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A study of the effect of acids and alkalis on gastric muscle strips in the rabbit
A STUDY OF THE EFFECT OF ACIDS AND ALKALIS ON GASTRIC
MUSCLE STRIPS IN THE RABBIT*
R. A. GORMAN, J. D. DREIER, AND MARTIN E. REHFUSS, M.D. PHILADELPHIA
0
NE of the most interesting phases of gastric physioIogy is the behavior of the stomach muscIe under conditions such as are observed with muscIe strip preparations. Our knowIedge of gastric function may be broadIy divided into that governing the secretion, and that vitaIIy concerned with the motor function of the stomach. The Iatter subject has been approached from many angIes. The clinician estimates it by the degree of chymefication of food, by the evacuation time, with a test-Ioad, and by the gross appearance of peristaIsis as reveaIed by x-ray examination. The physioIogist has not been content with these rather gross methods of approach. He has attempted by anima1 experimentation, by the examination of viscera under direct vision, by baIIoons which have been pIaced in the stomach, and finaIIy by the behavior of isoIated muscIe strips, to obtain information on the compIex mechanism which so remarkabIy reduces food to thyme. In a recent study, Thomas, Eads, and one of the authors, observed the action of the antrum and duodenum in order to determine the sequence of events which occur in the norma human subject, with baIIoons fIuoroscopicaIIy controIIed and pIaced in these organs. The information which this study reveaIed was of importance in estimating the sequence of events which occurred in that segment of the digestive tract. The rhythmicity and power of the antrum musculature are scarceIy reaIized unIess they are observed in this way. The natura1 question which arises is: What determines this rhythmicity, and what are the factors which are concerned in its evaIuation? This probIem brought us into direct contact with some of the recent work on the excised muscuIature. *Read
at the Thirty-third
AnnuaI Meeting
The norma movements of the stomach in situ have been described by M’Crea, M’Swiney, Morison and Stopford,l and the Iiterature is reviewed in their paper. The norma movements of the surviving strips of the stomach were first investigated by Sick and Tedesco2 who found that the movements of the strips and of the same parts of the compIete stomach were identica1. AIvarez3 found from a simiIar study of the excised strips of the stomachs of rabbits, cats, dogs, and man, that each region had a characteristic type of movement, and that the rate of contraction of the strips varied inverseIy as the distance from the cardia. Shut24 observed the action of the excised stomachs of dogs after the injection of drugs prior to the remova of the organ. The studies of Smith5 on the action of the surviving muscIe strips of the stomachs of guinea pigs, cats, rabbits, dogs and man, are compIete. HechV studied the action of atropine on the compIete surviving stomach of the rabbit, and Texner and TuroIt’ recorded the inhibitory effects of atropine and adrenaIin on the strips of human muscIe. Kuroda8 recorded the behavior of the IongitudinaI muscIe strips from the fundus of the dog’s stomach. One of the most recent and compIete studies on the movement, as we11 as the reaction of drugs, on strips of the gastric muscuIature of the cat and dog, is that of Brown and M’Swiney.9 Their investigation was carried out on the excised strips of the cat and dog, in order to obtain further information as to the mechanism of rhythmic contractions and tonus in the different and to ascertain the reaction regions, of the various parts to autonomic drugs. It is scarceIy necessary to go into further detai1 regarding the work of these various observers, except to point out that their
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method of approach was more or Iess simiIar in many instances, and to caII attention to the fact recorded by practicaIIy a11 of
FIG.
I. PowerfuI
of entire pyIoric end of stomach
American ~ournat of
and greater stomach.
curvature.
These
are
pyIorica, which wouId Iead one, according to these authors, to suspect the existence of the separate non-peristaItic motor mechanism in this region. Additiona support is given to this argument by the fact that the food in the stomach of this anima1 is aIwavs of a semi-soIid consistencv, and
has no effect on antra1 contractions
way aItering the reaction of the Locke’s soIution, which was used in these experiments, wouId aIter the response. For our purpose we seIected rabbits, which are admirably suited to this work. As M’Crea, M’Swiney, Morison and Stopford point out, the so-caIIed two-phase stomach, in which peristaIsis of the body, and systoIe and diastoIe of the antrum presumabIy is characteristic of the rabbit, occur, dog and man; whiIe the so-caIIed one-
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phase stomach is to be observed in cats. In the rabbit there occurs a rather marked thickening of the distal haIf of the pars
rhythmic contractions from strip obtained from antrum obtained apparentIy onIy from this region of rabbit’s
them that there was an inherent rhythmicas AIvarez has ity and tonus which, pointed out, was more or Iess characteristic of the portion of the stomach which was studied. Our investigation had for its purpose the confirmation of these findings. and an attempt
FIG. 2. Extract
of Acids
as this curve illustrates.
adapted ejector mechanism. The observations of AIvarez are too weII-known to need repetition. We were, therefore, interested not onIy in demonstrating the responses of the excised parts of the rabbit’s stomach, but inasmuch as they Ient themseIves so readily to movements which are easiIy demonstrated, we carried on observations on the action of the acids and aIkaIies on the excised muscIes, which are recorded in the foIIowing paper.
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TECHNIQUE
The animals used for these experiments were excIusiveIy young rabbits. These
FIG. 3. Typical
of Acids
Locke’s soIution of d°C. The stomach’
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at the same temperature was
aIIowed
to
contraction waves from antra1 region and greater curvature. Notice that addition of extract of entire cardiac portion including mucosa is without effect on contractions.
rabbits were kihed by a sharp blow on the head, and the abdomen opened. The stomach was then exposed and removed intact. In practically every instance the stomachs were fulf, as no attempt was made to starve the animals. The stomach
remain
of emulsion
in this solution for twenty minutes to half an hour, after which it was stretched out on a piece of cork under Locke’s solution. The mucosa was then very carefuIIy dissected away, Ieaving the muscularis and serosa which were then cut into
FIG. 4. Effect of smaI1 amount of dilute hydrochIoric acid on typical antral response with complete suppression of contraction waves. This amount is suffkient to carry pH to or just beyond neutrality according to observations of resulting mixture determined with caIome1 electrode.
