Tynety dpa eet a a f ahs ‘ sah nitty eiatawae a eat iy nine i oy a ints Dee na b ia p nt 4 i ia 4 ; iyi sh np in Ney tae ciait ai iat 1 “1 Pare te Rae i" ay ere y bea ; tit 4 pel AP nee Lyles agar tye gyal’ ne atte Wel ally tahe ADS MAD DLA Hg Ange F ahaa ‘ rat ‘ He ofits vi NE gigs Pana 1 a v4 hi gag . MARA eS iad er ay oh yt sa oil ow of PaO a i sie uF ‘ue {Qs ita e yt viteee erg aes: itn hit de ately a ) lhl iti iiivuie ab eat whe ity at haf Ve rH a etl ari fe ith ! at Bt aan . iy 4 ; 4 { inepen nig One ue rity ity ah Hn a it ane ie rete Ht watt rite rane ae fei Hike giant e ens eine ids i iabrates iiss ah csi i ai bins ely stel fied { na 7 Ht uh i M K elit ‘ah My By a hy BALE Ut lad Stud AAA OTT Pe Pane Oe a ‘i ee) ~ ny an 7 ie Lae Ae 1b hp tn age ae i i Ve i Mei ye Mah a % fF , ae “Wy t ay i }, e/a ae W ‘ 44 u . ‘ a ‘ a] & ; 7 # ig a wt ¥ 5, an Wy = : Ms bees : id ie + a i} ~ a7 Poll , - —S x ‘ \ i ¥ ve yy ef e’ i vse if f . ~ a ie y ; | aa, he LP i wed p Rie na } , Aa j ; Ne * ye a we ' Lal) rey itd i (hay my As “ok ' mae i Bn we 4) BEE AMERICAN JOURNAL Pat > KO Cyeay VoLuME II. BOSTON, -U:S:-A; CoaEN IN AN Ds COM.P AN Y. 1899 rs . Copyright, 1898 op By GINN AND CoMPANY i, Gniversity ress JouHNn WILSON AND SON, CAMBRIDGE, U.S.A. \ GAOEINS TEIN PS. No. I, NOVEMBER 22, 1898. ON THE EXCRETION OF KYNURENIC AcID. Sy Lafayette B. Mendel and Hiolmes* Cy. [GERSOW= is. oo) oe ON THE MODIFICATION OF RIGOR MORTIS RESULTING FROM PREVIOUS FATIGUE OF THE MUSCLE, IN COLD-BLOODED ANIMALS. Sy Caroline WES IELTS TE ae Se AER ERE CL ee ed tore ven tc hele ON THE RELATION OF THE BLOOD TO THE AUTOMATICITY AND SEQUENCE OF THE HEART-BEAT. By W.H. Howell . ON THE RELATION OF THE INORGANIC SALTS OF BLOOD TO THE AUTO- MATIC. ACTIVITY OF A STRIP OF VENTRICULAR MUSCLE. Sy Charles Wilson Greene No. Il, January 18, 1899. THE COORDINATION OF THE VENTRICLES. By W. 7. Porter... + ON THE PATHS OF ABSORPTION FOR PRoTEIDS. By Lafayette B. Mendel A CHEMICO-PHYSIOLOGICAL STUDY OF CERTAIN DERIVATIVES OF THE Proteips. By R: H. Chittenden, Lafayette B. Mendel, and Yandell Henderson Ss ON THE COURSE OF IMPULSES TO AND FROM THE CAT’S BLADDER. Sy PORN TEIUORE. ahaa hs Wel rat Aton cote lalla (e.! BSaG! wie ae Come Maren eae eek hee lee ON SECRETORY NERVES TO THE SUPRARENAL CAPSULES. By George P. LDPE EE ree CS Oe a ee Ee YL, CL, Mee RC AF mee On SOME ANALOGIES BETWEEN THE PHYSIOLOGICAL EFFECTS OF HIGH TEMPERATURE, LACK OF OXYGEN, AND CERTAIN Poisons. Sy LEAL ee OCLHN OUTER. ey, Rete ek Re ee ee Bake No. III, Marcu 1, 1899. INFARCTION IN THE HEART. By W. Baumgarten -. viele 6s es ON THE CAUSES OF THE ORDERLY PROGRESS OF THE PERISTALTIC MOVE- MENTS IN THE (EsopHaGus. Sy S. /. Meltzer : THE ACTION OF ANIMAL EXTRACTS, BACTERIAL CULTURES, AND CUL- TURE FILTRATES ON THE MAMMALIAN HEART MuSCLE. By Allen CE UTES ae 3 ote Bh eg ey On er ae Se ae Se PAGE v1 Contents. THE FORMATION OF MELANINS OR MELANIN-LIKE PIGMENTS FROM PAGE PROTEID SuBSTANCES. By R. H. Chittenden and Alice H. Albro . . 291 A NOTE ON THE CHOLESTERIN-ESTERS OF BirDs’ BLooD. Sy Lyrnest W. Brown. we es 306 No. IV, May 1, 1899. STUDIES ON REACTIONS TO STIMULI IN UNICELLULAR ORGANISMS. II. THE MECHANISM OF THE MOTOR REACTIONS OF PARAMECIUM. By Herbert S. Jennings «+046 Ve te ek ee On ABSORPTION FROM THE PERITONEAL CAVITY. By Lafayette B. Mendel 342 THE ORIGIN OF THE “ TRAUBE” WAVES. Sy Horatio C. Wood, Jr. . 352 STUDIES ON REACTIONS TO STIMULI IN UNICELLULAR ORGANISMS. IV. LAWS OF CHEMOTAXIS IN PARAMECIUM. Sy Herbert S. Jennings 355 THE CHEMISTRY OF THE MELANINS. Ly Walter Jones . 380 No. V,, JULY 1, 1690. DIRECT AND REFLEX ACCELERATION OF THE MAMMALIAN HEART, WITH SOME OBSERVATIONS ON THE RELATIONS OF THE INHIBITORY AND ACCELERATOR NERVES. Sy Retd Hunt 395 THE PHYSIOLOGICAL ACTION OF EXTRACTS OF THE SYMPATHETIC GAN- GLIA. | By Alien Checker es ss at Ve 471 THE DiastTatTic ACTION OF PANCREATIC JuIce. By B. K. Rachford 483 PROCEEDINGS OF THE AMERICAN PHYSIOLOGICAL SOCIETY .. . iii-xx1 TN DESO 6 oo Se ee Sb ne eee Sg eS PNB TO! eV OF: KT. geet J. J. On epinephrin, the active constituent of the suprarenal capsule, and its compounds, iii. ABEL, J. J. On the formation and com- position of highly active salts of epine- phrin, iv. Absorption of proteids, 137. ALBRO, A. H. See CHITTENDEN and ALBRO. Animal extracts, action on heart, 279, v. ACTERIA, fluorescent, xviii. Bacterial cultures, action on heart, 288. BAUMGARTEN, W._ Infarctionin the heart, 243. Bile, relation to pancreatic juice, 485. Bladder, urinary, innervation, 182. Blood, coagulation influenced by proteids, 153. ——,, cholesterin, 306. , influence of massage on corpuscles, xxi. Brain, vasomotor nerves, xil. Brown, E. W. A note on the cholesterin- esters of birds’ blood, 306. ARDIO-INHIBITORY centre, 449. CATTELL, J. McK. Instruments for the study of movement and fatigue, xe Cerebrum, development, xv. Chemotaxis, 355. CHITTENDEN, A. S. On the solution of mercury in the body-juices, vi. CHITTENDEN, R. H. A convenient form of sphygmograph, xx. CHITTENDEN, R. H. The behavior of inulin in the gastro-intestinal tract, xvii. CHITTENDEN, R. H., and A. H. ALBRO. The formation of melanins or melanin-like pigments from proteid substances, 291. CHITTENDEN, R. H., L..B. MENDEL, and Y. HENDERSON. A chemico-physiologi- cal study of certain derivatives of the proteids, 142. Cholesterin-esters, 306. Cholin, in intestine, viii. Chronoscope, xiv. CLEGHORN, A. The action of animal ex- tracts, bacterial cultures, and culture fil- trates on the mammalian heart muscle,273. CLEGHORN, A. The physiological action of extracts of the sympathetic ganglia, 471. Color, demonstration methods, xx. Coronary arteries, closure, 263. Coronary arteries, distribution, 248. Cortex, nerve cells, amceboid movements, X111. EGLUTITION, 266. Dendrites, amceboid movements, xiii. DREYER, G. P. On secretory nerves to the suprarenal capsules, 203. | Bi ebaep poco non-polarizable, xx. Epinephrin, iii, iv. Etherizing bottle, x. | ae G. W. A new chronoscope, xiv. Flicker photometer, xx. ODDARD, H. H. See Hopce and GODDARD, Xili, xix. GREENE, C. W. On the relation of the inorganic salts of blood to the automatic activity of a strip of ventricular muscle, 82. EART, accelerator nerves, 395, ix. , anzemia, 257. ——,, cause of contraction, 47. —,, conduction within, 404. , coordination, 127. ——, Engelmann’s incisions, 131. ——,, fatigue, 121, 414. , infarction, 243. ——,, inhibitory nerves, 395. XX1V Heart, normal sequence, 69. , nutrient solutions, 57, $2. ——, perfusion method, 274. , reaction to animal extracts, bacterial cultures, culture filtrates, 273, v. ——,, reflex acceleration, 429. , synchronism of ventricles, 131. ——, tone waves, 73. , voluntary control, 463. , work done, 113. HENDERSON, S. See CHITTENDEN, MEN- DEL, and HENDERSON. Hippuric acid, xiv. Hopegz, C. F., and H. H. GopparD. A new brain microtome, xix. Hopes, C. F., and H. H. GoDDARD. Pos- sible amceboid movements of the dendri- tic processes of cortical nerve cells, xiii. Howe 1, W. H. A convenient form of non-polarizable electrode, xx. Howe, W. H. On the relation of the blood to the automaticity and sequence of the heart-beat, 47. Huser, G. C. Observations on the in- nervation of the intracranial vessels, xii. Huser, G. C. A note on sensory nerve- endings in the extrinsic eye muscles of the rabbit—atypical motor-endings of Retzius, xvi. Huser, G. C. Methylene-blue preparation of sensory nerve-endings in tendon — Golgi’s tendon corpuscles, xx. Hunt, R. Direct and reflex acceleration of the mammalian heart, ix. Hunt, R. Direct and reflex acceleration of the mammalian heart, with some obser- vations on the relations of the inhibitory and accelerator nerves, 395. NFARCTION of heart, 243. Inulin, xvii. Iodine, organic compounds, xv. ACKSON, H. C. MENDEL and JACKSON, I. Jennincs, H.S. Studies on reactions to stimuli in unicellular organisms. II. The mechanism of the motor reactions of Paramecium, 311. JENNINGS, H. S. paramecium, 355. Jones, W. The chemistry of the melan- ines, 380, vi. JorpDAN, E. O. The production of fluor- escent pigment by bacteria, xvili. See Laws of chemotaxis in Lhdex. | a acid, excretion, I. ATIMER, C. W. On the modification of rigor mortis resulting from previous fatigue of the muscle, in cold-blooded animals, 29. LEE, F.S. Anew respiration apparatus, xx. LEE, F.S. A simple oncometer, xx. Lrg, F.S. The nature of muscle fatigue, xi. LEVENE, P. A. Iodine in the tissues after the administration of potassium iodide. XV. LEVENE, P. A., and I. Levin. Preliminary communication on the absorption of pro- teids, xvii. LEVIN, I. See LEVENE and LEVIN, xvii. Liquids, animal, molecular concentration and electrical conductivity, xxi. LomMBARD, W. P. An improved form of Ellis’s piston recorder, xx. Lusk, .G., and’ F. Hy PARKER Onethe maximum production of hippuric acid in rabbits, xiv. Lymph flow influenced by proteids, 162. NM ELANINS, 291, 380, vi. + MELTZER, S. J. On the causes of the orderly progress of the peri- staltic movements in the cesopha- gus, 266. MENDEL, L. B. On the paths of absorption for proteids, 137. MENDEL, L. B. On the paths of absorption from the peritoneal cavity, 342, xvi. MENDEL, L. B. See CHITTENDEN, MEN- DEL, and HENDERSON, 142. MENDEL, L. B., and H.C. JAcKson. On the excretion of kynurenic acid, I. Mental life, physiological basis, xx. Mercury, solution in body, vi. Microtome, xix. ; Mitts, W. Correlation of the functional and anatomical development of the cere- brum, xv. MITCHELL, J. K. Influence of massage upon the number of blood globules in the circulating blood, xxi. Mock, W.A. See WALLACE and MoGk, v. MiuNSTERBERG, H. The physiological basis of mental life, xx. Muscle fatigue, xi. Muscle, tonus, xxi. MuskENs, L. J. J. An instrument for measuring muscular tonicity in man, xxi. Lndlex. ERVE cells, amceboid movements, xiii. Nerve-endings, xvi. Nerve, local effects of stimulation, 411. Nerves, secretory, suprarenal, 203. Nessitr, B. On the presence of cholin and neurin in the intestinal canal during its complete obstruction, viii. Neurin, in intestine, vill. DORS, confusion with taste, xx. (Esophagus, peristalsis of, 266. Oncometer, xx. Oxygen, lack of, physiological effects, 220. j= ioe fistula, 484. Pancreatic juice, diastatic action, 483. Paramecium, affected by temperature, lack of oxygen, and poisons, 220. Paramecium, motor reactions, 311, 355. PARKER, F. H. See Lusk and PARKER, xiv: PaTRICK, G. T. W. Confusion of taste and odors, xx. Peritoneum, absorption from, 342, xvi. Proteid cleavage products, chemical nature, 168. Proteid cleavage products, their physiolog- ical effect, 142. Proteids, absorption, 137, xvii. Pigment, fluorescent, xviii. Piston-recorder, xx. PorTeErR, W. T. The codrdination of the ventricles, 127. Proceedings of the American Physiological Society, ili. Rc HFORD,B.kK. The diastatic action of pancreatic juice, 483. Respiration apparatus, xx. Respiratory centre, “ Traube ” waves, 352. Rigor caloris, 45. Rigor mortis, influenced by fatigue, etc., 20. Roop, O. N. On the flicker photometer, xx. XXV CRIPTURE, E. W. Methods of de- monstrating the physiology and psy- chology of color, xx. SCRIPTURE, E. W. New laboratory appa- ratus, Xx. Sphygmograph, xx. Spinal cord, micturition centre, 188. Spinal cord, path of bladder impulses, 197. STEWART, C. C. A simple etherizing bottle, x. STEWART, C.C. On the course of impulses to and from the cat’s bladder, 182. STEWART, G. N. Experiments on the molecular concentration and electrical conductivity of certain animal liquids, xxi. Suprarenal secretory nerves, 203. Sympathetic ganglia, action of their ex- tracts, 471. ASTE, confusion with odors, xx. Temperature, high, physiological effects, 220. Terminal arteries, 245. “ Traube ” waves, 352. | NICELLULAR organisms, reaction to stimuli, 311, 355. Urine secretion influenced by proteids, 164. gunk nerves, brain, xii. 7ALLACE, G. B: and W. A: MoeK. The action of suprarenal extract on the mammalian heart, v. Woop; EH. €., jr. Dhevorigin: ‘of sthe “Traube ” waves, 352. J ORT HOUE: W.D. On some analogies between the physiological effects of high temperature, lack of oxygen, and certain poisons, 220. at THE American Journal of Physiology. VOL._ II. NOVEMBER 1, 1898. NO. I. ON THE EXCRETION OF KYNURENIC ACID/ By LAFAYETTE B. MENDEL anp HOLMES C. JACKSON, Pu.B. [from the Sheffield Laboratory of Physiological Chemistry, Yale University. LTHOUGH it is nearly half a century since Liebig discovered kynurenic acid in the urine of the dog, and this compound has long been assigned the constitution of an oxyquinoline-carbox- ylic acid,” there is much investigation yet demanded regarding its an- tecedents and origin in the metabolic processes of the body. The occurrence of kynurenic acid in the animal organism is interesting, because with the exception of a-methylquinoline recently isolated by Aldrich and Jones® from the anal secretion of Mephitis mephitica (common American skunk), it is, so far as we recall, the only quino- line compound discovered in connection with the animal body. Furthermore, the study of kynurenic acid production is important, because of the light which it promises to throw upon the transforma- tions going on in the system, upon the constitution of the proteids from which the compound is derived, and possibly upon the physio- logical behavior of compounds like many of the alkaloids related to quinoline derivatives. The early investigations on kynurenic acid can scarcely demand detailed consideration at present, since in the absence of satisfactory 1 A preliminary account of some of the experiments described in this paper was presented at a meeting of the American Physiological Society, December 28, 1897. 2 SCHMIEDEBERG and SCHULTZEN: Ann. Chem. Pharm., 1872, clxiv, p. 155. KRETSCHY: Berichte d. deutsch. chem. Gesell., 1879, xii, p. 1673; Monatshefte fiir Chemie, 1881, ii, p- 57. 8 ALDRICH and JONES: Journal of experimental medicine, 1897, ii, p. 439. I 2 L. B. Mendel and H. C. Jackson. analytical methods the separation of uric acid (and possibly other substances) from the acid investigated was not accomplished.! It cannot be assumed that kynurenic acid completely replaces uric acid in the urine of the dog, inasmuch as the experiments of Solomin? have shown that both acids may occur together under appropriate conditions, and our own experience leads to a similar conclusion. Solomin found that although the uric acid nitrogen (determined by the Ludwig-Salkowski method) forms only a very small fraction of the total nitrogen excreted, the quantity of uric acid estimated per kilo of body weight may be as large as 0.01 gram, which corresponds with the average uric acid output per kilo in man. In the case of dogs in nitrogenous equilibrium, numerous experiments in this labo- ratory have given a considerably smaller excretion (0.003—0.004 eram per kilo).? The higher figures obtained by Solomin are per- haps attributable to the rather large quantities of proteid fed. Regarding the immediate origin of kynurenic acid, little of a posi- tive character is to be found in physiological literature. Its close relation to the diet, and its ready production after the ingestion of meat, have frequently been pointed out. Thus Schmidt® believed to have found kynurenic acid excretion to be greatest after feeding meat, and least with a bread diet, a milk diet yielding intermediate results. His figures for the various dietaries are, however, by no means comparable, since the quantities of the typical foodstuffs ingested in the three periods were not at all equivalent.6 The experiments of Schmidt and of Rosenhain,’ planned to observe the 1 Cf. for example, Vorr and RIEDERER: Zeitschrift fiir Biologie, 1865, i, p. 315. 2 SOLOMIN: Zeitschr. f. physiol. Chemie, 1897, xiii, p. 497. 