for Various Diseases, Materials and Drugs used in Antiseptic Surgery, Treatment of Asphyxia from Drowning, Surgical Remembrancer, Tables of Incompatibles, Eruptive Fevers, Weights and Measures, etc. Hand- somely bound in flexible morocco, with side index, wallet, and flap. ^1.75 net. " This little book, that can be conveniently carried in the pocket, contains an immense amount of material. It is very useful, and, as the name of the author of each prescription is given, is unusually reliable." — Medical Record, New York. SAYRE'S PHARMACY. Second Edition, Revised. Essentials of tlie Practice of Pharmacy. By Lucius E. Sayre, M.D., Professor of Pharmacy and Matetia Medica in the University of Kansas. Crown octavo, 200 pages. Cloth, ^i. 00 net ; interleavec for notes, ^1.25 net. [See Saunders' Question- Compends, page 21.I "The topics are treated in a simple, practical manner, and the work forms a very useful student's manual. ' ' — Boston Medical and Surgical Journal. SCUDDER'S FRACTURES. The Treatment of Fractures. By Chas. L. Scudder, M.D., As- sistant in Clinical and Operative Surgery, Harvard Medical School. Octavo, 433 pages, with nearly 600 original illustrations. Cloth t/i to net. ' ^'^ Medical Publications of W. B. Saunders & Co. 27 SEMPLE'S LEQAL MEDICINE, TOXICOLOGY, AND HYGIENE. Essentials of Legal Medicine, Toxicology, and Hygiene. By C. E. Armand Semple, B.A., M. B. Cantab., M. R. C. P. Lond., Physician to the Northeastern Hospital for Children, Hackney, etc. Crown octavo, 212 pages; 130 illustrations. Cloth, gi.oo net; inter- leaved for notes, ^1.25 net. [See Saunders' Question- Compends, page 21.] " No general practitioner or student can afford to be without this valuable work. The subjects are dealt with by a masterly h.a.nA."— London Hospital Gazette. SEMPLE'S PATHOLOGY AND MORBID ANATOMY. Essentials of Pathology and Morbid Anatomy. By C. E. Armand Semple, B.A., M.B. Cantab., M.R.C.P. Lend., Physician to the Northeastern Hospital for Children, Hackney, etc. Crown octavo, 174 pages; illustrated. Cloth, ;gi.oo net; interleaved for notes, $1.25 nn. [See Saunders' Question- Compends, page 21. J " Should take its place among the standard volumes on the bookshelf of both student and practitioner." — London Hospital Gazette. SENN'S GENITO=URINARY TUBERCULOSIS. Tuberculosis of the Qenito-Urinary Organs, Male and Female. By Nicholas Senn, M.D., Ph.D., LL.D., Professor of the Practice of Surgery and of Clinical Surgery, Rush Medical College, Chicago. Handsome octavo volume of 320 pages, illustrated. Cloth, ^3.00 net. " An important book upon an important subject, and written by a man of mature judg- ment and wide experience. The author has given us an instructive book upon one of the most important subjects of the day." — Clinical Reporter. " A work which adds another to the many obligations the profession owes the talented author." — Chicago Medical Recorder. SENN'S SYLLABUS OF SURGERY. A Syllabus of Lectures on the Practice of Surgery, arranged in conformity with " An American Text=Book of Surgery." By Nicholas Seen, M. D., Ph.D., Professor of the Practice of Surgery and of Clinical Surgery, Rush Medical College, Chicago. Cloth, ^1.50 net. " This syllabus will be found of service by the teacher as well as the student, the work- being superbly done. There is no praise too high for it. No surgeon should be without it. " — New York Medical Times. SENN'S TUMORS. Second Edition, Revised. Pathology and Surgical Treatment of Tumors. By N. Senn, M.D, Ph.D., LL.D., Professor of Surgery and of Clinical Surgery, Rush Medical College ; Professor of Surgery, Chicago Polyclinic ; Attending Surgeon to Presbyterian Hospital ; Surgeon-in-Chief, St. Joseph's Hospital, Chicago. Second Edition, Thoroughly Revised. Oc- tavo volume of 718 pages, with 478 illustrations, including 12 full-page plates in colors. Prices: Cloth, $5.00 net; Half Morocco, g6.oo net. " The most exhaustive of any recent book in Ergush on this subject. It is well illus- trated, and will doubtless remain as the principal monograph on the subject in our language 'or some years. The book is handsomely illustrated and printed, and the author has given a notable and lasting contribution to surgery." — Journal of the American Medical Association. 