was then transferred to Locke’s solution at a uniform temperature of 4’~. An incision was then made aIong the greater curvature from the esophagus to the pyIorus, and the material from the stomach compIeteIy evacuated. The stomach was then cIeaned, and the organ pIaced in
paraIle1 strips approximateIy 3 to 5 mm. in width, and 2 to 3 cm. in Iength. In severa of the experiments the strips remained with the mucosa intact, but for our routine work the mucosa was dissected away. The strips were then kept in Locke’s soIution in a refrigerator,
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the mean temperature being approximately In some instances the strips were 4O. empIoyed immediately, and in others they
FIG. 5. Typical rapid rhythm of cardiac end and greater curvature strip. Acid inhibits response.
were used on the foIlowing day or even as Iong as forty-eight hours after remova1. The apparatus consisted of an outer container, hoIding perhaps 3 qt. of warm water, kept at a constant temperature of 37.3’~. by means of an eIectric thermoreguIator. This container acted as a
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the strip was immersed in the solution was by means of a movable lever and side-arm, so that every change in the muscIe strip was automaticaIIy recorded on a moving kymographic drum. The levers were extremeIy sensitive and speciaIIy adapted to this work. The apparatus was a type recommended by Dr. J. EarIe Thomas as most effective for this purpose. Time was recorded by a Jacquette mechanism, and the injection of substances was marked by an eIectrica1 indicator. 1 It is interesting to remark at this point recorded from strips that the tracing from different regions of the stomach was so characteristic that the observer was able, after a reIativeIy short experience, to determine the region of the stomach invoIved. In other words, the contractions of any one strip were usuaIIy characteristic. Strips from the Iesser curvature showed a distinctly smaIIer ampIitude and greater frequency. In many instances the movements of strips from the cardia were very minute, and in some cases almost unrecognizable.
FIG. 6. Typical effect of addition of smaI1 amount of diIute hydrochIoric acid (3 C.C. of 0.5 per cent HCI to zso C.C. of Locke’s solution) on surviving muscle strip taken from greater curvature antral end of rabbit’s stomach.
water bath to maintain a constant temperature of the Locke’s soIution which was contained in an inner vesse1 hoIding approximateIy 230 CL. Through the inner the Locke’s soIution vesse1 containing was an arrangement by which oxygen couId be maintained at a given rate, so that the Locke’s solution was aerated by which constantIy. Th e arrangement
MuscIe strips from approximateIy go animaIs were used, and throughout this series of experiments one can almost predict from the record of the tracing the part of the stomach waI1 which was being investigated. In the great majority of cases our attention was directed to the phenomenon at the pyIoric end of the stomach. In
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about one-third of these cases records were made from the cardiac end of the stomach. Strips from the greater curvature
of Acids
from baIIoons pIaced in the normaI human antrum. The rhythmicity and the power of the contraction in that portion of the
FIG. 7. Pyloric end, midway between greater and lesser curvature. Response resembIes_cardiac cent HCI has onIy miId effect.
near the antrum and pyIorus gave the most characteristic tracings. These were characterized by reguIar recurring groups of waves with a wide ampIitude. In many instances the muscIe strips wouId shorten to haIf their origina Iength. Curves of
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strips and 0.5 per
antrum adjacent to the pyIorus and at the greater curvature, are out of a11 proportion to the response obtained in every other part of the stomach waI1. Even in the Iesser curvature and the antra1 portion no such contractions were recorded.
FIG. 8. Powerful rhythmic antraI contractions seen most characteristicahy in antrum and greater curvature of rabbits stomach. These in no way resemble response obtained under identical conditions in lesser curvature, cardia and fundus and suggest a specialized musculature which we believe is concerned in major part of mechanical work of stomach.
this description are to appended iIIustrations, technique was satisfactory to get a graphic tracing respects, resembIed the
be noted in the and when the it was possibIe which, in many tracing obtained
In records of the Iesser curvature, whiIe there are considerabIe differences in tone and rhythm, the contractions were frequentIy reguIar, but never of the same ampktude, and this is true of the entire
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fundus as weI1. In fact, we do not hesitate to make the statement that the important work in the rabbit’s stomach is in a11 prob-
American journalof Surgery I 2-5
that the tracing obtained from the cardia and the antrum are different in type, form and amplitude, as one wouId expect
Flc.‘g. Contractions from pyIoric end and greater curvature. results are in accord with DrobabiIitv that greatest amount of stomach wall.
ability carried out by that part of thestomach waI1 invoIving the greater curvature near the antra1 portion. AIvarez maintains that the excised strips of muscIe from the cardiac end, and particuIarIy that one on the Iesser curvature next to the cardia, show the strongest tendency to rhythmic contraction. If by this he speaks of the frequency of contraction, then we are incIined to agree with his statement; but if rhythmic contraction impIies a powerfu1 recurring group of movements, then in our judgment the antrum near the pyIorus undoubtedIy fuIfiIIs this idea. There are undoubtedIy marked differences in irritabiIity, Iatent period and contraction waves. As AIvarez maintains, to use his own words: “Speaking roughIy, the rate of contraction varies inverseIy as the distance from the cardia.” One gets the impression from this statement that the contraction rate at the pyIorus, therefore, is very much Iess than that at the cardia: this is IargeIy true; but as one studies these various responses, the fundamenta1 impression is that there is no comparison between the pyIoric and antra1 contractions on the one hand, and the characteristic response seen in the cardia. The observations of Sick, Tedesco, Smith, M’Swiney and others, certainIy suggest
of Acids
Notice amplitude of these contractions. These of work is performed specificaIIy by this portion
regarding their obvious differences in function. In a11 the muscIe strips that we studied, there was never encountered at or near the cardia a record which resembIed the characteristic tracing of the antrum, and the reverse is Iikewise true. It is diffIcuIt or impossibIe to estabIish any reIationship between the two, and if this
FIG. 10. Recurrence of gastric muscIe contraction which had been inhibited by addition of dilute HCI and in this response brought back by addition of sodium bicarbonate soIution.
reIationship exists it is not apparent from our studies. In the baIIoon work done on human beings by Thomas, Eads and Rehfuss, antra1 contractions were powerfu1, reguIar, and frequentIy preceded by a sIight increase in tonus. There is a striking simiIarity between many of our responses, and those which were seen by the intragastric balIoon such as one of us recorded some time ago.
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In practicalIy al1 instances the strips which we used in our work were taken IongitudinaIIy. We tried strips which were
FIG.
