`

`i!l:ambtibgr:
`PRINTED BY J. AND C. F. CLAY,
`
`AT THE UNIVERSITY PRESS.
`
`MPI EXHIBIT 1078 PAGE 2
`
`MPI EXHIBIT 1078 PAGE 2
`
`

`

`CONTENTS OF VOL. XXVIII.
`
`Nos. 1 & 2. March 27, 1902.
`
`A further research into fatigue of the central nervous system
`when caused by electrical stimulation. By A. G. LEVY, M.D. (Lond.).
`(Eight Figures in Text.)
`Path of impulses for inhibition under decerebrate rigidity. By
`A. FROHLICH, M.D., and C. S. SHERRINGTON, M.A., M.D., F.R.S.
`(Two Figures in Text.)
`Some effects of the ligature of the renal arteries in the frog.
`By A. P. BEDDARD, M.A., M.D.
`The effect of local injury upon the excitatory electrical response
`of nerve. By FRANCIS GOTCH, D.Sc., M.A. (Oxon.), F.R.S.
`The innervation of the frog's stomach. By WALTER E. DIXON,
`M.A., M.D.
`(Thirteen Figures in Text.)
`Some experiments on the functions of the medulla of the kidney.
`By FRANCIS D. BoYD, M.D., F.R.C.P. (Edinb.)
`The relationship of the spleen to the formation of the blood
`corpuscles. By D. NOEL PATON, G. LOVELL GuLLAND, and J . 8.
`FOWLER.
`(Ten Figures in Text.)
`The influence of subcutaneous injections of large quantities of
`dextrose on the metabolism in the dog. By JAMES SCOTT, M.D.
`Note on the absorption of the nitrogen of oatmeal by the dog.
`By D. NOEL PATON.
`. !
`On the residual pressures in the vascular system when the
`circulation is arrested. By LEONARD HILL, M.B:, F.R.S.
`(Eleven
`Figures in Text.)
`
`Pancreatic diastase, and its zymogen. By H. M. VERNON, M.A.,
`.
`(Six Figures in Text.)
`M.D.
`
`PAGE
`
`1
`
`14
`
`20
`
`32
`
`57
`
`76
`
`83
`
`107
`
`119
`
`12 2
`
`137
`
`The differences of action of various diastases. By H. M. VERNON,
`156
`M.A., M.D.
`(Two Figures in Text.)
`On the digestion of cane sugar. By J. H. WrnmcoMBE, M.A. 175
`
`UNDA HALL LIBRAR~
`KANSAS CITY, MO.
`
`MPI EXHIBIT 1078 PAGE 3
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`

`

`lV
`
`CONTENTS.
`
`No. 3. May 28, 1902.
`
`Fatigue in non-medullated nerves. By T. GREGOR BRODIE, M.D.,
`and W. D . HALLIBURTON, M.D., F.R.S.
`(Six Figures in Text.)
`Note on fretal muscle spindles. · By LAURA FORSTER, M.D.,
`L.R.C.P., L.R.C.S.
`On the formation of lymph by the liver. By F. A. BAINBRIDGE,
`M.B., M.R.C.P.
`(Two Figures in Text.)
`On the local reactions of the arterial wall to changes of internal
`pressure. By W. M. BAYLISS.
`(Eleven Figures in Text.)
`.A method of estimating the oxygen and carbonic acid in small
`quantities of blood. By JOSEPH BARCROFT, M.A., B.Sc., and J. S.
`HALDANE, M.D., F.R.S.
`(Three Figures in Text.)
`.
`Intestinal absorption of solutions. BY E. WAYMOUTH REID
`
`PAGB
`
`181
`
`201
`
`204
`
`220
`
`232
`241
`
`No. 4. July 21, 1902.
`
`257
`
`Metabolism on ordinary and forced diets in normal individuals.
`By FRANCIS w. GOODBODY, M.D., M.R.C.P., NOEL D. BARDSWELL,
`M.D., M.R.C.P., and J. E. CHAPMAN, M.R.C.S., L.R.C.P.
`Further researches on antidromic nerve-impulses. By W . M.
`276
`BAYLISS.
`(Twelve Figures in Text.)
`Taste and the fifth nerve. By Sir W. R. GOWERS, M.D., F.R.S. 300
`On the innervation of the urinary passages in the dog. By
`C. H. FAGGE, M.S.
`(Eight Figures in Text.) .
`The visual acuity of the natives of Sarawak. By CHARLES S.
`MYERS
`Reticulin and collagen. By M. SIEGFRIED
`
`304
`
`316
`319
`
`No. 5. September 12, 1902.
`
`The mechanism of pancreatic secretion. By W . M. BAYLISS and
`E. H. STARLING.
`(Seventeen Figures in Text.)
`The influence of oxygen upon the survival respii-ation of muscle.
`By W. M. FLETCHER, M.A., M.B.
`(Three Figures in Text.)
`On the products of the proteolytic action of an enzyme con-
`tained in the cells of the spleen. By J. B. LEATHES
`A further note on the pyramidal tract (Monakow's bundle).
`By E. H. FRASER, M.D.
`(Nine Figures in Text.) .
`
`325
`
`354
`
`360
`
`366
`
`MPI EXHIBIT 1078 PAGE 4
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`

