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Cornell University Library QP 401.C22 1915
Bodily changes in pain hunger fear and
3 1924 022 542 470
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Cornell University Library
The original of tliis book is in tlie Cornell University Library.
There are no known copyright restrictions in the United States on the use of the text.
http://www.archive.org/details/cu31924022542470
BODILY CHANGES IN PAIN, HUNGER, FEAR AND RAGE
AN ACCOUNT OF RECENT RE- SEARCHES INTO THE FUNCTION OF EMOTIONAL EXCITEMENT
BY , •
WALTER B.' CANNON
GEOBGB HIGGINSON PROFESSOR OF PH78IOLOOT IN HARVARD UNIVERSITY
NEW YORK AND LONDON D. APPLETON AND COMPANY
1915
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,^,^lgoG'i
Copyright, 1915, by D. APPLETON AND COMPANY
Printed in the United States of America
TO MY COLLABORATORS IN THESE RESEARCHES
DANIEL DE LA PAZ ALFRED T. SHOHL WADE S. WEIGHT ARTHUR L. WASHBURN HENRY LYMAN LEONARD B. NICE CHARLES M. GRUBER HOWARD OSGOOD HORACE GRAY WALTER L. MENDENHALL
WITH PLEASANT MEMORIES OF OUR WORK TOGETHER
PREFACE
Fear, rage and pain, and the pangs of hunger are all primitive experiences which human beings share with the lower animals. These experiences are properly classed \ as among the most powerful that determine the action of ^ men and beasts. A knowledge of the conditions | which attend these experiences, therefore, is of general and fundamental importance in the interpretation of behavior.
During the past four years there has been conducted,l\ in the Harvard Physiological Laboratory, a series of in- vestigations concerned with the bodily changes which ' occur in conjunction with pain, hunger and the major emotions. A group of remarkable alterations in the bodily economy have been discovered, all of which can reasonably be regarded as responses that are nicely adapted to the individual's welfare and preservation. Because these physiological adaptations are interesting both in themselves and in their interpretation, not only to physiologists and psychologists, but to others as well, it has seemed worth while to gather together in con- venient form the original accounts of the experiments, which have been published in various American medical and physiological journals. I have, however, attempted to arrange the results and discussions in an orderly and consecutive manner, and I have tried also to elim-
vii
viii PREFACE
inate or incidentally to explain the technical terms, so that the exposition will be easily understood by any intelligent reader even though not trained in the med- lical sciences.
My first interest in the conditions attending pain, hunger and strong emotional states was stimulated dur- ing the course of a previous series of researches on the imotor activities of the alimentary canal. A summary of these researches appeared in 1911, under the title, "The Mechanical Factors of Digestion." The studies recorded in the present volume may be regarded as a natural sequence of observations on the influence of emotional states on the digestive process, which were reported in that volume.
W. B. Cannon.
CONTENTS
CHAPTEE I
PAGES
THE EFFECT OF THE EMOTIONS ON DIGESTION
Emotions favorable to normal secretion of the digestive juices — ^Emotions unfavorable to normal secretion of the digestive juices — Emotions favorable and un- favorable to contractions of the stomach and in- testines— The disturbing effect of pain on di- gestion 1-21
CHAPTEE II i/^
THE GENERAL ORGANIZATION OF THE VIS- CERAL NERVES CONCERNED IN EMOTIONS
The outlying neurones — The three divisions of the out- lying neurones — The extensive distribution of neu- rones of the "sympathetic" or thoracico-lumbar di- vision and their arrangement for diffuse action — The arrangement of neurones of the cranial and sacral divisions for specific action — The cranial division a conserver of bodily resources — The sacral division a group of mechanisms for emptying — The sympa- thetic division antagonistic to both the cranial and the sacral— Neurones of the sympathetic division and adrenal secretion have the same action 22-39
ix
X CONTENTS
CHAPTER III
PAGES
METHODS OF DEMONSTRATING ADRENAL SECRE- TION AND ITS NERVOUS CONTROL
The evidence that splanchnic stimulation induces ad- renal secretion — The question of adrenal secretion in emotional excitement — The method of securing blood from near the adrenal veins — The method of testing the blood for adrenin 40-51
CHAPTER IV
ADRENAL SECRETION IN STRONG EMOTIONS AND PAIN
The evidence that adrenal secretion is increased in emo- tional excitement — The evidence that adrenal secre- tion is increased by "painful" stimulation — Confirma- tion of our results by other observers .... 52-65
CHAPTER V
THE INCREASE OF BLOOD SUGAR IN PAIN AND GREAT EMOTION
Glycosuria from pain — Emotional glycosuria — The role of the adrenal glands in emotional glycosuria . 66-80
CHAPTER VI
IMPROVED CONTRACTION OF FATIGUED MUSCLE AFTER SPLANCHNIC STIMULATION OF THE ADRENAL GLAND
The nerve-muscle preparation — The splanchnic prepara- tion— The effects of splanchnic stimulation on the contraction of fatigued muscle — The first rise in the muscle record — The prolonged rise in the muscle record — The two factors : arterial pressure and adre- nal secretion 81-94
CONTENTS xi
CHAPTEE VII
PAGES
THE EFFECTS ON CONTRACTION OF FATIGUED MUSCLE OF VARYING THE ARTERIAL BLOOD PRESSURE The effect of increasing arterial pressure — The effect of decreasing arterial pressure — An explanation of the effects of varying the arterial pressure — The value of increased arterial pressure in pain and strong emotion 95-109
CHAPTEE VIII
THE SPECIFIC r6lE OP ADRENIN IN COUNTER- ACTING THE EFFECTS OF FATIGUE
Variations of the threshold stimulus as a measure of irritability — The method of determining the threshold stimulus — The lessening of neuro-muscular irrita- bility by fatigue — The slow restoration of fatigued muscle to normal irritability by rest — jThg^uick res- toration of fatigued muscle to norrnM irritability by adrenin — The evidence that the restorative ac- tion of adrenin is specific — The point of action of adrenin in muscle 110-134
CHAPTEE IX
THE HASTENING OF THE COAGULATION OF BLOOD r- BY ADRENIN
The graphic method of measuring the coagulation time — The effects of subcutaneous injections of adrenin — The effects of intravenous injections — The hastening of coagulation by adrenin not a direct effect on the blood . . . . / 135-160
CHAPTEE X
THE HASTENING OF COAGULATION OF BLOOD IN PAIN AND GREAT EMOTION
Coagulation hastened by splanchnic stimulation — Co- agulation not hastened by splanchnic stimulation if
xii CONTENTS
PAGES
the adrenal glands are absent — Coagulation hast- ened by "painful" stimulation — Coagulation hastened in emotional excitement 161-183
CHAPTEE SI
THE UTILITY OF THE BODILY CHANGES IN PAIN AND GREAT EMOTION
The reflex nature of bodily responses in pain and the major emotions, and the useful character of re- flexes— The utility of the increased blood sugar as a source of muscular energy — The utility of in- creased adrenin in the blood as an antidote to the effects of fatigue — The question whether adrenin normally secreted inhibits the use of sugar in the body — The vascular changes produced by adrenin favorable to supreme muscular exertion — The changes in respiratory function also favorable to great effort — The effects produced in asphyxia similar to those produced in pain and excitement — The utility of rapid coagulation in preventing loss of blood . 184-214
'''^CHAPTER XII
THE ENERGIZING INFLUENCE OF EMOTIONAL EX- CITEMENT
"Reservoirs of power" — The excitements and energies of competitive sports — Frenzy and endurance in cere- monial and other dances — The fierce emotions and struggles of battle — The stimulating influence of witnesses and of music — The feeling of power . 215-231
^ CHAPTER XIII THE NATURE OF HUNGER
Appetite and hunger — The sensation of hunger — The theory that hunger is a general sensation — Weak- ness of the assumptions underlying the theory that hunger is a general sensation — Body need may exist without hunger — The theory that hunger is of gen-
CONTENTS xiii
PAGES
eral origin does not explain the quick onset and the periodicity of the sensation — The theory that hunger is of general origin does not explain the local refer- ence— Hunger not due to emptiness of the stomach — Hunger not due to hydrochloric acid in the empty stomach — ^Hunger not due to turgescence of the gas- tric mucous membrane — Hunger the result of con- tractions— The "empty" stomach and intestines con- tract— Observations suggesting that contractions cause hunger — The concomitance of contractions and hunger in man 232-266
•^CHAPTER XIV
THE INTERRELATIONS OF EMOTIONS
^Antagonism between emotions expressed in the sym- pathetic and in the cranial divisions of the auto- nomic system — Antagonism between emotions ex- pressed in the sympathetic and in the sacral di- visions of the autonomic system — The function of hunger — The similarity of visceral effects in differ- ent strong emotions and suggestions as to its psy- chological significance 267-284
CHAPTER XV
ALTERNATIVE SATISFACTIONS FOR THE FIGHT- ING EMOTIONS
Support for the militarist estimate of the strength of the fighting emotions and instincts — Growing op- position to the fighting emotions and instincts as displayed in war — The desirability of preserving the martial virtues — Moral substitutes for warfare — ^Phy- sical substitutes for warfare — The significance of in- ternational athletic competitions 285-301
^
A LIST OF PUBLISHED RESEARCHES FROM THE PHYSIOLOGICAL LABORATORY IN HARVARD UNIVERSITY 302-303
INDEX 305
BODILY CHANGES m PAIJ^, HUJ^GER, FEAR AI^D RAGE
CHAPTER I
THE EFFECT OF THE EMOTIONS ON DIGESTION
The doctrine of Imman development from sub- human antecedents lias done much to unravel the complex nature of man. As a means of interpre- tation this doctrine has been directed chiefly toward the solving of puzzles in the peculiarities of anatomical structure. Thus arrangements in the human body, which are without obvious util- ity, receive rational explanation as being vestiges of parts useful in or characteristic of remote an- cestors— parts retained in man because of age- long racial inheritance. This mode of interpreta- tion has proved applicable also in accounting for functional peculiarities. Expressive actions and( gestures — the facial appearance in anger, for ex-' ample — observed in children and in widely dis- tinct races, are found to be innate, and are best explained as the retention in human beings of responses which are similar in character in lower animals.
2 BODILY CHANGES
From this point of view biology has contributed much to clarify our ideas regarding the motives of human behavior. The social philosophies which prevailed during the past century either assumed that conduct was determined by a cal- culated search for pleasure and avoidance of pain or they ascribed it to a vague and undefined faculty named the conscience or the moral sense. Comparative study of the behavior of men and of lower animals under various circumstances, however, especially with the purpose of learning the source of prevailing impulses, is revealing the inadequacy of the theories of the older psychol- ogists. More and more it is appearing that in men of all races and in most of the higher ani- mals, the springs of action are to be found in the tafluence of_certain emotions which express themselves in characteristic instinctive act^.
The role which these fundamental responses in the higher organisms play in the bodily economy has received little attention. As a realm for in- vestigation the bodily changes in emotional ex- citement have been left by the physiologists to the philosophers and psychologists and to the students of natural history. These students, how- ever, have usually had too slight experience in the detailed examination of bodily functions to permit them to follow the clues which superficial observation might present. In consequence our
EMOTIONS AND DIGESTION 3
knowledge of emotional states has been meagre. There are, of course, many surface manifesta- tions of excitement. The contraction of blood vessels with resulting pallor,' the pouring out of "cold sweat," the stopping of saliva-flow so that the "tongue cleaves to the roof of the mouth," the dilation of the pupils, the rising of the hairs, the rapid beating of the heart, the hurried respira- tion, the trembling and twitching of the muscles, especially those about the lips — all these bodily ] changes are well recognized accompaniments of pain and great emotional disturbance, such as -f^r^ horror and deep disgust. But these dis- / turbances of the even routine of life, which have been commonly noted, are mainly superficial and therefore readily observable. Even the increased rapidity of the heart beat is noted at the surface in the pulsing of the arteries. There^re, how- ever^^other organs, hidden deep— io—the-^body, which do not reveal so obviously as the struc- tures near or in the 's1on^""tEe disturbances of action which attend states of intense feeling. Special methods^'musT he used to deteraiine whether thjesedeep-Jying organs also are included in the complex of an emotional* agitation.
* In the T^g of the term "emotign", the meaning here is not restricted tit violent affective states, but includes "feel-, mgs" and other affective experiences. At times, also, in order to avoid awkward expressions, the term is used in the popular manner, as if the "feeling" caused the bodily change.
A BODILY CHANGES
Among the organs that are affected to an im- portant degree by feelings are those concerned with digestion. And the relations of feelings to the activities of the alimentary canal are of par- ticular interest, because recent investigations have shoAvn that not only are the first stages of the digestive process normally started by the pleasur- able taste and smell and sight of food, but also ( that pain and great emotional excitement can seriously interfere with the starting of the pro- cess or its continuation after it has been started. Thus there may be a conflict of feelings and of their bodily accompaniments — a conflict the inter- esting bearing of which we shall consider later.
Emotions Favorable to Normal Secretion of the Digestive Juices
The feelings or affective states favorable to the digestive functions have been studied fruit- fully by Pawlow,^ of Petrograd, through in- genious experiments on dogs. By the use of care- ful surgical methods he was able to make a side pouch of a part of the stomach, the cavity of which was wholly separate from the main cavity in which the food was received. This pouch was supplied in a normal manner with nerves and blood vessels, and as it opened to the surface of the body, the amount and character of the. gastric juice secreted by it under various conditions
EMOTIONS AND DIGESTION 5
could be accurately determined. Secretion by that part of the stomach wall which was included in the pouch was representative of the secretory activities of the entire stomach; The arrange- ment was particularly advantageous in providing the gastric juice unmixed with iood. In some of the animals thus operated upon an opening was also made in the esophagus so that when the fQiM^a^s-swaile3sSkd7itdid~not pass to the stom- r ach but propped out on the way. All the pleas- ures of eating were thus experienced, and there was no necessity of stopping because of a sense of fulness. This process was called "sham feed- \ ingj.' The well-being of these animals was care- fully attended to, they lived the normal life of dogs, and in the course of months and years be- came the pets of the laboratory.
By means of sham feeding Pawlow showed that the chewing and swallowing of food which the dogs relishedi.resulted, after a delay of about five minutes, in a flow of natural gastric juice from the side pouch of the stomach — a flow which per- sisted as long as the dog chewed and swallowed the food, and continued for some time after eat- ing ceased. Evidently the presence of food in the stomach is not a prime condition for gastric secretion. And since the flow occurred only when the dogs had an appetite, and the material pre- sented to them was agreeable, the conclusion
BODILY CHANGES
as justified that this was a ivTiB-'^psjchie jcretion.
The mere sight or smell of a favorite food may tart the pouring out of gastric juice, as was oted many years ago by Bidder and Schmidt ^ 1 a hungry dog which had a fistulous opening irough the body wall into the stomach. This bservation, reported in 1852, was confirmed later y Schiff and also still later by Pawlow. That le mouth "watej*^" "with a flow of saliva when alatable food is seen or smelled has long been ach common knowledge that the expression, "It lakes my mouth water," is at once recognized as le highest testimony to the attractiveness of an ppetizing dish. That the stomach also "waters" 1 preparation for digesting the food which is to e taken is clearly proved by the above cited ob- Brvations on the dog.
The importance of the initial psychic secretion f saliva for further digestion is indicated when, 1 estimating the function of taste for the pleas- res of appetite, we realize that materials can e tasted only when dissolved in the mouth and lereby brought into relation with the taste or- ans. The saliva which "waters" the mouth as- ures the dissolving of dry but soluble food even ^hen it is taken in large amount.
The importance of the initial psychic secretion f gastric juice is made clear by the fact that con-
"EMOTIONS AND DIGESTION 7
timiance of the flow of tMs juice during diges- tion is provided by the action of its acid or its digestive products on the mucous membrane of the pyloric end of the stomach, and that secre- tion of the pancreatic juice and bile are called forth by the action of this same acid on the mu- cous membrane of the duodenum. _The_proper starting of the digesjdve. process, therefore, ,i8 conditioned by the satisfactions of the palate,and fhe~cons equent flow of the first digestive fluids., The facts brought out experimentally in studies on lower animals are doubtless true also of man. Not very infrequently, because of the accidental swallowing of corrosive substances, the esopha- gus is so injured that, when it heals, the sides grow together and the tube is closed. Under these circumstances an opening has to be made into the stomach through the side of the body and then the individual chews his food in the usual manner, but ejects it from his mouth into a tube which is passed through the gastric opening. The food thus goes from mouth to stomach through a tube outside the chest instead of inside the chest. As long ago as 1878, Eichet,* who had occasion to study a girl whose esophagus was closed and who was fed through a gastric fistula,, reported that whenever the girl chewed or tasted | a highly sapid substance, such as sugar or lemon \ juice, while the stomach was empty, there flowed I
8 BODILY CHANGES
from the fistula a considerable quantity of gastric juice. A number of later observers * have had similar cases in human beings, especially in chil- dren, and have reported in detail results which correspond remarkably with those obtained in the laboratory. Hornborg* found that when the little boy whom he studied chewed agreeable food a more or less active secretion of gastric juice invariably started, whereas the chewing of an indifferent substance, as gutta-percha, was fol- lowed by no secretion. All these observations clearly demonstrate that the normal flow of the first digestive fluids, the saliva and the gastric juice, is favored by the pleasurable feelings which accompany the taste and smell of food dur- ing mastication, or which are roused in anticipa- tion of eating when choice morsels are seen or smelled.
These facts are of fundamental importance in the serving of food, especially when, through ill- ness, the appetite is fickle. The degree of dainti- ness with which nourishment is served, the little attentions to esthetic details — the arrangement of the dishes, the small portions of food, the flower beside the plate — all may help to render food pleasing to the eye and savory to the nos- trils and may be the deciding factors in determin- ing whether the restoration of strength is to be- gin or not.
EMOTIONS AND DIGESTION 9
Emotions Unfavorable to the Normal Secretion of the Digestive Juices
The conditions favorable to proper digestion are wholly abolished when unpleasant feelings such as vexation and worry and anxiety, or great emotions such as anger and «f ear, are allowed to) prevail. This fact, so far as the salivary secre- tion is concerned, has long' been known. The dry mouth of the anxious person called upon to speak in public is a common instance; and the "ordeal of rice," as employed in India, was a prac- tical utilization of the knowledge that excitement is capable of inhibiting the salivary flow. When several persons were suspected of crime, the con- secrated rice was given to them all to chew, and after a short time it was spit out upon the leaf of the sacred fig tree. If anyone ejected it dry, that was taken as proof that fear of being discovered had stopped the secretion, and consequently he was adjudged guilty.^
What has long been recognized as true of the secretion of saliva has been provedOtrue also of the secretion of gastric juice. ^^ For example, Hornborg was unable to confirm in his little pa- tient with a gastric fistula the observation by Pawlow that when hunger is present the mere seeing of food results in a flow of gastric juice. Hornborg explained the difference between his and Pawlow's results by the different ways '•in
\
10 BODILY CHANGES
which, the boy and the dogs faced the situation. When food was shown, but withheld, the hungry dogs were all eagerness to secure it, and the juice very soon began to flow. The boy, on the con- trary, became vexed when he could not eat at once, and began to c^y; then no secretion ap- peared. Bogen also has reported the instance of a child with closed esophagus and gastric fistula, who sometimes fell into such a passion in con- sequence of vain hoping for food that the giving of the food, after the child was calmed^was not followed by any flow of the secretion.
The inhibitory influence of excitement has i^lso been seen in lower animals under laboratory con- ditions. Le Conte " declares that in studying gastric secretion it is necessary to avoid all cir- cumstances likely to provoke emotional reactions. In the fear which dogs manifest when first brought into strange surroundingsJie found that activity of the gastric glands may be completely suppressed. The suppression occurred even if the dog had eaten freely and was then disturbed — as, for example, by being tied to a table. "When the animals became accustomed to the experi- mental procedure, it no longer had an inhibitory effect. The studies of Bickel and Sasaki "^ con- firm and define more precisely this inhibitory effect of strong emotion on gastric secretion. They observed the inhibition on a dog with an
EMOTIONS AND DIGESTION 11
esophageal fistula, and with, a side pouch of the stomach, which, as in Pawlow's experiments, opened only to the exterior. In this dog Bickel and Sasaki noted, as Pawlow had, that sham feed- ing was attended by a copious flow of gastric juice, a true psychic secretion, resulting from the pleasurable taste of the food, (in a typical in-j stance the sham feeding lasted five minutes, and the secretion continued for twenty minuteg^, dur-j ing which time 66.7 cubic centimeters of pure gas- tric juice were produced.
vx\
On another day a cat was brought into the V^ v V ; ; presence of the dog, whereupon the dog flew into "^^^ , ^s,^i a great fury. The cat was soon removed, and ^^ '\/J'i' the dog pacified. Now the dog was again given \. >^^ the sham feeding for five minutes. In spite of "^ the fact that the animal was hungry and ate eagerly, there was no secretion worthy of men- tion. During a period of twenty minutes, cor- responding to the previous observation, only 9 cubic centimeters of acid fluid were produced, and this was rich in mucus. It is evident that in the dog, as in the boy observed by Bogen, strong emo- tions can so profoundly disarrange the mechanisms ^yK of secretion that the pleasurable excitation which accompanies the taking of food cannot cause th0 normal flow.
On another occasion Bickel and Sasaki started gastric secretion in the dog by sham feeding, and
12 BODILY CHANGES
when the flow of gastric juice had reached a cer- tain height, the dog was infuriated for five min- utes by the presence of the cat. During the next (fifteen minutes there appeared only a few drops ' of a very mucous secretion. Evidently in this instance a physiological process, started as an accompaniment of a psychic state quietly pleas- urable in character, was almost entirely stopped after another psychic state violent in character. It is noteworthy that in both the favorable and unfavorable results of the emotional excitement illustrated in Bickel and Sasaki's dog the effects persisted long after the removal of the exciting condition. This fact, in its favorable aspect, Bickel ^ was able to confirm in a girl with esophageal and gastric fistulas; the gastric se- cretion long outlasted the period of eating, al- though no food entered the stomach. (_ The in- fiuences unfavorable to digestion, however, are stronger than those which promote it. And evidently, if the digestive process, because of emotionah disturbance, is for some time inhibited, the swallowing of food which must lie stagnant in the stomach is a most irrational procedure.^ If a child has experienced an outburst of passion, it is well not to urge the taking of nourishment soon afterwards. Macbeth's advice that "good diges- tion wait on appetite and health on both," is now well-founded physiology.