8 Cf. CHITTENDEN: Journal of physiology, 1891, xii, p. 220. CHITTENDEN and GiEes: This journal, 1898, i, p. I. 4 The daily diet of the 9-kilo dog consisted of meat, 400 grams; milk, 250 c.c.; and NaCl, 10 grams (Joc. cit. p. 498). Regarding the increase in uric acid excre- tion following the ingestion of proteid, cf. SCHULTZE: Arch. f. d. ges. Physiol., 1889, xlv, p. 401; HERTER and SMITH: New York medical journal, June 4, 1892; Hop- KINS: Schaefer’s Physiology, 1898, i, p. 594. 5 ScHmiIpT: Ueber das Verhalten einiger Chinolinderivate im Thierkérper mit Riicksicht auf die Bildung von Kynurensaure. Inaugural-Dissertation. K6nigs- berg, 1884. (Jaffé’s laboratory.) 6 The dog was fed, (a) meat, 1 kilo, (4) milk, 2 litres, (c) bread, 1 pound, respec- tively, per day. 7 ROSENHAIN: Beitrage zur Kenntniss der Kynurensaurebildung im Thier- korper. Inaugural-Dissertation, Kénigsberg, 1886. (Jaffé’s laboratory.) Cf. also, R. CoHN: Zeitschr. f. physiol. Chemie, 1895, xx, p. 210. On the Excretion of Kynurenic Acid. 3 possible production of kynurenic acid from various quinoline deriva- tives } introduced directly into the organism, gave only negative results, The observations of Rosenhain and of Haagen,” in which a decrease of from thirty to fifty per cent of kynurenic acid was obtained after administration of intestinal antiseptics (¢. g. salol, thymol, naphtha- lin) suggested a connection between intestinal putrefaction and kynu- renic acid excretion. There is, however, no satisfactory evidence in these experiments that kynurenic acid has its origin in the decom- position going on in the intestine, since no data are given regarding the direct action of the drugs administered upon the food utiliza- tion and body metabolism. Thus it seems quite possible in view of our experiments that the diminished kynurenic acid excretion ob- served after naphthalin administration, for example, is to be attrib- uted to poorer absorption of the proteid fed. It may also be recalled in this connection how many drugs, e. g., antipyrin, antifebrin, sali- cylates, alcohol, exert a direct influence upon the production of uric acid; and accordingly similar specific effects may have been at work in Haagen’s experiments. Again, Baumann® observed an undimin- ished excretion of kynurenic acid in a dog in which several days’ starving and repeated doses of calomel had freed the intestine from putrefactive processes as shown by the absence of ethereal sulphates in the urine; while Haagen failed to find any decrease in kynurenic acid excretion after administering large doses of iodoform, which exerts a pronounced action upon the putrefactive processes in the intestine. In this connection we may point out that Nuttall and Thierfelder® have lately demonstrated the possible origin of aromatic oxyacids in tissue metabolism, since they have found them in the urine of animals which were entirely free from all bacteria. It seems desirable to emphasize the preceding facts because the experi- ments of Haagen have repeatedly been misinterpreted and quoted in evidence of the intestinal origin of kynurenic acid,® although Haagen 1 E. g. carbostyril, quinaldin, oxymethyl-quinoline, kynurin, antipyrin. 2 HAAGEN: Ueber den Einfluss der Darmfaulniss auf die Enstehung der Kynu- rensaure beim Hunde. Inaugural-Dissertation, Konigsberg, 1887. (Jaffé’s labo- ratory.) 3 BAUMANN: Zeitschr. f. physiol. Chemie, 1886, x, p. 131. 4 Cf. Morax: Zeitschr. f. physiol. Chemie, 1886, x, p. 321. 5 NUTTALL and THIERFELDER: Zeitschr. f. physiol. Chemie, 1895, xxi, p. 109; 1896, xxii, p. 62. 6 Cf. for example, HAUSER: Arch. f. exper. Pathol. u. Pharmakol., 1895, xxxvi, p. 3; also, NEUMEISTER: Lehrbuch der physiol. Chemie, 2te Auflage, 4 L. B. Mendel and H. C. Jackson. has carefully avoided such an interpretation of his observations.! Finally, the experiments of Capaldi? have given additional evidence against the assumed intestinal origin of kynurenic acid. In considering the immediate antecedents of kynurenic acid tyro- sin is at once suggested. The behavior of this aromatic compound with reference to its possible synthesis to oxyquinoline-carboxylic acid in the body has been investigated by Hauser® and Solomin,* both of whom failed to obtain evidence of any direct relationship between the two substances. Plan of present investigation. — The present investigation is an attempt to ascertain something more definite regarding the condi- tions which determine and modify kynurenic acid production and excretion. Unless otherwise stated, the data have been obtained with dogs. The animals were kept in suitable roomy cages which permit the separate collection of urine and faeces, and stand in a light, well-ventilated space. It was not found necessary to resort to catheterization, since the periods of observation always extended over more than one day and the animals soon became accustomed to discharge their urine with considerable regularity. The nitrogen was determined in the urine and diet by the Kjeldahl method; sugar, when present, was estimated by titration with Fehling’s or Purdy’s solution,? and kynurenic acid was found by the method of Capaldi,® which has proved very satisfactory. The product thus obtained always responded to Jaffé’s test’ and was crystalline; in a few urines a very small quantity of an amorphous substance was precipitated, 1897, p- 721. “ Eine altere, von Baumann stammende Angabe, dass die Quantitat der Kynurensaure von den Faulnissprocessen im Darm unabhangig sei, scheint durch die neueren Untersuchungen widerlegt zu sein.” 1 Cf. HAAGEN: Joc cit., p. 26, “. . . so ist es zweifelhaft, ob die nach anderen Antisepticis, besonders nach Naphthalin gefundene Verminderung der Kynurensaure auf Beschrankung der Darmfaulniss, oder ob sie nicht vielmehr auf anderen Umstanden beruht.” 2 CAPALDI: Zeitschr. f. physiol. Chemie, 1897, xxiii, p. 87. HAuseER: Arch. f. exper. Pathol. u. Pharmakol., 1895, xxxvi, p. I. SOLOMIN: Zeitschr. f. physiol. Chemie, 1897, xxiii, p. 497. Cf. J. Bishop TINGLE: American chemical journal, 1898, xx, p. 126. CAPALDI: Zeitschr. f. physiol. Chemie, 1897, xxiii, p. 92. Solomin (zbéd. p. 498 note) recovered by this method 99 per cent of 0.210 gram kynurenic acid added to urine. The following figures show average duplicates obtained by us from a dog’s urine containing small quantities: (2) 0.0852 gram, (4) 0.0872 gram. 7 JAFFE: Zeitschr. f. physiol. Chemie, 1883, vii, p. 399. 8 4 5 6 On the Excretion of Kynurentce Acid. 5 which failed to give the characteristic reaction. As an immediate test for kynurenic acid —in the urine —the bromine water reaction, first recommended by Baumann,! was frequently found useful. Bromine, as is well known, usually gives an insoluble yellow precipi- tate when added to dog’s urine, the composition of the precipitate depending upon the presence of phenol bodies, indol, or kynurenic acid. With a little experience it becomes easy to make use of the reaction in judging the relative amounts of kynurenic acid, since the latter ordinarily composes (as tetrabromkynurin”) by far the greater part of the precipitate formed. Experiments on dogs. — For these experiments commercial cracker- dust containing as an average 1.46 per cent nitrogen was obtained in large quantity and kept in glass-stoppered bottles. This constituted the carbohydrate food fed. The fat used was a good quality of lard practically free from nitrogen. The other foodstuffs used will be referred to in the protocols. The following experiments demonstrate the formation of kynu- renic acid after the ingestion of various proteids of both vegetable and animal origin. The “ dog biscuit” used was a commercial prep- _ aration containing dried meat, carbohydrates (sugar-beet), etc.; the albumin was commercial albumen e sanguine; the vegetable proteid was crystallized edestin (phytovitellin) prepared from hemp seed after the manner already described by one of us;? the Witte’s “pepton” was the widely used product made up almost entirely of proteoses (from fibrin). The latter preparation contained 14 per cent N. A mixture of inorganic salts as recommended by J. Munk# was daily added to the diet in experiment C. Various investigators have demonstrated that the proteoses and peptones may show caloric and nutritive values equivalent to those of the proteids from which they originate.® Several of our experi- ments (B, C, D) show a characteristic excretion of kynurenic acid after repeated feeding of proteoses (Witte’s “pepton”). No dis- turbances of the gastro-intestinal tract (as with ‘‘ Somatose,” p. 9) were observed with this product. 1 BAUMANN: Zeitschr. f. physiol. Chemie, 1877, i, p. 62. 2 BRIEGER: Zeitschr. f. physiol. Chemie, 1881, iv, p. 89. 3 CHITTENDEN and MENDEL: Journal of physiology, 1894, xvii, p. 49. 4 J. Munk: Virchow’s Arch. f. d. exper. Pathologie, cxxxii, p..102. ®° Cf. MuNK AND EWALD: Die Ernahrung, 1895, p. 34. L. B. Mendel and H. C. 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B. Mendel and H. C. Jackson. Io ‘Ob IPF SOOT “pAyoqaes {oy ,‘uojded ,, 8.0791 : ST ) ‘¢T “urmngys Gra ” ” a cL ” ‘Ob ‘IeF + SL “pAyoques ‘Og “urumaye 9¢0'0 ‘ymostq Jop O10'0 sweis oulexLy poy oulleaTy OY, snuijty ‘ploy ousmuAy | ‘uasorIN | ‘uoTORAY ‘Oo 9Ood ‘ANI 66 OO OOT OO OOr TOL 66 66 6'6 sory “LHOIGA M ACOG Te 0€ 62 82 Lé 9¢ SZ +2 £2 (Xo 1¢ “°W "g6g1 ‘ALVG II yf Kynurentce Acid. 207 O Ox the Excret ” »” ” ” “197eM SOP GeF fOS “pAyoqres ST ‘urmngye “Ajiep faoqzem Scy ,‘uoqded ,, SOUIM ‘Ob IRF ‘OS “pAyoqsvo : CT ‘urumngye ” ” ” ” "19}eM SOP GRE SOS “pAYyoqaeo ! oT ‘urumnqye suivis ” auou 90.1} é8T'0 9LE0 €fc0 L100 ouou 20vl} 8200 PV aulexLy jenny oUt[eATY poy sues snwyr| ‘ploy otuainudyy “UOTJOVIY ‘ad 90a ‘ANINQ) “LHOIDM AGO LT Wudy L. B. Mendel and H. C. Jackson. [2 ‘08 ” ‘Ob on : SI ” ‘CT ‘urumnaye ” sayeM {Ob Ge fg “PAyoques ‘og ‘uryETe8 ” ‘ST ” ” ‘ST ” ” pldyeM ! Op Ry ‘OS “pkyoqses ‘CT ‘urumngye suIeIs “WNIGY PV 1 ” ouoUu Lc0'0 080°0 8010 ouou +90°0 820'0 $s0'0 00¢'0 6tl0 SLT 0 auoUu 1400 6£0'0 ++0'0 Nwuorerea aulyey[V pena nN oulleyLV [etndN ploy ANDNDDANDADANNAAADAAA DOCHOHOMMNntM+MMtMowMw9 NMTMHOMOOD swueis SnuUrjyty ‘ploy otusinudyy | uas01j1Ny | uoTIROYT H JOd “ANIN ‘“LHOIAM AGO On the Excretion of Kynurentce Acid. 13 The results obtained in the preceding experiment are summar- ized in the following table, which gives the daily averages for various feeding periods. DOG E.— SUMMARY. (Giving daily averages for various feeding periods.) URINE. Foop. Nitrogen. | Kynurenic Acid. | Nitrogen. Proteid. grams May 21-23 3 0.027 : albumin, 15. 24-26 E 0.175 27, 28 6: 0.044 29-31 i 0.057 4 albumin, 40; gelatin, 40. June 1, 2 : 0.053 35 os tS: 3-5 : none 4 gelatin, S80. Gad = none ike albumin, 15. In view of the peculiar chemical and physiological behavior of gelatin in contrast to the ordinary proteids, some experiments were undertaken with this albuminoid (Dogs F, G, H). Commercial gelatin, containing 13.8 per cent N, was fed, it being eagerly eaten when mixed with water and the other food stuffs as indicated. Occasionally 1 to 2 grams of Liebig’s extract of beef were added to improve the flavor, while a mixture of inorganic salts as recommended by J. Munk! was daily given with the food. The following dog F, which had some- time previously been used in a phlorhizin experiment, had been fed very large quantities of casein on the days immediately preceding the experiment. At the conclusion of the experiment on the dog H, the animal was starved for eighteen days. Body-weight fell from 7.6 kilos to 6.0 kilos. During this period 1220 c.c. of urine, containing 107 mgr. kynurenic acid, were eliminated. 1 J. Munk: Virchow’s Arch. f. d. exper. Pathologie, cxxxii, p. 102. L. B. Mendel and H. C. Jackson. 14 “UINJIGI] PY UDAIS SVM IOJVA\ 7 [nS a a a a ea) i wn ee no re a ee ee ee a eae | ” ” Sure NT V LOL ” +” sy x” OLOL 0g 'CZ auou [enon +101 ” 9 6L0°0 So ” 9COL ‘OF » OF 9uou =. <) si ueeenenn 462 Summianytofresultsy “9 50 2) 20.) se tone sivte eis otto) meiner se a 469 PAR $f; EXPERIMENTS ON THE ACCELERATOR NERVES. Methods of investigation. — Most of the experiments described in this paper were performed on dogs, although some were made on cats and rabbits; it is to the dog, however, that the conclusions drawn are intended to apply primarily. The animals were always thoroughly anesthetized in some manner. Curare was also frequently given; in these cases an effort was made to prevent the animal’s temperature from falling during the experiment, either by warming the air (which was also saturated with aqueous vapor) or by keeping the animal on a zinc box filled with warm water. If during the course of an experiment the blood pressure became very low, intravenous injections of warm normal saline or of Ringer solution were frequently made; by means of such injections the blood pressure and heart rate could be kept near the normal for a long time, and results of value obtained from experiments which would otherwise have yielded none. The heart rate and blood pressure were recorded by the mercury manometer in the usual manner; the readings of the blood pressure given have been corrected for the weight of the solution of sodium carbonate used to prevent coagulation of the blood. In some experi- ments Hiirthle’s spring manometers, connected either with an artery Acceleration of the Mammalian Heart. 397 or with a cannula passed into one of the ventricles, were extensively used, The accelerators were usually exposed by resecting the first rib and opening the pleural cavities; such a procedure allows of a much more thorough exposure of the stellate ganglia and their branches than does the longer and more difficult method described by Schmiedeberg. Full details of the individual experiments will be given through- out the paper. TONIC ACTIVITY OF THE ACCELERATORS. The views of physiologists seem to differ widely on the question whether the accelerator nerves are in a condition of tonic activity or not. In some of the leading English* and German? text-books on physiology the statement is made that these nerves are only occa- sionally, not continually, in a condition of activity. In other text- books both of physiology and of medicine and frequently in the writings of physiologists it is either stated explicitly that these nerves are usually in a condition of activity or the assumption is made that this is the case. Other authors again do not refer to the question at all. Apparently the basis for the statement that the accelerators are not in a condition of tonic activity is the work of the Cyons.2 These physiologists, unlike von Bezold, failed to find any decrease in the heart rate in experiments on rabbits as a result of the section of the spinal cord or of the extirpation of the inferior cervical and stel- late ganglia. The later investigations of Tschirjew,* Stricker and Wagner,’ and of Timofeew,® all agree in showing that these nerves 1 WALLER: Introduction to human physiology, 3d ed., 1891, p. 107. 2 LAnboIs: Lehrbuch der Physiologie des Menschen, 7th ed., 1891, p. 807. 3 Cyon, M. and E.: Archiv f. Anat., Physiol., u. wiss. Medicin (Reichert and du Bois-Reymond), 1867, p. 406. 4 TscHIRJEW: Archiv fiir Physiologie, 1877, p. 164. 5 STRICKER and WAGNER: Sitz.-Ber. d. kais. Akad. d. Wiss., 1878, math.- naturw. Cl., 77, Abth. III, p. 111. 6 TIMOFEEW: Quoted in Centralblatt fiir Physiologie, 1889, p. 235. Timofeew did not observe any immediate effect upon the heart rate of cutting the accelera- tors; about three days after the operation. however, slowing of the heart began, and seems to have been permanent. That no immediate slowing of the heart occurred in these experiments may have been due to a reflex diminution of the tonicity of the vagi (which of itself would lead to an acceleration) resulting from 398 Red Flunt. are usually in a condition of tonic activity in rabbits as well as in dogs; moreover E. v. Cyon himself, in a recent article giving the results of experiments performed for the most part upon rabbits, speaks as though he considers these nerves to be ina condition of tonic activity.’ My own experiments, some of which have already been pub- lished,? lead me to believe that the accelerators must be considered as almost always in a condition of tonic activity, in fact much more constantly so than the cardio-inhibitory nerves. So far as I know the only question in relation to the tonic activity of the accelerators discussed by previous writers is the effect of the section of these nerves upon the rate of the beat of the ventricle; this as well as some other problems will be discussed below. Effect of the section of the accelerator nerves upon the heart rate ; resistance of the accelerator centres. —I have very little to add to what I have said in my previous paper as to the effect upon the heart rate of cutting the accelerator nerves; in the large number of additional experiments which I have made, I rarely have found a case in which they were not in a condition of tonic activity. This was true whatever the drug used for anesthesia, and when an- zsthesia was produced not by drugs but by section of the crura cerebri or by compression of the cerebrum; also whether the vagi were intact or had been divided. One criticism which may be made against some of the experiments upon the effect of cutting the accelerators should be referred to here. The operation necessary to expose thoroughly the accelerator nerves sometimes leads to a lowering of the mean blood pressure; since the work of v. Bezold? and Tschirjew it has been generally believed that a low blood pressure acts of itself as a stimulus to the centre of the operation; I have referred to this point in a previous paper (Journal of experi- mental medicine, 1897, ii, p. 160). Hering (Archiv f. d. ges. Physiol., 1895, Ix, p. 468) observed an increase in the heart rate to follow extirpation of the stellate ganglia (the vagi being intact) ; after a few days the rate returned partially to the normal. Subsequent section of the vagi caused but little increase in the heart rate. These results seem also to indicate a tonic activity of the accelerators, the acceleration immediately fol- lowing the operation probably being due to a diminution of the tonic activity of the vagi. 1 yon Cyon, E.: Archiv f. d. ges. Physiol., 1898, Ixx, p. 242. 2 Hunt: Journal of experimental medicine, 1897, ii, p. 158. 3 yon BEzo_Lp: Centralblatt f. d. med. Wissenschaften, 1866, pp. 819, 820. Acceleration of the Mammalian Fleart. 399 the accelerator nerves.! Unless this factor is taken into considera- tion the objection may be made that an abnormal stimulation of the accelerators by low blood pressure has been interpreted as tonic activity of the centre. There were however among my experiments many cases in which as a result of careful operation the blood pres- sure was high (probably very near the normal) when the accelerators were cut, and yet there was a very marked slowing of the heart. The following figures from an experiment upon a rather small dog may serve as an illustration of this point: the blood pressure was 130mm. of mercury, the heart rate 39} in 10 seconds; section of the accelerators on the right side caused the blood pressure to fall to 122 mm., while the heart rate decreased to 26! beats in 10 seconds; section of the accelerators on the left side caused no change in the heart rate, but the blood pressure fell to 95 mm. On the other hand I have ina few cases obtained results to which the above objection may properly be made. Occasionally an animal was found in which the accelerators seemed to be in a condition of maximum acceleration, that is, electrical stimulation of the nerves after their section did not cause the heart to beat more rapidly than it had been beating before their section; in all such cases the blood pressure was very low. An example of such an experiment will be given below. Section of the accelerator nerves in my experiments seldom led to a marked lowering of the blood pressure; hence the criticism can- not be made against these experiments which the Cyon brothers made against the work of von Bezold. Von Bezold cut the spinal cord and attributed the slowing of the heart which followed to the cutting off of the accelerator impulses; the Cyons attributed it to the fall of blood pressure resulting from the dilatation of the blood vessels of the abdominal organs when the spinal cord is divided. The resistance of the accelerator centre to influences which reduce or entirely abolish the irritability of other physiological centres is very marked. Thus, while the tonic activity of the cardio-inhibitory and of the vaso-motor centres is lowered by such drugs as chloral, chloroform, and ether, and by excessive amounts of curare, these drugs seem to have but little effect upon the accelerator centre. In 1 Asp (Sitz.-Ber. d. sachs. Gesellsch. d. Wiss., math.-phys. Cl., 1867, p. 173) and NAWROCKI (Beitrage z. Anat. u. Physiol., Festgabe fiir C. Ludwig, 1874, p. 220), however, consider the acceleration in these cases to be due to a diminution of the tonic activity of the vagi. 400 Reid Hunt. one experiment upon a dog, for example, after a very large amount of curare had been injected into a vein, the blood pressure fell from 83 to 22 mm. of mercury, and section of the vagi and stimulation of their peripheral ends had no effect upon the heart rate; yet section of the accelerator caused the heart rate to decrease from 29 to 23 beats in 10 seconds. In another experiment the blood pressure was 27mm.; section of the accelerators caused the heart rate to decrease from 36 to 26) in 10 seconds. The accelerators were also found to be in activity in an animal which had been under the influence of ether for five hours, and in others in which severe operations and great loss of blood had led to an extremely low blood pressure. In a few animals, however, the temperature of which had fallen very low, the accelerators were not found in tonic activity. Although section of the accelerator nerves has seldom failed to cause a slowing of the heart, yet the extent of this slowing has varied widely in the different experiments; in exceptional cases the rate after their section has been but one half or less than the previous rate. To what extent the variability of the results was due to differences in individual animals and to what extent to other causes it is impossible to state. In the case of the inhibitory fibres to the heart it is not difficult to determine the influences (drugs, etc.) which increase or diminish their tonus, and in the same animal this tonus may vary within wide limits in short periods of time; in fact the cardio-inhibitory centre seems to be in a condition of very unstable equilibrium. The tonus of the accelerator nerves is not so easily affected; I have been unable to find any constant relation between such factors, é. g., as the degree of anesthesia, the condition of the blood pressure and of the respiration, etc., and the extent of the tonus of the accelerators, nor do I know of any grounds for sup- posing that this tonus undergoes changes comparable to those of the cardio-inhibitory centre.* There are, moreover, indications that the condition of the heart itself plays a very important part in determin- ing the effect of cutting the accelerators; it is even probable that 1 The resistance of the peripheral endings of the accelerators is also remark- able. Thus stimulation of the spinal cord in the cervical region has caused a marked acceleration of the heart, although, as a result of excessively large doses of curare, the blood pressure was not affected. In the last stages of asphyxia, also, stimulation of the accelerators is effective, as has already been described by Bowditch. Even when the heart is dying and the ventricles have ceased to beat, stimulation of the accelerators will sometimes cause the latter to begin again. Cold, however, diminishes the irritability of the accelerators, as was observed by Baxt. Acceleration of the Mammalan Heart. 401 changes in this organ are of more weight in this connection than changes in the accelerator centre. Effect of section of the accelerator nerves upon the duration of systole and of diastole. —The duration of systole and diastole was deter- mined in the manner described by Hiirthle? from the curve of carotid pressure recorded by the spring manometer. As _ this method will be referred to frequently in later parts of this paper a few words will be said about it here. Hiirthle has shown that when tracings are taken with his manometers from the cavity of the left ventricle and from the aorta simultaneously the time elapsing between the appearance of the primary and the dicrotic waves of the aortic pulse curve is almost the duration of systole as deter- mined from the curve of intraventricular pressure. Of course these curves do not coincide in time; the primary elevation in the curve of aortic pressure does not appear until after the beginning of the systole of the ventricle and the dicrotic wave does not appear until a short time after the end of the systole. The former period, that is, the time elapsing between the beginning of the systole and the occurrence of the primary elevation on the curve of aortic pres- sure, corresponds to the time during which the intraventricular pressure is rising, but is not high enough to force open the semi- lunar valves (the Anspannungszeit); the latter period corresponds to the interval which elapses between the closure of the semi- lunar valves and the appearance of the dicrotic wave. Hiirthle found in a number of observations that these two periods were almost of equal length, and that therefore the duration of systole can be determined directly from the curve of aortic pressure by measur- ing the time interval between the primary and the dicrotic wave. He suggests that the duration of systole and diastole can be deter- mined in a similar manner from the curves obtained by his manom- eter from other large arteries. I have made use of the above method for determining the duration of systole and diastole in a number of experiments. A Hiirthle spring manometer was connected with one of the carotids and the pulse recorded upon the smoked paper of a Hiirthle kymograph; the speed of the latter was 100mm. per second. A cannula was also connected with the femoral artery and the blood pressure recorded by a mercury manometer in the usual manner. Ina number of experiments records of intraventricular and of aortic 1 HURTHLE: Archiv f. d. ges. Physiol., 1891, xlix, pp. 65-67. 2h 402 Reid Hunt. pressure were taken simultaneously, a spring manometer being connected with a catheter which had been passed down one carotid into the left ventricle,’ while a second manometer was connected with the other carotid. Comparison of the curves obtained in this manner sometimes showed a somewhat greater discrepancy than was to be expected from Hiirthle’s description; still the differences were so slight that the error could as a rule be disregarded. One difficulty in using the above method for determining the duration of systole and diastole should be mentioned: it not un- frequently happens that after some change in the heart rate or blood pressure (such, for example, as that following stimulation of the cardiac nerves) the dicrotic wave of the curve becomes so indistinct as to make exact measurements difficult or impossible. Most of the experiments, however, or at least parts of most of the experi- ments, gave very satisfactory results. The following experiment shows the effect upon the duration of systole and diastole of cutting the accelerator nerves. Lexperiment C.— Small dog, anesthetized by sulphate of morphine and ether; curare. Stellate ganglia exposed. Left femoral artery connected with mercury manometer ; left carotid with Hiirthle’s spring manometer. Duration in Blood Time. Heart beats in seconds of pressure laibes haan SEC 10 seconds. systole diastole mm. ° We BS 0 30 0.165 0.165 46 10 Branches of 1. stellate ganglion cut. Li 0 295 0.165— 0.170 46 = 0 28+ 0.160— 0.190 42 32— 0 28 0.160+ 0.185 34 10 Branches of r. stellate ganglion cut. 20 23 0.160+- 0.180 25 0.165 0.195 30 26+- 0.175 0.195 33 0 0.205 0.225 30 214 0.230 0.245 34 204? 0.235+- 0.270— 32 35 0.250 0.270+- 31 1 A silver male catheter was found most convenient for this purpose. * The maximum heart rate caused by stimulation of the accelerators in this experiment was 31 beats in Io seconds, 7. e., but very slightly greater than the heart rate before the nerves were divided. This was, therefore, one of the cases in which the accelerators were in a condition of almost maximal acceleration when they were cut. : Acceleration of the Mammatan ffeart. 403 The results obtained in the above experiment are better expressed in the form of a curve (Fig. 1) in which the ordinates represent the duration in 0.05 of a second of the systole and diastole of a single heart-beat at the end of «each thirty seconds and the abscissee represent periods of thirty seconds. Parts of the tracing taken with the Hiirthle manometer are re- produced in Fig. 2. Inspection of the above table and curves shows that in this experiment section of the accel- Ficuret. Experiment C. Accelerator nerves erators caused both systole and cut at x. .S shows the duration of systole, D that of diastole in 5 hundredths of a second. The abscissz represent periods prolongation of the former be- of 30 seconds. ing relatively (2. ¢. as compared with the previous rate) slightly greater than that of the latter. In nearly all of my experiments results similar to these were obtained ; usually however the prolongation of the systole, though a con- OE ce ees diastole to be prolonged, the FrGcurer 2. Two thirds the original size. Experiment C. Upper tracing before, lower tracing 2 minutes after, section of accelerators on right side. Time in intervals of 0.2 and o.or seconds. stant result of cutting the accelerators, was not so marked as in this case. The above experiment and the one quoted on p. 399, illustrate a point which I discussed in my earlier paper, namely, that section of 404 Red Hunt. the accelerator nerves on the right side usually causes a more marked slowing than section on the left side.’ Effect of section of the accelerator nerves upon the conduction of im- pulses from auricle to ventricle. — At least two experiments have been described which tend to show that the accelerator nerves contain fibres which affect especially the conduction of impulses from auricle to ventricle. Certain observations have led me to think that these fibres are, under some circumstances at least, in tonic activity; or BL ii i i ee ae FIGURE 3. Two fifths original size. Ex- FIGURE 4. Two fifths original size. Part of periment J. Curve of blood pressure the curve of Experiment J following before the accelerators were cut. JZ Z, Figure 3. Taken 44 minutes after the line of atmospheric pressure. Time in branches of the right stellate ganglion intervals of one second. were cut. perhaps it would be better simply to say that the tonic activity of the accelerators affects the conduction of impulses from auricle to ventricle as well as the rate of the heart. The following is one of a number of experiments from which this conclusion is drawn. 