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with the poor amplitude of contractions in the strips from that region. Nothing in the gross appearance of the strip would
I I. Surviving
muscle strip from cardiac end of stomach. Notice typica contractions totahy unlike those of cardia and notice that repeated additions of 0.5 per cent HCI fails to arrest cardiac contractions.
circular, but the records obtained were unsatisfactory. Therefore, for practica1 purposes, in a11 instances this work was recorded on IongitudinaI strips. There are, of course, many differences observed in
FIG.
of Acids
12.
Addition
of 3.5 cc.
suggest this fact. Alvarez aIso notes as he has commented elsewhere on the fact that as tone rises the ampIitude of contraction faIIs, untiI rhythmic activity may cease entirely. This may be true on some
of 0.5 per cent HCI causes alteration in muscle strip response which is inhibited aItogether by addition of I C.C. more of diIute HCI.
the tonus of the strips, and at times a distinct increase in tonus was recorded, when there were no contractions. Tonus naturaIly can onIy be recorded in this sort of work by the position of the Iever above the basehne, which records the contraction of the muscle strip. AIvarez suggests that high tonus of the Iesser curvature might have something to do
occasions, but it is certainIy not invariabIy true, as wiI1 be seen from certain contractions with bicarbonate of soda, for instance. Just what is the influence of the histologicaI structure in these different parts of the stomach, we are not prepared to state. We are convinced of the fact, however, that the reaction of the excised muscIe strip in the cardia and in the pyIoric antrum
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in the rabbit is very different. We are further of the opinion that this difference is a characteristic one inherent in the part
Effect
of Acids
Amcrican
Journal
offering the typical tracings this articIe. In view of the fact that
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in
it is possibIe
FIG. 13. Strip from lesser curvature all the way from the esophagus to the pyloric sphincter. Note simiIarity in response to type of contraction noted at cardia. Acid inhibits and :IIkaIi restores contractions as ensuing curves demonstrate.
of the stomach which was being observed. We furthermore be&eve that the greater curvature portion of the antrum is that part concerned in the most reguIar and powerfu1 rhythmic contraction, and finaIIy we are unabIe to demonstrate definitely any relationship between antra1 and cardiac contractions. They are different both
to obtain under ideal experimenta conditions tracings which can be reproduced and which are hiphIy characteristic, it was of great interest to note the effect of certain substances, notabIv those connected with gastric function, or what Babkin wouId caI1 natura1 chemical stimuli on these muscIe contractions. The most
FIG. 14. hluscle strip from antral region and greater curvature. Notice disappearance of contractions on addition of 4.5 C.C. of 0.5 per cent HCI and their reappearance after addition of sodium bicarbonate.
in form and type, and a study of our responses wouId make us hesitate to say that even roughIy the rate of contraction varies inverseIy as distance from the cardia. Our observations wouId suggest that the contractions are very different in both type, form and tone in the two parts of the stomach waI1. For that purpose we are
interesting substance is hydrochIoric acid. The action of diIute hydrochloric acid and aIkaIies such as sodium bicarbonate has been repeatedIy discussed in the Iiterature. The influence of natura1 chemica1 stimuIi on the movements of the frog’s stomach was studied by Babkin.‘” In this contribution the author points out that soIutions
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of hydrochIoric acid introduced into the stomach, according to GIassnerll are noneffective; according to Lussana12 they increase and afterwards arrest its spontaneous contractions; according to Patterson13 they arrest without previousIy increasing the hunger contractions; and finaIIy, Hoff14 noted an increase in contractions. Babkin asks the question as to whether the acting chemica1 agent being the same, the various motor responses are not due to unequa1 stimuIation of the neuromuscuIar apparatus of the stomach itseIf. He studied the stomach of the frog which was excised, and in which soIutions were introduced under the definite pressure. The voIumetric registering of stomach contractions was made on a kymograph, and at the same time the author made tracings of the separate contractions. He found that the most active part of the stomach of the frog was the pyIoric part. HydrochIoric acid exerted a varying action, depending upon its concentration. In weak soIutions it increases the contractions and diminishes the frequency at 0.5 HCL. In some concentrated soIutions (0.05 per cent to 0.2 per cent) it arrests them. He then found that the effect of sodium bicarbonate (0.03 per cent to 0.05 per cent) is to arrest the tone and increase the intensity and frequency of the contractions of the frog’s stomach. In other words, these experiments were performed by injecting the materia1 in the stomach. We are not famiIiar with the effect of the aIteration of the hydrogen iron concentration of Locke’s soIution on the excised muscIe strips. THE
EFFECT
OF
HYDROCHLORIC
ACID
In this experiment we arranged the apparatus in order that we couId obtain the typica responses. OrdinariIy a controIIed tracing was made after the contractions had reached a uniform type for at Ieast thirty or forty minutes. At this point from 1 to 5 C.C. of a 0.05 per cent soIution of hydrochIoric acid was injected into
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the Locke’s solution. It is needIess to point out that the amount of hydrochIoric acid in the soIution, when diIuted, represented an infinitesimaIIy smaI1 amount of acid. In other words, if 5 C.C. of 0.5 hydrochIoric acid were added to 250 C.C. of Locke’s soIution, the resuIting mixture wouId represent 0.01 per cent hydrochIoric acid. At this figure we were abIe to demonstrate unmistakabIe changes in the appearance of the waves. AImost uniformly it was possibIe, by the addition of hydrochIoric acid in the quantities mentioned before, to cause either marked inhibition or a tota arrest of the contractions. In some instances, the interva1 between the contractions was proIonged. In others, the contraction graduaIIy faded away, and in a number of these responses there was a compIete disappearance of the contraction. It was therefore evident that diIute hydrochIoric acid in diIutions far smaIIer than those commonIy encountered, but nevertheIess showing a change in the hydrogen iron concentrate caused a din& nution or cessation of the contractions. In view of this practicaIIy constant finding, it was of interest to note the effect of other substances. The first substance which was used was sodium citrate. The addition of smaI1 amounts of sodium citrate, I to 5 C.C. or more, a saturated soIution, not onIy caused a reappearance of the contractions, but in some of the preparations where hydrochIaric acid was not used, it caused an increase in tonus and sometimes in the frequency of contractions. This observation was strikingIy constant in the series of cases where it was used. Sodium bicarbonate used in the same a saturated soIution of way, nameIy, quantities of 5 C.C. and over, Iikewise had a sitiiIar effect. In some instances there was a very much greater increase in tonus, and if the tracing was recorded over considerabIe intervaIs, a compIete reappearance of contractions which were, if anything, more rhythmic and more pronounced than before hydrochIoric acid had been used. It is to be noted that not onIy is
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there an increase in tonus, but that in the majority of instances the inhibitory effect of hydrochIoric acid is overcome and foIIowed by pronounced contraction. It was interesting in this work to observe whether or not extracts from different parts of the stomach might not have the same effect. For this purpose we prepared macerations of the funda and pyIoric portions of the stomach in norma saIt soIution. We were unabIe to demonstrate any definite effect from either of these tissue extracts, as the foIIowing short tabIe wiI1 revea1. We aIso used in severa experiments Iiver extract 343 of LiIIie’s, and aIso the 4-C Iiver extract which was prepared in On one occasion we our Iaboratories. were abIe to get a response from Iiver extract. This finding, however, was an inconstant one, and we fee1 that our studies do not justify the concIusion that Iiver extract stimuIates the gastric muscufature. Studies which wiI1 be reported elsewhere by us, however, do prove that the upper digestive tract is certainIy influenced by this preparation. CONCLUSIONS I. The reaction of surviving muscIe strips from different portions of the stomach of a rabbit is highIy characteristic. 2. LongitudinaI preparations from the cardia gave a response which is essentiaIIy different from that obtained at the pyIoric antrum. 3. The most powerfu1 rhythmic contractions were obtained from that part of the antrum invoIving the greater curvature. 4. The most frequent waves of smaI1 ampIitude are obtained at or near the cardia. 5. HydrochIoric acid in dilutions mentioned in the text, inhibits or arrests the pyIoric antra1 contractions. 6. Sodium citrate in a number of instances causes a reappearance of the contractions foIIowing their disappearance due to hydrochIoric acid.