EMOTIONS AND DIGESTION 13
Other digestive glands than the salivary and the gastric may be checked ia emotional excite- ment. Eecently Oechsler^ has reported that in such psychic disturbances as were shown by Bickel and Sasaki to be accompanied by sup- pressed secretion of the gastric juice, the secre- tion of pancreatic juice may be stopped, and the | flow of bile definitely checked. All the means of bringing about chemical changes in the food may be thus temporarily abolished.
Emotions Favorable and Unfavorable to the Contractions OP THE Stomach and Intestines
The secretions of' the digestive glands and the chemical changes wrought by them are of little worth unless the food is carried onward through the alimentary canal into fresh regions of diges- tion and is thoroughly exposed to the intestinal wall for absorption. In studying these mechani- cal aspects of digestion I was led to infer ^^ that (^just as there is a psychic secretion, so likei wise there is probably a "psychic tone" or "psy-l chic contraction" of the gastro-intestinal musclesl as a result of taking food. For if the vagus nerve supply to the stomach is cut immediately before an animal takes food, the usual contractions of y the gastric wall, as seen by the Eontgen rays, dc not occur; but if these nerves are cut after fooc has been eaten with relish, the contractions which
14 BODILY CHANGES
have started continue without cessation?^ The nerves in both conditions were severed under anesthesia, so that no element of pain entered into the experiments. In the absence of hunger, which in itself provides a contracted stomach,^^ the pleasurable taking of food may, therefore, be a primary condition for the appearance of natural contractions of the gastro-intestinal canal.
Again just as the secretory activities of the stomach are unfavorably influenced by strong emotions, so also are the movements of the stom- ach; and, indeed, the movements of almost the entire alimentary canal are wholly stopped dur- ing great excitement. In my earliest observa- tions on the movements of the stomach ^^ I had difficulty because in some animals the waves of contraction were perfectly evident, while in others there was no sign of activity. Several weeks passed before I discovered that this difference was associated with a difference of sex. In order to be observed with Eontgen rays the animals were restrained in a holder. Although the holder was comfortable, the male cats, particularly the young males, were restive and excited on being fastened to it, and under these circumstances gastric peristaltic waves were absent; the female cats, especially if elderly, usually submitted with calmness to the restraint, and in them the waves had their normal occurrence. Once a female with
EMOTIONS AND DIGESTION 15
kittens turned from her state of quiet content- ment to one of apparent restless anxiety. The movements of the stomach immediately stopped, the gastric wall became wholly relaxed, and only after the animal had been petted and began to purr did the moving waves start again on their course, (^y covering the cat's mouth and nose\ with the fingers until a slight distress of breath- 1 ing is produced, the stomach contractions can be j stopped at willT^ In the cat, therefoje, anv sign[ilh of^ rage or fear, such as was seen in dogs by Le / Conte and by Bickel and Sasaki(was accompanied! J by a total abolition of the movements of the! stomach.y Even indications of slight anxiety may be attended by complete absence of the churning waves. In a vigorous young male cat I have watched the stomach for more than an hour by means of the Eontgen rays, and during that time not the .slightest beginning of peristaltic activity appeared; yet the only visible indication of ex- citement in the animal was a continued quick twitching of the tail to and fro. What is true of the cat I have found true also of the rabbit, dog and guinea-pig ^* — ^very mild emotional dis- turbances are attended by abolition of peristalsis. The observations on the rabbit have been con- firmed by Auer,^* who found that the handling of the animal incidental to fastening it gently to a holder stopped gastric peristalsis for a
16 BODILY CHANGES
variable length of time. And if the animal was startled for any reason, or struggled excitedly, peristalsis was again abolished. The observa- tions on the dog also have been confirmed; Lom- meP^ found that small dogs in strange sur- roundings might have no contractions of the stomach for two or three hours. And whenever the animals showed any indications of being un- comfortable or distressed, the contractions were inhibited and the discharge of contents from the stomach checked.
Like the peristaltic waves in the stomach, the
peristalsis and the kneading movements (seg-
// t mentation) in the small intestine, and the re-
; versed peristalsis in the large intestine all cease
' whenever the observed animal shows signs of
; emotional excitement.
There is no doubt that just as the secretory activity of the stomach is affected in a similar fashion in man and in lower animals, so likewise gastric and intestinal peristaltic waves are stopped in man as they are stopped in lower ani- mals, by worry and anxiety and the stronger f affective states. (^ The conditions of mental discord \ may thus give rise to a sense of gastric inertia. For example, a patient described by Miiller ^^ testified that anxiety was always accompanied by a feeling of weight, as if the food remained in the stomach. Every addition of food caused an
EMOTIONS AND DIGESTION 17
increase of the trouble. Strong emotional states in this instance led almost always to gastric dis- tress, which persisted, according to the grade and the duration of the psychic disturbance, between a half-hour and several days. The patient was not hysterical or neurasthenic, but was a very sensitive woman deeply affected by moods.
The feeling of heaviness in the stomach, men-| tioned in the foregoing case, is not uncommonlj complained of by nervous persons, and may be due to stagnation of the contents. That sue! stagnation occurs is shown by the following in- stance. A refined and sensitive woman, who had had digestive difficulties, came with her husband to Boston to be examined. They went to a hotel for the night. The next morning the woman ap- peared at the consultant's office an hour after having eaten a test meal. An examination of the gastric contents revealed no free acid, no diges- tion of the test breakfast, and the presence of a considerable amount of the supper of the pre- vious evening. The explanation of this stagna- tion of the food in the stomach came from the family doctor, who reported that the husband had made the visit to the city an occasion for be- coming uncontrollably drunk, and that he had by his escapades given his wife a night of turbu- lent anxiety. The second morning, after the woman had had a good rest, the gastric eon-
18 BODILY CHANGES
tents were again examined; the proper acidity was found, and the test breakfast had been nor- mally digested and discharged.
These cases are merely illustrative and doubt- less can be many times duplicated in the experi- ence of any physician concerned largely with di- gestive disorders., -^Indeed, the opinion has been expressed that a great majority of the cases of gastric indigestion that come for treatment are functional in character and of nervous origin. It is the emotional element that seems most char- acteristic of these cases.^To so great an extent is this true that Rosenbach has suggested that as a term to characterize the cause of the distur- bances, Q"emotional" dyspepsia is better than "nervous" dyspepsia.^'^
The Disturbing Effect of Pain on Digestion
The advocates of the theory of organic evolu- tion early pointed out the similarity between the bodily disturbances in pain and in the major emo- tions. The alterations of function of internal or- gans they could not know about. The general statement, however, that pain evokes the same changes that are evoked by emotion, is true also M these deep-lying structures. Wertheimer^^ proved many years since that stimulation of a I sensory nerve in an anesthetized animal — such Istimulation as in a conscious animal would in-
<
EMOTIONS AND DIGESTION 19
duce pain — quickly abolished the contractions of the stomach. And Netschaiev, working in Paw- low's ^® laboratory, showed that excitation of the sensory fibres in the sciatic nerve for two or three minutes resulted ia an inhibition of the secretion of gastric juice that lasted for several hours. Similar effects from painful experience have been not uncommonly noted in human be- ings. Mantegazzaj^"* in his account of the physi- ology of pain, has cited a number of such ex- amples, and from them he has concluded tha1(pain^ > interferes with digestion by lessening appetite and by producing various forms of dyspepsia, with arrest of gastric digestion, and with vomit- ing and diarrhea.^ The expression, "sickening, pain" is testimony to the power of strong sensory stimulation to upset the digestive processes pro- foundly. Vomiting is as likely to follow violent pain as it is to follow strong emotion. A "sick headache" may be, indeed, a sequence of events in which the pain from the headache is primary, and the nausea and other evidences of digestive disorder are secondary.
As the foregoing account has shown, emotional conditions or "feelings" may be accompanied by quite opposite effects in the alimentary canal, some highly favorable to good digestion, some highly disturbing. It is an interesting fact that the feelings having these antagonistic actions are
^
20 BODILY CHANGES
typically expressed through nerve supplies which are correspondingly opposed in their influence on the digestive organs. The antagonism between these nerve supplies is of fundamental impor- tance in understanding not only the operation of conditions favorable or unfavorable to digestion but also in obtaining insight into the conflicts of emotional states. Since a consideration of the arrangement and mode of action of these nerves will establish a firm basis for later analysis and conclusions, they will next be considered.
EEFEEENCES
^ Pawlow : The Work of the Digestive Glands, London, 1902.
^ Bidder and Schmidt : Die Verdauungssafte und der StofFwechsel, Leipzig, 1852, p. 35.
^ Eiehet : Journal de I'Anatomie et de la Physiologie, 1878, xiv, p. 170.
* See Hornborg : Skandinavisches Archiv f iir Physiologie, 1904, XV, p. 248. Cade and Latarjet : Journal de Physiologie et Pathologie Generale, 1905, vii, p. 221. Bogen : Archiv f iir die gesammte Physiologie, 1907, cxvii, p. 156. Lavenson: Archives of Internal Medicine, 1909, iv, p. 271.
^ Lea : Superstition and Force, Philadelphia, 1892, p. 344. 8Le Conte: La Cellule, 1900, xvii, p. 291. ^ Bickel and Sasaki : Deutsche medizinische Wochen- schrift, 1905, xxxi, p. 1829.
* Bickel : Berliner klinische Wochensohrift, 1906, xliii, p. 845.
° Oechsler : Internationelle Beitrage zur Pathologie und Therapie der Ernahrungstorungen, 1914, v, p. 1.
1" Cannon : The Mechanical Factors of Digestion, London and New York, 1911, p. 200.
EMOTIONS AND DIGESTION 21
''■ Cannon and Washburn : American Journal of Physi- ology, 1912, xxix, p. 441.
^2 Cannon : The American Journal of Physiology, 1898, i, p. 38.
^^ Cannon : American Journal of Physiology, 1902, vii, p. xxii.
^* Auer : American Journal of Physiology, 1907, xviii, p. 356.
^° Lommel : Miinchener medizinische Wochenschrift, 1903, i, p. 1634.
^* Miiller : Deutsches Archiv f iir klinische Medicin, 1907, Ixxxix, p. 434.
" Eosenbach : Berliner klinische Wochenschrift, 1897, xxxiv, p. 71
18 Wertheimer : Archives de Physiologic, 1892, xxiv, p. 379.
1' Pawlow : Loc. cU., p. 56.
^^ Mantegazza : Fisiologia del Dolore, Florence, 1880, p. 123.
CHAPTER II
THE GENEKAL ORGANIZATION OF THE VISCERAL NERVES CONCERNED IN EMOTIONS
The structures of the alimentary canal which are brought into activity during the satisfactions of appetite or are checked in their activity during pain and emotional excitement are either the se- creting digestive glands or the smooth muscle which surrounds the canal. Both the gland cells and the smooth-muscle cells differ from other tells which are subject to nervous influence — those of striated, or skeletal, muscle — in not being directly under voluntary control and in being slower in their response. The muscle connected with the skeleton responds to stimulation within two or three thousandths of a second; the delay with gland cells and with smooth muscle is more likely to be measured in seconds than in fractions of a second.
The Outlying Neurones The skeletal muscles receive their nerve supply direct from the central nervous system, i. e., the
22
VISCERAL NERVES 23
nerve fibres distributed to these muscles are parts of neurones whose cell bodies lie within the brain or spinal cord. The glands and smooth muscles! /^ of the viscera, on the contrary, are, so far as is ;: now known, never innervated directly from the central nervous system.* The neurones reaching! out from the brain or spinal cord never come into immediate relation with the gland or smooth- muscle cells ; there are always interposed between the cerebrospinal neurones and the viscera extra neurones whose bodies and processes lie wholly outside the central nervous system. They are represented in dotted lines in Fig. 1. I have sug- gested that possibly these outlying neurones act as "transformers," modifying the impulses re- ceived from the central source (impulses suited to call forth the quick responses of skeletal muscle), and adapting these impulses to the peculiar, more slowly-acting tissues, the secreting cells and vis- ceral muscle, to which they are distributed.^
The outlying neurones typically have their cell bodies grouped in ganglia (Gr's, Fig. 1) which, in the trunk region, lie along either side of the spinal cord and in the head region and in the pelvic part of the abdominal cavity are disposed near the organs which the neurones supply. In some instances these neurones lie wholly within the
* The special case of the adrenal glands will be considered later.
Tear gland Dilator of pupil
Artery of salivary gland
Hair
Surface artery
Sweat gland
Heart
Hair
Surface artery ^-—^ Sweat gland
(l^^ Liver
Stomach
Visceral artery Spleen
Intestine
Adrenal gland
Hair
Surface artery
Sweat gland
Colon
Bladder
Rectum
Artery of ejrternal genitals
Figure 1. — Diagram of the more important distributions of the autonomic nervous system. The brain and spinal cord are repre- sented at the left. The nerves to skeletal muscles are not repre- sented. The preganglionic fibres of the autonomic system are in solid Unes, the postganglionic in dash-lines. The nerves of the cranial and sacral divisions are distinguished from those of the thoracioo-lumbar or "sympathetic," division by broader lines. A -|- mark indicates an augmenting effect on the activity of the organ; a — mark, a depressive or inhibitory effect. For further descrip- tion see text.
yiSCERAL NEEVES 25
structure which they innervate (see e. g., the heart and the stomach, Fig. 1). In other instances the fibres passing out from the ganglia — the so-called "postganglionic fibres" — may traverse long dis- tances before reaching their destination. The in- nervation of blood vessels in the foot by neurones whose cell bodies are in the lower trunk region is an example of this extensive distribution of the fibres.
The Three Divisions of the Outlying Neurones
As suggested above, the outlying neurones are connected with the brain and spinal cord by neurones. whose cell bodies lie within the central nervous organs. These connecting neurones, rep- resented in continuous lines in Fig. 1, do not pass out in a continuous series all along the cerebro- spinal axis. Where the nerves pass out from the spinal cord to the fore and hind limbs, fibres are not given off to the ganglia. Thus these connect- ing or "preganglionic" fibres are separated into three divisions. In front of the nerve roots for the fore limbs is the head or cranial division, be- tween the nerve roots for the fore limbs and those for the hind limbs is the trunk division (or thorad- ico-lumbar division, or, in the older terminology, the "sympathetic system"); and after the nerve roots for the hind limbs the sacral division.
This system of outlying neurones, with post-
26 BODILY CHANGES
ganglionic fibres innervating the viscera, and with preganglionic fibres reaching out to them from the cerebrospinal system, has been called by Langley, to whom we are indebted for most of our knowledge of its organization, the autonomic nervous system.^ This term indicates that the structures which the system supplies are not sub- ject to voluntary control, but operate to a large degree independently. As we have seen, a highly potent mode of influencing these structures is through conditions of pain and emotional excite- ment. The parts of the autonomic system — the cranial, the sympathetic, and the sacral— have a number of peculiarities which are of prime im- portance in accounting for the bodily manifesta- tions of such affective states.
The Extensive Distribution of Neurones of the "Sympa- thetic" Division and Their Arrangement for Diffuse Action
/The fibres of the sympathetic divisioiJ^differ from those of the other two divisions inybeing /aistributed through the body very widely. They go to the eyes, ^causing dilation of the pupils. They go to the heart and, when stimulated, they cause it to beat rapidly. They carry impulses to arteries and arterioles of the skin, the abdominal viscera, and other parts, keeping the smooth mus- cles of the vessel walls in a state of slight con-
VISCEEAL' NERVES 27
traction or tone, and thus serving to maintain an arterial pressure sufficiently higli to meet sud- den demands in any special region; or, in times of special discharge of impulses, to increase the tone and thus also the arterial pressure. They are distributed extensively to the smooth muscle attached to the hairs; and when they cause this muscle to contract, the hairs are erected. They go to sweat glands, causing the outpouring of sweat. These fibres pass also to the entire length of the gastro-intestinal canal. And the inhibi- ^ion of diges^ve activity which, ^ as . we have learned, occurs in pain and emotional states, i_s due to impulses which are conducted outward by the splanchnic nerves — the preganglionic fibres that reach to the great ganglia in the upper abdo- men (see Fig. 1) — and thence are spread by post- ganglionic fibres all along the gut.* They in- nervate likewise the genito-urinary tracts, causing contraction of the smooth muscle of the internal genital organs, and usually relaxation of the blad- der. Finally they affect the liver, releasing the storage of material there in a manner which may be of great service to the body in tiine of need. The extensiveness of the distribution of the fibres of the sympathetic division is one of its most prominent characteristics.
Another typical feature of the sympathetic di- vision is an arrangement of neurones for diffuse
28 BODILY CHANGES
discharge of tlie nerve impulses. As shown dia- grammatically in Fig. 1, the preganglionic fibres from the central nervous system may extend through several of the sympathetic ganglia and give off in each of them connections to cell bodies of the outlying neurones. Although the neurones which transmit sensory impulses from the skin into spinal cord have similar relations to nerve cells lying at ditferent levels of the cord, the op- eration in the two cases is quite different. In the spinal cord the sensory impulse produces di- rected and closely limited effects, as, for example, when reflexes are being evoked in a "spinal" ani- mal (i. e., an animal with the spinal cord isolated from the rest of the central nervous system), the left hind limb is nicely lifted, in response to a harmful stimulus applied to the left foot, without widespread marked involvement of the rest of the body in the response.* In the action of the sympathetic division, on the contrary, the con- nection of single preganglionic fibres with nu- merous outlying neurones seems to be not at all arranged for specific effects in this or that par- ticular region. There are, to be sure, in different circumstances variations in the degree of ac- tivity of different parts; for example, it is prob- able that dilation of the pupil in the cat occurs more readily than erection of the hairs. It may be in this instance, however, that specially direct
VISCEEAL NEEVES 29
pathways to the eye are present for common use in non-emotional states (in dim light, e. g.), and that only slight general disturbance in the central nervous system, therefore, would be necessary to send impulses by these well-worn courses. Thus for local reasons (dust, e. g.) tears might flow from excitation of the tear glands by sympathetic impulses, although other parts innervated by this same division might be but little disturbed. We have no means of voluntarily wearing these path- ways, however, and^both from anatomical and physiological evidence^ the neurone relations in the sympathetic division of the autonomic system seem devised for widespread diffusion of nervous impulses.
The Arrangement of Neurones of the Cranial and Sacral Divisions for Specific Action
The cranial and sacral autonomic divisions differ from the sympathetic in having only re- stricted distribution (see Fig. 1). The third cran- ial nerves deliver impulses from the brain to ganglia in which lie the cell bodies of neurones innervating smooth muscle only in the front of the eyes. The vagus nerves are distributed to the lungs, heart, stomach, and small intestine. As shown diagrammatically in Fig. 1, the out- lying neurones in the last three of these organs lie within the organs themselves. By this ar- rangement, although the preganglionic fibres of
30 BODILY CHANGES
the vagi are extended in various directions to structures of quite diverse functions, singleness and separateness of connection of the peripheral organs with the central nervous system is as- sured. The same specific relation between effer- ent fibres and the viscera is seen in the sacral autonomic. In this division the preganglionic fibres pass out from the spinal cord to ganglia lying in close proximity to the distal colon, the bladder, and the external genitals. And the post- ganglionic fibres deliver the nerve impulses only to the nearby organs. Besides these innervations the cranial and sacral divisions supply individual arteries with "dilator nerves" — nerves causing relaxation of the particular vessels. Quite typi- cally, therefore, the efferent fibres of the two terminal divisions of the autonomic differ from those of the mid-division in having few of the distributed connections characteristic of the mid- division, and m. innervating distinctively the or- gans to which they are distributed. The cranial and sacral preganglionic fibres resemble thus the nerves to skeletal muscles, and their arrangement provides similar possibilities of specific and sepa- rate action in any part, without action in other parts.
The Cranial Division a Conserveb of Bodily Resources
\ The cranial autonomic, represented by the
yagus nerves, is the part of the visceral nervous
VISCEEAL NEEVES 31
system concerned in the psychic secretion of the gastric juice. Pawlow showed that when these nerves are severed psychic secretion is abolished. The cranial nerves to the salivary glands are sim- ilarly the agents for psychic secretion in these organs, and are known to cause also dilation of the arteries supplying the glands, so that during ac- tivity the glands receive a more abundant flow of blood. As previously stated (see p. 13), the evi- dence for a psychic tonus of the gastro-intestinal musculature rests on a failure of the normal con- tractions if the vagi are severed before food is taken, in contrast to the continuance of the con- tractions if the nerves are severed just after- wards. The vagi artificially excited are well- known as stimulators of increased tone in the smooth muscle of the alimentary canal. Aside from these positive effects on the muscles of the digestive tract and its accessory glands, cranial autonomic fibres cause contraction of the pupH of the eye, and slowing of the heart rate.
A glance at these various functions of the cra^ nial division reveals at once that they serve foi bodily conservation. By narrowing the pupil oi the eye they shield the retina from excessiv light. By slowing the heart rate, they give th cardiac muscle longer periods for rest and in'- vigoration. And by providing for the flow ol saliva and gastric juice and by supplying the mus
32 BODILY CHANGES
j cular tone necessary for contraction of the ali-
/ mentary canal, they prove fundamentally essen-
! tial to the processes of proper digestion and
i absorption by which energy-yielding material is
taken into the body and stored. To the cranial
division of the visceral nerves, therefore, belongs
;, the quiet service of building up reserves and forti-
f fying the body against times of need or stress.
The Sacral Division a Group of Mechanisms for Emptying
I Sacral autonomic fibres cause contraction of the ' rectum and distal colon and also contraction of '' the bladder. In both instances the effects result reflexly from stretching of the tonically con- tracted viscera by their accumulating contents. No affective states precede this normal action of the sacral division and even those which accom- pany or follow are only mildly positive ; a feeling of relief rather than of elation usually attends the completion of the act of defecation or mic- turition— though there is testimony to the con- trary.