`

`CONTENTS.
`
`V
`
`No. 6. December 15, 1902.
`
`The conditions of action oi the pancreatic secretion. By H. M.
`VERNON, M.A., M.D.
`The submaximal electrical response of nerve to a single stimulus.
`By FRANCIS GOTCH, D.Sc., M.A. (Oxon.), F.R.S.
`(Six Figures in
`395
`Text.)
`On the pitch of Galton-whistles. By CHARLES. S. MYERS, M.D. 417
`A preliminary communication on the changes in nerve cells
`after poisoning with
`the venom of
`the Australian
`tiger-snake
`(Hoplocephalus cwrtus). By BASIL KILVINGTON, M.S., M.D.
`(Nine
`Figures in Text.)
`On saline diuresis. By ARTHUR R. CusHNY, M.A., M.D.
`Pancreatic zymogens · and pro-zymogens. By H. M. VERNON,
`M.A., M.D.
`The relation of oxygen to the survival metabolism of muscle.
`By W. M. FLETCHER, M.A., M.B.
`(Thirteen Figures in Text.)
`The nature of
`the lesions which hinder the development of
`nerve-cells and their processes. By H. K. ANDERSON, M. D.
`On the effect exerted on the coagulability of the blood by an
`admixture of lymph. By A. E. WRIGHT, M.D.
`
`375
`
`426
`431
`
`448
`
`474
`
`499
`
`514
`
`PROCEEDINGS OF THE PHYSIOLOGICAL SOCIETY.
`
`January 18, 1902.
`
`E. H . Embley. The causation of sudden death during the administration
`of chloroform
`.
`
`February 8, 1902.
`E. L Spriggs. On a new method of observing peptic activity
`
`March 1, 1902.
`Thomas Lewis. On the structure and functions of the hoomolymph organs
`
`March 22, 1902.
`J. H erbert Parsons. Arcus Senilis
`
`V
`
`vii
`
`ix
`
`MPI EXHIBIT 1078 PAGE 5
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`

`

`Vl
`
`CONTENTS.
`
`May 10, 1902.
`
`Horace Darwin and W. H. R. Rivei·s. A method of measuring a visual
`illusion
`Dr Fraser Harris. On the rhythm of muscular tremor due to drying of the
`nerve
`J. Herbert Parsons. Degenerations following lesions of the retina in monkeys
`J. N. Langle,y. On the ruffling of feathers in the bird.
`(Preliminary Note)
`J. N. Langley. The thoracic vagus ganglion of the bird
`H. K. Anderson. Effect on the pupil of excision of the ciliary ganglion.
`(P1·eliminary Note)
`
`July 5, 1902.
`
`F. S. Locke. A method of equalising the "strength" of make- and break-
`induction-shocks
`Swale Vincent and William Sheen. On the physiological action of extracts
`of nervous, muscular and other animal tissues.
`(Preliminary
`Communication)
`Sutherland Simpson. Some observations on the temperature of the monkey.
`.
`(Preliminary Note)
`IV. Ramsden. Some new properties of urea.
`(Prelimina1·y Note)
`A. Croft Hill. Synthetic action on glucose with pancreatic ferments
`
`PAGE
`
`xi
`
`xii
`xii
`xiv
`xiv
`
`xv
`
`xvii
`
`xix
`
`xxi
`xxiii
`xxvi
`
`July 19, 1902.
`
`J. Burdon-Sanderson and F. Buchanan. The Jena researches on tho spasm
`of strychnine .
`.
`B. Edgell. Time judgment
`W. L egge Symes. Two graduated arc rheochords .
`A. D. Waller. Demonstration of a new method for rapidly estimating the
`percentage of CH013 vapour in mixtures of CHCl3 and air
`Sutherland Simpson. Temperature range in the monkey in ether anresthesia.
`.
`(Preliminary Note)
`
`xxix
`xxxi
`xxxii
`
`xxxv
`
`xxxvii
`
`Noveinber 8, 1902.
`
`W. M. Fletcli.er. Preliminary note on the changes in the osmotic properties
`of muscle due to fatigue
`.
`A. D. Waller. A demonstration of the "blaze-currents" of the crystalline
`lens .
`Natli.aniel H. Alcoclc. The action of anresthetics on mammalian nerve
`D. F. Harri..•. On periodic darkening in "retinal rivalry."
`.
`
`xli
`
`xlii
`xliii
`xliv
`
`MPI EXHIBIT 1078 PAGE 6
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`