28 Medical Publications of W. B. Saunders & Co. SHAW'S NERVOUS DISEASES AND INSANITY. Third Edition, Revised. Essentials of Nervous Diseases and Insanity. By John C. Shaw, M.D., Clinical Professor of Diseases of the Mind and Nervous System, Long Island College Hospital Medical School ; Consulting Neurologist to St. Catherine's Hospital and to the Long Island College Hospital. Crown octavo, i86 pages; 48 original illustrations. Cloth, $-s..oo net; interleaved for notes, gi.25 net. [See Saunders' Question- Compends, page 21.J "Clearly and intelligently written." — Boston Medical and Surgical Journal. "There is a mass of valuable material crowded into this small compass." — American Medico-Surgical Bulletin. STARR'S DIETS FOR INFANTS AND CHILDREN. Diets for Infants and Children in Health and in Disease. By Louis Starr, M.D., Editor of "An American Text-Book of the Diseases of Children." 230 blanks (pocket-book size), perforated and neatly bound in flexible morocco. ^1.25 net. The first series of blanks are prepared for the first seven months of infant life ; each blank indicates the ingredients, but not the quantities, of the food, the latter directions being left for the physician. After the seventh month, modifications being less necessary, the diet lists are printed in full. Formulae for the preparation of diluents and foods are appended. STELWAQON'S DISEASES OF THE SKIN. Fourth Ed., Revised. Essentials of Diseases of the Skin. By Henry W. Stelwagon, M.D., Clinical Professor of Dermatology in the Jefferson Medical College, Philadelphia; Dermatologist to the Philadelphia Hospital; Physician to the Skin Department of the Howard Hospital, etc. Crown octavo, 276 pages; 88 illustrations. Cloth, ^i. 00 net; inter- leaved for notes, ^1.25 net. [See Saunders' Question- Compends, page 21.] " The best student's manual on skin diseases we have yet seen." — Times and Register. STENGEL'S PATHOLOGY. Second Edition. A Text=Book of Pathology. By Alfred Stengel, M.D., Professor of Clinical Medicine in the University of Pennsylvania ; Physician to the Philadelphia Hospital ; Ph3'sician to the Children's Hospital, etc. Handsome octavo volume of 848 pages, with nearly 400 illustrations, many of them in colors. Cloth, ^4.00 net; Half Morocco, ^5.00 net. STEVENS' MATERIA MEDICA AND THERAPEUTICS. Second Edition, Revised. A Manual of Materia Medica and Therapeutics. By A. A. Stevens, A.M., M.D., Lecturer on Terminology and Instructor in Physical Diagnosis in the University of Pennsylvania ; Professor of Pathology in the Woman's Medical College of Pennsylvania. Post- octavo, 445 pages. Flexible leather, ^2.00 net. "The author has faithfully presented modern therapeutics in a comprehensive work, and, while intended particularly for the use of students, it will be found a reliable guide and sufficiently comprehensive for the physician in practice." — University Medical Magazine. Med ical ^uhlications of W. B. Saunders & Co. 29 STEVENS' PRACTICE OF MEDICINE. Fifth Edition, Revised. A Manual of the Practice of Medicine. By A. A. Stevens, A. M., M. D., Lecturer on Terminology and Instructor in Physical Diagnosis m the University of Pennsylvania; Professor of Pathology in the Woman s Medical College of Pennsylvania. Specially intended for students preparing for graduation and hospital examinations. Post- octavo, 519 pages; illustrated. Flexible leather, ^2.00 net. " The frequency with which new editions of this manual are demanded bespeaks its popularity. It