I The sacral autonomic fibres also include, how- lever, the nervi erigentes which bring about en- gorgement of erectile tissue in the external geni- Jtals. According to Langley and Anderson^ the sacral nerves have no effect on the internal gen- erative organs. The vasa deferentia and the seminal vesicles whose rhythmic contractions
VISCEEAL NEEVES 33
mark the acme of sexual excitement in the male, and the uterus whose contractions in the female are probably analogous, are supplied only by lumbar branches — part of the sympathetic divi- sion. These branches also act in opposition to the nervi erigentes and cause constriction of the blood vessels of the external- genitals. The sexual orgasm involves a high degree of emotional ex- citement; but it can be rightly considered as es- sentially a reflex mechanism; and, again in this instance, distention of tubules, vesicles, and blood vessels can be found at the beginning of the in- cident, and relief from this distension at the end. Although distention is the commonest occasion for bringing the sacral division into activity it is not the only occasion. Great emotion, such as is accompanied by nervous discharges via the sym- pathetic division, may also be accompanied by dis- charges via the sacral fibres. The involuntary voiding of the bladder and lower gut at times of violent mental stress is well-known. Veterans of wars testify that just before the beginning of a battle many of the men have to retire temporarily from the firing line. And the power of sights and smells and libidinous thouglits to disturb the regions controlled by the nervi erigentes proves that this part of the autonomic system also has its peculiar affective states. The fact that one part of the sacral division, e. g., the distribu-
34 BODILY CHANGES
tion to the bladder, may be in abeyance, while another part, e. g., the distribution to the rectum, is active, illustrates again the directive discharge of impulses which has been previously described as characteristic of the cranial and sacral portions of the autonomic system.
Like the cranial division, the sacral is engaged in internal service to the body, in the performance of acts leading immediately to greater comfort.
The Sympathetic DnasioN Antagonistic to Both the Cranial and the Sacral
As indicated in the foregoing description many of the viscera are innervated both by the cranial or sacral part of the autonomic and by the sym- pathetic. When the mid-part meets either end- part in any viscus their effects are antagonistic. Thus the cranial supply to the eye contracts the pupil, the sympathetic dilates it; the cranial slows the heart, the sympathetic accelerates it; the sacral contracts the lower part of the large intestine, the sympathetic relaxes it; the sacral relaxes the exit from the bladder, the sym- pathetic contracts it.N These opposed effects are indicated in Fig. i by 4- for contraction, ac- celeration or increased tone; and by - for inhibi- tion, relaxation, or decreased tone.*
* The vagus nerve, when artificially stimulated, has a pri- mary, brief inhibitory effect on the stomach and small intes- tine ; its main function, however, as already stated, is to pro-
VISCERAL NEEVES 35
Sherrington lias demonstrated that the setting of skeletal muscles in opposed groups about a joint or system of joints — as in flexors and ex- tensors— is associated with an internal organiza- tion of the central nervous system that provides for relaxation of one group of the opposed mus- cles when the other group is made to contract. This "reciprocal innervation of antagonistic mus- cles," as Sherrington has called it,** is thus a device for orderly action in the body. As the above description has shown, there are peripheral oppositions in the viscera corresponding to the oppositions between flexor and extensor muscles. In all probability these opposed innervations of the viscera have counterparts in the organization of neurones in the central nervous system. Sher4 rington has noticed, and I can confirm the obser-i vation, that even though the sympathetic supplv to the eye is severed and is therefore incapable on causing dilation of the pupil, nevertheless the pupil dilates in a paroxysm of anger — due, no doubt (because the response is too rapid to be mediated by the blood stream), to central inhibi- tion of the cranial nerve supply to the constrictor muscles — i. e., an inhibition of the muscles which naturally oppose the dilator action of the sym- pathetic. Pain, the major emotions — fear and
duce increased tone and contraction in these organs. This double action of the vagus is marked thus, q: , in Fig. 1.
36 BODILY CHANGES
I rage — and also intense excitement, are manifested ^ in the activities of the sympathetic division. When in these states impulses rush out over the neurones of this division they produce all the changes typical of sympathetic excitation, such las dilating the pupils, inhibitmg digestion, caus- I ing pallor, accelerating the heart, and various ' other well-known effects. The impulses of the sympathetic neurones, as indicated by their domi- nance over the digestive process, are capable of readily overwhelming the conditions established by neurones of the cranial division of the auto- nomic system.
Neurones of the Sympathetic Division and Adrenal Secretion Have the Same Action
Lying anterior to each kidney is a small body — the adrenal gland. It is composed of an external portion or cortex, and a central portion or me- dulla. From the medulla can be extracted a sub- stance, called variously suprarenin, adrenin, epi- nephrin. or "adrenalin,"* which, in extraordinarily minute amounts, affects the structures innervated by the sympathetic division of the autonomic sys-
* The name "adrenalin" is proprietary. "Epinephrin" and "adrenin" have been suggested as terms free from commer- cial suggestions. As adrenin is shorter and more clearly related to the common adjectival form, adrenal, I have fol- lowed Schafer in using adrenin to designate the substance produced physiologically by the adrenal glands.
VISCERAL NEEVES 37
tern precisely as if they were receiving nervous impulses. For example, -when adrenin is injected into the blood, it will cause pupils to dilate, hairs to stand erect, blood vessels to be constricted, the activities of the alimentary canal to be inhibited, and sugar to be liberated from the liver. These effects are not prfidueedJhy-action of the substance ' on the central nervous system, but by^ direct ac-j tion on the organ itself.'^ And the effects oc- cur even after the structures have been removed from the body and kept alive artificially. . The adrenals are glands of internal secretion, \ i. e., like the thyroid, parathyroid, and pituitary glands, for example ; they have no connection with the surface of the body, and they'' give out into^,^ the blood the material which they elaborate. /The blood is carried away from each of them by the lumbo-adrenal vein which empties either into the renal vein or directly into the inferior vena cava just anterior to the openings of the renal veins. The adrenal glands are supplied by preganglionic fibres of the autonomic group,* shown in solid line in Fig. 1. This seems an exception to the general rule that gland cells have an outlying neurone between them and the neurones of tho central nervous system. The medulla of the adre- nal gland, however, is composed of modified nerve cells, and may therefore be regarded as offering exceptional conditions.
38 BODILY CHANGES
The foregoing brief sketch of the organization of the autonomic system brings out a number of points that should be of importance as bearing on the nature of the emotions which manifest themselves in the operations of this system. Thus ' it is highly probable that the sympathetic division, because arranged for diffuse discharge, is likely to be brought into activity as a whole, whereas the sacral and cranial divisions, arranged for particular action on separate organs, may operate , in parts. Also, because antagonisms exist be- ^' tween the middle and either end division of the autonomic, affective states may be classified ac- cording to their expression in the middle or an end division and these states would be, like the nerves, antagonistic in character. And finally, since the adrenal glands are innervated by au- tonomic fibres of the mid-division, and since ad- renal secretion stimulates the same activities that are stimulated nervously by this division, it is possible that disturbances in the realm of the sympathetic, although initiated by nervous dis- charge, are .automatically augmented and pro- longed through chemical effects of the adrenal secretion.
EEFEEENCES
1 Cannon : The American Journal of Psychology, 1914, XXV, p. 257.
VISCERAL NERVES 39
" For a summary of his studies of the organization of the autonomic system, see Langley: Ergebnisse der Physiologie, Wiesbaden, 1903, ii^, p. 818.
^ See Cannon : American Journal of Physiology, 1905, xiii, p. xxii.
* See Sherrington : The Integrative Action of the Nerv- ous System, New York, 1909, p. 19.
° Langley and Anderson : Journal of Physiology, 1895, xix, see pp. 85, 122.
^Sherrington: Loc. cit., p. 90.
■^ Elliott : Journal of Physiology, 1905, xxxii, p. 426.
* See Elliott : Journal of Physiology, 1913, xlvi, p. 289 ff.
CHAPTEE III
METHODS OF DEMONSTEATING ADEENAL SECEETION AND ITS NEEVOUS CONTEOL
As stated in the first chapter, the inhibition of gastric secretion produced by great excitement long outlasts the presence of the object which' evokes the excitement. The dog that was en- raged by seeing a cat for five minutes secreted only a few drops of gastric juice during the next fifteen minutes. Why did the state of excitation persist so long after the period of stimulation had ended? This question, which presented itself to me while reading Bickel and Sasaki's paper, fur- nished the suggestion expressed at the close of the last chapter, that the excitement might pro- voke a flow of adrenal secretion, and that the changes originally induced in the digestive organs by nervous impulses might be continued by circu- lating adrenin. The prolongation of the effect might be thus explained. Whether that idea is correct or not has not been tested. Its chief serv- ice was ia leading to an enquiry as to whether
40
ADEENAL SECEETION 41
the adrenal glands are in fact stimulated to action in emotional excitement. The preganglionic fibres passing to the glands are contained in the splanch- nic nerves. What is the effect of splanchnic stim- ulation?
The Evidence that Splanchnic Stimulation Induces Adrenal Secretion
It was in 1891 that Jacobi ^ described nerve fibres derived from the splanchnic trunks which were distributed to the adrenal glands. Six years later BiedP found that these nerves conveyed vaso-dilator impulses to the glands, and he sug- gested that they probably conveyed also secre- tory impulses. Evidence in support of this sug- gestion was presented the following year by Dreyer,^ who demonstrated that electrical ex- citation of the splanchnic nerves produced in the blood taken from the adrenal veins an increased amount of a substance having the power of rais- ing arterial blood pressure, and that this result was independent of accompanying changes in the blood supply to the glands. The conclusion drawn by Dreyer that this substance was adrenin has been confirmed in various ways by later observers. Tscheboksaroff * repeated Dreyer's procedure and found in blood taken from the veins after splanchnic stimulation evidences of the presence of adrenin that were previously absent. Asher ®
42 BODILY CHANGES
observed a rise of blood pressure when tbe glands were stimulated in such, a ma-nner as not to cause constriction of the arteries — the rise was there- fore assumed to be due to secreted adrenin. Dilation of the pupil was used by Meltzer and Joseph « to prove secretory action of the splanch- nics on the adrenal glands ; they found that stim- ulation of the distal portion of the cut splanchnic nerve caused the pupil to enlarge— an effect char- acteristic of adrenin circulating in the blood. Elliott '^ repeated this procedure, but made it a more rigorous proof of internal secretion of the adrenals by noting that the effect failed to ap- pear if the gland on the stimulated side was re- moved. Additional proof was brought by myself and Lyman * when we found that the typical drop in arterial pressure produced in cats by in- jecting small amounts of adrenin could be ex- actly reproduced by stimulating the splanchnic nerves after the abdominal blood vessels, which contract when these nerves are excited, were tied so that no changes iu them could occur to in- fluence the rest of the circulation.
The problem of splanchnic influence on the ad- renal glands Elliott attacked by a still different method. Using, as a measure, the graded effects of graded amounts of adrenin on blood pressure, he was able to assay the quantity of adrenin in adrenal glands after various conditions had been
ADEENAL SECEETION 43
allowed to prevail. The tests were made on cats. In these animals each adrenal gland is supplied only by the splanchnic fibres of its own side, and the two glands normally contain almost exactly the same amount of adrenin. Elliott ^ found that when the gland on one side was isolated by cutting its splanchnic supply, and then impulses were sent along the intact nerves of the other side, either by disturbing the animal or by artificial excita- tion of the nerves, the gland to which these fibres reached invariably contained less adrenin, often very much less, than the isolated gland. Results obtained by the method employed by Elliott have been confirmed with remarkable exactness in re- sults obtained by Folin, Denis and myself,^" using a highly sensitive color test after adding the gland extract to a solution of phosphotungstic acid.
All these observations, with a variety of meth- ods, and by a respectable number of reliable in- vestigators, are harmonious in bringing proof that artificial stimulation of the nerves leading to the adrenal glands will induce secretory ac- tivity in the adrenal medulla, and that in conse- quence adrenin will be increased in the blood. The fact is therefore securely established that in the body a mechanism exists by which these glands can be made to discharge this peculiar sub- stance promptly into the circulation.
44 BODILY CHANGES
The Question of Adrenal Secretion in Emotional Excitement
As we have already seen, the phenomena of a great emotional disturbance in an animal indi- cate that sympathetic impulses dominate the vis- cera. When, for example, a cat becomes fright- ened, the pupils dilate, the activities of the stomach and intestines are inhibited, the heart beats rapidly, the hairs of the back and tail stand erect — from one end of the ailimal to the other there are abundant signs of nervous discharges along sympathetic courses. Do not the adrenal glands share in this widespread subjugation of the viscera to sympathetic control?
This question, whether the common excitements of an animal's life might be capable of evoking a discharge of adrenin, was taken up by D. de la Paz and myself in 1910. "We made use of the nat- ural enmity between two laboratory animals, the dog and the cat, to pursue our experiments. In these experiments the cat, fastened in a comfor- table holder (the holder already mentioned as be- ing used in X-ray studies of the movements of the alimentary canal), was placed near a barking dog. Some cats when thus treated showed al- most no signs of fear; others, with scarcely a movement of defence, presented the typical pic- ture. In favorable cases the excitement was al- lowed to prevail for five or ten minutes, and in
ADRENAL SECRETION 45
a few cases longer. Samples of blood were taken within a few minutes before and after tbe period.
The Method of Securing Blood from Near the Adrenal
Veins
The blood was obtained from the inferior vena cava anterior to the opening of the adrenal veins, i. e., at a point inside the body near the level of the notch at the lower end of the sternum. To get the blood so far from the surface without disturbing the animal was at first a difficult prob- lem. We found, however, that by making anes- thetic with ethyl chloride the skin directly over the femoral vein high in the groin, the vein could be quickly bared, cleared of connective tissue, tied, and opened without causing any general dis- turbance whatever. A long, fine, flexible catheter (2.4 millimeters in diameter) which had pre- viously been coated with vaseline inside and out, to lubricate it and to delay the clotting of blood within it, was now introduced into the opening in the femoral vein, thence through the iliac and on into the inferior cava to a point near the level of the sternal notch. A thread tied around this tube where, after being inserted to the proper dis- tance, it disappeared into the femoral vein, marked the extent of insertion, and permitted a later introduction to the same extent. This slight operation — a venesection, commonly practised on
46 BODILY CHANGES
our ancestors — consumed only a few minutes, and as the only possibility of causing pain was guarded against by local anesthesia, the animal remained tranquil throughout. Occasionally it was necessary to stroke the cat's head gently to keep her quiet on the holder, and under such cir- cumstances I have known her to purr during all the preparations for obtaining the blood, and while the blood was being taken.
The blood (3 or 4 cubic centimetres) was slowly drawn through the catheter into a clean glass syringe. Care was taken to avoid any marked suction such as might cause collapse of the vein near the inner opening of the tube. As soon as the blood was secured, the catheter was removed and the vein tied loosely, to prevent bleeding. The blood was at once emptied into a beaker, and the fibrin whipped from it by means of fringed rubber tubing fitted over a glass rod. Since this defibrinated blood was obtained while the ani- mal was undisturbed, it was labelled "quiet blood."
The animal was then exposed to the barking dog, as already described, and immediately there- after blood was again removed, from precisely the same region as before. This sample, after being defibrinated, was labelled "excited blood." The two samples, the "quiet" and the "excited," both obtained in the same manner and subse-
ADRENAL SECRETION 47
quently treated in the same manner, were now tested for their content of adrenin.
The Method op Testing the Blood for Adrenin
It was desirable to use as a test tissues to which the blood was naturally related. As will be recalled, adrenin affects viscera even after they have been removed from the body, just as if they were receiving impulses via sympathetic fibres, and further, that sympathetic fibres nor- mally deliver impulses which cause contraction of the internal genitals and relaxation of the stomach and intestines. The uterus has long been employed as a test for adrenin, the presence of which it indicates by increased contraction. That isolated strips of the longitudinal muscle of the intestine, which are contracting rhythmically, are characteristically inhibited by adrenin in dilu- tions of 1 part in 20 millions, had been shown by Magnus in 1905. Although, previous to our in- vestigation in 1910, this extremely delicate reac- tion had not been used as a biological signal for adrenin, it possesses noteworthy advantages over other methods. The intestine is found in all ani- mals and not in only half of them, as is the uterus ; it is ready for the test within a few minutes, in- stead of the several hours said to be required for the best use of the uterus preparation;" and it responds by relaxing. This last characteristic
48 BODILY CHANGES
is especially important, for in defibrinated blood there are, besides adrenin, other substances cap- able of causing contraction of smooth muscle," and liable therefore to lead to erroneous con- clusions when a structure which responds by con- tracting, such as uterus or artery, is used to prove whether adrenin is present. On the other hand, substances producing relaxation of smooth muscle are few, and are unusual in blood.^*
We used, therefore, the strip of intestinal mus- cle as an indicator. Later Ho skins ^* modified our procedure by taking, instead of the strip, a short segment of the rabbit intestine. The seg- ment is not subjected to danger of injury during its preparation, and when fresh it is almost in- credibly sensitive. It may be noticeably inhibited by adrenin, 1 part in 200 millions!
The strip, or the intestinal segment, was sus- pended between minute wire pincers {serres fines) in a cylindrical chamber 8 millimeters in diameter and 5 centimeters deep. By a thread attached to the lower serre fime the preparation was drawn into the chamber, and was held firmly ; by the upper one it was attached to the short end of a writing lever (see Fig. 2). When not ex- posed to blood, the strip was immersed in a nor- mal solution of the blood salts (Einger's). The blood or the salt solution could be quickly with- drawn from or introduced into the chamber, with-
ADRENAL SECRETION
49
out disturbing the muscle, by means of a fine pipette passed down along the inner surface. The chamber and its contents, the stock of Ringer's
Figure 2. — Diagram of the arrangements for recording con- tractions of the intestinal muscle.
solution, and the samples of "quiet" and "ex- cited" blood were all surrounded by a large vol- ume of water kept approximately at body tem- perature (37° C). Through the blood or the salt solution in the chamber oxygen was passed in a slow but steady stream of bubbles. Under these circumstances the strip will live for hours, and will contract and relax in a beautifully regular rhythm, which may be recorded graphically by the writing lever.
The first effect of surrounding the muscle with blood, whether "quiet" or "excited," was to send it into a strong contraction which might persist, sometimes with slight oscillations, for a minute or two (see Figs. 4 and 5). After the initial short- ening, the strip, if in quiet blood soon began to
50 BODILY CHANGES
contract and relax rhythmically and with each re- laxation to lengthen more, until a fairly even base line appeared in the written record. At this stage the addition of fresh "quiet" blood usually had no effect, even though the strip were washed once with Einger's solution before the second por- tion of the blood was added. For comparison of the effects of "quiet" and "excited" blood on the contracting strip, the two samples were each added to the muscle immediately after the Eing- er's solution had been removed, or they were ap- plied to the muscle alternately and the differences in effect then noted. The results obtained by these methods are next to be presented.
EEFEEENCES
1 Jacobi : Archiv f iir experimentelle Pathologie und Phar- makologie, 1891, xxix, p. 185.
^ Biedl : Archiv f iir die gesammte Physiologie, ISOY, Ixvii, pp. 456, 481.
^ Dreyer : American Journal of Physiology, 1898-99, ii, p. 219.
* Tscheboksaroff : Archiv f iir die gesammte Physiologie, 1910, cxxxvii, p. 103.
^ Asher : Zeitschrift f iir Biologie, 1912, Iviii, p. 274.
*> Meltzer and Joseph : American Journal of Physiology,
1912, xxix, p. xxxiv.
^Elliott: Journal of Physiology, 1912, xliv, p. 400.
' Cannon and Lyman : American Journal of Physiology,
1913, xxxi, p. 377.
" Elliott : Journal of Physiology, 1912, xliv, p. 400. ^^ Eolin, Cannon and Denis : Journal of Biological Chem- istry, 1913, xiii, p. 477.
ADEENAL SECRETION 51
^'^ Fraenkel : Archiv f iir experimentelle Pathologie und Pharmakolog-ie, 1909, Ix, p. 399.
^^ See O'Connor : Archiv fiir die experimentelle Patholo- gie und Pharmakologie, 1912, Ixvii, p. 206.
^' Grutzner : Ergebnisse der Physiologie, 1904, iii^, p. 66 ; Magnus: Loc. cit., p. 69.
^*Hoskins: Journal of Pharmacology and Experimental Therapeutics, 1911, iii, p. 95.
CHAPTER IV
ADEENAL SECRETION IN STEONG EMOTIONS AND PAIN
If the secretion of adrenin is increased in strong emotional states and in pain, that constitutes a fact of considerable significance, for, as already mentioned, adremn is capable of_grodncing many IJf of the bodily changes which are characteristically manifested in emotional and painful experiences, rt is a matter of prime importance for further discussion to determine whether the adrenal glands are in fact roused to special activity in times of stress.
The Evidence that Adrenal Secretion Is Increased in Emotional Excitement
That blood from the adrenal veins causes the relaxation of intestinal muscle characteristic of adrenal extract or adrenin is shown in Fig. 3. The muscle was originally beating in blood which contained no demonstrable amount of adrenal se- cretion ; this inactive blood was replaced by blood
52
ADRENAL SECRETION IN EMOTIONS 53
from the adrenal veins, obtained after quick etherization. Etherization, it will be recalled, is accompanied by a "stage of excitement." Re- laxation occurred almost immediately (at b). Then the rhythm was renewed in the former
FiGtTBB 3. — ^Intestinal muscle beat- ing in inactive blood, which was with- drawn from the chamber at a. Blood from the adrenal vein of an animal ex- cited by etherization was substituted at b, and withdrawn at c. Contrac- tions were restored in the original in- active blood which was removed at d. Blood from the renal vein (same ani- mal) was added at e.
In this and subsequent records time is marked in half minutes.
blood, and thereupon the muscle was surrounded with blood from the vein leading away from the left kidney, i. e., blood obtained from the same animal and under the same conditions as the adrenal blood, but from a neighboring vein. No relaxation occurred. By this and other similar tests the reliability of the method was proved.
54 BODILY CHANGES
In no instance did blood from the inferior vena cava of the quiet normal animal produce relaxa- tion. On the other hand, blood from the animal after emotional excitement showed more or less promptly the typical relaxation. In Fig. 4 is
Figure 4. — Alternate application of "excited" blood (at 6 and/) and "quiet" blood (at d), from the same animal, to in- testinal muscle initially beating in Ringer's solution.
represented the record of intestinal muscle which was beating regularly in Einger's solution. At a the Einger's solution was removed, and at b "ex- cited" blood was added; after the preliminary shortening, which, as already stated, occurs at the first immersion in blood, the muscle length- ened gradually into complete inhibition. At c the "excited" blood was removed, and at d "quiet" blood was added in its place. The muscle at once began, fairly regular rhythmic beats. At e the "quiet" blood was removed, and at / the "excited" blood was again applied. The muscle lengthened almost immediately into an inhibited state. In this instance the "excited" blood was taken after
ADEENAL SECEETION IN EMOTIONS 55
the eat had been barked at for about fifteen min- utes.