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7, Bicarbonate of soda has the same quaIity. 8. In the majority of our studies there was a perceptibIe increase of tonus on the addition of bicarbonate of soda. 9. Norma1 saIt soIution extracts of the fundus and antrum faiIed to show any strip muscIe effect on appreciabIe preparations. IO. It is possibie that some Iiver extracts may stimuIate these contractions. After studying these charts and the behavior of the muscIe strips under these experimenta conditions, one hesitates to assume changes in hydrogen iron concentration as important factors in peristaIsis. CertainIy there can be no question that minute amounts of acid and aIkaIi can markedIy aIter the sequence of events. A mechanism invoIving reguIar recurrent changes in hydrogen iron concentration might be suggested as a hypothesis for peristaIsis. In concIusion, the resuIts mentioned here were obtained from a series of studies on isoIated muscIe strips from different parts of the stomachs of about 90 rabbits. We are indebted to those who contributed to the MedicaI Research Foundation at Frankford for financia1 support in these experiments, nameIy, Mrs. Cyrus H. K. Curtis, Mr. Alvan Dinkey, Mrs. Henderson, Mr. H. M. Pierce, and Mrs. Buckner. REFERENCES I. M'CREA, M’SWINEY, MORISON and STOPFORD. Quart. J. Exper. Pbysiol., 14: 379, 1924. 2. SICK and TEDESCO. Deutscbe Arch. j. klin. Med., 92: 416, 1908. 3. ALVAREZ, Am. J. Pbysiol., 40: 585, 1916. 4. SHUTZ. Arch. f. exper. Patb. u. Pbarmakal., 21: 341, 1886. 5. SMITH, Am. J. Pbysiol., 46: 232, 1918. 6. HECHT, Deutscbe Arcb.j. klin. Med., 136: 296, 1921. 7. TEXNER and TUROLT. Ztscbr. j. d. ges. exper. Med., 24: I, 1921. 8. KURODA. Ztscbr.j. d. ges. exper. Med., 39: 341, 1924. 9. BROWN and M’SWINEY. Quart. J. Exper. Pbysiol. 16:9, 1926. IO. BABKIN. Quart. J. Exper. Pbysiol., 14: 259, 1924. II. GLASSNER, Pfluger’s Arch. f. d. ges. Pbysiol., 86:
291, 1904. 12. LUSSANA. Arch. difisiol., 7: 149, 1909. 13. PATTERSON. Am. J. Pbysiol., 47: 56, 1916. 14. HOFF. Ztscbr. j. Biol., 55: 409, 191 I.
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DISCUSSION
DR. BASTEDO: As an oId pharmacologist, I just want to emphasize something that Dr. Rehfuss mentioned, and that is the fact that the acids and alkaIies wiII not be found affecting this muscle strip in the Iiving stomach, but onIy in the mucous membrane. You must not get that impression, because the muscular layers are not affected chem,icalIy by what is in the stomach, but rather by what is brought to them by the bIood stream. DR. REHFUSS (closing): I am very much interested in the reference to the motion of the pyloric valve. These are the things that impressed us in our work. Dr. AIvarez’ idea is that this is more or less continuous, but I think that the phenomenon that I have presented here today is an aItogether different phase of digestion, an aItogether different thing. This beating of the pyIorus in rabbits is a beat which is powerfu1, regular, recurrent, and is, so far as I can find, the onIy part capabIe of doing work. Therefore, I was interested in Dr. Coles’ description of his idea regarding the fan shaped muscIe he describes. I wouId Iike to show him some of the records we have. There is
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another thing which I wouId like to point out, and that is, that if there is anything which affects the muscuIar tissue it is not in the stomach, but it is, rather, something perhaps chemical alterations in the bIood circuIating through that particuIar part of the stomach waI1. There is one thought that occurs to me, and that is, that, with the Iarge amount of acid which must be derived from the stomach may resuIt in changes in the tonus of this region of the stomach, any change which occurs must occur during the gastric digestion and not the intestina1 digestion. It is cIear that there is some general mechanism which brings about a change in the pH, which probably is induced by the formation of a Iarge amount of secretion. It seems aImost impossibIe for us to believe that we can get a pint or a quart of stomach secretion, without some radica1, chemical change. I beIieve that the dista1 end is motor in its function, and that the cardiac end is buiIt for storage. I think that the chemistry reIates to a hormone which is secreted by some mechanism which operates in the entire digestive tract, and is, perhaps, part of a far-flung mechanism which may reach further than the stomach.