is an excellent condensation of the essentials of medical practice for the student, and maybe found also an excellent reminder for the busy physician." Buffalo Medical journal. STEWART'S PHYSIOLOGY. Third Edition, Revised. A Manual of Physiology, with Practical Exercises. For Students and Practitioners. By G. N. Stewart, M.A., M.D., D.Sc, lately Examiner in Physiology, University of Aberdeen, and of the New Museums, Cambridge University ; Professor of Physiology in the Western Reserve University, Cleveland, Ohio. Octavo volume of 848 pages ; 300 illustrations in the text, and 5 colored plates. Cloth, ^3.75 net. " It will make its way by sheer force of merit, and amply deserves to do so. It is one of the very best English text-books on the subject." — London Lancet. ' ' Of the many text-books of physiology published, we do not know of one that so nearly comes up to the ideal as does Prof. Stewart's volume." — British Medical Journal. STEWART AND LAWRANCE'S MEDICAL ELECTRICITY. Essentials of Medical Electricity. By D. D. Stewart, M.D., Demonstrator of Diseases of the Nervous System and Chief of the Neurological Clinic in the Jefferson Medical College; and E. S. Lawrance, M.D., Chief of the Electrical Clinic and Assistant Demon- strator of Diseases of the Nervous System in the Jefferson Medical College, etc. Crown octavo, 158 pages; 65 illustrations. Cloth, 1 1. 00 net; interleaved for notes, ^1.25 net. [See Saunders' Question- Compends, page 21.J " Throughout the whole brief space at their command the authors show a discriminating knowledge of their subject." — Medical News. STONEY'S NURSING. Second Edition, Revised. Practical Points in Nursing. For Nurses in Private Practice. By Emily A. M. Stoney, Graduate of the Training-School for Nurses, Lawrence, Mass.; late Superintendent of the Training-School for Nurses, Carney Hospital, South Boston, Mass. 456 pages, illustrated with 73 engravings in the text, and 8 colored and half-tone plates. Cloth, ^1.75 net. " There are few books intended for non-professional readers which can be so cordially endorsed by a medical journal as can this one." — Therapeutic Gazette. " This is a well- written, eminently practical volume, which covers the entire range of private nursing as distinguished from hospital nursing, and instructs the nurse how best to meet the various emergencies which may arise, and how to prepare everything ordinarily needed in the illness of her patient." — American Journal of Obstetrics and Diseases of Women and Children. " It is a work that the physician can place in the hands of his private nurses with the assurance of benefit."— O^io Medical Journal. 30 Medical Publications of W. B. Saunders & Co. STONEY'S MATERIA MEDICA FOR NURSE& Materia Medica for Nurses. By Emily A. M. Stoney, Graduate of the Training-School for Nurses, Lawrence, Mass. ; late Superintendent of the Training-School for Nurses, Carney Hospital, South Boston, Mass. Handsome octavo volume of 306 pages. Cloth, ^1.50 net. The present book diflfers from other similar works in several features, all of which are intended to render it more practical and generally useful. The general plan of the contents follows the lines laid down in training-schools for nurses, but the book contains much use- ful matter not usually included in works of this character, such as Poison-emergencies, Ready Dose-list, Weights and Measures, etc., as well as a Glossary, defining all the terms used in Materia Medica, and describing all the latest drugs and remedies, which have been generally neglected by other books of the kind. SUTTON AND GILES' DISEASES OF WOMEN. Diseases of Women. By J. Bland Sutton, F.R.C.S., Assistant Surgeon to Middlesex Hospital, and Surgeon to Chelsea Hospital, London; and Arthur E. Giles, M.D., B.Sc. Lond., F.R.C.S. Edin., Assistant Surgeon to Chelsea Hospital, London. 