The increase of effect with prolongation of the period of excitement is shown in Fig. 5. A is the
Figure 5. — The effect of prolonging the excitement. A, the record in "quiet" serum; B, in defibrinated blood after eleven minutes of excitement; and C, in serum after fifteen minutes of excitement.
record of contractions after the muscle was sur- rounded with "quiet" blood serum. B shows the gradual inhibition which occurred when the mus- cle was surrounded with defibrinated blood taken when the animal had been excited eleven minutes. And C is the record of rapid inhibition after fif- teen minutes of excitement. In other instances the effect was manifested merely by a lowering of the tonus of the muscle, and a notable slowing of the beats, without, however, a total abolition of them.
The inference that this inhibition of contrac- tion of the intestinal muscle is due to an increased amount of adrenal secretion in the "excited"
56
BODILY CHANGES
blood de la Paz and I justified on several grounds : (1) The inhibition was produced by "excited" blood from the inferior vena cava anterior to the mouths of the adrenal veins, when blood from the femoral vein, taken at the same time, had no in- hibitory influence. Since blood from the femoral vein is typical of the cava blood below the en- trance of the kidney veins, the conclusion is war- ranted that the difference of effect of the two samples of blood is not due to any agent below the kidneys. But that blood from the kidneys does not cause the relaxation is shown in Fig. 3.
FiGTJRB 6. — Failure of the cava blood (added at a) to produce inhibition when excitement has occurred after removal of the adrenal glands. The muscle later proved sensitive to adrenin in blood in the ratio 1:1,000,000.
The only other structures which could alter the blood between the two points at which it was taken are the adrenal glands, and the material
ADEENAL SECEETION IN EMOTIONS 57
secreted by them would produce precisely the inhibition of contraction which was in fact pro- duced.
(2) If in ether anesthesia the blood vessels leading to and from the adrenal glands are first carefully tied, and then the glands are removed, ex-
FiGURE 7.— Effect of adding adrenin 1 :1,000,000 (A), 1 :2,000,000 (B), and 1:3,000,000 (C), to formerly inactive blood. In each case a marks the moment when the quiet blood was removed, and 6, the time when the blood with adrenin was added.
citement four or five hours later, before the weak- ness that follows the removal has become promi- nent, does not alter the blood so that the typical inhibition occurs (see Fig. 6). Thus, although the animal shows all the characteristic signs of sympathetic stimulation, the blood, in the absence of the adrenals, remains unchanged.
(3) As already shown, sometimes the effect pro-
68 BODILY CHANGES
duced by the "excited" blood was prompt inbibi- tion, sometimes tbe inhibition followed only after several beats, and sometimes a slowing and short- ening of contractions, with a lower tone, were the sole signs of the action of adrenin. All these degrees of relaxation can be duplicated by adding to inactive blood varying amounts of adrenin. Fig. 7 shows the effects, on a somewhat insensi- tive muscle preparation, of adding adrenin, 1:1,000,000 (A), 1:2,000,000 (B), and 1:3,000,000 (C), to different samples of blood joreviously with- out inhibitory influence. These effects of adrenin and the effects produced by blood taken near the opening of the adrenal veins are strikingly analo- gous.
(4) Emden and v. Furth ^ have reported that 0.1 gram of suprarenin chloride disappears almost completely in two hours if added to 200 cubic centimeters of defibrinated beef blood, and the mixture constantly aerated at body temperature. "Excited" blood which produces inhibition loses that power on standing in the cold for twenty-four hours, or on being kept warm and agitated with bubbling oxygen. This change is illustrated in Fig. 8 ; the power of the "excited" blood to inhibit the contractions of the intestinal muscle when rec- ord A was written was destroyed after three hours of exposure to bubbling oxygen, as shown by record B. The destruction of adrenin and
ADRENAL SECRETION IN EMOTIONS 59
the disappearance of the effect which adrenin would produce are thus closely parallel.
All these considerations, taken with the proof
Figure 8.— The effect of bubbling oxygen through active blood. A, re- laxation after active blood applied at a; B, failure of relaxation when the same blood, oxygenated three hours, was appHed to a fresh strip at b.
that sympathetic impulses increase secretion of the adrenal glands, and taken also with the evidence that, during such emotional excitement as was em- ployed in these experiments, signs of sympathetic discharges appeared throughout the animal from the dilated pupil of the eye to the standing hairs of the tail-tip, led us to the conclusions that the characteristic action of adrenin on intestinal mus- cle was in fact, in our experiments, due to secre- tion of the adrenal glands, and that that secretion is increased in great emotion.
The Evidence that Adrenal Secretion is Increased by
"Painful" Stimulation
As mentioned in the first chapter, stimulation of sensory fibres in one of the larger nerve trunks
60 BODILY CHANGES
is known to result in such nervous discliarges along sympathetic paths as to produce marked inhibi- tion of digestive processes. Other manifestations of sympathetic innervations — e. g., contraction of arterioles, dilation of pupils, erection of hairs — are also demonstrable. And since the adrenal glands are stimulated to activity by sympathetic impulses, it was possible that they would be af- fected as are other structures supplied with sym- pathetic fibres, and that they would secrete in greater abundance when sensory nerves were irri- tated.
The testing of this possibility was undertaken by Hoskins and myself in 1911. Since bodily changes from "painful" stimulation can in large degree be produced in an anesthetized animal, without, how- ever, an experience of pain by the animal, it was possible to make the test quite simply. The sen- sory stimulus was a rapidly interrupted induced current applied to the sciatic nerve. The current was increased in strength as time passed, and thus the intensity of the effect, indicated by continuous dilation of the pupils, was maintained. There was no doubt that such stimulation would have caused very severe pain if the animal had not been anes- thetized. Indeed, the stimulus used was probably much stronger than would be necessary to obtain a positive result in the absence of the anesthetic (urethane), which markedly lessens the irritabil-
ADEENAL SECEETION IN EMOTIONS 61
ity of visceral nerve fibres.^ In different in- stances the stimulation lasted from three to six minutes. Throughout the period there was mark- edly increased rapidity and depth of breathing. As Fig. 9 shows, the normal blood, removed
FiGXTEB 9. — Intestinal mus- cle beating in normal vena cava blood, removed at 1 and re- newed at 2. At 3 normal blood removed. At 4 contraction in- hibited by vena cava blood drawn after sensory stimula- tion; at 5 removed. At 6 Rin- ger's solution substituted.
62 BODILY CHANGES
from the vena cava before stimulation, caused no inhibition of the beating segment, whereas that removed afterwards produced a deep relaxation. Hoskins and I showed that the increased respira- tion which accompanies "painful" stimulation does not augment adrenal activity. We concluded, therefore, that when a sensory trunk is strongly excited the adrenal glands are reflexly stimulated, and that they pour into the blood stream an in- creased amount of adrenin.
Confirmation of Ocr Eesults by Other Observers
The foregoing experiments and conclusions were reported in 1911. In 1912, Elliott * brought con- firmatory evidence by use of a method quite differ- ent from ours. As previously stated, he studied the effects of experimental procedures on adrenal secretion by a careful comparative quantitative assay of the adrenin content of the glands when one gland was isolated from the central nervous system and the other left connected. He took advantage of the action of morphia and of the substance B-tetrahydronaphthylamine in evoking in cats all the appearances of great fright. After the animals had thus been "frightened," he found that the adrenal gland which was still connected with the spinal cord was much depleted of its adrenin content compared with the other, isolated gland. And he observed, further, that animals
ADEENAL SECEETION IN EMOTIONS 63
newly brought to the laboratory, and evidently disturbed by the strangeness of their surroundings, had a considerably smaller amount of adrenin in their glands than other animals grown accustomed to the situation. Elliott also observed that pro- longed excitation of a sensory nerve, such as the great sciatic, may cause the adrenin largely to disappear from the gland still connected with the central nervous system and subjected, therefore, to reflex influences.
Our conclusions have also been confirmed more recently (1913) by Hitchings, Sloan and Austin,* working in Crile's laboratory in Cleveland. They used the same method which we had used to ob- tain blood and to test for adrenin, and found that after great fear and rage had been induced in a cat by the attempt of a muzzled dog to fight it, the adrenin reaction was clearly demonstrable. And just as we had noted that the reaction did not occur if the adrenal glands had been removed, they showed that it did not occur if the nervous connec- tions with the spinal cord were previously severed.
The logic of all these experiments may be briefly summed up. That the adrenal glands are subject to splanchnic influence has been demonstrated anatomically and by the physiological effects of their secretion after artificial stimulation of the splanchnic nerves. Impulses are normally sent along these nerves, in the natural conditions of
64 BODILY CHANGES
life, when animals become greatly excited, as in fear and rage and pain. There is every probabil- ity, therefore, that these glands are stimulated to extra secretion at such times. Both by an ex- ceedingly delicate biological test (intestinal mus- cle) and by an examination of the glands them- selves, clear evidence has been secured that in pain and deep emotion the glands do, in fact, pour out an excess of adrenin into the circulating blood.
Here, then, is a remarkable group of phenomena — a pair of glands stimulated to activity in times of strong excitement and by such nerve impulses as themselves produce at such times profound changes in the viscera ; and a secretion given forth into the blood stream by these glands, which is capable of inducing by itself, or of augmenting, the nervous influences which induce the very changes in the viscera which accompany suffering and the major emotions. What may be the sig- nificance of these changes, occurring when condi- tions of pain and great excitement — experiences common to animals of most diverse types and probably known to their ancestors for ages past — lay hold of the bodily functions and determine the instinctive responses ?
Certain remarkable effects of injecting adrenin into the blood have for many years been more or less well recognized. For example, when injected it causes liberation of sugar from the liver into
ADRENAL SECRETION IN EMOTIONS 65
the blood stream. It relaxes the smooth, muscle of the bronchioles. Some old experiments indi- cated that it acts as an antidote for muscular fatigue. It alters the distribution of the blood in the body, driving it from the abdominal viscera into the heart, lungs, central nervous system and | limbs. And there was some evidence that it ren- ders more rapid the coagulation of the blood. There may be other activities of adrenin not yet discovered — it may co-operate with the products of other glands of internal secretion. And other glands of internal secretion may be stimulated by sympathetic impulses. But we were not concerned with these possibilities. We wished to know whether the adrenin poured out in pain and emo- tional excitement produced or helped to produce
the same effects that follow the injection of adre-
nin. Our later researches were concerned with an- swers to this question.
EEFEEENCES
' Embden and v. Eurtli : Hofmeister's Beitrage zur chemischen Physiologie und Pathologie, 1904, iv, p. 423.
2 Elliott : Journal of Physiology, 1905, xxxii, p. 448.
3 Elliott : Journal of Physiology, 1912, xliv, p. 409.
*Hitchings, Sloan and Austin: Cleveland Medical Jour- nal, 1913, xii, p. 686; see also Crile and Lower: Anoci-asso- ciation, Philadelphia, 1914, p. 56.
CHAPTEE V
THE INCEEASE OF BLOOD SIJGAE IN PAIN AND GREAT EMOTION
Sugar is the form in which carbohydrate mate- rial is transported in organisms ; starch is the stor- age form. In the bodies of animals that have been well fed the liver contains an abundance of glycogen or "animal starch," which may be called upon in times of need. At such times the glycogen is changed, and set free in the blood as sugar. Ordinarily there is a small percentage of sugar in the blood — from 0.06 to 0.1 per cent. When only this small amount is present the kidneys are capable of preventing its escape in any noteworthy amount. If the percentage rises to the neighbor- hood of 0.2-0.3 per cent, however, the sugar passes the obstacle set up by the kidneys, and is readily demonstrable in the urine by ordinary tests. The condition of "glycosuria," therefore, may prop- erly be considered, in certain circumstances, as evidence of increased sugar in the blood. The in- jection of adrenin can liberate sugar from the
66
INCEEASE OF BLOOD SUGAE 67
liver to sucli an extent that glycosuria results. Does the adrenal secretion discharged in pain and strong emotional excitement play a role in pro- ducing glycosuria under such conditions?
In clinical literature scattered suggestions are to be found that conditions giving rise to emo- tional states may be the occasion also of more or less permanent glycosuria. Great grief and pro- longed anxiety during a momentous crisis have been regarded as causes of individual instances of diabetes, and anger or fright has been followed by an increase in the sugar excreted by persons who already have the disease. Kleen ^ cites the instance of a German officer whose diabetes and whose Iron Cross for valor both came from a stressful experience in the Franco-Prussian War. The onset of the disease in a man directly after his wife was discovered in adultery is described by Naunyn;^ and this author also mentions two cases in his own practice — one started during the bombardment of Strassburg (1870), the other started a few days after a companion had shot himself. In cases of mental disease, also, states of depression have been described accompanied by sugar in the urine. Schultze^ has reported that in these cases the amount of glycosuria is de- pendent on the degree of depression, and that the greatest excretion of sugar occurs in the fear- psychoses. Eaimann * has reported that in both
68 BODILY CHANGES
melancholia and mania the assimilation limit of sugar may be lowered. Similar results in the insane have recently been presented by Mita,^ and by Folin and Denis.« The latter investiga- tors found glycosuria in 12 per cent of 192 insane patients, most of whom suffered from depression, apprehension, or excitement. And Arndt '' has observed glycosuria appearing and disappearing as alcoholic delirium appeared and disappeared in his patients.
Although clinical evidence thus indicates an emotional origin of some cases of diabetes and glycosuria, the intricacies of existence and the complications of disease in human beings throw some doubt on the value of that evidence. Both Naunyn * and Hirschfeld, although mentioning instances of diabetes apparently due to an emo- tional experience, urge a skeptical attitude to- ward such statements. It is desirable, therefore, that the question of an emotional glycosuria be tested under simpler and more controllable con- ditions. "Emotional glycosuria" in experimental animals has indeed been referred to by Water- man and Smit * and more recently by Hender- son and Underhill.i" Both these references, how- ever, are based on the work of Bohm and Hoff- mann,^^ reported in 1878.
INCREASE OF BLOOD SUGAR 69
Glycosuria From Pain
Bohm and Hoffmann found that cats, when bound to an operating board, a tube inserted into the trachea (without anesthesia), and in some instances a catheter inserted into the urethra through an opening above the pubis, had in about half an hour an abundance of sugar in the urine. In three determinations sugar in the blood proved slightly above "normal" so long as sugar was ap- pearing in the urine, but returned to "normal" as the glycosuria disappeared. Since they were able to produce the phenomenon by simply bind- ing animals to the holder, they called it "Fes- selungsdiabetes."
As possible causes af this glycosuria in bound animals, they considered opening the trachea, cooling, and pain. The first two they readily eliminated, and still they found sugar excreted. Pain they could not obviate, and since, without binding the animals, they caused glycosuria by merely stimulating the sciatic nerves, they con- cluded that painful confinement was itself a suffi- cient cause. Other factors, however, such as cool- ing and circulatory disturbances, probably co- operated with pain, they believed, to produce the result. Their observations on cats have been proved true also of rabbits ;i2 and recently it has been shown that an operation involving some pain increases blood sugar in dogs.^^ Temporary gly-
70 BODILY CHANGES
cosuria has likewise been noted in association with intense pain in human beings.
Inasmuch as Bohm and Hoffmann did not men- tion the emotional element in discussing their re- sults, and inasmuch as they admitted that they could not obviate from their experimental pro- cedure pain, which they themselves proved was effective in causing glycosuria, desig-nating what they called "Fesselungsdiabetes" as "emotional glycosuria" is not justified.
Emotional Glycosuria
The discovery that during strong emotion adre- nal secretion is increased, and the fact that injec- tion of adrenin gives rise to glycosuria, suggested that glycosuria might be called forth by emotional excitement, and then that even without the painful element of Bohm and Hoffmann's experiments, sugar might be found in the urine. The testing of this possibility was undertaken by A. T. Shohl, W. S. Wright and myself in 1911.
Our first procedure was a repetition of Bohm and Hoffmann's experiments, freed from the factor of pain. The animals (cats) were bound to a comfortable holder, which left the head unfastened. This holder I had used hundreds of times in X-ray studies of digestion, with many different animals, without causing any signs of even so much as uneasiness. Just as in obser-
INCEEASE OF BLOOD SUGAE 71
vations on the movements of ttie alimentary canal, however, so here, the animals reacted differently to the experience of being confined. Young males usually became quite frantic, and with eyes wide, pupils dilated, pulse accelerated, hairs of the tail more or less erect, they struggled, snarling and growling, to free themselves. Females, on the contrary, especially if elderly, were as a rule much more calm, and resignedly accepted the novel situation.
According to differences in reaction the animals were left in the holder for periods varying in length from thirty minutes to five hours. In order to insure prompt urination, considerable quantities of water were given by stomach tube at the beginniag of the experiment and in some cases again later. Arrangements were made for draining the urine promptly, when the animal was on the holder or when afterwards in a metal metab- olism cage, into a glass receiver containing a few drops of chloroform to prevent fermentation. The diet in all cases consisted of customary raw meat and milk. In every instance the urine was proved free from sugar before the animal was excited.
In our series of observations twelve cats were used, and in every one a well-marked glycosuria was developed. The shortest periods of confine- ment to the holder which were effective were thirty
72 BODILY CHANGES
and forty minutes ; the longest we employed, five hours. The average time required to bring about a glycosuria was less than an hour and a half; the average in seven of the twelve cases was less than forty minutes. In all eases no sugar was found in the urine passed on the day after the excitement.
The promptness with which the glycosuria de- veloped was directly related to the emotional state of the animal. Sugar was found early in animals which early showed signs of being frightened or in a rage, and much later in animals which took the experience more calmly.
As cooling may result in increased sugar in the blood, and consequent glycosuria, the rectal tem- perature was observed from time to time, and it was found to vary so slightly that in these experi- ments it was a wholly negligible factor. In one cat the rectal temperature fell to 36° C. while the animal was bound and placed in a cold room (about 2° C.) for fifty minutes, but no sugar appeared in the urine.
Further evidence that the appearance of sugar in the urine may arise purely from emotional ex- citement was obtained from three cats which gave negative results when bound in the holder for varying periods up to four hours. It was note- worthy that these animals remained calm and passive in their confinement. When, however,
INCREASE OF BLOOD SUGAR 73
they were placed, separately, in a small wire cage, and were barked at by an energetic little dog, that jumped at them and made signs of attack, the cats became much excited, they showed their teeth, humped their backs, and growled defiance. This sham fight was permitted to continue for a half hour in each of the three cases. In each case the animal, which after four hours of bondage had ex- hibited no glycosuria, now had sugar in the urine. Pain, cooling, and bondage were not factors in these experiments. The animal was either fright- ened or enraged by the barking dog, and that ex- citement was attended by glycosuria.
The sugar excreted in the twenty-four hours which included the period of excitement was de- termined by the Bertrand method.^* It ranged from 0.024 gram to 1.93 grams, or from 0.008 gram to 0.62 gram per kilo body weight, for the twenty-four hours' quantity.
The presence of sugar in the urine may be used as an indication of increased sugar in the blood, for unless injury has been done to the cells of the kidneys, they do not permit sugar to escape imtil the percentage in the blood has risen to a considerable degree. Thus, though testing the urine reveals the instances of a high content of blood sugar, it does not show the fine variations that appear when the blood itself is examined. Recently Scott ^^ has concluded a thorough in-
74 BODILY CHANGES
vestigation of the variations of blood sugar in cats, and has found that merely incidental conditions, producing even mild excitement, as indicated by crying or otherwise, result in a noticeable rise in the amount. Indeed, so sensitive is the sugar-lib- erating mechanism that all the early determina- tions of the "normal" content of sugar in blood which has been drawn from an artery or vein in the absence of anesthesia, are of very doubtful value. Certainly when care is taken to obtain blood suddenly from a tranquil animal, the per- centage (0.069, Scott; 0.088, Pavy) is much less than when the blood is drawn without anesthesia (0.15, Bohm and Hoffmann), or after light nar- cosis (0.282, Bona and Takahashi").
Our observations on eats have since been found valid for rabbits. EoUy and Oppermann, Jacob- sen, and Hirseh and Eeinbach ^'^ have recently recorded that the mere handling of a rabbit pre- paratory to operating on it will increase the per- centage of blood sugar (in some cases from 0.10 to 0.23 and 0.27 per cent). Dogs are said to be much less likely to be disturbed by the nature of their surroundings than are rabbits and cats. Nevertheless, pain and excitement are such funda- mental experiences in animals that without much doubt the same mechanism is operative in all when these experiences occur. Probably, just as the digestion of dogs is disturbed by strong emotion,
INCEEASE OF BLOOD SUGAE 75
the blood sugar likewise is increased, for sym- pathetic impulses occasion both changes.* Gib has given an account of a bitch that became much agitated when shut up, and after such enforced seclusion, but never otherwise, she excreted small quantities of sugar in the urine.^^
The results noted in these lower animals have been confirmed in human beings. One of my for- mer students, W. G. Smillie, found that four of nine medical students, all normally without sugar in their urine, had glycosuria after a hard exami- nation, and only one of the nine had glycosuria after an easier examination. The tests, which were positive with Fehling's solution, Nylander's reagent, and also with phenyl-hydrazine, were made on the first urine passed after the exam- ination. Furthermore, 0. H. Fiske and I ex- amined the urine of twenty-five members of the Harvard University football squad immedi- ately after the final and most exciting contest of the season of 1913, and found sugar in twelve cases. Five of these positive cases were among substitutes not called upon to enter the game. The only excited spectator of the Har-
* Since the foregoing sentences were written Hirsch and Eeinbach have reported (Zeitschrift fiir physiologische Chemie, 1914, xci, p. 292) a "psychic hyperglycemia" in dogs, that resulted from fastening the animals to a table. The blood sugar rose in one instance from 0.11 to 0.14 per cent, and in another from 0.09 to 0.16 per cent.
76 BODILY CHANGES
vard victory whose urine was examined also had a marked glycosuria, which on the following day had disappeared.
Other tests made on students before and after important scholastic examinations have been pub- lished by Folin, Denis and Smillie.i" Qf thirty- four second-year medical students tested, one had sugar before the examination as well as after- wards. Of the remaining thirty-three, six, or 18 per cent, had small but unmistakable , traces of sugar in the urine passed directly following the ordeal. A similar study was made on second-year students at a women's college. Of thirty/-six stu- dents who had no sugar in the urine on the day before, six, or 17 per cent, eliminated sugar with the urine passed immediately after the examina- tion.
From the foregoing results it is reasonable to conclude that just as in the cat, dog, and rabbit, so also in man, emotional excitement produces tem- porary increase of blood sugar.