1 In most of my experiments in which the accelerators were stimulated on both the left and right sides, the latter caused greater acceleration than the former. Stricker and Wagner (of. cz¢., p. 10g) made the same observation, but Frangois- Franck (Travaux du laboratoire de Marey, 1878-1879, iv, p. 83) failed to find any such differences in all but two of his experiments, —in these stimulation of the right accelerators caused a greater effect. These observations show that the dis- tribution of the nerves varies in different individuals ; but from my experiments I am convinced that, as a rule, more accelerator fibres pass to the heart on the right than on the left side. 2 BayLiss and STARLING: Journal of physiology, 1892, xiii, p. 407; Hunr and HARRINGTON : Journal of experimental medicine, 1897, ii, p. 725. In the present series of experiments I have often observed results similar to those described by Bayliss and Starling, namely, that stimulation of the accelerators after these nerves had been stimulated a number of times caused an acceleration of the auricles, but that the ventricles frequently failed to follow all of the auticular beats. SS Acceleration of the Mammahan Fleart. 405 LEixperiment J. — Bitch, weighing 22.5 kilo. Anesthesia produced by 4.8 grams acetone chloroform (trichloride of acetonic acid) and a little ether. Curare. Vagi cut. A catheter had been passed down one carotid into the left ventricle and a record of intraventricular pressure taken. ‘The right stellate ganglion and its branches were exposed. ‘The blood pressure was 57 mm. of mercury ; the pulse rate 30 in 1o seconds. The accompanying curves (Figs. 3 and 4) show the effect upon the heart rate of cutting the accelerator nerves on the right side. The heart had been beating very regularly before the accelerators were cut; soon after they were cut there began to appear, occasion- ally, beats of unusual length. The number of these long beats in- creased very rapidly until finally there were periods of several seconds’ duration in which the heart was beating at but one half its previous rate. The record of intraventricular pressure showed that this irreg- ularity of the heart resulted from the ‘“ dropping” of some of the ventricular beats; that is, the duration of one of these long beats was just twice that of a normal beat. In some cases there was a slight, sudden rise of short duration of the intraventricular pressure during these long beats; this probably was due to the auricular beat.1 The vagi had been divided in this experiment so that the change in the heart rate cannot be regarded as a reflex effect nor can it be attributed to changes in the blood pressure, for none occurred. The auricular beats were not recorded, and therefore the follow- ing explanation of this irregularity cannot be considered as estab- lished with absolute certainty. But all observations seem to agree in showing that the ventricle when it suddenly begins to beat at one half its previous rate is responding to but every second auricular beat; the most probable explanation of the cardiac irregularity in the above experiment would seem to be that section of the acceler- ators had caused a diminution of the irritability of the muscle fibres connecting the auricle and ventricle. Of course another explanation may be offered, namely, that section of the accelerators had simply diminished the irritability of the ventricle so that it was unable to respond to all the impulses reaching it from the auricles. I think however that in the light of the work of Gaskell, MacWilliam, and Bayliss and Starling upon the conduction of impulses from the auricle to the ventricle, the former explanation is the more probable. 1 Cf. HURTHLE: Archiv f. d. ges. Physiol., 1891, xlix, p. 55. 406 Red unt. In other experiments upon dogs and cats and in one upon an opossum similar irregularities of the heart occurred after section of the accelerators, but as a rule they were less marked than in the ex- periment just described; in some, for example, a ventricular beat was dropped only occasionally. It is interesting that in all these cases it was section of the accelerators on the right side which led to these irregularities. Inasmuch as the mammalian heart will continue under proper conditions to beat with great regularity for hours after it is entirely separated from the central nervous system, the question may be raised why in the above experiments section of the accelerators caused it to beat irregularly. It is quite probable that in these cases the irritabil- ity of the heart had been decreased in some manner to such an ex- tent that the stimulus afforded by the accelerators was necessary to maintain regular cardiac action. In experiment J, for example, there were a number of influences which may have affected the heart. Thus the anesthetic employed, acetone chloroform, seems to cause a loss of irritability of the heart, for in animals to which this drug has been given the heart rate is usually slow and the beat weak * after section of all the cardiac nerves; moreover, the blood pressure was low and perhaps the heart had been injured by the sound passed into the left ventricle. In the other experiments also in which section of the accelerators led to cardiac irregularity there were conditions which make it prob- able that the irritability of the heart was abnormally low. If the explanation offered above is the correct one, we should expect stimulation of the accelerators to cause the cardiac irregular- ity to disappear, especially as Bayliss and Starling? have shown that stimulation of these nerves makes the transmission of impulses from auricle to ventricle more easy; as a matter of fact electrical stimula- tion of the accelerators not only caused an increase of the heart rate but an entire disappearance of the irregularity. The latter also followed the intravenous injection of hot normal saline solution, an agent which undoubtedly increases irritability of the heart. It is also interesting to note that in some of the exceptional cases in which section of the accelerators showed that they were not in tonic activity the heart was irregular both before and after all the cardiac nerves were divided. 1 The injurious action of acetone chloroform upon the heart may be due to im- purities which are usually found in specimens of this drug. 2 BAYLIss and STARLING: Journal of physiology, 1892, xiii, p. 414. Acceleration of the Mammathan Freart. 407 From such observations and considerations as the above I think the conclusion may safely be drawn that at times the tonic activity of the accelerators is very important for the regular action of the heart. FATIGUE OF THE ACCELERATOR NERVES. The statement is frequently made that the accelerator nerves are not easily fatigued, but the only basis for this assertion with which I am acquainted is an observation by Bohm.’ This investigator stated that he had stimulated the accelerators for two minutes with- out observing any indication of fatigue and expressed a doubt as to whether they can be fatigued at all. When it is remembered that even in cases of maximal acceleration the heart rate is rarely doubled, it does not seem reasonable to suppose that if any fatigue did occur it would be observed when these nerves were stimulated for so short a period as two minutes. That these nerves are not easily fatigued when subjected to a moderate stimulation follows from the fact that they are in a condi- tion of tonic activity; on the other hand it will be shown that fatigue may readily occur when the nerves are subjected to strong electrical stimulation. My experiments bearing on this point will be discussed in two parts; the first will be entirely descriptive, in the second an effort will be made to ascertain so far as possible where the fatigue occurs. Changes in the rate of the heart-beat. — When the accelerator nerves are stimulated continuously for some time (ten minutes for example) the heart does not remain long at the maximum rate but shows a ten- dency to return to the rate at which it was beating before the stimula- tion began. If these changes in the heart rate be expressed in the form of a curve in which the abscisse represent the time and the or- dinates the number of heart-beats in a given time (e. g. ten seconds) it will be found that as a rule the decrease in the heart rate occurs in two periods. There is first a comparatively rapid fall in the curve; this is followed by a much longer period in which the descent is very slight. Under some circumstances — these being determined by the condition of the heart and nerves, the character of the stim- ulus employed, etc. —the curve is continued in an almost straight line during the second period; in other words, the heart continues beating throughout this period at nearly a constant rate. The dura- 1 Boum: Archiv f. exper. Pathol. u. Pharmakol., 1875, iv, p. 275. 408 Red Hunt. tion of these two periods is very variable; occasionally they are absent altogether, there being in this case either no decrease at all in the heart rate (if the stimulation is of comparatively short duration) or the heart rate may decrease regularly; 7. ¢., the curve becomes an almost straight line. The following experiment and curve show the usual result of stimulating the accelerators continuously for some time. ea Ti ase On ee Ea cadieaacls LNG ses (ed 6a Kee Pe FIGURE 5. Experiment 117. Stimulation of the accelerator * ; nerves for 9} minutes (x to x). The ordinatesrepresent 10 Fig. ee the number of heart-beats in 10 seconds; the abscissz periods of one minute. Curves similar to the above are nearly always obtained when the accelerators are stimulated, whatever the condition of the heart or the strength or character of the stimulus employed. The same form of curve is also obtained in whatever part of their course the nerve fibres are stimulated, whether in the spinal cord, the rami communicantes, the annulus of Vieussens, or the small nerves running directly from the inferior cervical or the stel- late ganglion to the cardiac plexus. When the same nerve is stimu- lated a number of times in succession there is a gradual lowering of the height of the curve, but the form remains the same; the latent period also becomes longer with the successive stimulations. The above results recall those obtained when the peripheral end of the vagus is stimulated: in this case the heart, after a short period during which it is stopped or slowed, tends to return partially to its previous rate; it often reaches a constant rate, at which it continues to beat for hours.’ Martin? found that when the isolated mammalian heart is warmed the beat is at first increased in frequency, but presently the heart returns partially to the former frequency and continues beating at this slower rate; in fact, if his results were Experiment 117. Small dog. Morphine and ether. Accelerators and vagi cut. The ac- celerators had been stimulated a number of times with results very similar to those shown 26 ' See Houcu: Journal of physiology, 1895, xviii, p. 176; also LAULANIE > Comptes rendus de l’académie des sciences, 1889, cix, p. 408. 2 MARTIN: Physiological papers, 1895, p. 104. Acceleration of the Mammalian Heart. 409 expressed as a curve, the latter would have very nearly the same form as that obtained when the accelerator nerves are stimulated. Martin also called attention to the fact that similar changes in the heart rate are observed in some cases of fever — that is, the rate tends to return to the normal although the temperature remains the same. When the accelerators are stimulated in the course of a long continued stimulation of the vagus, the curve of fatigue is the same as when they are stimulated alone. Effect of the strength of the stimulus upon the course of fatigue. — The effect upon the heart in any given case of stimulating the accelerators with currents of varying strength and rate seems to be determined largely by the condition of the heart and nerves at the time of stimulation. If the heart is vigorous and the nerves have not been stimulated often it may be said that in general the stronger the current, the longer continued is the phase of maximal acceleration ; if on the other hand the heart is not very vigorous or the nerves have been stimulated a number of times, fatigue occurs more quickly with a strong than with a weak current although the maximal rate reached by the heart may be the same in both cases. Also asa rule the stronger the stimulus the higher is the level at which the heart continues to beat during the stimulation. It is interesting that a slight initial decrease in the heart rate occurs when the accelerators are stimulated with a current too weak to cause a maximum acceleration; this resembles the ‘escape ”’ ob- served by Hough when slight slowing was caused by stimulation of the peripheral end of the vagus. Effect of the rate of stimulation upon the fatigue of the accelerators. — The rate of the stimuli applied to the accelerators seems to have a greater effect upon the course of fatigue than does their strength. This was shown in many experiments in which the primary circuit of the du Bois-Reymond induction coil was interrupted by Ludwig’s Schlagwahler or by an “ oscillating rod” kept in vibration by an electromagnet; the number of stimuli per second could be varied within wide limits by either of these instruments. The following experiment shows how much more quickly fatigue is produced with a rapid rate of stimulation than with a slower rate. 1 An experiment illustrating this is given on pages 174 and 175 of my article in the Journal of experimental medicine, 1897, ii. AIO Reid Hunt. o Experiment 187.— Dog. Morphine and ether. Curare. Spinal cord cut in mid cervical region. Branches of stellate ganglia divided. The result of stimulating the accelerators is shown in the following table. Time. Heart-beats Time. Heart-beats | Hrs. min. in 10 seconds. | Hrs. min. in Io seconds. Caer cal ll 55 Secondary coill0cm. 17+ R. annulus stimulated ; 14— ce primary circuit inter- 213+ 20+ rupted 5+ times per 203 56 20+ second ;_ secondary 19= Coil 5 cm. — coil 13 cm. 163 — 42 —! 20+ Stimulus off annulus. 163 59 20— a Coil 0 cm. — 164— -— 164 20 16 4 2 20 : ie R. annulus stim.; 24 12- s stimull per seconds ei in coil 0 cm. 21 stimuli per second ; — secondary coil 13 cm. ane 18+ 17— 4 17} — 17 In the above experiment no diminution of the acceleration occurred when the accelerators were stimulated with 2} stimuli per second, whereas 5-++ stimuli per second caused such a diminu- tion to occur very quickly. In almost every experiment there was found a rate at which the accelerators could be stimulated for some time with but little decrease in the acceleration. This, which may be called the opti- mum rate, varied greatly in different experiments and seemed to be determined by the condition of the heart and nerves. Thus in one experiment stimulation of the right annulus with an ordinary du Bois- Reymond coil in which the primary circuit was interrupted by the Neef hammer, caused the heart rate to increase from 23 to 29 beats in 10 seconds; but in the course of three minutes during which the stimulation continued the rate decreased to 24}+: after a few minutes’ rest the annulus was again stimulated but now the primary circuit of the coil was interrupted by the Schlagwdéhler at the rate of 6 times per second; the rate of the heart increased from 22 to 294 beats in 10 seconds; after three minutes’ stimulation the rate was 29, showing that no fatigue had occurred. 