MUSCLE STRIPS IN THE RABBIT*
R. A. GORMAN, J. D. DREIER, AND MARTIN E. REHFUSS, M.D. PHILADELPHIA
0
NE of the most interesting phases of gastric physioIogy is the behavior of the stomach muscIe under conditions such as are observed with muscIe strip preparations. Our knowIedge of gastric function may be broadIy divided into that governing the secretion, and that vitaIIy concerned with the motor function of the stomach. The Iatter subject has been approached from many angIes. The clinician estimates it by the degree of chymefication of food, by the evacuation time, with a test-Ioad, and by the gross appearance of peristaIsis as reveaIed by x-ray examination. The physioIogist has not been content with these rather gross methods of approach. He has attempted by anima1 experimentation, by the examination of viscera under direct vision, by baIIoons which have been pIaced in the stomach, and finaIIy by the behavior of isoIated muscIe strips, to obtain information on the compIex mechanism which so remarkabIy reduces food to thyme. In a recent study, Thomas, Eads, and one of the authors, observed the action of the antrum and duodenum in order to determine the sequence of events which occur in the norma human subject, with baIIoons fIuoroscopicaIIy controIIed and pIaced in these organs. The information which this study reveaIed was of importance in estimating the sequence of events which occurred in that segment of the digestive tract. The rhythmicity and power of the antrum musculature are scarceIy reaIized unIess they are observed in this way. The natura1 question which arises is: What determines this rhythmicity, and what are the factors which are concerned in its evaIuation? This probIem brought us into direct contact with some of the recent work on the excised muscuIature. *Read
at the Thirty-third
AnnuaI Meeting
The norma movements of the stomach in situ have been described by M’Crea, M’Swiney, Morison and Stopford,l and the Iiterature is reviewed in their paper. The norma movements of the surviving strips of the stomach were first investigated by Sick and Tedesco2 who found that the movements of the strips and of the same parts of the compIete stomach were identica1. AIvarez3 found from a simiIar study of the excised strips of the stomachs of rabbits, cats, dogs, and man, that each region had a characteristic type of movement, and that the rate of contraction of the strips varied inverseIy as the distance from the cardia. Shut24 observed the action of the excised stomachs of dogs after the injection of drugs prior to the remova of the organ. The studies of Smith5 on the action of the surviving muscIe strips of the stomachs of guinea pigs, cats, rabbits, dogs and man, are compIete. HechV studied the action of atropine on the compIete surviving stomach of the rabbit, and Texner and TuroIt’ recorded the inhibitory effects of atropine and adrenaIin on the strips of human muscIe. Kuroda8 recorded the behavior of the IongitudinaI muscIe strips from the fundus of the dog’s stomach. One of the most recent and compIete studies on the movement, as we11 as the reaction of drugs, on strips of the gastric muscuIature of the cat and dog, is that of Brown and M’Swiney.9 Their investigation was carried out on the excised strips of the cat and dog, in order to obtain further information as to the mechanism of rhythmic contractions and tonus in the different and to ascertain the reaction regions, of the various parts to autonomic drugs. It is scarceIy necessary to go into further detai1 regarding the work of these various observers, except to point out that their
of the American Gastro-EnteroIogicaI May 5 and 6, 1930. 120
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method of approach was more or Iess simiIar in many instances, and to caII attention to the fact recorded by practicaIIy a11 of
FIG.
I. PowerfuI
of entire pyIoric end of stomach
American ~ournat of
and greater stomach.
curvature.
These
are
pyIorica, which wouId Iead one, according to these authors, to suspect the existence of the separate non-peristaItic motor mechanism in this region. Additiona support is given to this argument by the fact that the food in the stomach of this anima1 is aIwavs of a semi-soIid consistencv, and
has no effect on antra1 contractions
way aItering the reaction of the Locke’s soIution, which was used in these experiments, wouId aIter the response. For our purpose we seIected rabbits, which are admirably suited to this work. As M’Crea, M’Swiney, Morison and Stopford point out, the so-caIIed two-phase stomach, in which peristaIsis of the body, and systoIe and diastoIe of the antrum presumabIy is characteristic of the rabbit, occur, dog and man; whiIe the so-caIIed one-
surgery 12 1
phase stomach is to be observed in cats. In the rabbit there occurs a rather marked thickening of the distal haIf of the pars
rhythmic contractions from strip obtained from antrum obtained apparentIy onIy from this region of rabbit’s
them that there was an inherent rhythmicas AIvarez has ity and tonus which, pointed out, was more or Iess characteristic of the portion of the stomach which was studied. Our investigation had for its purpose the confirmation of these findings. and an attempt
FIG. 2. Extract
of Acids
as this curve illustrates.
adapted ejector mechanism. The observations of AIvarez are too weII-known to need repetition. We were, therefore, interested not onIy in demonstrating the responses of the excised parts of the rabbit’s stomach, but inasmuch as they Ient themseIves so readily to movements which are easiIy demonstrated, we carried on observations on the action of the acids and aIkaIies on the excised muscIes, which are recorded in the foIIowing paper.
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TECHNIQUE
The animals used for these experiments were excIusiveIy young rabbits. These
FIG. 3. Typical
of Acids
Locke’s soIution of d°C. The stomach’
APRIL, ,931
at the same temperature was
aIIowed
to
contraction waves from antra1 region and greater curvature. Notice that addition of extract of entire cardiac portion including mucosa is without effect on contractions.
rabbits were kihed by a sharp blow on the head, and the abdomen opened. The stomach was then exposed and removed intact. In practically every instance the stomachs were fulf, as no attempt was made to starve the animals. The stomach
remain
of emulsion
in this solution for twenty minutes to half an hour, after which it was stretched out on a piece of cork under Locke’s solution. The mucosa was then very carefuIIy dissected away, Ieaving the muscularis and serosa which were then cut into
FIG. 4. Effect of smaI1 amount of dilute hydrochIoric acid on typical antral response with complete suppression of contraction waves. This amount is suffkient to carry pH to or just beyond neutrality according to observations of resulting mixture determined with caIome1 electrode.
was then transferred to Locke’s solution at a uniform temperature of 4’~. An incision was then made aIong the greater curvature from the esophagus to the pyIorus, and the material from the stomach compIeteIy evacuated. The stomach was then cIeaned, and the organ pIaced in
paraIle1 strips approximateIy 3 to 5 mm. in width, and 2 to 3 cm. in Iength. In severa of the experiments the strips remained with the mucosa intact, but for our routine work the mucosa was dissected away. The strips were then kept in Locke’s soIution in a refrigerator,
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the mean temperature being approximately In some instances the strips were 4O. empIoyed immediately, and in others they
FIG. 5. Typical rapid rhythm of cardiac end and greater curvature strip. Acid inhibits response.