, The Eole op the Adrenal Glands in Emotional
Glycosuria ,
Since artificial stimulation of the splanchnic nerves produces glycosuria,^** and since major emotions, such as rage and fright, are attended by nervous discharges along splanchnic pathways, glycosuria as an accompaniment of emotional ex-
INCREASE OF BLOOD SUGAR 77
citement would naturally be expected to occur. To what extent the adrenal glands which, as already mentioned, are stimulated to increased secretion by excitement, might play a part in this process, has been in dispute. Removal of these glands or cutting of the nerve fibres supplying them, according to some observers,^^ prevents glycosuria after puncture of the fourth ventricle of the brain (the "sugar puncture," which typically induces glycosuria) and also after stimulation of the splanchnics.22 On the other hand, Wert- heimer and Battez ^* have stated that removal of the glands does not abolish the effects of sugar puncture in the cat. It was questionable, there- fore, whether removal of the adrenal glands would affect emotional glycosuria.
Evidence on this point I secured with Shohl and Wright in observations on three animals in which the adrenals were removed aseptically under ether. The animals selected had all become quickly ex- ' cited on being bound to the holder, and had mani- fested glycosuria after about an hour of confine- ment. In the operation, to avoid' discharge of adrenin by handling, the adrenal veins were first tied, and then the glands freed from their attach- ments and removed as quickly and with as little manipulation as possible. In one cat the entire operation was finished in twenty minutes. In two of the cats a small catheter was introduced into the
78 BODILY CHANGES
urethra througli an incision, so that the bladder could be emptied at any time.
In all three cases urine that was free from sugar was obtained soon after the operation. Al- though the animals deprived of their adrenals manifested a general lessening of muscular tone, they still displayed much of their former rage or excitement when bound. Indeed, one was more ex- cited after removal of the adrenals than before. That the animals might not be excessively cooled they were kept warm with coverings or an elec- tric heating pad. Although they were now bound for periods from two to three times as long as the periods required formerly to cause glycosuria, no trace of sugar was found in the urine in any instance. The evidence thus secured tends, there- fore, to support the view that the adrenal glands perform an important contributory role in the glycosuria resulting from splanchnic stimula- tion.
Possibly the emotional element is in part ac- countable for the glycosuria observed after pain- ful stimulation, but conditions causing pain alone will reasonably explain it. As we have already seen, strong stimulation of sensory fibres causes the discharge of impulses along the splanchnic nerves, and incidentally calls forth an increased secretion of the adrenal glands. In glycosuria re- - suiting from painful stimulation, as well as in emo-
INCEEASE OF BLOOD SUGAR 79
tional glycosuria, the adrenal glands may be es- sential factors.
Later the evidence will be given that sugar is the optimum source of muscular energy. In pass- ing, we may note that the liberation of sugar at a time when great muscular exertion is likely to be demanded of the organism may be interpreted as a highly interesting instance of biological adaptation.
EEFEEENOES
^ Kleen : On Diabetes Mellitus and Glycosuria, Philadel- ptia, 1900, pp. 22, 37-39.
='Naunyn: Der Diabetes Mellitus, Vienna, 1898, p. 72.
^ Schultze : Verhandlungen der Gesellschaft deutscher Naturforscher und Aerzte, Cologne, 1908, ii, p. 358.
* Eaimann : Zeitscbrif t f iir Heilkunde, 1902, xxiii, Ab- theilung iii, pp. 14, 19.
= Mita : Monatshefte fiir Psychiatrie und Neurologie, 1912, xxxii, p. 159.
^Eolin, Denis and Smillie: Journal of Biological Chem- istry, 1914, xvii, p. 519.
' Arndt : Zeitschrif t fiir Nervenheilkunde, 1897, x. p. 436.
^Naunyn: Loc. ciL, p. 73; Hirschfeld: Die Zuckerkrank- heit, Leipzig, 1902, p. 45.
9 Waterman and Smit: Archiv fiir die gesammte Physi- ologie, 1908, cxxiv, p. 205.
" Henderson and Underbill : American Journal of Physi- ology, 1911, xxviii, p. 276.
11 Bohm and Hoffmann : Archiv fiir experimentelle Pa- thologie und Pharmakologie, 1878, viii, p. 295.
"Eckhard: Zeitschrif t fiir Biologic, 1903, xliv, p. 408.
13 Loewy and Rosenberg : Biochemische Zeitschrift, 1913,
Ivi, p. 114.
1* See Abderhalden : Handbuch der biochemischen Ar- beitsmethoden, Berlin, 1910, ii, p. 181.
80 BODILY CHANGES
1^ Scott : American Journal of Physiology, 1914, xxxiv, p. 283.
1" Cited by Scott : Loc. cit., p. 296.
1' Roily and Oppermann : Biochemische Zeitschrift, 1913, xlix, p. 201. Jacobsen: Ihid., 1913, li, p. 449. Hirsch and Eeinbach: Zeitschrift fiir physiologiscbe Chemie, 1913, Ixxxvii, p. 122.
Incited by Kleen: Loc. cit., p. 3Y.
1^ Folin, Denis and Smillie : Loc. cit., p. 520.
-" See Macleod : American Journal of Physiology, 1907, xix, p. 405, also for other references to literature.
^^ See Meyer : Comptes rendus de la Societe de Biologie, 1906, Iviii, p. 1123; Nishi: Archiv fiir experimentelle Pa- thologic und Pharmakologie, 1909, Ixi, p. 416.
^^ Gautrelet and Thomas : Comptes rendus de la So- ciete de Biologie, 1909, Ixvii, p. 233 ; and Macleod : Pro- ceedings of the Society for Experimental Biology and Medi- cine, 1911, viii, p. 110 (true for left adrenal and left splanch- nic).
^^ Wertheimer and Battez : Archives Internationales de Physiologic, 1910, ix, p. 392.
CHAPTER VI
IMPEOVED CONTEACTION OF FATIGUED
MUSCLE AFTEE SPLANCHNIC STIMULATION OF
THE ADEENAL GLAND
In the older literature on the adrenal glands the deleterious effect of their absence, or the beneficial effect of injected extracts, on the contraction of skeletal muscle was not infrequently noted. As evidence accumulated, however, tending to prove an important relation between the extract of the adrenal medulla (adrenin) and the sympathetic nervous system, the relations with the efficiency of skeletal muscle began to receive less consideration.
The muscular weakness of persons suffering from diseased adrenals (Addison's disease) was well recognized before experimental work on the glands was begun. Experiments on rabbits were reported in 1892 by Albanese,^ who showed that muscles which were stimulated after removal of the glands were much more exhausted than when stimulated the same length of time in the same animal before the removal. Similarly Boi-
81
82 BODILY CHANGES
net 2 reported, in 1895, that rats recently deprived of their adrenals were much, more quickly ex- hausted in a revolving cage than were normal animals.
More direct evidence of the favorable influence of adrenal extract on skeletal muscle was brought forward by Oliver and Schafer.^ After inject- ing the extract subcutaneously into a frog they found that the excised gastrocnemius muscle regis- tered a curve of contraction about 33 per cent higher and about 66 per cent longer than the corresponding muscle not exposed to the action of the extract. Similar prolongation of the muscle curve was observed after injecting the extract intravenously into a dog. A beneficial effect of adrenal extract on fatigued muscle, even when applied to the solution in which the isolated muscle was contracting, was claimed by Dessy and Urandis,* who studied the phenomenon in a salamander.* Further evidence leading to the same conclusion was offered in a discriminat-
* These earlier investigations, in which an extract of the entire gland was used, made no distinction between the action of the medulla and that of the cortex. It may be that the weakness following removal or disease of the adrenals is due to absence of the cortex (see Hoskins and Wheelon: Am- erican Journal of Physiology, 1914, xxxiv, p. 184). Such a possible effect, however, should not be confused with the demonstrable influence of injected adrenin (derived from the adrenal medulla alone) and the similar effects from adrenal secretion caused by splanchnic stimulation.
CONTRACTION OF FATIGUED MUSCLE 83
ing paper I)y Panella.^ He found that in cold- blooded animals the active principle of the adre- nal medulla notably reinforced skeletal muscle, prolonging its ability to do work, and improv- ing its contraction when fatigued. In warm- blooded animals the same effects were observed, but only after certain experimental procedures, such as anesthesia and section of the bulb, had changed them to a condition resembling the cold- blooded.
The foregoing evidence indicates that removal of the adrenals has a debilitating effect on muscu- lar power, and that injection of extracts of the glands has an invigorating effect. It seemed pos- sible, therefore, that increased secretion of the adrenal glands, whether from direct stimulation of the splanchnic nerves or as a reflex result of pain or the major emotions, might act as a dyna- mogenic factor in the performance of muscular work. With this possibility in mind L. B. Nice and I ^ first concerned ourselves in a research which we conducted in 1912.
The general plan of the investigation consisted primarily in observing the effect of stimulating the splanchnic nerves, isolated from the spinal cord, on the contraction of a muscle whose nerve, also isolated from the spinal cord, was rhyth- mically and uniformly excited with break induc- tion shocks. When a muscle is thus stimulated it
84 BODILY CHANGES
at first responds by strong contractions, but as time passes the contractions become weaker, the degree of shortening of the muscle becomes less, and in this state of lessened efficiency it may con- tinue for a long period to do work. The tired muscle which is showing continuously and evenly its inability to respond as it did at first, is said to have reached the "fatigue level." This level serves as an excellent basis for testing influences that may have a beneficial effect on muscular perform- ance, for the benefit is at once manifested in greater contraction.
In the experimental arrangement which we used, only a connection through the circulating blood existed between the splanchnic region and the muscle — all nervous relations were severed. Any change in muscular ability, therefore, occurring when the splanchnic nerve is stimulated, must be due to an alteration in the quantity or qual- ity of the blood supplied to the laboring muscle.
Cats were used for most experiments, but re- sults obtained with cats were confirmed on rab- bits and dogs. To produce anesthesia in the cats and rabbits, and at the same time to avoid the fluctuating effects of ether, urethane (2 grams per kilo body-weight) was given by a stomach tube. The animals were fastened back downward, over an electric warming pad, to an animal holder.
CONTEACTION OF FATIGUED MUSCLE 85
Care was taken to maintain the body temperature at its normal level throughout each experiment.
The Nerve-muscle Preparation
The muscle selected to be fatigued was usually the extensor of the right hind foot (the tibialis anticus), though at times the common extensor muscle of the digits of the same foot was em- ployed. The anterior tibial nerve which supplies these muscles was bared for about two centimeters, severed toward the body, and set in shielded elec- trodes, around which the skin was fastened by spring clips. Thus the nerve could be protected, kept moist, and stimulated without stimulation of neighboring structures. By a small slit in the skin the tendon of the muscle was uncovered, and after a strong thread was tied tightly about it, it was separated from its insertion. A nerve-muscle preparation was thereby made which was still con- nected with its proper blood supply. The prepa- ration was fixed firmly to the animal holder by thongs looped around the hock and the foot, i. e., on either side of the slit through which the tendon emerged.
The thread tied to the tendon was passed over a pulley and down to a pivoted steel bar which bore a writing point. Both the pulley and this steel writing lever were supported in a rigid tri- pod. In the earliest experiments the contracting
86 BODILY CHANGES
muscle was made to lift weights (125 to 175 grams) ; in all the later observations, however, the muscle pulled against a spring attached below the steel bar. The tension of the spring as the muscle began to lift the lever away from the sup- port was, in most of the experiments, 110 grams, with an increase of 10 grams as the writing point was raised 4.5 millimeters. The magnification of the lever was 3.8.
The stimuli delivered to the anterior tibial nerve were, in most experiments, single break shocks of a value barely maximal when applied to the fresh preparation. The rate of stimulation varied be- tween 60 and 300 per minute, but was uniform in any single observation. A rate which was found generally serviceable was 180 per minute.
Since the anterior tibial nerve contains fibres affecting blood-vessels, as well as fibres causing contraction of skeletal muscle, the possibility had to be considered that stimuli applied to it might disturb the blood supply of the region. Constric- tion of the blood vessels would be likely to pro- duce the most serious disturbance, by lessening the blood flow to the muscle. The observations of Bowditch and Warren,'^ that vasodilator rather than vasoconstrictor effects are produced by single induction shocks repeated at intervals of not more than five per second, reassured us as to the danger of diminishing the blood supply, for
CONTRACTION OF FATIGUED MUSCLE 87
the rate of stimulation in onr experiments never exceeded five per second and was usually two or three. Furthermore, in using these different rates we have never noted any result which could rea- sonably be attributed to a diminished circulation.
The Splanchnic Preparation The splanchnic nerves were stimulated in vari- ous ways. At first only the left splanchnics in the abdomen were prepared. The nerves, sepa- rated from the spinal cord, were placed upon shielded electrodes. The form of electrodes which was found most satisfactory was that illustrated
FiGTjKB 10. — The shielded electrodes used in stimulating the splanchnic nerves. For description see text.
in Fig. 10. The instrument was made of a round rod of hard wood, bevelled to a point at one end, and grooved on the two sides. Into the grooves were pressed insulated wires ending in platinum hooks, which projected beyond the bevelled sur- face. Around the rod was placed an insulating rubber tube which was cut out so as to leave the hooks uncovered when the tube was slipped down- ward.
In applying the electrodes the left splanchnic nerves were first freed from their surroundings and tightly ligatured as close as possible to their
88 BODILY CHANGES
origin. By means of strong compression the con- ductivity of the nerves was destroyed central to the ligature. The electrodes were now fixed in place by thrusting the sharp end of the wooden rod into the muscles of the back. This was so done as to bring the platinum hooks a few milli- meters above the nerves. "With a small seeker the nerves were next gently lifted over the hooks, and then the rubber tube was slipped downward until it came in contact with the body wall. Ab- sorbent cotton was packed about the lower end of the electrodes, to take up any fluid that might appear ; and finally the belly wall was closed with spring clips. The rubber tube served to keep the platinum hooks from contact with the muscles of the back and the movable viscera, while still per- mitting access to the nerves which were to be stimulated. This stimulating apparatus could be quickly applied, and, once in place, needed no further attention. In some of the experiments both splanchnic nerves were stimulated in the thorax. The rubber-covered electrode proved quite as serviceable there as in the abdo- men.
The current delivered to the splanchnic nerves was a rapidly interrupted induced current of such strength that no effects of spreading were notice- able. That splanchnic stimulation causes secre- tion of the adrenal glands has been proved in
CONTEACTION OF FATIGUED MUSCLE 89
many different ways whicH have already been de- scribed (see p. 41).
The Effects of Splanchnic Stimulation on the Contraction of Fatigued Muscle
When skeletal muscle is repeatedly stimulated by a long series of rapidly recurring electric shocks, its strong contractions gradually grow weaker until a fairly constant condition is reached. The record then has an even top — the muscle has reached the "fatigue level." The effect of splanch- nic stimulation was tried when the muscle had been fatigued to this stage. The effect which was often obtained by stimulating the left splanchnic nerves is shown in Fig. 11. In this instance the muscle while relaxed supported no weight, and
FiGtTBB 11. — ^Upper record, contraction of the tibialis anticus, 80 times a minute, lifting a weight of 125 grams. Lower record, stimulation of the left splanchnic nerves, two minutes. Time, half minutes.
while contracting lifted a weight of 125 grams. The rate of stimulation was 80 per minute.
90
BODILY CHANGES
The muscle record shows a brief initial rise from the fatigue level, followed by a drop, and that in turn by another, prolonged rise. The maxi- mum height of the record is 13.5 millimeters, an increase of 6 millimeters over the height recorded before splanchnic stimulation. Thus the muscle was performing for a short period 80 per cent more work than before splanchnic stimulation, and for a considerably longer period exhibited an in- termediate betterment of its efficiency.
The First Eise in the Muscle Eecord
The brief first elevation in the muscle record when registered simultaneously with arterial blood pressure is observed to occur at the same time
Figure 12. — Top record, arterial blood pressure with membrane manometer. Mid- dle record, contractions of tibialis anticus loaded with 125 grams and stimulated 80 times a minute. Bottom record, splanchnic stimulation (two minutes). Time, half min- utes.
CONTEACTION OF FATIGUED MUSCLE 91
with the sharp initial rise in the blood-pressure curve (see Fig. 12). The first sharp rise in blood pressure is due to contraction of the vessels in the area of distribution of the splanchnic nerves, for it does not appear if the alimentary canal is removed, or if the celiac axis and the superior and inferior mesenteric arteries are ligated. The betterment of the muscular contraction is prob- ably due directly to the better blood supply result- ing from the increased pressure, for if the adrenal veins are clipped and the splanchnic nerves are stimulated, the blood pressure rises as before and at the same time there may be registered a higher contraction of the muscle.
The Prolonged Eise in the Muscle Eecord
As Fig. 12 shows, the initial quick uplift in the blood-pressure record is quickly checked by a drop. This rapid drop does not appear when the adrenal veins are obstructed. A similar difference in blood-pressure records has been noted before and after excision of the adrenal glands. As Elli- ott,^ and as Lyman and I " have shown, this sharp drop after the first rise, and also the subse- quent elevation of blood pressure, are the conse- quences of liberation of adrenal secretion into the circulation. Fig. 12 demonstrates that the pro- longed rise of the muscle record begins soon after this characteristic drop in blood pressure.
92 BODILY CHANGES
If after clips have been placed on the adre- nal veins so that no blood passes from them, the splanchnic nerves are stimulated, and later the clips are removed, a slight bnt distinct improve- ment in the muscular contraction occurs. As in the experiments of Young and Lehmann,^" in which the adrenal veins were tied for a time and then released, the release of the blood which had been pent in these veins was quickly followed by a rise of blood pressure. The volume of blood thus restored to circulation was too slight to ac- count for the rise of pressure. In conjunction with the evidence that splanchnic stimulation calls forth adrenal secretion, the rise may reasonably be attributed to that secretion. The fact should be noted, however, that in this instance the prolonged improvement in muscular contraction did not ap- pear until the adrenal secretion had been admitted to the general circulation.
Many variations in the improvement of activity in fatigued muscle after splanchnic stimulation were noted in the course of our investigation. The improvement varied in degree, as indicated by in- creased height of the record. In some instances the height of contraction was doubled — a better- ment by 100 per cent ; in other instances the con- traction after splanchnic stimulation was only a small fraction higher than that preceding the stim- ulation; and in still other instances there was no
CONTRACTION OP FATIGUED MUSCLE 93
betterment whatever. Never, in our experience, were the augmented contractions equal to the original strong contractions of the fresh muscle. The improvement also varied ia degree as in- dicated by persistence of effect. In some in- stances the muscle returned to its former working level within four or five minutes after splanchnic stimulation ceased (see Fig. 11) ; and in other cases the muscle continued working with greater effi- ciency for fifteen or twenty minutes after the stim- ulation.
The Two Factors: Arterial Pressure and Adrenal Secretion
The evidence just presented has shown that splanchnic stimulation improves the contraction of fatigued muscle. Splanchnic stimulation, however, has two effects — it increases general arterial pres- sure and it also causes a discharge of adrenin from the adrenal glands. The questions now arise — Does splanchnic stimulation produce the improve- ment in muscular contraction by increasing the arterial blood pressure and thereby flushing the laboring muscles with fresh blood? Or does the adrenin liberated by splanchnic stimulation act itself, specifically, to improve the muscular con- traction? Or may the two factors cooperate? These questions will be dealt with in the next two chapters.
94 BODILY CHANGES
EEFEEENCES
^ Albanese : Archives Italiennes de Biologie, 1892, xvii, p. 243.
2 Boinet : Comptes rendus, Societe de Biologie, 1895, xlvii, pp. 273, 498.
^ Oliver and Schiif er : Journal of Physiology, 1895, xviii, p. 263. See also Eadwanska, Anzeiger der Akademie, Krakau, 1910, pp. '728-'736. Eeviewed in Zentralblatt fiir Biochemie und Biophysik, 1911, xi, p. 467.
*.Dessy and Grandis: Archives Italiennes de Biologie, 1904, xli, p. 231.
^ Panella : Archives Italiennes de Biologie, 1907, xlviii, p. 462.
•^ Cannon and Nice : American Journal of Physiology, 1913, xxxii, p. 44.
' Bowditch and Warren : Journal of Physiology, 1886, vii, p. 438.
^ Elliott: Journal of Physiology, 1912, xliv, p. 403.
^ Cannon and Lyman : American Journal of Physiology, 1913, xxxi, p. 376.
^° Young and Lehmann : Journal of Physiology, 1908, xxxvii, p. liv.
CHAPTER VII
THE EFFECTS ON CONTEAOTION OF FATIGUED
MUSCLE OF VARYING THE ARTERIAL
BLOOD PRESSURE
That great excitement is accompanied by sym- pathetic innervations which increase the contrac- tion of the small arteries, render unusually forc- ible the heart beat, and consequently raise arterial pressure, has already been pointed out (see p. 26). Indeed, the counsel to avoid circumstances likely to lead to such excitement, which is given to per- sons with hardened arteries or with weak hearts, is based on the liability of serious consequences, either in the heart or in the vessels, that might arise from an emotional increase of pressure in these pathological conditions. That great muscu- lar effort also is accompanied by heightened arte- rial pressure is equally well known, and is avoided by persons likely to be injured by it. Both in ex- citement and in strong exertion the blood is forced in large degree from the capacious vessels of the abdomen into other parts of the body. In excite-
95
96 BODILY CHANGES
ment the abdominal arteries and veins are con- tracted by impulses from the splanchnic nerves. In violent effort the diaphragm and the muscles of the belly wall are voluntarily and antagonistic- ally contracted in order to stiffen the trunk as a support for the arms ; and the increased abdominal pressure which results forces blood out of that region and does not permit reaccumulation. The general arterial pressure in man, as McCurdy ^ has shown, may suddenly rise during extreme physical effort, from approximately 110 millime- ters to 180 millimeters of mercury.
The Effect of Increasing Arterial Pressure
What effect the increase of arterial pressure, re- sulting from excitement or physical strain, may have on muscular efficiency, has received only slight consideration. Nice and I found there was need of careful study of the relations between arterial pressure and muscular ability, and, in 1913, one of my students, 0. M. Gruber, under- took to make clearer these relations.
The methods of anesthesia and stimulation used by Gruber were similar to those described in the last chapter. The arterial blood pressure was registered from the right carotid or the femoral artery by means of a mercury manometer. A time marker indicating half -minute intervals was placed at the atmospheric pressure level of the
FATIGUE AND BLOOD PRESSURE 97
manometer. And since the blood-pressure style, the writing point of the muscle lever, and the time signal were all set in a vertical line on the surface of the recording drum, at any given muscular con- traction the height of blood pressure was simul- taneously registered.