`

`LIST OF AU1'HORS.
`
`ANDERSON, H . K.
`Injury Changes in Nerve-Cells
`BAINBRIDGE, F. A. Lymph Formation.
`BARCROFT, J . and HALDANE, J. S. Gases of Blood
`BARDSWELL, N. D., CHAPMAN, J. E . and GooDBODY, F. W. Metabolism
`and Diet
`BAYLISS, W. M. Reaction of Arterial Wall
`· BAYLISS, W . M. Antidromic Nerve-Impulses
`BAYLISS, W. M. and STARLING, E. H. Pancreatic Secretion
`BEDDARD, A . P. Ligature of Renal Arteries .
`BOYD, F. D. Medulla of Kidney
`BRODIE, T. G. and HALLIBURTON, W. D. F atigue in Nerves .
`CHAPMAN, J. E., GooDBODY, F. W. and BARDSWELL, N. D. Metabolism
`and Diet
`CusHNY, A. R. Saline Diuresis
`DIXON, W. E. Nerves of Frog's Stomach
`F AGGE, C. H.
`Innervation of Urinary Passages
`FLETCHER, W . M. Respiration of Mnscle
`FLETCHER, W. M. Oxygen and Muscle Metabolism
`FORSTER, L. Fretal Muscle Spindles
`FOWLER, J . S., PATON, D. N. and GuLLAND, G. L. Spleen .and Blood
`Corpuscles .
`FRASER, E. H . Prepyramidal Tract
`Impulse Path in Spinal Cord
`FROHLICH, A. and SHERRINGTON, C. S.
`GooDBODY, F. W., BARDSWELL, N . D. and CHAPMAN, J. E. Metabolism
`and Diet
`GOTCH, F. Electrical Response of Nerve
`GOTCH, F. Electrical Response of Nerve
`GowERS, SIR W. R. Taste and the Fifth Nerve
`GuLLAND, G. L., FOWLER, J. S. and PATON, D. N . Spleen and Blood
`Corpuscles .
`HALDANE, J. S. and BARCROFT, J. Gases of Blood
`HALLIBURTON, W. D. and BRODIE, T. G. Fatigue in_ Nerves .
`HILL, L. Residual Vascular Pressures
`KILVINGTON, B. Action of Venom on Nerve Cells
`LEATHES, J. B. Enzyme of Spleen
`LEVY, A. G. Fatigue of Central N ervous System
`MYERS, C. S. Visual Acuity
`MYERS, C. S. Hearing and Galton-Whistles
`PATON, D. N., GuLLAND, G. L. and FOWLER J. S. Spleen and Blood
`C~~cl~.
`
`PAGE
`499
`204
`232
`
`257
`220
`276
`325
`20
`76
`181
`
`257
`431
`57
`304
`354
`474
`201
`
`83
`366
`14
`
`257
`32
`395
`300
`
`83
`232
`181
`122
`426
`360
`1
`316
`417
`
`M
`
`MPI EXHIBIT 1078 PAGE 7
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`