1 The dash (—) indicates that the heart-beats were not counted for ro seconds. Acceleration of the Mammatan Heart. AII Duration of systole and diastole in fatigue. — A number of experi- ments was made to determine whether both systole and diastole became longer when fatigue occurred in the course of a prolonged stimulation of the accelerators; it was found that they were longer, ‘and that the prolongation occurred to about the same extent in both cases, so that the curve representing these changes were almost parallel. It is interesting to compare these results with those observed when the heart is ‘‘ escaping”’ during a prolonged stimulation of the vagus. When the peripheral end of the vagus is stimulated the diastole is always prolonged; as a rule the systole is also prolonged, but to a less extent; but while the diastole becomes shorter as the heart “escapes” to a more rapid rate, the systole remains about the same length throughout the stimulation. Thus during the “ escape” of the heart from slowing as well as during the slowing caused by stimulation of the vagus it is the diastole which is most easily affected. On the other hand when the heart is slowed by section of the accelerators or when it is accelerated by the stimulation of these nerves or when fatigue occurs during their stimulation, both systole and diastole are affected; in fact, it seems almost as if one was affected through the other. If however the accelerators are stim- ulated when the heart is beating very slowly, as a result for example of stimulation of the vagus, then shortening of the diastole may occur before that of the systole; this point will be referred to later. Local effects in the nerve. — It became evident very early in the investigation of the cause of the decrease in the heart rate during a prolonged stimulation of the accelerators that two factors are involved; first, a local action upon the nerve at the point stimulated, and, secondly, an effect upon the heart itself or upon the nerve end- ings in the heart. The latter effect is the more interesting in this ‘connection, but it is necessary to consider the former or a serious error will be introduced into the experiment. Local effect upon the nerve at the point of stimulation.— Howell has shown that when certain nerves, especially some of the non-medul- lated variety, are stimulated with the faradic current for some time there occurs a loss of irritability at the point of stimulation; he called this loss of irritability “stimulation fatigue,’ without how- ever expressing any opinion as to its real nature. 1 HOWELL, BUDGETT, and LEONARD: Journal of physiology, 1894, xvi, p. 311. 412 Reid FTunt. This local effect of the current upon the nerve is easily demon- strated in the case of the accelerators. If the stimulating electrodes be held on one point of the nerve until the heart rate has begun to decrease and they then be moved a few millimetres nearer the heart, a second increase in the heart rate occurs; this, like the first acceler- ation, continues a short time and then the heart rate again decreases. This experiment may be repeated a number of times. The following experiment will serve to illustrate this point. Experiment 179. Dog. Morphine and ether; curare. Accelerators and vagi cut. Blood pressure 82 mm. Time. Heart-beats | Time. Heart-beats Hrs. min. sec. in Io seconds. | Hrs. min. sec. in 10 seconds. a AOr SO 283 26 20 36 Stimulation of r. an- 27 344 nulus begun; sec- Electrodes moved ondary coil 17 cm. slightly. 40 32+ 20 394 21 40+ 28 374 22 373+ 30 34 25 325 Electrodes moved 26 31 slightly. Electrodes moved | 20 383 slightly. In the above experiment the electrodes were moved towards the heart, but the same result is obtained when they are moved farther away from the heart,-—a fact which shows that the conductivity of the nerve fibres at the point of stimulation is not lost. If instead of moving the electrodes to a different part of the nerve after the acceleration has begun to decrease, the strength of the stimulating current suddenly be increased, the pulse rate may again be accelerated for a short time. By increasing the strength of the stimulus repeatedly at short intervals the heart may be kept beating at the maximal rate for some time. Effect of stimulating the accelerators in different parts of their course. — Howell has shown that it is in the non-medullated nerve fibres that this local loss of irritability most often occurs, while the medullated fibres are less subject to it. In view of these results it is of interest to compare the effects of stimulating the accelerator nerves in that part of their course in which they are medullated with those observed when they are stimulated at a point where they are non- medullated. According to the prevailing view, these nerve fibres Acceleration of the Mammatan Heart. 413 belong to the medullated variety while passing from the spinal cord through the rami communicantes to the stellate, inferior cervical, and perhaps other ganglia of the sympathetic system; from these ganglia they are continued as non-medullated fibres to the cardiac plexus. According to this view, therefore, in order to compare the effects of stimulating the medullated and non-medullated accelerator fibres we have only to stimulate the spinal cord or the rami communicantes on the one hand and the small nerves passing from the annulus and the inferior cervical ganglion on the other. The annulus itself probably contains both medullated and non-medullated fibres. It has been already stated that the form of the curves of fatigue was the same in whatever part of their course the nerves were stim- ulated; it is impossible in most of the experiments, however, to state whether the fatigue occurred in the heart or was a local effect upon the nerve, as at the time no special attention was given to this point. The following experiment indicates, however, that the local effect upon the nerves varies according to the part of the course in which they are stimulated. Lexperiment 125. Dog. Morphineand ether. Right accelerators cut. Vagi intact. The second thoracic ramus communicans had been stimulated a number of times, during and probably as a result of which the heart rate had decreased from 34 to 22 beats in ro seconds. The right annulus was now stimulated for the first time, with the result shown in the following table. Time. Heart-beats Time. Heart-beats Hrs. min. sec. in 10 seconds. Hrs. min. sec. in 10 seconds. 124030 224— 43 264 R. annulus coil 16cm. 46 25 264+ 40 Current turned to 2d 35— ram. com, 35+ 47 36 Soa 48 Sass 41 30 31— 49 33+ 42 27+ 52 40 304 30 263+ Thus during a stimulation of the right annulus continuing 6 min- utes the heart rate fell to 25 beats in to seconds, while during a stimulation of the ramus communicans of the same duration it fell to but 303 and this notwithstanding the fact that the latter nerve had been stimulated a number of times while the former was stimulated ATA Reid Hunt. for the first time and that also a much larger number of accelerator fibres was doubtless stimulated when the current was applied to the annulus than when the ramus was stimulated. The explanation of the above difference is probably to be found in the fact that the nerve fibres in the ramus are medullated while many at least of those in the annulus are non-medullated.* There is also a difference in the rapidity with which the different accelerator nerve fibres recover their irritability after stimulation. Thus in the above experiment stimulation of the annulus after 20 minutes’ rest caused an acceleration of from 23 to but 26 beats in 10 seconds, whereas stimulation of the second ramus after a rest of 20 minutes caused the heart rate to increase to 35 in 10 seconds. Fatigue occurring in the heart as a result of stimulating the acceler- ators. —While the experiment described above shows that the de- crease in the heart rate occurring after a prolonged stimulation of the accelerators is due in part to a local action upon the nerve fibres at the point of stimulation, there is very clear evidence that the heart itself can be fatigued by excessive stimulation of these nerves. That the heart is not easily fatigued by stimulation of the accelerators follows from the fact that they are usually in a condition of tonic activity ; it was also shown above that moderate electrical stimulation, especially stimulation with a weak, slowly interrupted current, does not easily cause fatigue. If, however, the electrical stimulation is excessive or often repeated, and especially if the heart has been subjected to injurious influences, distinct indications of fatigue in the heart? occur, as will be shown below. It is very probable that 1 Similar results were obtained in a few experiments in which the spinal cord and the accelerator nerves were stimulated; most of these experiments, however, were complicated by an unexpected factor. Ina number in which the spinal cord had been divided in the cervical region not only was the acceleration from stimula- tion of the cord and of the accelerators very slight, but fatigue occurred with extraordinary rapidity. The section of the cord seemed to reduce the irritability not only of the accelerator fibres in the cord, but also of those in the annulus and the branches of the stellate ganglia. Munk and Schultz (Archiv fiir Physiologie, 1898, p. 307) have observed a similar loss of irritability in the phrenic nerve after section of the spinal cord ; one explanation which they suggest, with considerable reserve, is that the irritability of the nerve was affected by the changes in the cir- culation following section of the cord. It is doubtful whether this explanation would hold for the accelerators; for, as has been pointed out above, these nerves are not easily affected by changes in the blood pressure. 2 The expression “fatigue in the heart” is meant to include either fatigue of the endings of the accelerator nerves or of the cardiac muscle, or of both; it is by no means easy in many cases to distinguish between the two. Acceleration of the Mammatan Fleart. 415 the same thing occurs whenever the accelerators are thrown into excessive action by causes originating in the body itself. Effect of repeated stimulations of the accelerators upon the pulse rate, irritability of the heart, etc.— After repeated stimulation of the accel- erators the pulse rate very often decreases. This decrease frequently occurs in cases where the vagi have been cut and therefore it can- not always be referred to an increased influence of the inhibitory nerves; nor can it in many cases be due to changes in the blood pressure or to a decrease in the animal’s temperature, for it takes place when no such changes occur. Moreover in many experiments no change in the heart rate occurs during periods of rest of the same duration as the periods of stimulation. From such considerations as these I think the conclusion must be drawn that the slowing of the heart following stimulation of the accelerators is due to fatigue of the heart itself. The following data may serve as an illustration of the extent to which the heart may be slowed as a result of repeated and lorg continued stimulation of the accelerators. The experiment was per- formed upon a dog anesthetized by morphine and ether. After section of the vagi and accelerators the heart rate was 40+ in 10 seconds. The accelerators were stimulated 39 minutes; soon after the stimulation the rate was 34 in 10 seconds and it remained at this level during the period of rest which followed the stimulation. After a second stimulation of the accelerators continuing 9 minutes the heart was beating at the rate of 28 in 10 seconds and continued at this rate during a period of 5 minutes’ rest. The nerves were now stimulated a third time. The stimulation continued only five min- utes, but after it the rate sank to 22}. During this entire period the blood pressure had fallen very slightly, only about 10 mm. of mercury. Results similar to the above are often observed, but it is not always so easy to exclude factors other than that of the stimulation of the accelerators. That the irritability of the heart is lowered by long continued stimulations of the accelerators is shown by such an experiment as the following; the animal used was a dog anesthetized by morphine and ether. Early in the experiment a small branch of the right annulus was stimulated for 20 seconds; the heart rate increased from 20 to 33 in 10 seconds. The ventral limb of the right annulus was now stimulated for 21 minutes, the position of the electrodes upon 416 Reid Hunt. the nerve being frequently changed. After the cessation of the stimulation the small branch of the annulus mentioned above was stimulated again with the same strength of current as before: the heart rate increased from 20 to but 25} in 10 seconds. The only plausible explanation of the slight effect caused by the second stim- ulation of this small nerve is that the irritability of the heart had been diminished by the long continued stimulation of the annulus. Numerous other cases could be quoted in which stimulation of the annulus or of the small branches passing from the inferior cer- vical ganglion had but little effect upon the heart after repeated or long continued stimulation of the spinal cord or of those rami communicantes through which the accelerator fibres pass. Another indication that stimulation of the accelerators causes a diminution of the irritability of the heart is found in the study of the effects of the intravenous injection of extracts of the suprarenal gland. As is well known, the injection of such extracts into an animal in which all the cardiac nerves have been cut leads to a great acceleration of the heart-beat; in a number of my experiments the maximum rate reached after such an injection coincided almost exactly with the maximum rate resulting from stimulation of the accelerators. Small quantities of the extract may be injected a number of times in succession without any diminution of the effect. If, however, the accelerators be stimulated for some time with a strong current between two such injections, it is found that the second injection has less effect than the first one. Thus, early in one experiment stimulation of the right annulus caused an accelera- tion from 313 to 40} beats in 10 seconds, while the injection of an aqueous extract of the suprarenal of a dog caused the heart rate to increase to 39. The accelerators were now stimulated for about an hour, and then after a period of rest they were again stimulated for a short time; the result of the second stimulation’ was that the heart rate increased from 31 to 35} beats in 10 seconds; the injection of the same quantity of the suprarenal extract as above caused the heart rate to increase to 35.! 1 The interpretation of these results will depend upon the view held as to the action of suprarenal extracts upon the heart. If we accept the view of v. Cyon (Archiv f. d. ges. Physiol., 1898, Ixxii, p. 371) that these extracts act upon the endings of the accelerator nerves, these experiments can only be regarded as evi- dence that the stimulation of the accelerators caused fatigue of the endings of these nerves; if, however, we adopt the view of Cleghorn (This journal, 1899, ii. p. 281), based upon experiments with the isolated apex of the dog’s heart, that the Acceleration of the Mammalian Heart. 417 In another experiment suprarenal extract caused a marked accel- eration before the accelerators were stimulated; after the nerves were stimulated until they ceased to have any effect upon the heart another injection of the suprarenal extract was made, but with entirely negative results.1 At times on the other hand the injection of suprarenal extract seems to restore the influence of the accelera- tors over the heart. Two other results of repeated stimulations of the accelerators which probably indicate a loss of irritability of the heart may be mentioned: first, the latent period of acceleration is prolonged, and secondly, the after-effect of the stimulation is much less marked, 2. ¢., the heart returns much more quickly to its previous rate after stimu- lation of the accelerators.2, This rapid return of the heart to the action of these extracts is upon the cardiac muscle itself, then I think my experi- ments can be regarded as evidence that the heart muscle is fatigued by stimulation of the accelerators. 