To increase general arterial pressure two meth- ods were used: the spinal cord was stimulated in the cervical region through platinum electrodes, or the left splanchnic nerves were stimulated after the left adrenal gland had been excluded from the circulation. This was done in order to avoid any influence which adrenal secretion might exert. It is assumed in these experiments that vessels sup- plying active muscles would be actively dilated, as Kaufmann ^ has shown, and would, therefore, in case of a general increase of blood pressure, de- liver a larger volume of blood to the area they supply. The effects of increased arterial pressure are illustrated in Figs. 13, 14 and 15. In the ex- periment represented in Fig. 13, the rise of blood pressure was produced by stimulation of the cer- vical cord, and in Figs. 14 and 15 by stimulation of the left splanchnic nerves after the left adre- nal gland had been tied off.
The original blood pressure in Fig. 13 was 120 millimeters of mercury. This was increased by 62 millimeters, with a rise of only 8.4 per cent in the height of contraction of the fatigued muscle.
98
BODILY CHANGES
Figure 13. — In this and the following records, the upper curve indicates the blood pressure, the middle Mne muscu- lar contraction, and the lower line the time in 30 seconds (also zero blood pressure.) Between the arrows the exposed cervical spinal cord was stimulated.
In Fig. 14 the original blood pressure was 100 millimeters of mercury. By increasing this pres-
FATIGUE AND BLOOD PRESSURE 99
sure 32 millimeters there resulted simultaneous betterment of 9.8 per cent in the height of muscu- lar contraction. In Fig. 14 B the arterial pres- sure was raised 26 millimeters and the height of
V-'
''^tUiWutflUkttflWiM^
^2
T i
t 4.
A B C
FiGTJRB 14. — Stimulation of the left splanchnic nerves (left adrenal gland tied off) during the periods indicated by the arrows.
contraction increased correspondingly 7 per cent. In Fig. 14 C no appreciable betterment can be seen although the blood pressure rose 18 millimeters. In Fig. 15 the original blood pressure was low — 68 millimeters of mercury. This was increased in Fig. 15 A by 18 millimeters (the same as in
100 BODILY CHANGES
Fig. 14 C without effect), and there resulted an in- crease of 20 per cent in the height of contraction. In Fig. 15 B the pressure was raised 24 millime-
|
■\,,.. |
|
|
- ,-, . 1 p : , 1 ,-, 1 — 1 1 r |
A B C
Figure 15. — During the periods indicated in the time line the left splanchnic nerves were stimulated. The vessels of the left adrenal gland were tied off.
ters with a corresponding increase of 90 per cent in the muscular contraction ; and in Fig. 15 C 30 millimeters with a betterment of 125 per cent.
Comparison of Figs. 13, 14 and 15 reveals that the improvement of contraction of fatigued mus- cle is much greater when the blood pressure is raised, even slightly, from a low level, than when it is raised, perhaps to a very marked degree, from a high level. In one of the experiments per- formed by Nice and myself the arterial pressure
FATIGUE AND BLOOD PRESSURE 101
was increased by splanchnic stimulation from the low level of 48 millimeters of mercury to 110 milli- meters, and the height of the muscular contrac- tions was increased about sixfold (see Fig. 16).
Figure 16. — The bottom record (zero of blood pressure) shows stimulation of left splanchnics; between the arrows the pressure was kept from rising by compression of heart.
Results confirming those described above were obtained by Gruber in a study of the effects of splanchnic stimulation on the irritability of mus- cle when fatigued. In a series of eleven observa- tions the average value of the barely effective stimulus (the "threshold" stimulus) had to be in- creased as the condition of fatigue developed. It
102 BODILY CHANGES
was increased for the nerve-muscle by 25 per cent and for the muscle by 75 per cent. The left splanchnic nerves, disconnected from the left adre- nal gland, were now stimulated. The arterial pres- sure, which had varied between 90 and 100 milli- meters of mercury, was raised at least 40 milli- meters. As a result of splanchnic stimulation there was an average recovery of 42 per cent in the nerve-muscle and of 46 per cent in the muscle. The increased general blood pressure was effec- tive, therefore, quite apart from any possible action of adrenal secretion, in largely restoring to the fatigued structures their normal irritability.
The Effect of Decreasing Arterial Pressure
Inasmuch as an increase in arterial pressure produces an increase in the height of contraction of fatigued muscle, it is readily supposable that a decrease in the pressure would have the oppo- site effect. Such is the case only when the blood pressure falls below the region of 90 to 100 milli- meters of mercury. Thus if the arterial pressure stands at 150 millimeters of mercury, it has to fall approximately 55 to 65 millimeters before causing a decrease in the height of contraction. Fig. 17 is the record of an experiment in which the blood pressure was lowered by lessening the output of blood from the heart by compressing the thorax. The record shows that when the pressure
FATIGUE AND BLOOD PRESSURE 103
was lowered from 120 to 100 millimeters of mer- cury (A), there was no appreciable decrease in the height of contraction; when lowered to 90
Figure 17. — The arrows indicate the points at which the thorax began to be compressed in order to lessen the output of blood from the heart.
millimeters (B), there resulted a decrease of 2.4 per cent; when to 80 millimeters of mercury (C), a decrease of 7 per cent; and when to 70 milli- meters (D), a decrease of 17.3 per cent. Results similar to those represented in Fig. 17 were ob- tained by pulling on a string looped about the
104 BODILY CHANGES
aorta just above its iliac branches, thus lessening the flow to the hind limbs.
The region of 90 to 100 millimeters of mercury may therefore be regarded as the critical region at which a falling blood pressure begins to be ac- companied by a concurrent lessening of the effi- ciency of muscular contraction, when the muscle is kept in continued activity. It is at that region that the blood flow is dangerously near to being inadequate.
An Explanationotjth^ Effects op Varying the Arterul ""■ Pressure
How are these effects of ^ucreasing and decreas- ing the arterial blood pressure most reasonably explained? There is abundant evidence that fa- tigue products accumulate in a muscle which is doing work, and also that these metabolites inter- fere with efficient contraction. As Eanke ^ long ago demonstrated, if a muscle, deprived of circu- lating blood, is fatigued to a standstill, and then the circulation is restored, the muscle again re- sponds for a short time to stimulation, because the waste has been neutralized or swept away by the fresh blood. When the blood pressure is at its normal height for warm-blooded animals (about 120 millimeters of mercury, see Fig. 13), the flow appears to be adequate to wash out the depressive metabolites, at least in the single muscle
FATIGUE AND BLOOD PRESSURE 105 used in these experiments, because a large rise of
pressuTe_praduQ©s-%at4ittte-S level. On the other hand, when the pressure is abnormally low, the flow is inadequate, and the waste products are permitted to accumulate^ahd clog the action of the muscle. Under such circum- stances a rise of pressure has a. very striking bene- ficial effect.
It is noteworthy that the best results of adre- nin on fatigued muscle reported by previous ob- servers were obtained from studies on cold-blooded animals. In these animals the circulation is main- tained normally by an arterial pressure about one- third that of warm-blooded animals. Injection of adrenin in an amount which would not shut off the blood supply would, by greatly raising the arterial pressure, markedly increase the circulation of blood in the active muscle. In short, the conditions in cold-blooded animals are quite like those in the pithed mammal with an arterial pressure of about 50 millimeters of mercury (see Fig. 16). Under these conditions the improved circulation causes a remarkable recovery from fatigue. That notable results of adrenin on fatigue are observed in warm-blooded animals only, when they are deeply anaesthetized or are ^epriVed of the medulla was claimed by Panella.* He apparently believed that in normal mammalian conditions adrenia has little effect because quickly destroyed, whereas in
106 BODILY CHANGES
the cold-blooded animals, and in mammals whose respiratory, circulatory, and thermogenic states are made similar to the cold-blooded by anaesthesia or pithing, the contrary is true. In accordance with our observations of the effects of blood pres- sure on fatigued muscle, we would explain Panel- la's results not as he has done but as due to two factors. First, the efficiency of the muscle, when blood pressure is low, follows the ups and downs of pressure much more directly than when the pressure is high. And second, a given dose of adrenin always raises a low blood pressure in atonic vessels. The improvement of circulation is capable of explaining, therefore, the main re- sults obtained in cold-blooded animals and in pithed mammals.
Oliver and Schafer reported unusually effective contractions in muscles removed from the body after adrenal extract had been injected. As shown in Fig. 16, however, the fact that the circulation had teen improved results in continued greater effi- ciency of the contracting muscle. Oliver and Scha- fer's observation may reasonably be accounted for on this basis.
The Value of Increased Arterial Pressure m Pain and Strong Emotion
As stated in a previous paragraph, there is evi- dence that the vessels supplying a muscle dilate
FATIGUE AND BLOOD PEESSUEE 107
when the muscle becomes active. And although the normal blood pressure (about 120 millimeters of mercury) may be able to keep adequately sup- plied with blood the single muscle used in our in- vestigation, a higher pressure might be required when more muscles are involved in activity, for a more widely spread dilation might then reduce the pressure to the point at which there would be insufficient circulation in active organs. Further- more, with many muscles active, the amount of waste would be greatly augmented, and the need for abundant blood supply would thereby to a like degree be increased. For both reasons a rise of general arterial pressure would prove advan- tageous. The high pressure developed in excite- ment and pain, therefore, might be specially ser- viceable in the muscular activities which are likely to accompany excitement and pain.
Tn connection with the foregoing considerations, the action of adrenin on the distribution of blood in the body is highly interesting. By measuring alterations in the volume of various viscera and the limbs, Oliver and Schafer ^ proved that the viscera of the splanchnic area — e. g., the spleen, the kidneys, and the intestines — suffer a consider- able decrease of volume when adrenin is adminis- tered, whereas the limbs into which the blood is forced from the splanchnic region actually in- crease in size. The action of adrenin indicates the
108 BODILY CHANGES
relative degrees of sympathetic innervations. In other words, at times of pain and excitement sym- pathetic discharges, probably aided by the adrenal secretion simultaneously liberated, will drive the blood out of the vegetative organs of the interior, which serve the routine needs of the body, into the skeletal muscles which have to meet by extra action the urgent demands of struggle or escape. But there are exceptions to the general state- "nient thai •by'Sdrenin the viscera are emptied of their blood, ^t is well known that adrenin has a vasodilator, not a vasoconstrictor, action on the arteries of the heart; it is well known also that adrenin affects the vessels of the brain and the lungs only slightly if at all. From this evidence we may infer that sympathetic impulses, though causing constriction of the arteries of the abdomi- nal viscera, have no effective influence on those of the pulmonary and intracranial areas and actually increase the blood supply to the heart. Thus the absolutely and immediately essential organs — those the ancients called the "tripod of life" — the heart, the lungs, the brain (as well as its instru- ments, the skeletal muscles) — are in times jjf, ex- citement abundantly supplied with blood taken from organs of less importance in criticar"in6- inents. This shifting of the blood so that there is an assured adequate supply to structures" eSMntlal for the preservation of the individual may reason-
FATIGUE AND BLOOD PRESSURE 109
ably be interpreted as a fact of prime biological significance. It willJbej'Msgjd . in .its.,.pr,ape]j- setti-ng- / when the_otb.eX-,eziclence of bodily changes in pain I and excitement have. been. presented. ^
EEFEEENCES
^ McOurdy : American Journal of Physiology, 1901, v, p. 98.
2 Kaufmann : Archives de Physiologie, 1892, xxiv, p. 283.
^Eanke: Archiv fiir Anatomie, 1863, p. 446.
* Panella : Archives Italiennes de Biologie, 190Y, xlviii, p. 462.
° Oliver and Schafer : Journal of Physiology, 1895, xviii, p. 240.
/
CHAPTER VIII
THE SPECIFIC EOLE OE ADEENIN IN COUNTERACTING THE EFFECTS OF FATIGUE
As a muscle approaches its fatigue level, its con- tractions are decreased in height. Higher contrac- tions will again be elicited if the stimulus is in- creased. Although these phenomena are well known, no adequate analysis of their causes has been advanced. A number of factors are probably operative in decreasing the height of contraction : (1) The using up of available energy-producing material; (2) the accumulation of metabolites in the fatigued muscle; (3) polarization of the nerve at the point of repeated electrical stimulation ; and (4) a decrease of irritability. It may be that there are interactions between these factors within the muscle, e. g., the second may cause the fourth.
Variations of the Threshold Stimulus as a Measure of Irritability
The last of the factors mentioned above — the effect of fatigue on the irritability of the nerve- muscle combination, or on the muscle alone — can
110
FATIGUE AND ADRENIN 111
be tested by determining variations in the least stimulus capable of causing the slightest contrac- tion, the so-called "threshold stimulus." As the irritability lessens, the threshold ' stimulus must necessarily be higher. The height of the threshold is therefore a measure of irritability. How does fatigue affect the irritability of nerve-muscle and muscle ? How is the irritability of fatigued struc- tures affected by rest? How is it influenced by adrenin or by adrenal secretion? Answers to these questions were sought in researches carried on by C. M. Gruber ^ in 1913.
The Method of Determining the Threshold Stimulus
The neuro-muscular arrangements used in these researches were in many respects similar to those already described in the account of experiments by Nice and myself. To avoid the influence of an anesthetic some of the animals were decerebrated under ether and then used as in the experiments in which urethane was the anesthetic. The nerve (the peroneus communis) supplying the tibialis an- ticus muscle was bared and severed ; and near the cut end shielded platinum electrodes were applied. These electrodes were used in fatiguing the muscle. Between these electrodes and the muscle other platinum electrodes could be quickly applied to de- termine the threshold stimulus and the tissue re- sistance. These second electrodes were removed
112 BODILY CHANGES
except wlien in use, and when replaced were set always in the same position. Care was taken, be- fore replacing them, to wipe off moisture on the nerve or on the platinum points.
For determining the threshold stimulus of the muscle the skin and other overlying tissues were cut away from the tibialis anticus in two places about 5 centimeters apart. Through these open- ings platinum needle electrodes could be thrust into the muscle whenever readings were to be taken. Local polarization was avoided by rein- serting the needles into fresh points on the exposed areas whenever new readings were to be taken.
The tendon of the tibialis anticus was attached, as in the previous experiments, by a strong thread passing about pulleys to a lever which when lifted stretched a spring. During the determination of the threshold the spring was detached from the lever, so that only the pull of the lever itself (about 15 grams) was exerted on the muscle.
The method of measuring the stimulating value of the electric current which was used in testing the threshold was that devised by E. Gr. Martin* of the Harvard Laboratory — a method by which the strength of an induced electric shock is calculable in definite units. If the tissue resistance enters
* For a full account of Dr. Martin's method of calculating' the strength of electric stimuli, see Martin : The Measurement of Induction Shocks, New York, 1912.
FATIGUE AND ADEENIN 113
into the calculation these are called ^ units. When the threshold of the nerve-muscle was taken, the apparatus for the determination was connected with the nerve through the electrodes nearer the muscle. They were separated from the fatiguing electrodes by more than 3 centimeters, and ar- ranged so that the kathode was next the muscle. When the threshold of the muscle was taken direct- ly the apparatus was connected with the muscle through platinum needle electrodes thrust into it. The position of the secondary coil of the inducto- rium, in every case, was read by moving it away from the primary coil until the very smallest pos- sible contraction of the muscle was obtained. Four of these readings were made, one with tissue resist- ance, the others with 10,000, 20,000, and 30,000 ohms additional resistance in the secondary cir- cuit. Only break shocks were employed — the make shocks were short-circuited. Immediately after the determination of the position of the sec- ondary coil, and before the electrodes were re- moved or disconnected, three readings of the tis- sue resistance were made. From these data four values for /3 were calculated.
The strength of the primary current for deter- mining the threshold of the nerve-muscle was usu- ally .01 ampere, but in a few cases .05 ampere was used. For normal muscle it was .05 ampere and for denervated muscle 1.0 ampere. The inducto-
114 BODILY CHANGES
rium, which was used throughout, had a secondary resistance of 1400 ohms. This was added to the average tissue resistance in making corrections — corrections were made also for core magnetiza- ti on.
The Lessening op Neuro-musculae Irritability by Fatigue The threshold for the peroneus communis nerve in decerebrate animals varied from 0.319 to 2.96 units, with an average in sixteen experiments of 1.179.* This average is the same as that found by E. L. Porter ^ for the radial nerve in the spinal cat. For animals under urethane anesthesia a higher average was obtained. In these it varied from .644 to 7.05, or an average in ten experiments of 3.081.
The threshold for the tibialis anticus muscle varied in the decerebrate animals from 6.75 units to 33.07, or an average in fifteen experiments of 18.8. Ten experiments were performed under ure- thane anesthesia and the threshold varied from 12.53 to 54.9, with an average of 29.84 j3 units. From these results it is evident that anesthesia notably affects the threshold.
E. L. Porter proved, by experiments carried on in the Harvard Physiological Laboratory, that the threshold of an undisturbed nerve-muscle remains
* For the detailed data of these and other quantitative ex- periments, the reader should consult the tables in the original papers.
FATiaUE AND ADRENIN 115
constant for hours, and his observation was con- firmed by Gruber (see Fig. 19). If, therefore, after fatigue, a change exists in the threshold, this change is necessarily the result of alterations set up by the fatigue process in the nerve-muscle or muscle.
After fatigue the threshold of the nerve-muscle, in sixteen decerebrate animals, increased from an average of 1.179 to 3.34 — an increase of 183 per cent. In ten animals under urethane anesthesia the threshold after fatigue increased from a nor- mal average of 3.08 to 9.408 — an increase of 208 per cent.
An equal increase in the threshold stimulus was obtained from the normal muscle directly. In de- cerebrate animals the normal threshold of 18.8 units was increased by fatigue to 69.54, or an in- crease of 274 per cent. With urethane anesthesia the threshold increased from 29.849 to 66.238, or an increase of 122 per cent.
Fig. 18, plotted from the data of one of the many experiments, shows the relative heights of the threshold before and after fatigue. The corre- spondence of the two readings of the threshold, one from the nerve supplying the muscle and the other from the muscle directly, served as a check on the electrodes. The broken line in the figure repre- sents the threshold (in units) of the nerve-muscle, and the continuous line that of the muscle. The
116 BODILY CHANGES
threshold values of the nerve-muscle have been magnified ten times in order to bring the two rec- ords close together. In this experiment the thresh-
FiGTJEE 18. — A record plotted from the data of one experiment. The time intervals in minutes are registered on the abscissa; the value of the threshold in units is registered on the ordinate. The continuous line is the record of the muscle, the broken Une that of the nerve-muscle. The values for the nerve-muscle have been magnified ten times, those for the muscle are normal.
(1) Normal values of the threshold.
(2) Fatigue thresholds after one hour's work, hfting 120 grams 240 times a minute.
(3 and 4) The threshold after rest.
old of the muscle after fatigue (i.e., at 2) is 167 per cent higher than the normal threshold (at 1), while that of the nerve-muscle after fatigue is 30.5 per cent higher than its normal.
Evidently a direct relation exists between the duration of work and the increase of threshold. For instance, the threshold is higher after a muscle is fatigued for two hours than it is at the end of
FATIGUE AND ADEENIN 117
the first hour. The relation between the work done and the threshold is not so clear. In some animals the thresholds were higher after 120 grams had been lifted 120 times a minute for 30 minutes than they were in others in which 200 grams had been lifted 240 times a minute for the same period. The muscle in the latter instances did almost four times as much work, yet the threshold was lower. The difference may be due to the general condi- tion of the animal.
A few experiments were performed on animals in which the nerve supplying the muscle was cut seven to fourteen days previous to the experiment. The muscle, therefore, had within it no living nerve fibres. The average normal threshold for the denervated muscle in 6 animals was 61.28 units. As in the normal muscle, the percentage increase due to fatigue was large.
The Slow Eestoration of Fatigued Muscle to Normal Ireitability by Eest
That rest decreases the fatigue threshold of both nerve-muscle and muscle can be seen in Fig. 18. The time taken for total recovery, however, is de- pendent upon the amount of work done, but this change, like that of fatigue, varies widely with different individuals. In some animals the thresh- old returned to normal in 15 minutes; in others, in which the same amount of work was done, it was
118 BODILY CHANGES
still above normal even after 2 hours of rest. This may be due to the condition of the animals — in some the metabolites are probably eliminated more rapidly than in others. There were also variations in the rate of restoration of the normal threshold when tested on the nerve and when tested on the muscle in the same animal. In Fig. 18 (at 3) the nerve-muscle returned to normal in 30 miautes, whereas the muscle (at 4) after an hour's rest had not returned to normal by a few /3 units. This, however, is not typical of all nerve-muscles and muscles. The opposite condition — that in which the muscle returned to normal before the nerve- muscle — occurred in as many cases as did the con- dition just cited. The failure of the two tissues to alter uniformly in the same direction may be ex- plained as due to variations in the location of the electrodes when thrust into the muscle at different times (e. g., whether near nerve filaments or not). The results from observations made on the nerve are more likely to be uniform and reliable than are those from the muscle.
The time required for the restoration of the threshold from fatigue to normal, in denervated muscles, is approximately the same as that for the normal muscle.
FATiaUE AND ADEENIN 119
The Quick Eestoration of Fatigued Husole to Normal Irritability by AoRENDf
The foregoing observations showed that fatigue raises the normal threshold of a muscle, on the av- erage, between 100 and 200 per cent (it may be in- creased more than 600 per cent) ; that this increase is dependent on the time the muscle works, but also varies with the animal ; that rest, 15 minutes to 2 hours, restores the normal irritability ; and that ^ this recovery of the threshold depends upon the time given to rest, the duration of the work, and also upon the condition of the animal. The prob- lem which was next attacked by Gruber was that of learning whether the higher contractions of fa- tigued muscle after splanchnic stimulation could be attributed to any influence which adrenal secre- tion might have in restoring the normal irritability. To gain insight iato the probabilities he tried first the effects of injecting slowly into the jugular vein physiological amounts of adrenin.*
The normal threshold of the peroneus communis nerve varied in the animals used in this series of observations from 0.35 to 5.45 units, with an aver- age in nine experiments of 1.3, a figure close to the 1.179 found in the earlier series on the effect of fatigue. For the tibialis anticus muscle, in which the nerve-endings were intact, the threshold varied
* The form of adrenin used in these and in other injections was fresh adrenalin made by Parke, Davis & Co.