`

`Vlll
`
`LIST OF A UTHORS.
`
`PATON, D. N. Oatmeal as Food for Dogs
`REID, E. W.
`Intestinal Absorption
`SCOTT, J. Dextrose and Metabolism
`SHERRINGTON, C. S. and FROHLICH, A.
`SIEGFRIED, M. Reticulin and Collagen
`STARLING, E. H. and BAYLISS, W. M.
`VERNON, H. M. Pancreatic Diastase
`VERNON, H. M. Action of Diastases
`VERNON, H. M. Pancreatic Secretion
`VERNON, H. M. Pancreatic Zyrqogens
`WrnDICOMBE, J. H. Digestion of Cane Sugar
`WRIGHT, 1\. E. Coagulation of Blood
`
`Impulse Path in Spinal Cord
`
`·Pancreatic Secretion
`
`Proceedings of the Pliysiological Society.
`
`ALCOCK, NATHANIEL H. Anresthetics on mammalian nerve
`ANDERSON, H. K. Ciliary ganglion and pupil
`.
`BUCHANAN, F. and BURDON-SANDERSON, J. Spasm of strychnine
`BURDON-SANDERSON, J. and BUCHANAN, F. Spasm of strychnine
`DARWIN, HORACE and RIVERS, W . H. R. Measuring a visual illusion
`EDGELL, B. Time judgment
`EMBLEY, E. H . Death by chloroform
`FLETCHER, W. M. Osmotic properties of muscle in fatigue
`HARRIS, D. FRASER. Rhythm of muscle tremor
`HARRIS, D. FRASER. Periodic darkening in "retinal rivalry "
`HILL, A. CROFT. Synthetic action of pancreatic ferments
`LANGLEY, J. N . Ruffling of feathers .
`LANGLEY, J. N. Thoracic vagus ganglion of bird
`LEWIS, THOMAS. H remolymph organs
`LOCKE, F . S. Equalizing ma ke- and break-shocks
`PARSONS, J. HERBERT. Arens senilis .
`PARSONS, J. HERBERT. Degenerations from retinal lesions
`RAMSDEN, W. N ew properties of urea
`RIVERS, W. H. R. and DARWIN, HORACE. Measuring a visual illusion
`SHEEN, W. and VINCENT, SWALE. Action of tissue-extracts
`SIMPSON, SUTHERLAND. Temperature of monkey
`SIMPSON, SUTHERLAND. Temperature in anresthesia
`SPRIGGS, E. I. E stimation of peptic activity
`SYMES, W. LEGGE. Rheochords
`.
`VINCENT, SWALE and SHEEN, W. Action of tissue-extracts
`WALLER, A. D. E stimation of chloroform vapour
`WALLER, A. D.
`"Blaze-currents" of lens .
`
`PAGE
`119
`241
`107
`14
`319
`325
`137
`156
`375
`448
`175
`514
`
`xliii
`xv
`xxix
`xxix
`XI
`xxxi
`i
`xli
`xii
`xliv
`xxvi
`xiv
`xiv
`vii
`xvii
`ix
`xii
`xxiii
`xi
`xix
`xxi
`xxxvii
`V
`xxxii
`xix
`XXXV
`xiii
`
`MPI EXHIBIT 1078 PAGE 8
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`

`

`THE MECHANISM OF PANCREATIC SECRETION.
`BY W. M. BAYLISS AND E. H. STARLING.
`(Seventeen
`Figures in Text.)
`
`(F1·orn the Physiological Laboratory of University College, London.)
`
`CONTENTS.
`
`I.
`Historica.l.
`II. Experimental methods.
`III. The effect of the injection of acid into the duodenum and jejunum.
`IV. The crucial experiment.
`V.
`Properties and action of "secretin."
`VI.
`"Prosecretin."
`VII. The normal mechanism, chemical or nervous?
`VIII. Fate of secretin in the organism.
`IX. Properties of secretin-juice.
`X. Action of secretin on other glands.
`XI. Action of other substances on the pancreatic secretion.
`XII.
`Incidental obse;vations on specific chemical vaso-dilators.
`XIII. Summary of conclusions.
`
`1 HISTORICAL.
`
`IT bas long been known that the activity of the pancreas is normally
`called into play by events occurring in the alimentary canal. Bernard 1
`found that the pancreatic secretion could be evoked by the introduction
`of etuer into the stomach or duodenum, and Heiden b ai n 2 studied the
`relation of the time-course of the secretion to the processes of digestion
`going on in the stomach and intestines.
`Our exact knowledge of many of the factors determining pancreatic
`secretion we owe to the work of Paw low and his pupils 3, who have
`shown that the flow of pancreatic juice begins with the entry of the
`chyme into the duodenum and is not excited directly by the presence of
`
`1 P11ysiologie experi111entale, ·u. p. 226. Paris, 1856.
`2 Hermann's Handbuch d. Physiologie, v. p. 183. 1883.
`3 Die Arbeit der Verdauungsdrilsen. Trans. from Russian, Wiesbaden. 1898. Also Le
`travail des glandes digestives. Paris, 1901.
`
`PH. XXVIII.
`
`21
`
`MPI EXHIBIT 1078 PAGE 9
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`