436 pages, hand- somely illustrated. Cloth, $2.50 net. "The text has been carefully prepared. Nothing essential has been omitted, and its teachings are those recommended by the leading authorities of the day. " — Journal of the American Medical Association. THOMAS'S DIET LISTS. Second Edition, Revised. Diet Lists and Sick=Room Dietary. By Jerome B. Thomas, M.D., Visiting Physician to the Home for Friendless Women and Children and to the Newsboys' Home ; Assistant Visiting Physician to the Kings County Hospital. Cloth, ^1.25 net. Send for sample sheet. THORNTON'S DOSE-BOOK AND PRESCRIPTION=WRITINQ. Dose=Book and Manual of Prescription-Writing. By E. Q. Thornton, M.D., Demonstrator of Therapeutics, Jefferson Medical College, Philadelphia. 334 pages, illustrated. Cloth, I1.25 net. " Full of practical suggestions ; will take its place in the front rank of works of this sort." — Medical Record, New York. VAN VALZAH AND NISBET'S DISEASES OF THE STOMACH. Diseases of the Stomach. By William W. Van Valzah, M.D., Professor of General Medicine and Diseases of the Digestive System and the Blood, New York Polyclinic; and J. Douglas Nisbet, M.D., Adjunct Professor of General Medicine and Diseases of the Digestive System and the Blood, New York Polyclinic. Octavo volume of 674 pages, illustrated. Cloth, ^3.50 net. " Its chief claim lies in its clearness and general adaptability to the practical needs of the general practitioner or student. In these relations it is probably the best of the recent special works on diseases of the stomach." — Chicago Clinical Review. VECKI'S SEXUAL IMPOTENCE. The Pathology and Treatment of Sexual Impotence. By Victor G. Vecki, M.D. From the second German edition, revised and en- larged. Demi-octavo, 291 pages. Cloth, ^2.00 net. The subject of impotence has seldom been treated in this country in the truly scientific spirit that it deserves. Dr. Vecki's work has long been favorably known, and the German book has received the highest consideration. This edition is more than a mere translation, tor, although based on the German edition, it has been entirely rewritten in English. Medical Publications of W. B. Saunders & Co, 31 VIERORDT'S MEDICAL DIAGNOSIS. Fourth Edition, Revised. Medical Diagnosis. By Dr. Oswald Vierordt, Professor of Medi- cine at the University of Heidelberg. Translated, with additions, from the fifth enlarged German edition, with the author's permission, by Francis H. Stuart, A. M., M. D. Handsome royal octavo volume of 603 pages; 194 fine wood-cuts in text, many of them in colors. Cloth, ^4.00 net; Sheep or Half Morocco, ^5.00 net. " Rarely is a book published with which a reviewer can find so little fault as with the volume before us. Each particular item in the consideration of an organ or apparatus, which is necessary to determine tt diagnosis of any disease of that organ, is mentioned; nothing seems forgotten. The chapters on diseases of the circulatory and digestive 'apparatus and nervous system are especially full and valuable. The reviewer would repeat that the book is one of the best — ^probably the best — which has fallen into his hands." — University Medical Magazine. WATSON'S HANDBOOK FOR NURSES. A Handbook for Nurses. By J. K. Watson, M.D., Edin. Ameri- can Edition, under supervision of A. A. Stevens, A.M., M.D., Lecturer on Physical Diagnosis, University of Pennsylvania. i2mo, 413 pages, 73 illustrations. Cloth, ^1.50 net. WARREN'S SURGICAL PATHOLOGY. Second Edition. Surgical Pathology and Therapeutics. By John Collins Warren, M.D., LL.D., Professor of Surgery, Harvard Medical School. Hand- some octavo, 832 pages ; 136 relief and lithographic illustrations, 33 in colors ; with an Appendix on Scientific Aids to Surgical Diagnosis, and a series of articles on Regional Bacteriology. Cloth, ^5.00 net; Half Morocco, $6.00 net. " A most striking and very excellent feature of this book is its