120 BODILY CHANGES
from 6.75 to 49.3 units, with an average in the nine experiments of 22.2. This is slightly higher than that cited for this same muscle in the earlier series. By fatigue the threshold of the nerve-muscle was increased from an average of 1.3 to an average of 3.3 units, an increase of 154 per cent. The muscle increased from an average of 22.2 to an average of 59.6, an increase of 169 per cent. After an injec- tion of 0.1 to 0.5 cubic centimeters of adrenin (1:100,000) the fatigue threshold was decreased ivithin five minutes in the nerve-muscle from an average of 3.3 to 1.8, a recovery of 75 per cent, and in the muscle from an average of 59.6 to 42.4, a re- covery of 46 per cent. To prove that this effect of adrenin is a counteraction of the effects of fatigue, Gruber determined the threshold for muscle and nerve-muscle in non-fatigued animals before and after adrenin injection. He found that in these cases no lowering of threshold occurred, a result in marked contrast with the pronounced and prompt lowering induced by this agent in muscles when fatigued.
Figs. 19 and 20, plotted from the data of two of the experiments, show the relative heights of the threshold before and after an injection of adrenin. The close correspondence of the two readings of the threshold, one from the nerve supplying the muscle, the other from the muscle directly, served to show that there was no fault in the electrodes.
FATIGUE AND ADEENIN 121
The continuous line in the Figures represents the threshold (in units) of the muscle, the broken line that of the nerve-muscle. The threshold of the nerve-muscle is magnified 100 times in Fig. 19 and 10 times in Fig. 20. In Fig. 19 (at 2 and 4) the threshold was taken after an intravenous injection of 0.1 and 0.2 cubic centimeter of adrenin respec- tively.
These examples show that adrenin does not af- fect the threshold of the normal non-fatigued mus- cle when tested either on the muscle directly or on the nerve-muscle. In Fig. 19 (at 3) the observa- tion taken after two hours of rest illustrates the constancy of the threshold under these circum- stances.
In Fig. 19 the normal threshold was increased by fatigue (at 5) — the muscle had been pulling 120 times a minute for one hour on a spring hav- ing an initial tension of 120 grams — from 30.0 to 51.6 units, an increase of 72 per cent; and in the nerve-muscle from 0.62 to 0.89 units, an increase of 46 per cent. The threshold (at 6) was taken five minutes after injecting 0.1 cubic centimeter of adrenin (1:100,000). The thresh- old of the muscle was lowered from 51.6 to 38.0 units, a recovery of 62 per cent; that of the nerve-muscle from 0.89 to 0.79 units, a recovery of 37 per cent. After another injection of 0.5 cubic centimeter of adrenin the thresholds (at 7) were
122
BODILY CHANGES
taken; that of the nerve-muscle dropped to normal — 0.59 miits — a recovery of 100 per cent, and that
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Figure 19. — A record plotted from the data of one experiment. The time inter- vals in hours and minutes are represented on the abscissa; the values of the threshold in ;3 units are represented on the ordinate. The continuous line is the record of the muscle, the broken line that of the nerve- muscle. The nerve-muscle record is mag- nified 100 times; that of the muscle is nor- mal.
(1) Normal threshold stimulus. (2) Threshold five minutes after an intraven- ous injection of 0.1 cubic centimeter of ad- renin (1:100,000) without previous fatigue.
(3) Threshold after a rest of two hours.
(4) Threshold five minutes after an injec- tion of 0.2 cubic centimeter of adrenin (1:100,000) without previous fatigue. (5) Threshold after one hour's fatigue. The muscle contracted 120 times per minute against a spring having an initial tension of 120 grams. (6) Threshold five minutes after an injection (0.1 cubic centimeter) of adrenin (1:100,000). (7) Threshold five minutes after another injection of adrenin (0.5 cubic centimeter of a 1:100,000 solu- tion).
of the muscle remained unaltered — 26 per cent above its normal threshold. In Fig. 20 the threshold (at 5) was taken five
FATIGUE AND ADEENIN 123
mimites after an injection of 0.1 cubic centimeter of adrenin. The drop here was as large as that shown in Fig. 19. The threshold taken from the
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Figure 20. — A record plotted from the data of one experiment. The time intervals in hours and minutes are registered on the abscissa; the values of the threshold in units are registered on the ordinate. The continuous line is the record of the muscle, the broken line that of the nerve-muscle. The record of the nerve- muscle is magnified ten times; that of the muscle is normal.
(1) Normal threshold. (2) The threshold after one hour's fatigue. The muscle contracted 120 times per minute against a spring having an initial tension of 120 grams. (3 and 4) Thresh- olds after rest; after 60 minutes (3), and after 90 minutes (4). (5) Threshold five minutes after an injection of adrenin (0.1 cubic centimeter of a 1:100,000 solution). (6 and 7) Thresholds after rest; after 60 minutes (6), and after 90 minutes (7).
muscle directly was lowered from 30.6 to 18 units, a recovery of 61 per cent; the nerve-muscle from 1.08 to 0.87 units, a recovery of 51 per cent. That this sudden decrease cannot be due«to rest is shown in the same Figure (at 3 and 4). These readings were made after 60 and 90 minutes' rest respective- ly. The sharp decline in the record (at 5) indi- cates distinctly the remarkable restorative influ-
124 BODILY CHANGES
enee of adrenin in promptly lowering tlie high fatigue threshold of neuro-muscular irritability.
The Evidence that the Eestorative Action op Adrenin is Specific
As stated in describing the effects of arterial blood pressure, an increase of pressure is capable of causing a decided loweriug of the neuro-muscu- lar threshold after fatigue. Is it not possible that adrenin produces its beneficial effects by better- ing the circulation 1
Nice and I had argued that the higher contrac- tions of fatigued muscle, that follow stimulation or injection of adrenin, could not be wholly due to improved blood flow through the muscle, for when by traction on the aorta or compression of the thorax arterial pressure in the hind legs was pre- vented from rising, splanchnic stimulation still caused a distinct improvement, the initial appear- ance of which coincided with the point in the blood- pressure curve at which evidence of adrenal secre- tion appeared. And, furthermore, the improve- ment was seen also when adrenin was given intra- venously in such weak solution (1:100,000) as to produce a fall instead of a rise of arterial pressure. Lyman and I had shown that this fall of pressure was due to a dilator effect of adrenin. Since the blood vessels of the fatigued muscle were dilated by severance of their nerves when the nerve trunk was
FATIGUE AND ADEENIN
125
cut, and, besides, as previously stated (see p. 86), were being stimulated through, their nerves at a rate favorable to relaxation, it seemed hardly prob-
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FiGtTRB 21. — Top record, blood pressure with mercury manometer. Middle record, contractions of the tibialis anticus muscle 240 times per minute against a spring with an initial tension of 120 grams. Bottom record (zero blood pressure), injection of 0.4 cubic centimeter of adrenin (1:100,- 000). Time in half minutes.
able that adrenin could produce its beneficial effect by further dilation of the vessels and by consequent flushing of the muscle with an extra supply of blood.^ The lowering of blood pressure had
126 BODILY CHANGES
been proved to have no other effect than to impair the action of the muscle ( see p. 103 ) . Although the chances were thus against an interpretation of the beneficial influence of adrenin through action on the circulation, it was thought desirable to test the possibility by comparing its effect with that of another vasodilator — amyl nitrite.
Figs. 21 and 22 are curves obtained from the left tibialis anticus muscle. The rate of stimulation was 240 times a minute.
The muscle in Fig. 21 contracted against a spring having an initial tension of 120 grams, and that in Fig. 22 against an initial tension of 100 grams. In Fig. 21, at the point indicated on the base line, 0.4 cubic centimeter of adrenin (1:100,000) was in- jected into the left external jugular vein. There resulted a fall of 25 millimeters of mercury in the arterial pressure and a concurrent betterment of 15 per cent in the height of contraction, requiring two minutes and fifteen seconds of fatigue (about 540 contractions) before it returned to the former level. In Fig. 22, at the point indicated by the arrow, a solution of amyl nitrite was injected into the right external jugular vein. There resulted a fall of 70 millimeters of mercury in arterial pres- sure and a betterment of 4.1 per cent in the height of muscular contraction, requiring fifteen seconds of fatigue (about 60 contractions) to decrease the height of contraction to its former level. In
FATIGUE AND ADEENIN
127
Figure 22. — Top record, blood pressure with mercury manometer. Middle record, con- tractions of tibialis anlicus mus- cle 240 per minute against a spring with an initial tension of 100 grams direct load. Bottom record (zero blood pressure), time in half minutes. The arrow indi- cates the point at which a solu- tion of amyl nitrite was injected.
128 BODILY CHANGES
neither case did the blood pressure fall below the critical region (see p. 104).*
Although the fall in arterial pressure caused by dilation of the vessels due to amyl nitrite was al- most three times as great as that produced by the adrenin, yet the resultant betterment was only about one-fourth the percentage height and lasted but one-ninth the time. In all cases in which these solutions caused an equal fall in arterial pressure, adrenin caused higher contractions, whereas amyl nitrite caused no appreciable change.
The Point op Action of Adrenin in Muscle
From the evidence presented in the foregoing pages it is clear that adrenin somehow is able to bring about a rapid recovery of normal irritability of muscle after the irritability has been much less- ened by fatigue, and that the higher contractions of a fatigued muscle after an injection of adrenin are due, certainly in part, to some specific action of this substance and not wholly to its influence~o5~ tlie circulation. Some of the earlier investigators
* In some cases after injection of amyl nitrite the normal blood pressure, which was high, dropped sharply to a point below the critical region. There resulted a primary increase in muscular contraction due to the betterment in circulation caused by the dilation of the vessels before the critical region was reached. During the time that the pressure was below the critical region the muscle contraction fell. As the blood pressure again rose to normal the muscle contraction in- creased coincidently.
FATIGUE AND ADEENIN 129
of adrenal function, notably Albanese,* and also Abelous and Langlois,^ inferred from experi- ments on tbe removal of the glands that the role they played in the bodily economy was that of neu- tralizing, destroying or transforming toxic sub- stances produced in the organism as a result of muscular or nervous work. It seemed possible that the metabolites might have a checking or blocking influence at the junction of the nerve fibres with the muscle: fibres, and might thus, like curare, lessen the efficiency of the nerve impulses. Eadwanska's ob- servation ® that the beneficial action of adrenin is far greater when the muscle is stimulated through its nerve than when stimulated directly, and Panel- la's discovery ^ that adrenin antagonizes the ef- fect of curare, were favorable to the view that adrenin improves the contraction of fatigued mus- cle by lessening or removing a block established by accumulated metabolites.
The high threshold of fatigued denervated mus- cle, however, Gruber found was quite as promptly lowered by adrenin as was that of normal muscles stimulated through their nerves. Fig. 23 shows that the height of contraction, also, of the fatigued muscle is increased when adrenin is administered. In this experiment the left tibialis anticus muscle was stimulated directly by thrusting platinum needle electrodes into it. The peroneus communis nerve supplying the muscle had been cut and two
130 BODILY CHANGES
centiineters of it removed nine days previous to the experiment. The rate of stimulation was 120 times per minute and the initial tension of the spring about 120 grams. At the point indicated
Figure 23. — Top record, blood pressure with mercury manometer. Middle record, contractions of a denervated muscle {tibialis anticus) 240 per per minute against a spring having an initial ten- sion of 120 grams {peroneus communis nerve was cut nine days before this record was taken). Bot- tom record (zero blood pressure), time in half min- utes. At the point indicated by an arrow 0.1 cubic centimeter of adrenin (1:100,000) was injected intravenously.
by the arrow an injection of 0.1 cubic centimeter of adrenin (1:100,000) was made into a jugular vein. A fall in arterial pressure from 110 to 86 millimeters of mercury and a simultaneous better- ment of 20 per cent in the height of contraction
FATIGUE AND ADRENIN ;i31
were obtained. It required four minutes of fatigue (about 480 contractions) to restore the muscle curve to its former level. Eesults similar to this were obtained from animals in which the nerve had been cut 7, 9, 12, 14, and 21 days. In all instances the nerve was inexcitable to strong f aradic stimula- tion.
In Eadwanska's experiments, mentioned above, the muscle was stimulated directly when the nerve endings were intact. It seems reasonable to sup- pose, therefore, that in all cases he was stimulat- ing nerve tissue. Since a muscle is more irritable when stimulated through its nerve than when stimulated directly (nerve and muscle), a slight change in the irritability of the muscle by adrenin would naturally result in a greater contraction when the nerve was stimulated. Panella's results also are not inconsistent with the interpretation that the effect of adrenin is on the muscle substance rather than on the nerve endings. A method which has long been used to separate muscle from nerve is that of blocking the nervous impulses by the drug curare. Gruber found that when curare is in- jected the threshold of the normal muscle is in- creased as was to be expected from the removal of the highly efficient nervous stimulations. And also, as was to be expected on that basis, curare did not increase the threshold in a muscle in which the nerve endings had degenerated. Adrenin antago-
132 BODILY CHANGES
nizes curare with great promptness, decreasing the heightened threshold of a curarized muscle, in five minutes or less, in some cases to normal. From this observation it might be supposed that curare and fatigue had the same effect, and that adrenin had the single action of opposing that effect. But fatigue raises the threshold of a curarized muscle, and adrenin then antagonizes this fatigue. Lang- ley ^ has argued that curare acts upon a hypo- thetical "receptive substance" in muscle. If so, probably curare acts upon a substance, or at a point, different from that upon which fatigue acts ; for, as the foregoing evidence shows, fatigue in- creases the threshold of a muscle whether deprived of its nerve supply by nerve section and degenera- tion or by curare, whereas curare affects only the threshold of a muscle in which the nerve endings are normal.^ And since adrenin can oppose the effects of both curare and fatigue, it may be said to have two actions, or to act on two different substances or at two different points in the muscle. The evidence adduced in the last chapter indi- cated that the greater "head" of arterial pressure produced by the more rapid heart beat and the stronger contraction of many arterioles in times of great excitement would be highly serviceable to the organism in any extensive muscular activity which the excitement might involve. By assuring an abundant flow of blood through the enlarged ves-
FATIGUE AND ADKENIN 133
sels of the working muscle, the waste products resulting from the wear and tear in contraction would be promptly swept away and thus would be prevented from impairing the muscular effi- ciency. The adrenin discharge at such times would, as was pointed out, probably reinforce the effects of sympathetic impulses. The evidence presented in this chapter shows that adrenin has also another action, a very remarkable action, that of restor- ing to a muscle its original ability to respond to stimulation, after that has been largely lost by continued activity through a long period. What rest will do only after an hour or more, adrenin will do in five minutes or less. The bearing of this striking phenomenon on the functions of the or- ganism in times of great need for muscular activ- , ity will be considered in a later discussion.
EEFEEENCES
^ Gruber : American Journal of Physiology, 1913, xxxii, p. 437.
" E. L. Porter : American Journal of Physiology, 1912, xxxi, p. 149.
^ Cannon and Nice : American Journal of Physiology, 1913, xxxii, p. 55.
* Albanese : Archives Italiennes de Biologie, 1892, xvii, p. 239.
^ Abelous and Langlois : Archives de Physiologie, 1892, xxiv, vv- 269-278, 465-476.
"Eadwanska: Anzeiger der Akademie, Krakau, 1910, pp. 728-736. Reviewed in the Centralblatt fiir Biochemie und Biophysik, 1911, xi, p. 467.
134 BODILY CHANGES
' Panella : Archives Italiennes de Biologie, 1907, xlvii, p. 30.
* Langley : Proceedings of the Royal Society of London, 1906, Ixxviii, B, p. 181. Journal of PhysiBldgy, 1905-6, xxxiii, pp. 374-413.
^ See Gruber : American Journal of Physiology, 1914, xxxiv, p. 89.
CHAPTEE IX
THE HASTENING OF COAGULATION OF BLOOD BY ADRENIN
The primary value of blood to the body must have been one of the earliest observations of rea- soning beings. When we consider the variety of fundamental services which this circulating fluid performs — the conveyance of food and oxygen to all the tissues, the removal of waste, the delivery of the internal secretions, the protection of the body against toxins and bacterial invasion, and the dis- tribution of heat from active to inactive regions — the view of the ancient Hebrews that the "life of the flesh is in the blood" is well justified. It is naturally of the utmost importance that this pre- cious fluid shall be safeguarded against loss. And its property of turning to a jelly soon after escap- ing from its natural channels assures a closure of the opening through which the escape occurred, and thus protection of the body from further bleeding. The slight evidence that adrenin hastens the clot- ting process has already been hinted at. When we
135
136 BODILY CHANGES
found that adrenin is set free in pain and intense emotion, it seemed possible that there might exist in the body an arrangement for making doubly sure the assurance against loss of blood, a proc- ess that might nicely play its role precisely when the greatest need for it would be likely to arise. It was in 1903, while tracing in dogs the rise and fall of sugar in the blood after administering adrenin, that Vosburgh and Richards ^ first noted that simultaneously with the increase of blood sugar there occurred more rapid coagulation. In some cases the diminution was as much as four- fifths the coagulation time of the control. Since this result was obtained by painting "adrenalin" on the pancreas, as well as by injecting it into the abdominal cavity, they concluded that "the phe- nomenon appears to be due to the application of adrenalin to the pancreas." Six years later, dur- ing a study of the effect of adrenalin on internal hemorrhage, Wiggers ^ examined incidentally the evidence presented by Vosburgh and Eichards, and after many tests on five dogs found "never the slightest indication that adrenalin, either when injected or added to the blood, appreciably hast- ened the coagulation process." In 1911 von den Velden^ reported that adrenin (about 0.007 mil- ligram per kilo of body weight) decreased the coagulation time in man about one-half — an effect appearing 11 minutes after administration by
FASTER COAGULATION BY ADEENIN 137
mouth, and 85 miniites after subcutaneous injec- tion. He affirmed also, but without describing the conditions or giving figures, that adrenin de- creases coagulation time in vitro. He did not at- tribute the coagulative effect of adrenin in patients to this direct action on the blood, however, but to vasoconstriction disturbing the normal circulation and thereby the normal equilibrium between blood and tissue. In consequence, the tissue juices with their coagulative properties enter the blood, so he assumed. In support of this theory he offered his observation that coagulation time is decreased after the nasal mucosa has been rendered anemic by adrenin pledgets. Von den Velden's claim ^ for adrenin given by mouth was subjected to a single test on man by Dale and Laidlaw,* but their re- sult was completely negative.
The importance of Vosburgh and Richards' ob- servation, the thoroughly discordant testimony of later investigators, as well as the meager and inci- dental nature of all the evidence that has been ad- duced either for or against the acceleration of clot- ting by adrenin, made desirable a further study of this matter. Especially was this further study de- sirable because of the discharge of adrenin into the blood in pain and emotional excitement. Ac- cordingly, in 1914, H. Gray and I ^ undertook an investigation of the question. In doing so we em- ployed cats as subjects. Usually they were quickly
138
BODILY CHANGES
decerebrated under etlier, and tlien continuance of the drug became unnecessary. Body temperature was maintained by means of an electric heating pad. Eespiration proceeded normally except in a few instances (in which, presumably, there was hemorrhage into the medulla), when artificial res- piration had to be given.
The Graphic Method op Measuring the Coagulation Time
In order to avoid, so far as possible, the personal element in determining when the blood was clotted.
^
F&
i s
Figure 24. — Diagram of the graphic coagulometer. The can- nula at the right rests in a water bath not shown in this diagram. For further description see text.
the blood was made to record its own clotting. The instrument by means of which this was done was the graphic coagulometer devised by W. L. Men- denhall and myself,® and illustrated diagram- matically in Fig. 24. It consists essentially of a light aluminum lever with the long arm nearly counterpoised by a weight W. The long arm is
FASTER COAGULATION BY ADEENIN 139
prevented from falling by a support 8, and is pre- vented from rising by a horizontal right-angled rod reaching over the lever at R^ and fixed into the block B which turns on the axis A. Into the same block is fixed the vertical rod R^. When this rod is moved from the post P^, against which it is held by the weight of the horizontal rod iJ^ towards the other post P^, the check on the long arm of the lever is lifted, and if the short arm is heavier, the long arm will then rise.
The cannula C, into which the blood is received, is two centimeters in total length and slightly more than two millimeters in internal diameter. It is attached by a short piece of rubber tubing to the tapered glass tube T, five centimeters long and five millimeters in internal diameter. The upper end of this tube is surrounded by another piece of rub- ber which supports the tube when it is slid into the U-shaped support U, fixed directly below the end of the short arm of the lever.
By drawing the cannulas from a single piece of glass tubing and by making the distance from shoulder to upper end about twelve millimeters, receptacles of fairly uniform capacity are assured. All the dimensions, the reach of the rubber con- nection over the top of the cannula (2-3 milli- meters), the distance of the upper rubber ring from the lower end of the glass chamber (4 centi- meters), etc., were as nearly standard as possible.
140 BODILY CHANGES
A copper wire D, eiglit centimeters long and 0.6 millimeters ia diameter, bent above into a hook and below into a small ring slightly less than two millimeters in diameter, is hung in a depression at the end of the short arm of the lever. The small ring then rests in the upper part of the cannula (see Fig. 24). The weight of the copper wire makes the short arm of the lever heavier than the long arm by 30 milligrams, when the delicate writ- ing point is moving over a lightly smoked drum. Half a dozen of these standard wires are needed.
For accurate determination of the coagulation time Addis '^ has defined the following conditions as essential:
1. The blood must always be obtained under the same conditions.
2. Estimates must all be made at the same tem- perature.
3. The blood must always come in contact with the same amount and kind of foreign material.
4. The end point must be clear and definite and must always indicate the same degree of coagula- tion.
The precautions taken to fulfill these conditions were as follows:
1. Drawing the blood. — The blood was taken from the femoral artery. The artery (usually the right) was laid bare in the groin and freed from surrounding tissue. A narrow artery clip, with
FASTER COAGULATION BY ADRENIN 141
each limb enclosed in soft rubber tubing (to pre- vent injury of the tissues), and with its spring ex- erting gentle pressure, was placed on the artery immediately below the deep femoral branch, thus allowing no blood to stagnate above the clip. Be- tween the clip and a ligature applied about 1.5 centimeters below, an opening was made. The blood was carefully milked out of the vessels be- tween a blunt dissector moved beneath, and a small forceps, twisted into a pinch of absorbent cotton, moved above.