`

`326
`
`.
`W. M. BAYLISS AND E. H. STARLING .
`food in the stomach itself. The exciting influence of the chyme is <lue
`chiefly to its acidity, and a large secretion can be brought about by the
`introduction of 0·4 °Jo hydrochloric acid into the stomach, whence it is
`rapidly transferred to the duodenum. Paw I ow found, however, that
`other substances, e.g. water, oil, introduced into the stomach had a
`In each case the effect was
`similar, though less pronounced, effect.
`produced only when the substances had passed into the duodenum.
`Pawlow bas, moreover, drawn attention to a remarkable power of
`adaptation presented by the pancreas, the juice which is secreted
`varying in composition according to the nature of the food which has
`passed into the duodenum. Thus, with a diet of meat the tryptic
`ferment is present in relatively largest amount, while .a diet of bread
`causes the preponderance of the amylolytic ferment, and a diet of milk
`or fat that of the fat-splitting ferment.
`Paw Io w regards the secretion evoked by the pr~sence of acid in the
`duodenum as reflex in origin, and ascribes the varying composition of
`the juice in different diets to a marvellous sensibility of the duodenal
`mucous membrane, so that different constituents of the chyme excite
`different nerve-endings, or produce correspondingly different kinds of
`nerve-impulses, which travel to the gland, or its nerve-centres, and
`determine tbe varying activity of the gland-cells.
`In searching for the channels of this reflex, Pawlow has shown
`that, if proper precautions be taken, it is possible to excite a secretion
`of pancreatic juice by excitation of the divided vagus or splancbni~
`nerves. The vagus nerves, also, according to him, contain inhibitory
`fibres.
`The question as to the mechanism by which a pancreatic secretion
`is evoked by the introduction of acid into the duodenum has been
`narrowed still further by the independent researches of Popielski 1 and
`of Wertheimer and Lepage 2• These observers have shown that the
`introduction of acid into the duodenum still excites pancreatic secretion
`after section of both vagi and splancbnic nerves, or destruction of the
`spinal cord, or even after complete extirpation of the solar plexus.
`Popielsk{ concludes, therefore, that the secretion is due to a peripheral
`reflex action, the centres of which are situated in the scattered ganglia
`found throughout the pancreas, and ascribes special importance to a
`large collection of ganglion cells in the head of the pancreas close to
`the pylorus. Wertheimer and Lepage, while accepting Popielski's
`
`1 Gazette clinique de Botkin (Russ.) 1900.
`2 Journal de Physiologie, m. p. 335. 1901.
`
`MPI EXHIBIT 1078 PAGE 10
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`

`

`PANCREATIC SECRETION.
`
`327
`
`explanation of the secretion excited from the duodenum, found that
`secretion could also be induced by injection of acid into the lower
`portion of the small intestine, the effect, however, gradually diminishing
`as the injection was made nearer the lowei·. end of the small intestine,
`so that no effect at all was produced from the lower two feet or so of
`the ileum. Secretion could be excited from a loop of jejunum entirely
`isolated from the duodenum. They conclude that, in this latter case,
`the reflex centres are situated in the ganglia of the solar plexus, but
`they did not perform the obvious control experiment of injecting acid
`into an isolated loop of jejunum after extirpation of these ganglia.
`They showed that the effect was not abolished by injection of large
`doses of atropin, but compared with this the well-known insusceptibility
`to thiR drug of the sympathetic fibres of the salivary glands.
`The apparent lqcal character of this reaction interested us to make
`further experiments on the subject, in the idea that we might have
`here to do with an extension of the local reflexes whose action on the
`movements of the intestines we have already investigated1. We soon
`found, however, that we were dealing with an entirely different order
`of phenomena, and that the secretion of the pancreas is normally called
`into play not by nervous channels at all, but by a chemicaf substance
`which is formed in the mucous membrane of the upper parts of the
`small intestine under the influence of acid, and is carried thence by the
`blood-stream to the gland-cells of the pancreas 2.
`
`II. EXPERIMENTAL METHODS.
`
`All our experiments were made on dogs which had received a
`previous injection of morphia, and were anresthetized with A.C.E. mixture
`In or<ler to keep the animals'
`during the course of the experiment.
`condition constant, artificial respiration was usually employed, a pro(cid:173)
`cedure which
`is especially Qecessary when both vagi are divide<l,
`the anresthetic bottle being introduced in the course of the blast of
`air from the pump. The animals had received no food for a period
`In the earlier experiments, where
`of 18 to 24 hours previously.
`a considerable degree of preliminary operative manipulation was re-
`
`1 This Journal, xxrv. p. 99. 1899.
`2 A preliminary abstract of the main results of this work was published in the
`Proc. Roy. Soc. LXIx. p. 352. 1902. The experiments, of which an account is given
`in the present paper, were completed in March, 1902, their publication being delayed by
`extraneous circumstances.
`
`21-2
`
`MPI EXHIBIT 1078 PAGE 11
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`