illustrations. Without exception, from the point of accuracy and artistic merit, they are the best ever seen in a work of this kind. Many of those representing microscopic pictures are so perfect in their coloring and detail as almost to give the beholder the impression that he is looking down the barrel of a microscope at a well-mounted section." — Annals of Surgery. WOLFF ON EXAMINATION OF URINE. Essentials of Examination of Urine. By Lawrence Wolff, M.D., Demonstrator of Chemistry, Jefferson Medical College, Philadelphia, etc. Colored (Vogel) urine scale and numerous illustrations. Crown octavo. Cloth, 75 cents net. [See Saunders' Question- Compends, page 21. J ** A very good work of its kind — very well suited to its purpose. " — Times and Register. WOLFF'S MEDICAL CHEMISTRY. Fifth Edition, Revised. Essentials of Medical Chemistry, Organic and Inorganic. Containing also Questions on Medical Physics, Chemical Physiology, Analytical Processes, Urinalysis, and Toxicology. By Lawrence Wolff, M.D., Demonstrator of Chemistry, Jefferson Medical College, Philadelphia, etc. Crown octavo, 222 pages. Cloth, ;^i.oo net; inter- leaved for notes, ^1.25 net. [See Saunders' Question- Compends, page 21. J " The scope of this work is certainly equal to that of the best course of lectures on Medical Chemistry." — Pharinaceutical Era. CLASSIFIED LIST Medical Publications W. B. SAUNDERS & COMPANY, 925 "Walnut Street, Philadelphia. ANATOMY, EMBRYOLOGY, HISTOLOGY. Clarkson — A Text-Book of Histology, Haynes — A Manual of Anatomy, . Heisler — A Text-Book of Embryology, Nancrede — Essentials of Anatomy, . Nancrede — Essentials of Anatomy and Manual of Practical Dissection, . Semple — Essentials of Pathology, BACTERIOLOGY. Ball — Essentials of Bacteriology, . . Crookshank — A Text- Book of Bacteri ology, ■ ■ . Frothingham— Laboratory Guide, . Levy and Klemperer's Clinical Bacte- riology, Mallory and \Wright — Pathological Technique, . . .... McFarland — Pathogenic Bacteria, CHARTS, DIET-LISTS, ETC Griffith— Infant's Weight Chart, . Hart — Diet in Sickness and in Health Keen — Operation Blank, .... Lrjne — Temperature Chart, . . . Meigs — Feeding in Early Infancy, . Starr — Diets for Infants and Children, Thomas — Diet-Lists, . ... CHEMISTRY AND PHYSICS Brockway — Essentials of Medical Phys II 15 20 27 Wolff — Essentials of Medical Chemistry, 31 CHILDREN. An American Text-Book of Diseases of Children, . . 5 Griffith — Care of the Baby, 14 Griffith— Infant's Weight Chart, ... 14 Meigs — Feeding in Early Infancy, . . 19 Powell — Essentials of Dis. of Children, 21 Starr — Diets for Infants and Children, . 28 DIAGNOSIS. Cohen and Eshner— Essentials of Di- agnosis, II Corwin — Physical Diagnosis, .... 11 Macdonald — Surgical Diagnosis and Treatment, 18 Vierordt — Medical Diagnosis, .... 31 DICTIONARIES. Dorland — Pocket Dictionary, .... 12 Keating — Pronouncing Dictionary, . i6 Morten — Nurse's Dictionary, . . 20 EYE, EAR, NOSE, AND THROAT. An American Text- Book of Diseases of the Eye, Ear, Nose, and Throat, . 5 De Schweinitz — Diseases of the Eye, . 12 Gleason — Essentials of Dis. of the Ear, 13 Jackson — Manual of Diseases of Eye, . 16 Jackson and Gleason — Essentials of Diseases of the Eye, Nose, and Throat, 16 Kyle — Diseases of the Nose and Throat, 17 GEN1T0=URINARY. An American Text-Book of Genito- urinary and Skin Diseases, 6 Hyde and Montgomery — Syphilis and the Venereal Diseases, 15 Martin — Essentials of Minor Surgery, Bandaging, and Venereal Diseases, . 18 Saundby — Renal and Urinary Diseases, 26 Senn — Genito-Urinary Tuberculosis, . 27 Vecki — Sexual Impotence, 30 GYNECOLOGY. American Text- Book of Gynecology, 6 Cragin — Essentials of Gynecology, Garrigues — Diseases of Women, . Long — Syllabus of Gynecology, . Penrose — Diseases of Women, . . Pryor — Pelvic Inflammations, . . Sutton and Giles — Diseases of Women, 13 17 20 34 30 MATERIA MEDICA, PHARMACOL- OGY, AND THERAPEUTICS. An American Text-Book of Applied Therapeutics, 5 Butler— Text-Book of Materia Medica, Therapeutics and Pharmacology, ... 