The cannula, cleaned in water, alcohol, and ether, was set in the rubber connection of the glass tube ; the point of the cannula was then lubricated with vaseline and slipped into the artery. The pres- sure of the clip on the artery was next very slightly released and blood was allowed to flow into the cannula up to the lower border of the rubber con- nection. Only a good-sized drop of blood was needed. Sometimes the blood ran one or two milli- meters above or below, but without appreciably changing the result. Since the clip was situated on the femoral immediately below a branch in which the circulation persisted, the blood received in the cannula was always fresh from the moving stream. As soon as the clip gripped the artery again, the cannula was slipped out. A helper then promptly milked the vessel in the manner described above, and covered it with a pad of absorbent cotton
142 BODILY CHANGES
smeared with, vaseline to prevent drying. There- by blood was not permitted to stagnate ; and when a new sample was to be taken, the vessel was clean and ready for use.
The tip of the cannula was at once plugged by plunging it into a flat mound of plasticine about three millimeters high. It was drawn off sidewise lest the plasticine plug be pulled out again. One of the copper wires D was now slid into the tube and cannula, the tube slipped into the U-support, and the wire lifted and hung on the lever. This procedure, from the moment blood began to flow until the wire was hung, consumed usually about twenty seconds.
2. Uniform temperature. — Under the U-support was placed a large water bath, in which the can- nula and the tapering part of the tube were sub- merged. A thermometer was fixed to the U-sup- port so that the bulb came near the cannula in the bath. The water was kept within a degree of 25° C. This temperature was chosen for several rea- sons : (a) The cannula has room temperature and rapidly cools the small volume of blood that enters it. To heat blood and cannula to body tempera- ture would take time. A bath near room tempera- ture, therefore, seems preferable to one near body temperature, (b) The test of clotting was conveni- ently made at intervals of a half -minute, and if the clotting process were hastened by higher tempera-
FASTER COAGULATION BY ADKENIN 143
tures, this interval would become relatively less exact, (c) A temperature of 25° C. rather than lower was selected because, as Dale and Laidlaw * have shown, the coagulation time is much slower for a given change in temperature below 25° than for the same change above. And with slow- ing of the process the end point, when the determin- ation depends on supporting a weight, is less likely to be sharp, (d) The researches undertaken with use of this coagulometer were concerned with fac- tors hastening the process. For that reason and for reason (b), a long rather than a short coagula- tion time for normal conditions was desirable.
3. Uniformity in the amount and kind of con- tact with foreign surface. — The capacity of the can- nulas was fairly uniform, as stated above; the amount received in them was fairly constant ; and the wire hanging in the blood presented approxi- mately the same surface in different observations.
A further condition for insuring consistent treat- ment of the blood in different cases was that of making the tests for coagulation always at the same intervals. Below the writing point of the lever was set an electromagnetic signal E, which recorded half-minutes. At the moment a record was made by the signal (see first signal mark. Fig. 25) the clip on the artery was opened, the blood taken, and the process thus begun. In about 20 seconds the cannula was suspended in the water
144
BODILY CHANGES
as
.a 5 .a I
^^
•43 2
S^ 03 o
8|
CO H
s a
c
GO CQ
CQ S
«o >-, o
^^
? "t^ *
^•- g.
^ U (U ffl h S
CI
« ^ a
^-1 CQ
"^S s <^ ,2
1 CI 2
I
n
g
FASTER COAGULATION BY ADEENIN 145
batli and the wire was hanging on the lever. At the next record by the signal and at every subsequent record the vertical rod R^ was pushed with the index finger from post P^ to post P^ and allowed to move back. This motion was uniform and lasted about one second. The check R^ on the long arm of the lever was thus raised, and as the wire sank in the blood the writing poiat rose, recording that coagulation had not taken place (see Fig. 25).
4. Definite end point. — As soon as the blood clot- ted, the weight of 30 milligrams was supported, and the failure of the lever to rise to the former height in the regular time allowed, recorded that the change had occurred.
Very rarely the swing of the lever would be checked for a moment and would then begin to move rapidly, indicating that a strand of fibrin had formed but not sufficiently strong to support the weight, and that when the strand broke, the weight quickly sank in the blood. If this occurred, the next record almost always was the short line, which signified that the weight was well supported.
A very slight strand of fibrin was able to pre- vent the weight from dropping, though at different times the amount of support differed, as shown by the varying length of the final lines (compare first and last series, Fig. 25). These variations are probably a rough indication of the degree of coagu- lation. In our experiments, however, the length of
146 BODILY CHANGES
the final line was disregarded, and merely the fact that the lever failed to swing through its usual distance was taken as evidence of a clot, and the consequent short record was taken as the end point.
As soon as this end point was registered, the tube, wire and cannula were lifted out of the bath ; the cannula was then separated from the tube and pulled away from the wire. The clot was thus dis- closed, confirming the graphic record.
The method, at least when used at half-minute intervals, did not reveal in all instances the same degree of clotting. Usually, when the process was very rapid, the revealed clot was a thick jelly; whereas, when the process was slow, a strand of fibrin or at most a small amount of jelly was found. This difference in the degree of coagulation intro- duced, of course, an element of inexactness. In our experiments, however, this inexactness was unfa- vorable to the result we were seeking for, i. e., the acceleration of the process — because the jelly is a later stagfe than the fibrin strand; and since we nevertheless obtained good evidence of accelera- tion, -^e did not in these experiments attempt to determine more accurately differences in the stage of the clotting process.
5. Cleaning of apparatus. — After the wire waS removed from the tube, the clot attached to; its ring-tip was carefully brushed away under Coo^ running water. Under the running water, also, a.
FASTER COAGULATION BY ADRENIN 147
trimmed feather was introduced into the cannula and the tube to push out the plasticine and to wash out the blood. Wire, cannula and tube were then dropped into a beaker receiving running hot water (about 80° C.) and there allowed to remain for about five minutes. On removal from this the parts were shaken free from water, passed through 95 per cent alcohol and again shaken free, passed through ether and let dry.
By having a half-dozen cannulas and wires of standard size, it was possible to save trouble by cleaning a number at one time.
Not infrequently the first few samples of blood taken from an animal showed rapid or somewhat irregular rates of clotting. Some causes for these initial variations will be presented in following pages. The fairly uniform rate of clotting in any individual after the initial stage, varied in twenty- one different animals from an average of 3 to an average of 10.6 minutes, with a combined average of 5.9 minutes. The conditions for these variations among the individuals have not been wholly deter- mined.
The Effects of Subcutaneous Injections of Adrendt
The first observations were of this class.
Oct. 27. A cat weighing about 3 kilos was given 3 cubic centimeters of adrenin 1 :1,000, i.e., 1 milli- gram per kilo, under the skin. The animal, in this
148 BODILY CHANGES
instance, was kept in uniform ether anesthesia. Following is a record showing when blood was taken, and the coagulation time in each instance :
2.56 — Injection made 3.27 — 3.5 minutes
.59—6 minutes .44—2 "
3.07—5.5 " .55—2.5
.13—5 " 4.07—3
.20—6.5 " .20—2 "
Average 5.7 minutes Average 2.6 minutes
4.44 — 6 minutes 5.00—4.5 " 5.50—5 "
Average 5.2 minutes
In this case the coagulation time remained at its usual level for about 20 minutes after the subcu- taneous injection.* Thereafter for about an hour the coagulation time averaged 45 per cent of its previous duration. And widely separated tests made during the following hour indicated that ap- proximately the initial rate of clotting had been re- gained.
The rather long period (nearly 30 minutes), in the case just cited, between the injection and the
* This period is longer than is expected after the subcuta- neous injection of any drug. As will be shown later, strong doses of adrenin, if injected rapidly, may not at first shorten the clotting process. Probably in some instances of subcu- taneous injection of these strong doses, the drug enters the circulation more rapidly than in others and in consequence coagulation is not at first accelerated.
FASTER COAGULATION BY ADRENIN 149
first appearance of rapid clotting was not the rule. As the following figures show, the coagulation time may become shortened quite promptly after sub- cutaneous injection.
Oct. 29. 3.30 — 5.5 minutes 3.53 — 4 minutes '
.36—5.5 " 4.01—3.5
.44 Adrenin, 3 cu- .08—3.5
bic centimeters, .16 — 4.5
1:1,000, injected .23—5
subeutaneously. .30 — 5.5 .46 — 5.5 minutes
In this case nine minutes after the injection the change in the rate of clotting had begun, and it con- tinued more rapid for the subsequent half -hour.
We did not attempt to find the minimal subcu- taneous dose which would shorten clotting. A dose of 0.01 milligram per kilo, however, has proved effective, as shown by the following figures :
Feb. 3. 11.34—10 minutes
.45— 9
.50 to .52 Adrenin, 2.8 cubic centimeters, 1 :100,000, injected under skin of groin in cat weighing 2.8 kilos.
As will be shown later, the dose in this instance was ten times the minimal effective intravenous dose. On the basis of these figures, less than a milligram of adrenin given subeutaneously would be necessary to shorten clotting to a marked degree in a man of average weight (70 kilograms).
|
.■55—10 |
minutes |
|
12 .06— 7 |
it |
|
.14— 4 |
u |
|
.19— 5.5 |
u |
|
;31— 6 |
u |
|
.37— 7 |
u |
|
;45— 9 |
il |
150 BODILY CHANGES
Not many observations were made by us on the effects of adrenin administered subcutaneonsly. The amount reaching the vascular system and the rate of its entrance into the blood could be so much more accurately controlled by intravenous than by subcutaneous introduction that most of our atten- tion was devoted to the latter method.
The Effects of Intravenous Injections
In this procedure a glass cannula was fastened in one of the external jugular veins and filled with the same solution as that to be injected. A short rubber tube was attached and tightly clamped close to the glass. Later, for the injection, the syringe needle was inserted through the rubber and into the fluid in the cannula, the clip on the vein was removed, and the injection made.
The solutions employed intravenously were adrenin 1 :10,000, 1 :50,000, and 1 :100,000, in dis- tilled water.
The smallest amount which produced any change in clotting time was 0.1 cubic centimeter of a dilu- tion of 1 :100,000 in a cat weighing two kilos, a dose of 0.0005 milligram per kilo. Four tests previous to the injection averaged 5 minutes, and none was shorter than 4 minutes. Immediately after the in- jection the time was 2 minutes, but at the next test the effect had disappeared. Doubling the dose in the same cat— i. e., giving 0.2 cubic centi-
FASTEE COAGULATION BY ADEENIN 151
meter (0.001 milligram per kilo) — shortened tlie coagulation time for about 40 minutes :
|
Dec. 23. 10 .30—4 minutes |
10.53 — 3.5 minutes |
|
.35—4 |
11 .00—1.5 " |
|
.41—4 |
.05—1.5 |
|
.46 Adrenin, 0.001 |
.10—3 |
|
milligram per |
.15—2 |
|
kilo. |
.20—4 |
|
.47 — 2.5 minutes |
.26—4.5 " |
|
.50—3 |
.31—5 " |
From 10.47, immediately after the second injec- tion, till 11.20 the average time for clotting was 2.5 minutes, whereas both before and after this period the time was 4 minutes or longer. At 11.00 o'clock and 11.05, when the end point was reached in 1.5 minutes ( a reduction of 63 per cent), a thick jelly was found on examining the cannula. The changes in clotting time in this case are represented graph- ically in Fig. 26.
In another case a dose of 0.0005 milligram per kilo failed to produce any change, but 0.001 milli- gram per kilo (0.28 cubic centimeter of adrenin, 1 :100,000, given a cat weighing 2.8 kilos) brought a sharp decline in the record, as follows :
Jan. 9. 11 .32 — 6 minutes 11.48 — 5.5 minutes
.40—6 " .55^ "
.47 Adrenin, 0.001 12.00—5.5 "
milligram per .06 — 7 "
kilo.
In these instances the animals were decere- brated. For decerebrate cats, the least amount of
152
BODILY CHANGES
adrenin, intravenously, needed to produce shorten- ing of coagulation time is approximately 0.001 milligram per kilo.
In the above cases rapid clotting was manifest directly after minute doses. Larger doses, how-
I0:S0 :40 :£0 11:00 : 10 : 30 :30
Figure 26. — Shortening of coagulation time after injection of adrenin, 0.2 cubic centimeter, 1:100,000, (0.001 milligram per kilo), at 10:46. In this and following Fig- ures a scale for coagulation time is given in minutes at the left.
ever, may produce primarily not faster clotting but slower, and that may be followed in turn by a much shorter coagulation time. The figures below pre- sent such an instance :
|
Nov. 25. 2 .36—3 minutes |
3 .00—2.5 |
minutes |
|
.40—3 |
.03—1.5 |
|
|
.43 Adrenin, 0.5 |
05—1.5 |
|
|
cubic centime- |
.OY—2.5 |
|
|
ter, 1:10,000. |
.10—1.5 |
|
|
.44 — 4 minutes |
.14—1.5 |
|
|
.49—3.5 |
.16—2.5 |
|
|
.53—1.5 |
19—3 |
|
|
.55—1.5 |
.23—3 |
|
|
.58—2 |
.30—3 |
FASTER COAGULATION BY ADRENIN 153
This unexpected primary increase of coagula- tion time, lasting at least six minutes, is in strik- ing contrast to the later remarkable shortening of the process from 3 to an average of 1.7 minutes for more than 20 minutes (see Fig. 27, A).
If a strong solution, i. e., 1 :10,000, is injected rapidly, the process may be prolonged as above, but not followed as above by shortening, thus :
|
Nov. 28. 9 .59—3 minutes |
10.14^3.5 minutes |
|
10.03—3 |
.18—3.5 |
|
.08 Adrenin, 0.5 |
.22—3.5 " |
|
cubic centi- |
.26—3 " |
|
meter, 1 :10,- |
.29—3 « |
|
000. |
,33—3 " |
|
.10 — 3 minutes |
There was in this case no decrease in coagulation time at any test for a half -hour after the injection, but instead a lengthening (see Fig. 27, B). How- ell ^ has reported the interesting observation that repeated massive doses of adrenin given to dogs may so greatly retard coagulation that the animals may be said to be hemophilic. These two instances show that on coagulation large doses have the contrary effect to small, just as Hoskins ^^ showed was true for intestinal and Lyman and I ^^ showed was true for arterial smooth muscle.
In a few experiments the brain and the cord to midthorax were destroyed through the orbit. Arti- ficial respiration then maintained the animal in uni-
154
BODILY CHANGES
form condition. Under these circumstances, adre- nin intravenously had more lasting effects than when given to the usual decerebrate animals with intact cord. Fig. 28 illustrates such a case. For thirty minutes before injection the clotting time* averaged 5.4 minutes. Then, about ten minutes after one cubic centimeter of adrenin, 1 :50,000, had
J L
SM
:S0 10:00 :10
:20 ;S0
FiGUBB 27. — A, Primary lengthening followed by shortening of the coagulation time when adrenin, 0.5 cubic centimeter 1:10,000 (0.05 milligram), was injected slowly at 2 :43. B, Lengthening of the coagulation time without shortening when the same dose was injected rapidly at 10:08.
been slowly injected, clotting began to quicken; during the next twenty minutes the average was 3.4 minutes, and during the following forty-five min- utes the average was 1.9 minutes — only 35 per cent as long as it had been before the injection.
In another case in which the brain and upper cord were similarly destroyed, the clotting time, which for a half -hour had averaged 3.9 minutes, was reduced by one cubic centimeter of adrenin.
FASTEE COAGULATION BY ADEENIN 155
1 :100,000, to an average for the next hour and forty minutes of 2.3 minutes, with 1.5 and 3 minutes as extremes. During the first forty minutes of this period of one hour and forty minutes of rapid clot- ting all of eight tests except two showed a coagula- tion time of 2 minutes or less. The explanation of this persistent rapid clotting in animals with spinal cord pithed is not yet clear.
As indicated in Figs. 26, 27 and 28, the records of coagulation show oscillations. Some of these ups and downs are, of course, within the limits of
tt 1 1 1 1 1 1 1 1 1 r
10:40 :50 11:00 :10 :«0 :30 : 40 :50 12:00 .-10 :S0
Figure 28. — ^Persistent shortening of the coagulation time after injecting (in an animal with brain and upper cord pithed) adrenin, 1 cubic centimeter, 1:50,000 (0.02 milligram), at 11:01-02. The dash lines represent averages.
error of the method, but in our experience they have occurred so characteristically after injection of adrenin, and so often have appeared in a rough
156 BODILY CHANGES
rhythm, that they have given the impression of be- ing real accompaniments of faster clotting. It may be that two factors are operating, one tending to hasten, the other to retard the process, and that the equilibrium disturbed by adrenin is recovered only after interaction to and fro between the two factors.
The oscillations in coagulation time after the in- jections suggest that clotting might vary with changes in blood pressure, for that also commonly oscillates after a dose of adrenin (see, e. g., Fig. 23). Simultaneous recording of blood pressure and determining of coagulation time have revealed that each may vary without corresponding varia- tion in the other. Withinj)rdinary limits, there- fore, changes of blood pressure do not change the rate of clotting.
The Hastening of Coagulation by Adrenin Not a Direct Effect on the Blood
As previously stated, von den Velden has con- tended that shortening of coagulation time by adre- nin is due to exudation of tissue juices resulting from vasoconstriction. The amount of adrenin which produces markedly faster clotting in the cat, is approximately 0.001 milligram per kilo. As Lyman and I ^^ showed, however, this amount when injected slowly, as in the present experi- ments, results in brief vasodilation rather than
FASTEE COAGULATION BY ADRENIN 157
vasoconstriction. Von den Velden's explanation can therefore not be applied to these experiments. He has claimed, furthermore, that adrenin added to blood in vitro makes it clot more rapidly, but, as already noted, he gives no account of the condi- tions of his experiments and no figures. It is im- possible, therefore, to criticise them. His claim, however, is contrary to Wiggers's ^^ earlier ob- servations that blood with added adrenin coagulat- ed no more quickly than blood with an equal amount of added physiological salt solution. Also contrary to this claim are the following two experi- ments : (1) Ligatures were tied around the aorta and inferior vena cava immediately above the dia- phragm, and thus the circulation was confined al- most completely to the anterior part of the animal. Indeed, since the posterior part ceases to function in the absence of blood supply, the preparation may be called an "anterior animal." When such a preparation was made and 0.5 cubic centimeter of adrenin, 1:100,000 (half the usual dose, because, roughly, half an animal), was injected slowly into one of the jugulars, coagulation was not shortened. Whereas for a half -hour before the injection the clotting time averaged 4.6 minutes, for an hour thereafter the average was 5.3 minutes — a pro- longation which may have been due, not to any in- fluence of adrenin, but to failure of the blood to circulate through the intestines and liver. ^* In an-
158 BODILY CHANGES
other experiment after the gastro-intestinal canal and liver had been removed from the animal, the average time for coagulation during twenty-five minutes before injecting adrenin (0.23 cubic centi- meter, 1 :100,000, in an animal weighing originally 2.3 kilos) was 5.5 minutes, and during forty min- utes after the injection it was 6.8 minutes, with no case shorter than 6 minutes. In the absence of cir- culation through the abdominal viscera, therefore, adrenin fails to shorten the clotting time. (2) The cannulas were filled with adrenin, 1:1,000, and emptied just before being introduced into the artery. The small amount of adrenin left on the walls was thus automatically mixed with the drawn blood. Alternate observations with these cannulas wet by adrenin and with the usual dry cannulas showed no noteworthy distinction.
Feb. 19. 2.21 — 6 minutes, with usual cannula .30—6.5 "
.36—6.5 " " adrenin
.49—6 « " "
.56—7 " " usual
3.04—6 " " adrenin
The results of these experiments have made it impossible for us to concede either of von den Velden's claims, i. e., that clotting occurs faster be- cause adrenin is added to the blood, or because adrenin by producing vasoconstriction causes tis- sues to exude coagulant juices.
Vosburgh and Eichards found that coagulation.
FASTER COAGULATION BY ADEENIN 159
became more rapid as the blood sugar mcreased. Conceivably, faster clotting might result from this higher percentage of blood sugar. Against this assumption, however, is the fact that clotting is greatly accelerated by 0.001 milligram adrenin per kilo of body weight, much less than the dose necessary to increase the sugar content of the blood.^^ And furthermore, when dextrose (3 cubic centimeters of a 10 per cent solution) is added to the blood of an anterior animal, making the blood sugar roughly 0.3 per cent, the coagulation time is not markedly reduced. Adrenin appears to act, therefore, in some other way than by increasing blood^sugar^
Since adrenin makes the blood clot much faster than normally in the intact animal, and fails to have this effect when the circulation is confined to the anterior animal, the inference is justified that in the small doses here employed adrenin produces its remarkable effects, not directly on the blood it- self, not through change in the extensive neuro- muscular, bony, or surface tissues of the body, but through some organ in the abdomen.
That exclusion of the liver from the bodily econ- omy, by ligature of its vessels or by phosphorus poisoning, will result in great lengthening of the coagulation time has been clearly shown. .The liver, therefoxe,-seems^t^#urnish continuously to l;he blood a factor in the clotting process which is
160 BODILY CHANGES
being continuously destroyed in the body. It is not unlikely tbat adrenin makes the blood clot more rapidly by stimulating the liver to discharge this factor in greater abimdance. But proof for this suggestion has not yet been established.
EEFEEENCES
^ Vosburgh and Bichards : American Journal of Physi- ology, 1903, ix, p. 39.
2 Wiggers : Archives of Internal Medicine, 1909, iii, p. 152.
^ Von den Velden : Miinchener medizinische Wochen- schrift, 1911, Iviii, p. 187.
* Dale and Laidlaw : Journal of Pathology and Bacteriol- ogy, 1912, xvi, p. 362.
^ Cannon and Gray : American Journal of Physiology, 1914, xxxiv, p. 321.
^ Cannon and Mendenhall : American Journal of Physi- ology, 1914, xxxiv, p. 225.
' Addis : Quarterly Journal of Experimental Physiology, 1908, i, p. 314.
* Dale and Laidlaw : Loc. cit., p. 359.
° Howell : American Journal of Physiology, 1914, xxxiii, p. xiv.
'^'' Hoskins : American Journal of Physiology, 1912, xxix, p. 365.
'^^ Cannon and Lyman : American Journal of Physiology, 1913, xxxi, p. 376.
'^^ Cannon and Lyman : Loc. cit., p. 381.
^'Wiggers: Loc. cit., p. 152.
1* See Pawlow : Archiv f iir Physiologic, 1887, p. 458. Bohr : Centralblatt f iir Physiologic, 1888, ii, p. 263. Meek : American Journal of Physiology, 1912, xxx, p. 173. Gray and Lunt: Ihid., 1914, xxxiv, p. 332.
''Cannon: American Journal of Physiology, 1914, xxxiii, p. 396.
CHAPTER X
THE HASTENING OF THE OOAGTJIATION OF