`

`PANCREATIC SECRETION.
`
`329
`
`section of the spinal cord at the level of the foramen magnum,
`destruction of the spinal cord, section of the splancbnic nerves, or
`extirpation of the solar plexus, or any combination of these operations•
`Fig. 1 will serve as an illustration of the fact.
`In this case the
`spinal cord was destroyed from the 6th thora ic vertebra downwards,
`and both vagi and splancbnic nerves were cut. At the period of time
`marked by the signal, 50 c.c. of acid were injected into the duodenum,
`about 2 minutes from the beginning of the injection tho first drop
`of secretion is recorded, and a rapid series of drops commences at
`4 minutes, to last for some 3 or 4 minutes and gradually cease after
`11 or 12 minutes.
`In two or three of these experiments we noted an effect which is
`perhaps worth recording. During Lhe injection of repeated doses of
`acid, the effect of each dose was less than that of tho preceding one,
`and sooner or later a point was reached at which no effect wa produced,
`even by 1 ·6 ¼ ROI. On now injecting into a vein about 50 c.c. of
`3 ¼ sodium carbonate olution a considerable flow of juice was obtained
`without any further injection of acid into the duodenum.
`Intravenous injection of sodium carbonate solution, without pre(cid:173)
`vious introduction of acid into the gut, had no effect on the pancreatic
`secretion.
`Our experiments, therefore, confirm those of previous observers in
`so far a we find that after exclusion of all nerve-centres, except those
`in tho pancreas itself, a secretion of pancreatic juice is obtained by the
`introduction of acid into the duodenum. But, as pointed out above,
`the ea:perimenturn crucis of taking an isolated loop of intestine, dividing
`the mesenteric nerves supplying it, and then injecting acid into it, had
`not been performed.
`It is plain that this experiment cannot be performed on the duo(cid:173)
`denum for anatomical reasons. Fortunately, however, as Wertheimer
`and Le page have shown, the jejunum, separated by section from the
`duodenum, is also capable of exciting the pancreas to activity, when
`acid is introduced, and in this case the centre for the "reflex" must
`be in the cceliac or mesenteric ganglia. The possibility of our crucial
`experiment 1s given here, and the results are contained ill the next
`section.
`
`MPI EXHIBIT 1078 PAGE 13
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`