1 There are other points of similarity between the action of the accelerators and suprarenal extracts. Thus it has been my experience that when stimulation of the former from any cause failed to cause an acceleration of the heart, injection of the latter was also without effect. The effect of repeating the injections at short intervals is, moreover, very much like that of moving the electrodes slightly during along continued stimulation of the nerves; after each injection, as after each shifting of the electrodes, there is a fresh increase in the heart rate. The heart can be kept beating at the maximum rate for some time in this manner. It is also interesting to note in this connection that it was impossible to obtain any summation of the effect of the maximal stimulation of the accelerators and of the injection of suprarenal extracts ; thus, when the injection was made simultane- ously with the stimulation, the maximum rate of the heart was no greater than when it was made alone or when the accelerators were stimulated alone. If, how- ever, the stimulus applied to the accelerators was sub-maximal, the injection of suprarenal extract would cause the heart rate to reach the same level as when the stimulus was maximal or when a considerable amount of extract was injected alone. There seemed to be a limit to the rate to which the heart could be accel- erated (just as in cases of Basedow’s disease, fever is said to cause no farther acceleration of the heart); in these experiments this limit was the same for the injection of suprarenal extract and for the electrical stimulation of the accelerators. It may be added that in one experiment injection of warm Ringer solution caused the same acceleration as did stimulation of the spinal cord and of the annulus. Bohm states that in cats certain drugs cause a greater increase in the heart rate than does stimulation of the accelerators, and that therefore the acceleration of the latter case is not maximal; it should be noted, however, that these comparisons were not made upon the same animal. 2 Boum (Archiy f. exper. Pathol. u. Pharmakol , 1875, iv, p. 275) made a similar observation, but did not offer any explanation of it. led — 7 418 Red Hunt. previous rate is especially marked if the irritability of the heart has been reduced by the action of cold as well as by repeated stimulation of the accelerators. Stimulation of the vagus after repeated stimulation of the accelerators. —J] think further evidence of fatigue occurring in the heart as a result of stimulating the accelerators is to be found in the comparison of the effects of stimulating the vagus before and after repeated stimula- tions of the accelerators. We know from the experiments of Hough* (and I have had many opportunities of confirming his results) that the less vigorous the heart the greater is the effect of the stimulation of the vagus. Hence if stimulation of the accelerators does reduce the vigor of the heart we should expect to find the effect of the vagus increased after a long continued stimulation of these nerves; experi- ment shows this to be the case. This result is shown in a striking manner if, as was the case in the following experiment, the acceler- ators are stimulated during a prolonged stimulation of the vagus. Experiment of July 2d. Bitch. Morphine and ether; curare. Vagi and accelerators cut. The accelerators had been stimulated a number of times with the result that the maximum acceleration was less with each successive stimulation. The following table shows that the effect of the vagus became greater after stimulation of the accelerators. Time. Heart-beats Time. Heart-beats Hrs. min. sec. in 1o seconds. | Hrs. min. sec. in ro seconds. 272 40 24 364 Stimulation of r. vagus 25 31 begun; 13. stimuli Stimulus off annulus. per second ; second- 26 24+ ary coil 0 cm. + «26)) 0 24 10 27 30 21 20 23+ R. annulus stimulated; 23 : ; 25 secondary coil. Stimulation of r. annu- 27 10 243+ lus begun; second- 98 231 ary coil 17 cm. Stimulus off annulus. ; 10 324 29 18 20 41 Stimulus off vagus. 30 413 35 38 In this experiment the slowing of the heart caused by stimulation of the vagus became greater after each stimulation of the accelera- tors. That this was due to a change in the heart resulting from the stimulation of the accelerators is shown by the fact that when 1 HouGuH: Journal of physiology, 1895, xviii, p. 162. Acceleration of the Mammatan Fleart. 419 the vagus was stimulated alone the heart rate tended to return to the normal rather than to become slower; an indication of this tendency is shown in the first part of the above table. In another experiment very similar to the above, stimulation of the vagus caused the heart to be slowed from 27 to 173 beats in Io seconds; after a stimulation of the accelerators of but 28 seconds’ duration stimulation of the vagus caused the heart to be slowed to I1 beats in 10 seconds. It should be added that in order to show the greater efficiency of the stimulation of the vagus after stimula- tion of the accelerators the former must follow the latter imme- diately, that is, the diminution of the irritability of the heart is of short duration unless the stimulation of the accelerators is continued for a long time. If the vagi are intact and in tonic activity the slowing following stimulation of the accelerators seems to be due in part to an increased influence of the vagi over the heart, for the slowing occurs much more quickly in experiments in which the vagi are intact than in those in which they have been divided. Such experiments as those just described seem to me to be of special interest and importance since they seem to show very clearly that stimulation of the accelerators causes diminished irritability of the cardiac muscle and not simply fatigue of the endings of the accelerator nerves; it is very difficult in most cases in which there are indications of fatigue in the heart to distinguish between these two possibilities. Effect of some drugs upon fatigue of the accelerators. — The results of a few observations which I have made incidentally upon the effect of two or three drugs upon the occurrence of fatigue from stimula- tion of the accelerators may be referred to here. After the intravenous injection of large doses of atropine and curare stimulation of the accelerators causes very rapid fatigue; whereas after the injection of sodium iodide ' the fatigue is much less marked and the same is apparently the case after the injection of extracts of the suprarenal glands. The following experiment illustrates the effect of a large dose of curare and of the injection of sodium iodide. 1 The use of sodium iodide was suggested to me by the work of Barbéra (Archiv f. d. ges. Physiol., 1897, Ixviii, p. 436) and v. Cyon (/ézd., 1898, Ixii, p. 176), who found that this salt acts as a powerful stimulus to the vasomotor and accelerator nerves; it also increases the irritability of these nerves while markedly lowering that of the vagi. 420 Red Huni. Experiment 148. Dog. Morphine and ether. A very large amount of curare was injected into the femoral vein as a result of which the blood pres- sure had fallen from 83 to 20mm. of mercury: it rose later to 22mm. ‘The accelerators on the right side had been divided. ‘The results are given in the following table. Time. Heart-beat in Blood Hrs. min. ro seconds. pressure, 1 50 21+ 22 R. annulus stim. for 70 sec., coil 14 cm. 33 32 30 254 23 (Record not good for 20 ? fy seconds.) Stimulus off annulus. 19 53 20 21 5.2 ccm. 20% sol. Nal in- jected into femoral vein. 54 20 132 R. annulus stim. as above. 29-4. 19 Stim. off annulus. 56 28 The experiment was continued for 25 minutes, during which the accelerators were stimulated a number of times with results very similar to the above, 2. ¢., there were very slight indications of fatigue. The fatigue caused by stimulation of the accelerators is also less after the intravenous injection of warm Ringer solution; the accelera- tion is also greater. Thus in one experiment stimulation of the spinal cord, which had been divided in the upper cervical region, ' As a rule the injection of sodium iodide causes first a fall and then a rise of blood pressure ; that this did not occur in this experiment was probably due to the action of the very large dose of curare. Acceleration of the Mammahan Heart. A21 caused an acceleration from 19 to 25 beats in 10 seconds but this rate was maintained for but a very short time. After the intravenous injection of 400c.c. of warm Ringer solution, which caused the blood pressure to increase from 27 to 61mm. of mercury, stimulation of the cord caused an acceleration to 29 beats in 10 seconds and there was very little evidence of fatigue when the stimulation was continued for some time. Of course the greater efficiency of the stimulation of the accelerators may have been due in part to the higher blood pressure. A large amount of atropine suddenly injected into a vein causes the heart (or the endings of the accelerators) to be fatigued by stimulation of the accelerators almost as rapidly as did curare in the above experiment. Death from stimulation of the accelerators. — It happened not unfre- quently that death resulted from stimulation of the accelerators in these experiments. This usually occurred after a long experiment in which the accelerators had been stimulated repeatedly with strong currents or after the irritability of the heart had been reduced by the action of curare or of cold. Sometimes the ventricle suddenly went into fibrillar contractions either during or immediately after the stimulation of the accelerators, in other cases the heart-beats became slower and weaker until they were no longer recorded. An example of the latter mode of death is the following. Experiment 120. Small dog. Morphine and ether. A very large amount of curare was injected into the femoral vein, as a consequence of which the blood pressure fell to 27 mm. The results of stimulating the accelerators are shown in the following table. Time. Heart-beats Time. Heart-beats Hrs. min. sec. in 10 seconds. | Hrs. min. sec. in 10 seconds. 3 45 244 48 25 R. annulus stimu- 50 23— lated; coil 14 cm. Sy, 20 20 37 54 123— 30 384 55 124 47 33 56 11 The heart became so weak that the beat was not recorded ; it soon stopped altogether. Death caused by fibrillar contractions, together with the effect of cold on the heart, is well illustrated by the following experiment. 422 Reid unt. Experiment 147. Small bitch. Morphine and ether. Vagi cut. A small opening was made in the pericardium and a considerable quantity of normal saline solution at about 10° C. injected ; the heart was slowed slightly for a short time and then it returned to its previous rate (31 in ro seconds). Time. Heart-beats Time. Heart-beats Hrs. min. sec. in 10 seconds. | Hrs. min. sec. in Io seconds. Be Bes 31 10 23 Branches of r. stellate 4 l 23+ ganglion cut. R. annulus stimulated ; 154 ; secondary coil 12 cm. 55 12 24+ 12 273 56 24 304 Normal saline (10° C.) 29+ injected into pericar- 28 dial cavity. ; re AE 24 eae Ventricles going into 2044 fibrillar contractions; 57 Branches of 1. stellate : auricles beating regu- ganglion cut. larly. Death from stimulation of the accelerators frequently occurred with as much suddenness as in the above experiment, although in those cases in which the accelerators had been stimulated repeatedly the heart rate had as a rule decreased somewhat (from 28 to 19 in one experiment, for example). Sometimes the heart beat regularly and rapidly during a stimula- tion of the accelerators but died a few seconds after the stimulations ceased. The strength of the current used in these experiments in which death occurred was no greater than that used in other experiments, and the nerves were usually stimulated near the stellate ganglion; it is very improbable therefore that death was due to an escape of current to the heart: it probably was due simply to the inability of the heart in its weakened and exhausted condition to respond to the demands made upon it by the stimulation of the accelerators. RELATION OF THE VAGI TO THE ACCELERATORS; PROTECTIVE ACTION OF THE VAGI UPON THE HEART. Stimulation of the vagus after section of the accelerators. — In my previous paper I have called attention to two effects of the section of the accelerators upon the results of stimulating the vagi; (1) the Acceleration of the Mammalan Heart. A423 same stimulus applied to the vagus causes a greater slowing of the heart after the accelerators are cut, than before, and (2) the ‘‘escape” of the heart during a long continued stimulation of the vagus is less complete after the accelerators are cut. Other effects of the section of the accelerators in relation to the stimulation of the vagus will be described later in this paper; one other point may be mentioned here although I have but few experi- ments to quote. A number of physiologists’ state that while stimu- lation of the accelerators causes a shortening of both systole and diastole, stimulation of the vagus causes a prolongation of diastole and as a rule but little effect upon the duration of systole. In com- paring the effects of stimulating the vagus in different experiments of my own I often have observed that in those cases in which the accelerators were intact and in tonic activity stimulation of the vagus had little effect upon the duration of the systole, while in those in which the accelerators had been cut a very considerable prolongation of systole frequently occurred. Thus in experiment C (see p. 402) after the accelerators were cut stimulation of the vagus caused the systole to be prolonged from 0.26 to 0.345 seconds or over 32 per cent. Stimulation of the accelerators after section of the vagi. — The tonic activity of the vagi limits the effect of stimulating the accelerators; this is shown in two ways. In the first place stimulation of the accelera- tors with sub-maximal stimuli has a greater effect upon the heart after than before section of the vagi if these are in tonic activity. Thus in one experiment stimulation of the accelerators with a weak current caused the heart rate to increase from 16 to 24 beats in 10 seconds when the vagi were intact; section of the vagi caused the heart rate to increase to 26}; stimulation of the accelerators with the same strength of current as before caused the heart rate to increase to 34 in 10 seconds. With very strong stimuli, however, the acceleration is the same before and after section of the vagi, for now the effect of the vagi is completely overcome and the heart is accelerated to its maximum rate. In the second place, the after-effect of stimulation of the accelera- tors is much more marked after section of the vagi; the heart returns more slowly to the previous rate. The following experiment illus- trates this point. 1 Cf. HURTHLE: Archiv f. d. ges. Physiol., 1891, xlix, pp. 86-88. 424 Reid Hunt. Experiment M. Large dog. Morphine andether. Curare. Accelerators cut. Time. Heart-beats Time. Heart-beats Hrs. min. sec. in to seconds. | Hrs. min. sec. in 1o seconds. Deal 20— R. annulus stimulated R. annulus stimulated for 10 seconds; coil for 10 seconds; coil 10 cm. 24 10 cm. 223 28 234+ 1 58 264 30 193-+- 23 55 R. vagus cut. 215- yf slo) Aloe 30 204 20 Antagonism of the accelerator and inhibitory nerves in their effects upon the duration of systole and diastole. — I have shown elsewhere that, contrary to the view of Baxt, when the accelerators and vagi are stimulated simultaneously, the effect upon the heart rate is determined by the relative strength of the two stimulating currents, and that for sub-maximal stimuli the result is approximately the arithmetical mean of the effects of stimulating the nerves separately.t Does this law of the antagonism of these nerves hold good for both systole and diastole? My experiments, which however have not been very numerous upon this point, indicate that this is the case. In such experiments as these it is necessary to use currents the strength of which can properly be compared with each other as regards their effect upon the heart; for while a relatively weak stimulation of the accelerators will cause a shortening of the systole, a stronger stimu- lation of the vagus is required to prolong this phase of the heart’s contraction, and on the other hand a stimulus which, when applied to the vagus, will cause a very great prolongation of diastole may, when applied to the accelerators, affect neither systole nor diastole. In order to cause a prolongation of the systole by stimulating the vagus, it is sometimes necessary to use a current strong enough to bring the heart to a standstill; then, as the heart escapes from this stand- still, the systoles are found to be prolonged. If we accept a suggestion that has been made,? namely, that those 1 Hunt: Journal of experimental medicine, 1897, ii, p. 171. These results have since been confirmed by v. Cyon (Archiv f. d. ges. Physiol , 1898, lxx, p. 244), Wertheimer (Journal of physiology, 1899, xxiii, supplement, p. 20), and at least the essential part of them by Frank (Sitz.