10 Cerna — Notes on the Newer Remedies, 10 Griffin— Materia Med. and Therapeutics, 14 Morris— Essentials of Materia Medica and Therapeutics, . ... 19 Saunders' Pocket Medical Formulary, 26 Sayre — Essentials of Pharmacy, . . 26 Stevens — Essentials of Materia Medica and Therapeutics, 28 Stoney — Materia Medica for Nurses, . . 30 Thornton — Dose-Book and Manual of Prescription-Writing, 30 MEDICAL JURISPRUDENCE AND TOXICOLOGY. Chapman — Medical Jurisprudence and Toxicology, 10 Semple — Essentials of Legal Medicine, Toxicology, and Hygiene 27 Medical Publications of W. B. Saunders & Co. 33 NERVOUS AND MENTAL DISEASES, ETC. Burr — Nervous Diseases, 9 Chapin — Compendium of Insanity, . . lo Cbuicb and Peterson — Nervous and Mental Diseases, lo Shaw — Essentials of Nervous Diseases and Insanity, 28 NURSING. Griffith— The Care of the Baby, . . . H Hampton — Nursing, '4 Hart — Diet in Sickness and in Health, 15 Meigs— Feeding in Early Infancy, . . '9 Morten — Nurse's Dictionary 20 Stoney — Materia Medica for Nurses, . . 30 Stoney— Practical Points in Nursing, . 29 Watson — Handbook for Nurses, ... 3^ OBSTETRICS. An American Text-Book of Obstetrics, 6 Ashton— Essentials of Obstetrics, ... ° Boisliniere — Obstetric Accidents, . . 9 Dorland — Manual of Obstetrics, ... 12 Hirst— Text-Book of Obstetrics, . . . I5 Norris— Syllabus of Obstetrics 20 PATHOLOGY. An American Text-Book of Pathology, 7 Mallory and ^W^ight — Pathological Technique, '^ Semple — Essentials of Pathology and Morbid Anatomy, 27 Senn — Pathology and Surgical Treat- ment of Tumors, 27 Stengel— Text- Book of Pathology, . . 28 Warren — Surgical Pathology and Thera- peutics, . . • • 31 PHYSIOLOGY. An American Text-Book of Physi- ology, • ■ 7 Hare — Essentials of Physiology, ... 14 Raymond — Manual of Physiology, . . 21 Stewart — Manual of Physiology, ... 29 PRACTICE OF MEDICINE. An American Text-Book of the The- ory and Practice of Medicine, • • • • 7 An American Year-Book of Medicine and Surgery, ■••„■■" r ^ Anders— Text-Book of the Practice of Medicine, . r ^ Lockwood— Manual of the Practice of Medicine, . • r '■' Morris— Essentials of the Practice of Medicine, ' W ' •' ' r ^9 Stevens— Manual of the Practice ol Medicine 29 SKIN AND VENEREAL. An American Text-Book of Genito- urinary and Skin Diseases, . . - . • 5 Hyde and Montgomery— Syphilis and the Venereal Diseases, . . • '5 Martin — Essentials of Minor Surgery, Bandaging, and Venereal Diseases, . 18 Pringle — Pictorial Atlas of Skin Dis- eases and Syphilitic Affections, ... 21 Stelwagon — Essentials of Diseases of the Skin, . . ... 28 SURGERY. An American Text-Book of Surgery, 7 An American Year-Book of Medicine and Surgery . . 8 Beck — Fractures 9 Beck — Manual of Surgical Asepsis, . . 9 DaCosta — Manual of Surgery 12 International Text-Book of Surgery, . 15 Keen— Operation Blank, 17 Keen — The Surgical Complications and Sequels of Typhoid Fever 17 Macdonald — Surgical Diagnosis and Treatment, 18 Martin— Essentials of Minor Surgery, Bandaging, and Venereal Diseases, . 18 Martin— Essentials of Surgery, . . .18 Moore— Orthopedic Surgery, 19 Nancrede- Principles of Surgery, . 20 Pye— Bandaging and Surgical Dressing, 21 Scudder— Treatment of Fractures, . . 26 Senn— Genito-Urinary Tuberculosis, . 27 Senn — Syllabus of Surgery 27 Senn — Pathology and Surgical Treat- ment of Tumors, ... ... 27 Warren — Surgical Pathology and Ther- apeutics, • '3' URINE AND URINARY DISEASES. Saundby — Renal and Urinary Diseases, 26 Wolff— Essentials of Examination of Urine 31 MISCELLANEOUS. Abbott — Hygiene of Transmissible Dis- eases, . ' 1^ Bastin — Laboratory Exercises in Bot- any, • • ; Gould and Pyle — Anomalies and Curi- osities of Medicine, . . • Grafstrom— Massage, . . • ■ • • Keating— Hovir to Examine for Lite Insurance, ' . • ° Rowland and Hedley— Archives ol the Roentgen Ray, • ■ Saunders' Medical Hand-Atlases. . 