`

`330
`
`W. M. BAYLISS AND E. H. STARLING.
`
`IV. THE CRUCIAL EXPERIMENT.
`
`On January 16th, 1902, a bitch of about 6 kilos weight, which had
`been fed about 18 hours previously, was given a hypodermic injection
`of morphia some 3 hours before the experiment, and during the experi(cid:173)
`ment itself received A.C.E. in addition. The nervous masses around the
`superior mesenteric artery and craliac axis were completely removed
`and both vagi cut. A loop of jejunum was tied at both ends and the
`mesenteric nerves supplying it were carefully dissected out and divided,
`so that the piece of intestine was connected to the body of the animal
`merely by its arteries and veins. A cannula was inserted in the large
`pancreatic duct and the drops of secretion recorded. The blood-pressure
`in the carotid was also recorded in the usual way. The animal was in
`the warm saline bath and under artificial respiration.
`The introduction of 20 c.c. of 0·4 ¼ HCl into the duodenum produced
`a well-marked secretion of 1 drop every 20 secs. lasting for some
`6 minutes; this result merely confirms pre_vious work.
`But, and this is the important point of the experiment, and the
`turning-point of the whole research, the introduction of 10 c.c. of
`the same acid into the enervated loop of jejunum produced
`a similar and equally well-marked effect.
`Now, since this part of the intestine was completely cut off from
`nervous connection with the pancreas, the conclusion was inevitable that
`the effect was produced by some chemical substance finding its way into
`the veins of the loop of jejunum in question and being carried in the
`blood-stream to the pancreatic cells. Wertheimer and Lepage have
`shown1, however, that acid introduced into the circulation bas no effect
`on the pancreatic secretion, so that the body of which we were in search
`could not be the acid itself. But there is, between the lumen of the
`gut and the absorbent vessels, a layer of epithelium, whose cells are
`as we know endowed with numerous important functions.
`It seemed
`therefore possible that the action of acid on these cells would produce a
`body capable of exciting the pancreas to activity. The next step in our
`experiment was plain, viz. to cut out the loop of jejunum, scrape off the
`mucous membrane, rub it up with sand and 0·4 ¼ HCl in a mortar,
`filter through cotton-wool to get rid of lumps and sand, and inject the
`extract into a vein. The result is shown in Fig. 2. The first effeot is
`a considerable fall of blood-pressure, due, as we shall show later, to a
`
`1 Journal de Physiologie, m. p. 695. 1901.
`
`MPI EXHIBIT 1078 PAGE 14
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`MPI EXHIBIT 1078 PAGE 14
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`PANCREATIC SECRETION.
`
`335
`
`effect of such a solution is shown in Fig. 5.
`It will be seen however
`that by this treatment alone the body causing fall of blood-pressure is
`not removed.
`Secretin is non-volatile, it does not appear in the distillate obtained
`by passing steam through its solution.
`It dialyses through parchment paper, but not readily.
`The action of its solutions does not depend on their inorganic
`constituents, since the ash, prepared for us by Dr Osborne, has no
`effect on the pancreas.
`It is destroyed by digestion with active tryptic solutions for one
`hour; the effect of peptic solutions is somewhat uncertain, digestion
`with gastric juice from the dog for one hour did not destroy the activity
`of a solution of secretin, but considerably diminished it.
`Taking these facts together it will be seen that we cannot as yet
`give any definite suggestion as to the chemical nature of secretin, its
`solubility in alcohol and diffusibility point to its being a body of low
`molecular weight; since it is not destroyed by boiling it is not a
`ferment ; and that it is not of the nature of an alkaloid or diamino-acid
`is shown by the fact of its not being precipitated by tannin.
`The mode of action of secretin.
`In attempting to form some idea
`as to the mode of action of this body, the first necessity is to decide
`whether the substance causing fall of blood-pressure, which we shall in
`future, for the sake of brevity, call the depressor substance, is the same
`as that exciting the pancreas to secretion ; the importance of this being
`because the vascular dilatation producing the fall of blood-pressure
`might be thouglit to be the cause of the increased activity of the
`pancreas, which organ no doubt would share in the general splanchuic
`dilatation. That this is not so, however, can be shown in several ways.
`Albumoses (Witte's pepton) cause considerable vaso-dilatation in the
`ab<lominal viscera, but no secretion of the pancreas, at least not in the
`doses by which a large fall of blood-pressure is produced (5 c.c. of -~ °lo
`solution). But we have been able to obtain secretin solutions acting
`powerfully on the pancreas, with minimal or zero effects on the blood(cid:173)
`pressure. The mucous membrane of duodenum and jejunum is rubbed
`up with sand in a mortar without the addition of acids, this mass
`is then folded in filter-paper and extracted with absolute alcohol in a
`Soxhlet apparatus for 24 hours, the mass removed, and boiled · with
`0·4 °/o HCl, neutralized and filtered in the usual way. The effect of
`injecting this preparation is shown in Fig. 6. There is no fall of blood(cid:173)
`pressure, but a powerful effect on the pancreas.
`
`MPI EXHIBIT 1078 PAGE 19
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`337
`PANCREATIC SECRETION.
`in this condition for l½ hrs., the water then let out and the obturator
`withdrawn sufficiently far to allow the circulation in the intestines to
`be reestablished. After half-an-hour the animal was killed and a
`secretin preparation made in the usual way from the desquamated
`epithelium found in the lumen of the upper part of the small intestine.
`The result of injecting this is shown in Fig. 7. The fall of blood(cid:173)
`pressure is negligible, while the secretory effect is large. The slow rise
`of blood-pressure is due to a diminution in the amount of A..C.E. given,