-Ber. d. Ges. f. Morphol. u. Physiol., Munich, 1897, i), quoted from the Jahres-Ber. d. Physiol., 1898, vi, p. 64. 2 HUrTHLE: Archiv f. d. ges. Physiol., 1891, xlix, p. 89. Acceleration of the Mammathan Fleart. 425, nerve fibres which affect systole are different physiologically from those which affect diastole, the differences noted above may be ex- plained by supposing that one set of fibres is much more irritable to electrical stimulation than the other. Whatever the explanation, it is undoubtedly a fact that at times when the accelerators ‘and vagi are stimulated simultaneously the systole may be shortened as greatly as when the accelerators are stimulated alone, while the duration of diastole may be either un- changed or even slightly prolonged.* Such results as these do not prove, however, that these nerves are not purely antagonistic; they only show that when the effects upon the different phases of the cardiac cycle are considered, the strength of the currents were not comparable, and that in order to bring out the true relations it is necessary to consider the phases separately. If the accelerator and inhibitory nerves are stimulated with currents which when applied separately to the nerves cause changes in one or other of the phases which are comparable (2. e. neither stimulus must be a super-maximal one), the result is almost the exact arithmetical mean of the effect produced when the nerves are stimulated separately. It is very easy to pass the limits of strengths of current which are comparable, and then the accelerator or inhibitory influence will preponderate in the one or the other phase, just as it does when the entire cardiac cycle is considered and one set of fibres is stimulated with a relatively much stronger current than the other. The above considerations explain the cases in which one nerve gains the mastery in the one or the other phases of the heart’s action. The table on page 426, from one of my experiments, illustrates these points, and shows how perfect the antagonism of the accelera- tor and inhibitory nerves may be if care is taken to select stimuli of proper strength. Thus when the two nerves were stimulated together the influence of the acclerators predominated during systole and that of the vagus during diastole, but in each case the effect of the one nerve was diminished by that of the other. Mutual antagonism of the inhibitory and accelerator nerves in virtue of their tonic activity. — Since both the inhibitory and accelerator 1 Frank (oc. cz¢.) obtained similar results, but seems (I have not seen the original paper) to have interpreted them as indicating that the antagonism of the accelerators and inhibitory fibres is not perfect when their effect upon systole is considered, 426 Reid Flunt. Duration of | Duration of Systole. Diastoie. Before stimulation . . . . tal A iat ake ” Systole prolonged . Vagus stimulated alone 0.61 Diastole prolonged Systole shortened . f = at; // Accelerators stimulated alone f 0.30 Diastale sbostewenl Systole shortened . Diastole prolonged § Both nerves stimulated . . ey 0.45” nerves are usually in tonic activity and are also antagonistic, it would seem to follow necessarily that the tonic activity of the one would limit the tonic activity of the other, so that the heart rate at any time (so far as it depends upon the cardiac nerves) is determined by the relative strength and number of the impulses reaching the heart from the central nervous system. In order to test this sup- position it is desirable to determine the heart rate (1) when both nerves are intact and in tonic activity, (2) when the heart is under the influence of the accelerators alone, (3) when it is under the influence of the inhibitory nerves alone, and (4) when both nerves are divided. Such an experiment can be performed by suspending the activity of one of the nerves in such a manner that it can readily be restored again; this may easily be done by cooling the vagus. When the dog's vagus is cooled to about o.° C., the power of the inhibitory fibres to conduct impulses is lost,’ but it can readily be restored by warming the nerve; this method was employed in a number of experiments, of which the following is an example. Experiment 153. Small bitch. Morphine and ether. Curare. Stellate ganglia carefully exposed. Vagi cooled by passing cold alcohol through metal tubes upon which the nerves lay. Time. Heart-beats Time. Heart-beats Hrs. min. in 10 seconds. | Hrs. min. in To seconds. 10 45 17+ IS 163 Vagi cooled. 12 Vagi cooled. 48 DS 16 19+ 5S 29+- 17 20 Vagi warmed. Vagi cut. 5) 16 18 203 Accelerators cut. 1 HOWELL, BUDGETT, and LEONARD: Journal of physiology, 1894, xvi, p. 304. Acceleration of the Mammalian Fleart. 427 These results may be expressed in the following tabular form : — Under the influence of both nerves the heart ratewas . ... . . 17+ Under the influence of the accelerator nerves the heart rate was . . 294 Under the influence of the inhibitory nerves the heart rate was . . . 16 After section of both nerves the heart ratewas. . . .... . . 204 This experiment shows very clearly that the acceleration following section of the vagi is due in part to the tonic activity of the acceler- ators, but it shows also that it is not due entirely to this factor, for section of the vagi still caused some increase in the heart rate after section of the accelerators. It follows from such experiments as the above that the extent of the acceleration following section of the vagi is determined not only by the condition of the cardio-inhibitory centre, but also by that of the accelerator centre. If the tonic activity of the accelerator centre is very great and that of the cardio-inhibitory centre small, section of the vagi will lead to but little increase in the heart rate. In the exceptional cases in which the accelerators are not in activity, the increase of the heart rate following section of the vagi is determined solely by the condition of the cardio-inhibitory centre. In some experiments the entire tonus of the inhibitory nerves seemed to be exerted in holding the accelerators in check; for while cooling of the vagi caused an acceleration of the heart when the accelerators were intact, after section of the latter nerves neither cooling nor section of the vagi caused any change in the heart rate. In a similar manner the extent of the slowing of the heart follow- ing section of the accelerator nerves is determined not only by the condition of the accelerator centres, but also by that of the cardio- inhibitory centre. That the normal heart rate is determined by the tonic activity of the cardiac nerves, can scarcely be doubted; the varying effect of cutting all the nerves is strong evidence for this view. Thus after section of both the accelerator and inhibitory nerves one of three conditions results: (1) the heart rate is faster, (2) the heart rate is slower, or (3) the heart rate is the same as before the nerves were divided. Which of these three conditions results is determined by the relative strength of the impulses reaching the heart through the cardiac nerves. If the inhibitory impulses are the stronger, section of all the cardiac nerves causes the heart to beat more mCi vy. Cvon: Archiv t. dages. Physiol: 1908; lax; p. 242: 428 Red Flunt. rapidly; if the accelerator impulses are the stronger, section of the nerves causes the heart rate to become slower. In many of the experiments described above it is evident that the vagi restrained the activity of the accelerators; * and so, since fatigue and decrease in the irritability of the heart result from the action of the latter nerves, the vagi acted as a protection to the heart. Moreover, there is evidence that, so far as the condition of the heart can be judged by its rate, stimulation of the vagus has a bene- ficial influence upon the mammalian heart, as Gaskell showed it to have in cold-blooded animals. Thus if the accelerators be intact and the peripheral end of one vagus (both vagi having been divided) be stimulated a number of times with currents of moderate intensity, the heart rate is frequently greater after than before the vagus was stim- ulated. This increase in the heart rate is not to be confounded with the acceleration which sometimes follows immediately after stimula- tion of the vagus, and which is due to the accelerator nerve fibres present in the vagus or vago-sympathetic trunk; the former is of much longer duration than the latter, and seems to be due to an im- provement in the condition of the heart, as a result of which the impulses reaching this organ through the accelerator nerves become more effective. This effect of stimulating the vagus was well shown in an experiment upon a dog: the heart rate some time after section of the vagi was 33 in 10 seconds; the peripheral end of one vagus was stimulated with a weak, slowly interrupted induced current for 25 minutes, short intervals of rest alternating with longer periods of stimulation; after the stimulation the heart rate was 42 in 10 seconds, and it continued at this rate for some time. Such changes in the rate did not occur during periods of rest of equal duration. Another illustration of the protective influence of the vagus over the heart is found in some experiments in which the vagus and accelerators were stimulated simultaneously for some time. Atten- tion was called above to the fact that when the accelerators were 1 In a similar manner the tonic activity of the accelerators checks the action of the vagi; if the latter are thrown into activity reflexly, or if the nerves be stimu- lated directly, the effect upon the heart is less when the accelerators are intact ; thus the accelerators prevent excessive action of the vagi, and so a long continued lowering of the blood pressure which might be injurious to the functions of some of the organs. Of course, if the stimulation of the vagi is excessive, as in asphyxia, for example, the effect of the accelerators may be entirely overcome, just as the effect of the tonic activity of the vagi may be entirely overcome by a powerful stimulation of the accelerators. Acceleration of the Mammatan fleart. 429 thus stimulated it happened frequently that after the stimulation the rate of beat was considerably less than it was before the stimu- lation, and this was considered to be due to fatigue in the heart. If, however, the vagus was stimulated at the same time as the accel- erators, the decrease in the rate after the stimulation ceased was, as a rule, much less, or did not occur at all. In other experiments, instead of stimulating the two nerves simultaneously the effect of stimulating the accelerators after a period of rest was compared with the effect of stimulating them after an equally long period of stimu- lation of the vagus; not only was the maximum acceleration greater in the latter case, but it was of much longer duration. It should be added that in order to obtain this result the stimulation of the accel- erators must follow that of the vagus immediately ; if a short interval, even one of a few minutes, elapsed between the two stimulations, the result was the same as when the accelerators were stimulated after a period of rest. Finally, in most of the experiments in which death resulted from stimulation of the accelerators the vagi had been divided.1 PAR ae Eb. REFLEX ACCELERATION OF THE HEART. The cause of reflex acceleration. — Many text-books of physiology allude to the possibility of reflex acceleration of the heart being pro- duced in two ways: (1) by diminution of the tonus of the vagus, and (2) by stimulation of the accelerator centres. Very few of those who have studied this subject, however, speak of the former possi- bility; usually all cases of reflex acceleration are referred to stimula- 1 Death of the heart also resulted sometimes from the intravenous injection of hot normal saline solution or of Ringer solution, and it seemed to occur much more frequently in those animals in which the vagi had been divided. One experiment of this kind was especially interesting. Before the vagi were divided a consider- able quantity of normal saline solution was slowly injected into the femoral vein from a fountain syringe; the temperature of the solution in the syringe was 53° C., but it was probably several degrees colder when it entered the vein. The injection increased the rate of beat, but not markedly (from 26} to 344 beats in ro seconds), and no bad effects were produced; on the contrary, the condition of the circulation seemed to be decidedly improved. The vagi were divided, and some time after- wards a much smaller amount of the same solution was injected. The temperature of the liquid in the syringe was now but 50° C.; the heart-beats, however, were increased to 47 in ro seconds ; soon they could not be counted; the blood pressure fell and the dog died. 430 Reid Hunt. tion of the accelerator nerve. This attitude is well illustrated by two of the most elaborate articles dealing with the innervation of the mammalian heart which have appeared within recent years — that of Roy and Adami,’ and of v. Cyon.? Roy and Adami describe reflex acceleration resulting from the stimulating of sensory nerves, and attribute it to a stimulation of the accelerator nerves; in fact, when studying the effect of these nerves upon the heart, these authors stimulated, as a rule, a sensory nerve instead of the accelerators directly, as they considered the reflex acceleration obtained in this manner to be equivalent to the effect of stimulating the nerves themselves. Von Cyon describes reflex acceleration following the stimulation of a number of afferent nerves, and seems to ascribe it in all cases to a stimulation of the accelerators. Thus stimulation of a third root of the depressor,®? which he has found in certain animals of different species, causes a reflex acceleration, and v. Cyon thinks that this shows that the nerve fibres of this root are connected in a special manner with the accelerator centre. It is worthy of note, however, that v. Cyon emphasizes the fact that in these experiments the vagi were intact, and in at least one experiment the vagus centre seemed to be in a condition of exaggerated activity as a result of the mor- phine used as an anesthetic; hence there is no evidence that in these experiments the reflex acceleration was not due to a diminution of the tonic activity of the vagi. Von Cyon also describes an experi- ment in which stimulation of the central end of the superior laryngeal caused reflex acceleration; * but here also the vagi were intact and in tonic activity, as their subsequent section showed. Moreover, the increase in the heart rate from stimulating the superior laryngeal was far less than that following division of the vagi. Careful examination of the accounts of various other experiments on this subject shows that in most of the cases in which reflex acceler- ation has been described the vagi were intact, and there is frequently 1 Roy and ADAMI: Philosophical transactions, 1892, 183 B, p. 254. 