were used on the foIlowing day or even as Iong as forty-eight hours after remova1. The apparatus consisted of an outer container, hoIding perhaps 3 qt. of warm water, kept at a constant temperature of 37.3’~. by means of an eIectric thermoreguIator. This container acted as a
of Acids
American
.Iournal
of Surncrv
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the strip was immersed in the solution was by means of a movable lever and side-arm, so that every change in the muscIe strip was automaticaIIy recorded on a moving kymographic drum. The levers were extremeIy sensitive and speciaIIy adapted to this work. The apparatus was a type recommended by Dr. J. EarIe Thomas as most effective for this purpose. Time was recorded by a Jacquette mechanism, and the injection of substances was marked by an eIectrica1 indicator. 1 It is interesting to remark at this point recorded from strips that the tracing from different regions of the stomach was so characteristic that the observer was able, after a reIativeIy short experience, to determine the region of the stomach invoIved. In other words, the contractions of any one strip were usuaIIy characteristic. Strips from the Iesser curvature showed a distinctly smaIIer ampIitude and greater frequency. In many instances the movements of strips from the cardia were very minute, and in some cases almost unrecognizable.
FIG. 6. Typical effect of addition of smaI1 amount of diIute hydrochIoric acid (3 C.C. of 0.5 per cent HCI to zso C.C. of Locke’s solution) on surviving muscle strip taken from greater curvature antral end of rabbit’s stomach.
water bath to maintain a constant temperature of the Locke’s soIution which was contained in an inner vesse1 hoIding approximateIy 230 CL. Through the inner the Locke’s soIution vesse1 containing was an arrangement by which oxygen couId be maintained at a given rate, so that the Locke’s solution was aerated by which constantIy. Th e arrangement
MuscIe strips from approximateIy go animaIs were used, and throughout this series of experiments one can almost predict from the record of the tracing the part of the stomach waI1 which was being investigated. In the great majority of cases our attention was directed to the phenomenon at the pyIoric end of the stomach. In
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about one-third of these cases records were made from the cardiac end of the stomach. Strips from the greater curvature
of Acids
from baIIoons pIaced in the normaI human antrum. The rhythmicity and the power of the contraction in that portion of the
FIG. 7. Pyloric end, midway between greater and lesser curvature. Response resembIes_cardiac cent HCI has onIy miId effect.
near the antrum and pyIorus gave the most characteristic tracings. These were characterized by reguIar recurring groups of waves with a wide ampIitude. In many instances the muscIe strips wouId shorten to haIf their origina Iength. Curves of
APRIL, 193,
strips and 0.5 per
antrum adjacent to the pyIorus and at the greater curvature, are out of a11 proportion to the response obtained in every other part of the stomach waI1. Even in the Iesser curvature and the antra1 portion no such contractions were recorded.
FIG. 8. Powerful rhythmic antraI contractions seen most characteristicahy in antrum and greater curvature of rabbits stomach. These in no way resemble response obtained under identical conditions in lesser curvature, cardia and fundus and suggest a specialized musculature which we believe is concerned in major part of mechanical work of stomach.
this description are to appended iIIustrations, technique was satisfactory to get a graphic tracing respects, resembIed the
be noted in the and when the it was possibIe which, in many tracing obtained
In records of the Iesser curvature, whiIe there are considerabIe differences in tone and rhythm, the contractions were frequentIy reguIar, but never of the same ampktude, and this is true of the entire
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fundus as weI1. In fact, we do not hesitate to make the statement that the important work in the rabbit’s stomach is in a11 prob-
American journalof Surgery I 2-5
that the tracing obtained from the cardia and the antrum are different in type, form and amplitude, as one wouId expect
Flc.‘g. Contractions from pyIoric end and greater curvature. results are in accord with DrobabiIitv that greatest amount of stomach wall.
ability carried out by that part of thestomach waI1 invoIving the greater curvature near the antra1 portion. AIvarez maintains that the excised strips of muscIe from the cardiac end, and particuIarIy that one on the Iesser curvature next to the cardia, show the strongest tendency to rhythmic contraction. If by this he speaks of the frequency of contraction, then we are incIined to agree with his statement; but if rhythmic contraction impIies a powerfu1 recurring group of movements, then in our judgment the antrum near the pyIorus undoubtedIy fuIfiIIs this idea. There are undoubtedIy marked differences in irritabiIity, Iatent period and contraction waves. As AIvarez maintains, to use his own words: “Speaking roughIy, the rate of contraction varies inverseIy as the distance from the cardia.” One gets the impression from this statement that the contraction rate at the pyIorus, therefore, is very much Iess than that at the cardia: this is IargeIy true; but as one studies these various responses, the fundamenta1 impression is that there is no comparison between the pyIoric and antra1 contractions on the one hand, and the characteristic response seen in the cardia. The observations of Sick, Tedesco, Smith, M’Swiney and others, certainIy suggest
of Acids
Notice amplitude of these contractions. These of work is performed specificaIIy by this portion
regarding their obvious differences in function. In a11 the muscIe strips that we studied, there was never encountered at or near the cardia a record which resembIed the characteristic tracing of the antrum, and the reverse is Iikewise true. It is diffIcuIt or impossibIe to estabIish any reIationship between the two, and if this
FIG. 10. Recurrence of gastric muscIe contraction which had been inhibited by addition of dilute HCI and in this response brought back by addition of sodium bicarbonate soIution.
reIationship exists it is not apparent from our studies. In the baIIoon work done on human beings by Thomas, Eads and Rehfuss, antra1 contractions were powerfu1, reguIar, and frequentIy preceded by a sIight increase in tonus. There is a striking simiIarity between many of our responses, and those which were seen by the intragastric balIoon such as one of us recorded some time ago.
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In practicalIy al1 instances the strips which we used in our work were taken IongitudinaIIy. We tried strips which were
FIG.