2, 3 Saunders' New Series of Manuals, 24, Saunders' Pocket Medical Formulary, Saunders' Question-Compends, 22, Senn— Pathology and Surgical Ireat- ment of Tumors, . , i- Stewart and Lawrance— Essentials of Medical Electricity, . • • • ■ Thornton— Dose-Book and Manual of Prescription-Writing, . . ^, Van Valzah and Nisbet-Diseases of the Stomach, 9 13 14 16 21 , 4 2, 26 23 27 29 30 3a BOOKS JUST ISSUED. THE AMERICAN ILLUSTRATED MEDICAL DICTIONARY. For Students and Practitioners* A Complete Dictionary of the Terms used in Medi- cine and the Allied Sciences, with a large number of Valuable Tables and Numerous Handsome Illustrations. Edited by W. A. Newman Dorland, M. D., Editor of the American Pocket Medical Dictionary. Handsome large octavo, 800 pages, bound in full limp leather, and printed on thin paper of the finest quality, forming a handy volume, only ij^ inches thick. This is an entirely new and unique work, intended to meet the need of practitioners and students for a complete, up-to-date dictionary of moderate price. The book is designed to furnish a maximum amount of matter in a minimum space and at the lowest possible cost. It contains double the material in the ordinary students' dictionary, and yet, by the use of a clear, condensed type and thin paper of the finest quality, is only i^i inches in thickness. It is bound in full flexible leather, and is just the kind of a book that a man will want to keep on his desk for constant reference. The book makes a special feature of the newer words, and defines hundreds of important terms not to be found in any other dictionary. It is especially full in the matter of tables, containing more than a hundred of great practical value. A new feature is the inclusion of numerous handsome illustrations, many of them in colors, drawn and engraved specially for this book. These have been chosen with great care and add infinitely to the value of the work. The book will appeal to both practitioners and students, since, besides a complete vocabulary, it gives to the more important subjects extended consideration of an encyclopedic character. BOHM, DAVIDOFF, AND HUBER'S HISTOLOGY. A Text-Book of Human Histology. Including Microscopic Technic. By Dr. A. A. BiJHM and Dr. M. von Davidoff, of Munich, and G. C. Huber, M. D., Junior Professor of Anatomy and Histology, University of Michigan. FRIEDRICH AND CURTIS ON THE NOSE, THROAT, AND EAR. Rhinology, Laryngology, and Otology in their Relations to General Medicine. By Dr. E. P. Friedrich, of the University of Leipsig. Edited by H. HoLBROOK Curtis, M. D., Consulting Surgeon to the New York Nose and Throat Hospital. LEROY'S HISTOLOGY. The Essentials of Histology. By Louis Leroy, M. D., Professor of Histology and Pathology, Vanderbilt University, Nashville, Tennessee. OQDEN ON THE URINE. Clinical Examination of the Urine. By J. Bergen Ogden, M. D., Assistant in Chemistry, Harvard Medical School. Handsome octavo volume of over 408 pages, with 54 illustrations and 1 1 full-page plates, many in colors. PYLE'S PERSONAL HYGIENE. A Manual of Personal Hygiene. Edited by Walter L. Pyle, M. D., Assist- ant Surgeon to Wills Eye Hospital, Philadelphia. Octavo volume of 344 pages, fully illustrated. SALINGER AND KALTEYER'S MODERN MEDICINE. Modern Medicine. By Julius L. Salinger, M. D., Demonstrator of Clinical Medicine, Jefferson Medical College, and F. J. Kalteyer, M. D., Assistant Demon- strator of Clinical Medicine, Jefferson Medical College. Handsome octavo volume of over 800 pages, fully illustrated. STONEY'S SURGICAL TECHNIC FOR NURSES. Surgical Technic for Nurses. By Emily A. M. Stoney, late Superintendent of the Training-School for Nurses, Carney Hospital, South Boston, Massachusetts.