`which ha<l been accidentally given in too great an amount previously.
`
`Fig. 7. EjJ'ect of acid extract of desquamated epithelial cells from duodenum.
`Explanation as before. Blood-pressure zero=level of time-marker.
`
`A secretin preparation was also made from the mucous membrane
`of the same animal from which the epithelium had for the most part
`been shed, the effect-being shown in Fig. 8. A very considerable fall
`of blood-pressure is produced and also · a powerful secretory effect, the
`latter most probably being due to the fact that much of the epithelial
`layer bad been left in situ, or, although desquamated, was held between
`the villi, and so escaped removal by the short washing under the tap to
`which the intestine was subjected before the preparation was made.
`We think, however, that the conclusion is justified that the secretin
`comes from the epithelial cells, and the depressor substance from more
`deeply lying structures, possibly the muscularis mucosre.
`We had also an opportunity of investigating the effect of the de(cid:173)
`squamated epithelial cells found in the intestine of a dog which had
`received repeated doses of leech extract, for the purpose of another
`research which was being carried on in the laboratory. Fig. 9 shows
`
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`PANCREATIC SECRETION.
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`339
`
`It may be well to mention here that we have made special experi(cid:173)
`ments to test whether the action of these extracts on the pancreas is
`due to bile salts; this is not so, bile salts have no effect on the pancreas
`when injected intravenously, and the very active preparations made
`from alcohol-extracted mucous membrane contained no bile-salts.
`Geneml conditions of action of secretin. So far as we have as yet
`made out this action is wonderfully independent of the state of tbe
`It is shown equally well in a dog in the stage of digestion or
`animal.
`20 honrs after a meal. Tbe height of the blood-pressure has very little
`effect, as shown by Fig. 10. Amesthetics in all usual doses have no
`._ ,,,.,..____
`
`. -'---~ ·~--
`
`.
`
`·--~_::_~.:.-
`
`-
`
`-
`
`---· -
`
`"
`
`'
`I
`
`--=-
`
`~ ··----- - - - - - - · -
`
`-· -
`
`- --- - - - - - - - - - - -~ -
`
`~ - -
`
`-
`
`- - ~....._ ______ ----1. __ ~ - - - - · - - • • - · -
`
`•
`
`•
`
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`
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`
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`
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`
`Fig. 10.
`E_U-ect of ordinm·y sec retin 11repamtion in cr1se of very low blood-p1·essure.
`Blood-pressure zero is the line immediately below that of the clrop-ma;rker. Other
`explanations as previous figures.
`
`appreciable influence; in this connection we may refer to a statement
`made by Cam us 1, who, having found the effect of secretin diminished
`by a previous dose of chloroform and abolished by a strong dose,
`concludes that the nervous system plays a considerable part in the
`excitation of the pancreas by this substance. So far as the central
`nervous system is concerned its influence is excluded by the first
`experiments in which we injected secretin solutions, since in these the
`pancreas was cut off from the central nervous system, as well as from
`the peripheral ganglia, except those in its own substance. With regard
`to these latter it is plain that we cannot absolutely deny the possibility
`of secretin acting indirectly through nerve-cells, but we submit that
`the well-known effect of chloroform as a general protoplasmic poison is
`quite sufficient to explain the results of Cam us.
`The effect of secretin is unaltered by previous injection of atropin.
`In fact it is impossible to paralyse the pancreatic secretion by any dose
`of this drug. The same insusceptibility to atropin was found by
`Wertheimer to hold good for the secretion evoked by introduction of
`acid into the duodenum.
`The relations in some other animals. All the experiments described
`
`1 C.R. Soc, de Biologie, 25 Avril, 1902, p. 443.
`
`MPI EXHIBIT 1078 PAGE 23
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`PANCREAT'[!;_ SECRETION.
`
`343
`
`of acid from the stomach into the duodenum was not absolutely ex(cid:173)
`cluded in these experiments. Popielski 1 in answer to our article, and
`while admitting the justice of our criticism of the above-mentioned
`vagus experiments, states that he has been able to separate fibres from
`the vagus immediately above the diaph:r:agm, excitation of which causes
`a secretion from the pancreas. This secretion is stated by him to come
`on as rapidly as is the case with the saliva obtained by stimulating the
`chorda tympani nerve, and not to be affected by previous ligature of
`the duodenum below the pylorus.
`If this fact is confirmed it un(cid:173)
`doubtedly proves the existence of nerves capable of causing secretion of
`the pancreas, and we may call to mind that we have in no way stated
`that our experiments disproved the existence of secretory nerves to the
`pancreas. So far, however, as our own experiments go we have been
`unable to obtain secretory effect from the vagus in the neck, either
`after administration of atropin, or without atropin but after section of
`the cardiac branches of the vagus. We hope to return to the question
`of the influence of nerves on the pancreas in a subsequent communica(cid:173)
`tion, and will content ourselves for the present with the statement that
`in our opinion the chemical mode of excitation, viz. by the production
`of secretin in the mucous membrane by the action of the acid chyme
`from the stomach upon it, is the normal one. At all events this mode
`of stimulation must take place, whether there is a concomitant nervous
`process or not, so that this latter is superfluous and therefore improb(cid:173)
`able.
`It is of interest and importance that Wertheimer has recently 2
`found that the blood coming from a loop of intestine into which essence
`of mustard had been introduced · was capable of exciting the pancreas,
`and this fact seems