APRIL,
,931
with the poor amplitude of contractions in the strips from that region. Nothing in the gross appearance of the strip would
I I. Surviving
muscle strip from cardiac end of stomach. Notice typica contractions totahy unlike those of cardia and notice that repeated additions of 0.5 per cent HCI fails to arrest cardiac contractions.
circular, but the records obtained were unsatisfactory. Therefore, for practica1 purposes, in a11 instances this work was recorded on IongitudinaI strips. There are, of course, many differences observed in
FIG.
of Acids
12.
Addition
of 3.5 cc.
suggest this fact. Alvarez aIso notes as he has commented elsewhere on the fact that as tone rises the ampIitude of contraction faIIs, untiI rhythmic activity may cease entirely. This may be true on some
of 0.5 per cent HCI causes alteration in muscle strip response which is inhibited aItogether by addition of I C.C. more of diIute HCI.
the tonus of the strips, and at times a distinct increase in tonus was recorded, when there were no contractions. Tonus naturaIly can onIy be recorded in this sort of work by the position of the Iever above the basehne, which records the contraction of the muscle strip. AIvarez suggests that high tonus of the Iesser curvature might have something to do
occasions, but it is certainIy not invariabIy true, as wiI1 be seen from certain contractions with bicarbonate of soda, for instance. Just what is the influence of the histologicaI structure in these different parts of the stomach, we are not prepared to state. We are convinced of the fact, however, that the reaction of the excised muscIe strip in the cardia and in the pyIoric antrum
NEW SERIES VOL. XII,
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in the rabbit is very different. We are further of the opinion that this difference is a characteristic one inherent in the part
Effect
of Acids
Amcrican
Journal
offering the typical tracings this articIe. In view of the fact that
01 Surgery
iIIustrated
I27
in
it is possibIe
FIG. 13. Strip from lesser curvature all the way from the esophagus to the pyloric sphincter. Note simiIarity in response to type of contraction noted at cardia. Acid inhibits and :IIkaIi restores contractions as ensuing curves demonstrate.
of the stomach which was being observed. We furthermore be&eve that the greater curvature portion of the antrum is that part concerned in the most reguIar and powerfu1 rhythmic contraction, and finaIIy we are unabIe to demonstrate definitely any relationship between antra1 and cardiac contractions. They are different both
to obtain under ideal experimenta conditions tracings which can be reproduced and which are hiphIy characteristic, it was of great interest to note the effect of certain substances, notabIv those connected with gastric function, or what Babkin wouId caI1 natura1 chemical stimuli on these muscIe contractions. The most
FIG. 14. hluscle strip from antral region and greater curvature. Notice disappearance of contractions on addition of 4.5 C.C. of 0.5 per cent HCI and their reappearance after addition of sodium bicarbonate.
in form and type, and a study of our responses wouId make us hesitate to say that even roughIy the rate of contraction varies inverseIy as distance from the cardia. Our observations wouId suggest that the contractions are very different in both type, form and tone in the two parts of the stomach waI1. For that purpose we are
interesting substance is hydrochIoric acid. The action of diIute hydrochloric acid and aIkaIies such as sodium bicarbonate has been repeatedIy discussed in the Iiterature. The influence of natura1 chemica1 stimuIi on the movements of the frog’s stomach was studied by Babkin.‘” In this contribution the author points out that soIutions
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of hydrochIoric acid introduced into the stomach, according to GIassnerll are noneffective; according to Lussana12 they increase and afterwards arrest its spontaneous contractions; according to Patterson13 they arrest without previousIy increasing the hunger contractions; and finaIIy, Hoff14 noted an increase in contractions. Babkin asks the question as to whether the acting chemica1 agent being the same, the various motor responses are not due to unequa1 stimuIation of the neuromuscuIar apparatus of the stomach itseIf. He studied the stomach of the frog which was excised, and in which soIutions were introduced under the definite pressure. The voIumetric registering of stomach contractions was made on a kymograph, and at the same time the author made tracings of the separate contractions. He found that the most active part of the stomach of the frog was the pyIoric part. HydrochIoric acid exerted a varying action, depending upon its concentration. In weak soIutions it increases the contractions and diminishes the frequency at 0.5 HCL. In some concentrated soIutions (0.05 per cent to 0.2 per cent) it arrests them. He then found that the effect of sodium bicarbonate (0.03 per cent to 0.05 per cent) is to arrest the tone and increase the intensity and frequency of the contractions of the frog’s stomach. In other words, these experiments were performed by injecting the materia1 in the stomach. We are not famiIiar with the effect of the aIteration of the hydrogen iron concentration of Locke’s soIution on the excised muscIe strips. THE
EFFECT
OF
HYDROCHLORIC
ACID
In this experiment we arranged the apparatus in order that we couId obtain the typica responses. OrdinariIy a controIIed tracing was made after the contractions had reached a uniform type for at Ieast thirty or forty minutes. At this point from 1 to 5 C.C. of a 0.05 per cent soIution of hydrochIoric acid was injected into
of Acids
APRIL,,938
the Locke’s solution. It is needIess to point out that the amount of hydrochIoric acid in the soIution, when diIuted, represented an infinitesimaIIy smaI1 amount of acid. In other words, if 5 C.C. of 0.5 hydrochIoric acid were added to 250 C.C. of Locke’s soIution, the resuIting mixture wouId represent 0.01 per cent hydrochIoric acid. At this figure we were abIe to demonstrate unmistakabIe changes in the appearance of the waves. AImost uniformly it was possibIe, by the addition of hydrochIoric acid in the quantities mentioned before, to cause either marked inhibition or a tota arrest of the contractions. In some instances, the interva1 between the contractions was proIonged. In others, the contraction graduaIIy faded away, and in a number of these responses there was a compIete disappearance of the contraction. It was therefore evident that diIute hydrochIoric acid in diIutions far smaIIer than those commonIy encountered, but nevertheIess showing a change in the hydrogen iron concentrate caused a din& nution or cessation of the contractions. In view of this practicaIIy constant finding, it was of interest to note the effect of other substances. The first substance which was used was sodium citrate. The addition of smaI1 amounts of sodium citrate, I to 5 C.C. or more, a saturated soIution, not onIy caused a reappearance of the contractions, but in some of the preparations where hydrochIaric acid was not used, it caused an increase in tonus and sometimes in the frequency of contractions. This observation was strikingIy constant in the series of cases where it was used. Sodium bicarbonate used in the same a saturated soIution of way, nameIy, quantities of 5 C.C. and over, Iikewise had a sitiiIar effect. In some instances there was a very much greater increase in tonus, and if the tracing was recorded over considerabIe intervaIs, a compIete reappearance of contractions which were, if anything, more rhythmic and more pronounced than before hydrochIoric acid had been used. It is to be noted that not onIy is
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there an increase in tonus, but that in the majority of instances the inhibitory effect of hydrochIoric acid is overcome and foIIowed by pronounced contraction. It was interesting in this work to observe whether or not extracts from different parts of the stomach might not have the same effect. For this purpose we prepared macerations of the funda and pyIoric portions of the stomach in norma saIt soIution. We were unabIe to demonstrate any definite effect from either of these tissue extracts, as the foIIowing short tabIe wiI1 revea1. We aIso used in severa experiments Iiver extract 343 of LiIIie’s, and aIso the 4-C Iiver extract which was prepared in On one occasion we our Iaboratories. were abIe to get a response from Iiver extract. This finding, however, was an inconstant one, and we fee1 that our studies do not justify the concIusion that Iiver extract stimuIates the gastric muscufature. Studies which wiI1 be reported elsewhere by us, however, do prove that the upper digestive tract is certainIy influenced by this preparation. CONCLUSIONS I. The reaction of surviving muscIe strips from different portions of the stomach of a rabbit is highIy characteristic. 2. LongitudinaI preparations from the cardia gave a response which is essentiaIIy different from that obtained at the pyIoric antrum. 3. The most powerfu1 rhythmic contractions were obtained from that part of the antrum invoIving the greater curvature. 4. The most frequent waves of smaI1 ampIitude are obtained at or near the cardia. 5. HydrochIoric acid in dilutions mentioned in the text, inhibits or arrests the pyIoric antra1 contractions. 6. Sodium citrate in a number of instances causes a reappearance of the contractions foIIowing their disappearance due to hydrochIoric acid.
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American JOWL UFsurgery
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7, Bicarbonate of soda has the same quaIity. 8. In the majority of our studies there was a perceptibIe increase of tonus on the addition of bicarbonate of soda. 9. Norma1 saIt soIution extracts of the fundus and antrum faiIed to show any strip muscIe effect on appreciabIe preparations. IO. It is possibie that some Iiver extracts may stimuIate these contractions. After studying these charts and the behavior of the muscIe strips under these experimenta conditions, one hesitates to assume changes in hydrogen iron concentration as important factors in peristaIsis. CertainIy there can be no question that minute amounts of acid and aIkaIi can markedIy aIter the sequence of events. A mechanism invoIving reguIar recurrent changes in hydrogen iron concentration might be suggested as a hypothesis for peristaIsis. In concIusion, the resuIts mentioned here were obtained from a series of studies on isoIated muscIe strips from different parts of the stomachs of about 90 rabbits. We are indebted to those who contributed to the MedicaI Research Foundation at Frankford for financia1 support in these experiments, nameIy, Mrs. Cyrus H. K. Curtis, Mr. Alvan Dinkey, Mrs. Henderson, Mr. H. M. Pierce, and Mrs. Buckner. REFERENCES I. M'CREA, M’SWINEY, MORISON and STOPFORD. Quart. J. Exper. Pbysiol., 14: 379, 1924. 2. SICK and TEDESCO. Deutscbe Arch. j. klin. Med., 92: 416, 1908. 3. ALVAREZ, Am. J. Pbysiol., 40: 585, 1916. 4. SHUTZ. Arch. f. exper. Patb. u. Pbarmakal., 21: 341, 1886. 5. SMITH, Am. J. Pbysiol., 46: 232, 1918. 6. HECHT, Deutscbe Arcb.j. klin. Med., 136: 296, 1921. 7. TEXNER and TUROLT. Ztscbr. j. d. ges. exper. Med., 24: I, 1921. 8. KURODA. Ztscbr.j. d. ges. exper. Med., 39: 341, 1924. 9. BROWN and M’SWINEY. Quart. J. Exper. Pbysiol. 16:9, 1926. IO. BABKIN. Quart. J. Exper. Pbysiol., 14: 259, 1924. II. GLASSNER, Pfluger’s Arch. f. d. ges. Pbysiol., 86:
291, 1904. 12. LUSSANA. Arch. difisiol., 7: 149, 1909. 13. PATTERSON. Am. J. Pbysiol., 47: 56, 1916. 14. HOFF. Ztscbr. j. Biol., 55: 409, 191 I.
‘30
American Journal of Surgery
Gorman,
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DISCUSSION
DR. BASTEDO: As an oId pharmacologist, I just want to emphasize something that Dr. Rehfuss mentioned, and that is the fact that the acids and alkaIies wiII not be found affecting this muscle strip in the Iiving stomach, but onIy in the mucous membrane. You must not get that impression, because the muscular layers are not affected chem,icalIy by what is in the stomach, but rather by what is brought to them by the bIood stream. DR. REHFUSS (closing): I am very much interested in the reference to the motion of the pyloric valve. These are the things that impressed us in our work. Dr. AIvarez’ idea is that this is more or less continuous, but I think that the phenomenon that I have presented here today is an aItogether different phase of digestion, an aItogether different thing. This beating of the pyIorus in rabbits is a beat which is powerfu1, regular, recurrent, and is, so far as I can find, the onIy part capabIe of doing work. Therefore, I was interested in Dr. Coles’ description of his idea regarding the fan shaped muscIe he describes. I wouId Iike to show him some of the records we have. There is
of Acids
APRIL, 19x1
another thing which I wouId like to point out, and that is, that if there is anything which affects the muscuIar tissue it is not in the stomach, but it is, rather, something perhaps chemical alterations in the bIood circuIating through that particuIar part of the stomach waI1. There is one thought that occurs to me, and that is, that, with the Iarge amount of acid which must be derived from the stomach may resuIt in changes in the tonus of this region of the stomach, any change which occurs must occur during the gastric digestion and not the intestina1 digestion. It is cIear that there is some general mechanism which brings about a change in the pH, which probably is induced by the formation of a Iarge amount of secretion. It seems aImost impossibIe for us to believe that we can get a pint or a quart of stomach secretion, without some radica1, chemical change. I beIieve that the dista1 end is motor in its function, and that the cardiac end is buiIt for storage. I think that the chemistry reIates to a hormone which is secreted by some mechanism which operates in the entire digestive tract, and is, perhaps, part of a far-flung mechanism which may reach further than the stomach.