2 von Cyon: Archiv f. d. ges. Physiol., 1898, Ixx, p. 126. 8 This “third root ” of the depressor springs from the superior cervical ganglion or from the cervical sympathetic. I may mention in this connection that Dr. Har- rington and I found a small nerve in a calf lying very near the vagus and ending in the superior cervical ganglion ; stimulation of this nerve caused a marked fall of blood pressure and a slight slowing of the heart. Thus this nerve corresponded. physiologically, to the depressor. 4 von Cyon: of. cit., p. 149, Table ITI. Acceleration of the Mammatan Heart. 431 evidence to show that they were in a condition of tonic activity. In the description of other experiments nothing is said as to whether the vagi were intact or not, while in a few the statement is made that reflex acceleration occurred after division of the vagi. Almost every statement of the latter kind with which I am acquainted is, however, open to criticism. Thus in some of the older experiments not only was the acceleration very slight, but it was accompanied in many instances by changes in the blood pressure sufficiently great to account for the changes in the heart rate. Reflex acceleration has been described as resulting from stimula- tion of the depressor after section of the vagi; Bayliss,’ for example, describes such an experiment, and reproduces a tracing showing the acceleration. An examination of this tracing shows that the accel- eration is very different from that observed when the accelerators are stimulated directly, and arouses the suspicion that it is not a case of true reflex acceleration at all. When the accelerator nerves are stimulated directly, there is a long latent period, and the acceleration is developed slowly; after the stimulation ceases the heart returns slowly to its previous rate. In this tracing the heart rate remained unchanged during the first two or three seconds of stimulation; then it suddenly doubled, and the heart continued at this greater rate until after the stimulation had ended, when it suddenly returned to its previous rate, z. ¢. to just one half the accelerated rate. An examination of the heart in such cases as the above, in which the rate is slowed suddenly to one half the previous rate, usually shows that this is due to the failure of the ventricles to follow one half of the auricular beats; when, on the contrary, the heart rate is suddenly doubled, the ventricles are found to be responding to all of the auricular beats. In many animals this lack of co-ordination in the beats of the auricles and ventricles is made to disappear by influences causing slight changes in the blood pressure or respiration, by movements of the animal, by slightly pulling the vagi, etc., and it is possible that some such changes as these were the cause of the acceleration in Bayliss’s experiment. On the other hand it must be remembered that stimulation of the accelerators increases the ease with which impulses are conducted from auricle to ventricle, and it is possible that in the above experiment the doubling of the heart rate was after all due to a reflex stimulation of the accelerators acting in this manner; still, I know of no experiments in which direct stim- 1 BAyYLIss: Journal of physiology, 1893, xiv, p. 313. 432 keiwd Flunt. ulation of the accelerators produced this effect without at the same time causing an increase in the rate of the entire heart. An experiment by Barbéra very similar to the one described by Bayliss is brought forward by v. Cyon* as evidence that reflex acceleration may under some circumstances be produced by stimula- tion of the central end of the cervical sympathetic. In this experi- ment, in which the vagi had been cut, the injection ofa solution of sodium phosphate had caused a decrease of the heart rate to one half the previous rate; stimulation of the cervical sympathetic, as is shown by the curve published, caused the heart rate to increase from 10 to 20 beats in 5 seconds; 2 the latter was practically the rate at which the heart was beating before the injection of sodium phosphate. Apparently the heart continued to beat at this rate for some time after the stimulation ended. Evidently this experiment is open to the same criticism as the one discussed above, and it hardly can be regarded as a satisfactory case of true reflex acceleration. Barbéra® describes the effect of stimulating the depressor after section of the vagi in the experiment cited by Cyon, just men- tioned. He does not publish the curve, or give many details of the stimulation, but merely states that the heart rate increased as a result of stimulating the depressor from 240 to about 270 beats per minute, while the blood pressure fell from 103 to 86 mm. This may bea case of true reflex acceleration; but it may fairly be asked if in an animal in which, apparently as a result of repeated injections of sodium phosphate, the heart rate was as easily affected, as numerous statements show it to have been in this one, the fall of blood pressure may not have been the cause of this acceleration of the heart. I may add, moreover, that I know of no experiment in which the evidence for the occurrence of reflex acceleration after section of the vagi is stronger than in this one. Attention was called above to the fact that very few of the authors who speak of reflex acceleration take into consideration the possi- bility of its being caused by diminution of the tonus of the vagi; in fact I know of but one paper (by MacWilliam) dealing directly with 1 von Cyon: of. cit., pp. 202-203. 2 It may be that in some of these cases the doubling of the rate of the ventricle was only apparent, one strong beat being followed by a weaker beat; the result being that the two beats were recorded by the mercury manometer as one. How- ever these changes are produced, they are evidently not satisfactory evidence of a reflex stimulation of the accelerators. 8 BARBERA: Archiv f. d. ges. Physiol., 1897, Ixvili, p. 444. Acceleration of the Mammalian Feart. 433 this subject. Before speaking of MacWilliam’s work a few words may be said about some experiments of other physiologists bearing upon this question. Schmiedeberg,’ in his classical paper on the accelerator nerves of the dog, describes two experiments in which reflex acceleration was obtained by stimulating the central end of one of the limbs of the annulus of Vieussens. Schmiedeberg does not state whether the vagi were cut or not, but I infer that they were not, and from the fact that the heart rate increased later in the experiment I infer that they were in a condition of tonic activity. Schmiedeberg calls attention to the fact that in one of these two experiments the course of the acceleration was different from that resulting from direct stimulation of the accelerators, in that the after-effect was very short, and he expresses a doubt as to whether the acceleration was due to a reflex stimulation of the accelerator nerves; he does not suggest, how- ever, that it may have been due to a diminution of the vagus tonicity. Asp? made a number of experiments on the effect upon the heart rate of stimulating sensory nerves both before and after section of the vagi; he also made four experiments in which the accelerators were cut. Asp observed slight acceleration upon stimulating sensory nerves after the vagi were cut; the effect upon the blood pressure was variable. In two of the four experiments in which the acceler- ator nerves had been cut slight reflex acceleration occurred; in the two other it did not occur, although it had been obtained in all four experiments before the accelerators were cut. Asp was endeavoring to determine whether reflex acceleration is due to a stimulation of the accelerator nerves or, as he puts it, to “a constriction of the arteries of the brain, caused by a stimulation of the sensory nerve, by which the pressure on the vagus centres was reduced and the heart became more rapid.” Neither Asp nor Schmiedeberg seems to have considered the possibility of the reflex inhibition of the cardio-inhibitory centre. These experiments of Asp are sometimes cited as evidence of reflex stimulation of the accelerator nerves, and Asp himself was inclined to interpret them in this manner, although he states dis- tinctly that he did not consider the question closed. The reflex acceleration was not marked; blood pressure changes could not be 1 SCHMIEDEBERG: Sitz.-Ber. d. sachs. Gesell. d. Wiss., math.-phys. Cl., 1871, p. 152: * Asp: Sitz-Ber. d. sachs. Gesell. d. Wiss., math.-phys. Cl., 1867, p. 188. 28 434 Red unt. excluded, and finally, as Asp points out, the heart was irregular and the effect of stimulating sensory nerves very uncertain. Knoll* found that compression of the heart, either by the finger or by inflating the pericardium with air, caused an acceleration of the heart, and he showed that this acceleration was due to a diminu- tion of the tonicity of the vagi. MacWilliam? is apparently the only author who has given careful attention to the question as to the manner in which reflex accelera- tion is brought about when an ordinary sensory nerve is stimulated, but he has published only a preliminary paper containing few details. MacWilliam compared the latent period of direct and of reflex acceleration, and reached the conclusion that the latent period of the latter is too short for the acceleration to be referred to a stimulation of the accelerator nerves; he thinks it is due to a diminution of the tonus of the vagi. The effect upon the heart rate of stimulating the sensory nerves before and after section of the vagi, and of stimulating the accelerators, was also studied by MacWilliam, with the result that reflex acceleration was obtained after the accelerators were cut if the vagi were intact, but not after the vagi were cut, although the accelerators were intact. From these experiments MacWilliam drew the conclusion that, ordinarily, reflex acceleration is due to a diminu- tion of the tonus of the vagi. The afferent nerves by which reflex acceleration is produced. — The nature of the afferent nerve fibres by which reflex acceleration and reflex slowing of the heart are produced has received but little attention. Tigerstedt,? after discussing the various experiments on this subject, states what may perhaps be regarded as the current view of physiologists, namely, that both the accelerator and inhibitory nerves can be thrown into reflex activity by the stimulation of almost all afferent nerves. There is evidence, however, that the various sensory nerves differ in their effect upon the heart; some for example cause as a rule reflex acceleration, others, reflex slowing. To the latter class, as Tiger- stedt pointed out, belongs the trigeminus; stimulation of this nerve 1 KNOLL: Lotos, neue Folge, 1881, ii, p. 14. 2 MACWILLIAM: Proceedings of the royal society, London, 1893, liii, p. 464. It is but fair to myself to state that most of my experiments were performed before I learned of MacWilliam’s paper; in fact, the greater part of this section of my paper was written a number of years ago, and originally included in a thesis pre- sented to the Johns Hopkins University for the degree of doctor of philosophy. * TIGERSTEDT: Lehrbuch der Physiologie des Kreislaufes, 1893, p. 289. Acceleration of the Mammatan Fleart. 435 seems always to cause reflex slowing, if it has any effect at all upon the heart. Asp‘ states that, as a rule, he observed acceleration to follow stimulation of the central end of muscular branches of nerves; but in some experiments reflex slowing occurred. Tengwell,? how- ever, found the stimulation of muscular nerves had but little effect upon the heart rate. Roy and Adami?® found reflex acceleration usually resulted from stimulation of the sciatic nerve; sometimes the acceleration was followed by a slowing of the heart. The latter nearly always occurred when the splanchnic nerve was stimulated. Schmiedeberg* observed in two of his experiments that stimulation of the central end of one limb of the annulus of Vieussens caused reflex acceleration, whereas stimulation of the other limb caused reflex slowing; he suggests that there are several varieties of afferent nerve fibres, some of which cause reflex acceleration and some reflex slowing. Statements and speculations as to the nature of the afferent nerve fibres concerned in reflex acceleration, however, have only a second- ary interest, so long as the question of the manner in which this acceleration is caused is left undecided; for if it should be shown that reflex acceleration is in reality due to an inhibition of the cardio- inhibitory centre, the effect of stimulating various nerves might be determined solely by the condition of this centre at the time of stimulation. ON THE MANNER IN WHICH REFLEX ACCELERATION IS PRODUCED. The problem whether the reflex acceleration resulting from the stimulation of sensory nerves is caused by a diminution of the to- nicity of the vagi, or by an increased action of the accelerators, was approached from three standpoints: (1) the details of some of the 1 Asp: of. cit., p. 183. The statement of Asp that mechanical stimulation of the sciatic plexus causes a reflex slowing of the heart, whereas electrical stimula- tion causes an acceleration. is often quoted. I can find but one experiment of this kind described in Asp’s paper (p. 182), and this is most unsatisfactory on account of the great differences produced in the blood pressure in the two cases; with mechanical stimulation the blood pressure rose 106 mm., while with electrical stimulation there was a rise of but 37 mm. Some of Asp’s experiments upon the effect of stimulating the lumbar cord are open to a similar criticism ; thus he com- pares the effects of two stimuli (one mechanical and the other electrical) upon the heart rate, although in the one case the blood pressure rose to too mm. and in the other to 174mm. Some of these experiments will be referred to again. 2 TENGWELL: Skandinavisches Archiv f. Physiol., 1895, vi, p. 230. ® Roy and ADAMI: Philosophical transactions, 1892, 183 B, p. 258. 4 SCHMIEDEBERG: Ber. d. sachs. Gesell. d. Wiss., math.-phys. Cl., 1870, p. 152. 436 Reid Hunt. o events occurring in the heart when it was thrown into a condition of ac- celeration in various ways were investigated, (2) the accelerators were cut and sensory nerves stimulated, and (3) the vagi were divided and sensory nerves stimulated. The duration of systole and diastole and the latent period when the heart rate is increased in various ways. — The duration of systole and diastole, and the latent period of acceleration, were determined when the heart rate was increased by the stimulation of a sensory nerve, and these results were compared with those obtained by cutting the vagi and by stimulating the accelerators directly. If the acceleration occurring in the former case is due to a diminution of the tonic activity of the vagi, we should expect to find the course of the acceleration similar to that resulting from section of the vagi, rather than to that observed when the accelerators are stimulated directly ; the former is, as a rule, the case, as the following experiments show. The duration of systole and diastole, and of the latent period, was determined by means of Hiirthle’s manometer, in the manner described in the first part of this paper. At times the dicrotic wave on the curve of carotid pressure became so indistinct that it was impossible to determine accurately the duration of systole; such tracings could be used, however, for determining the latent period. The results obtained from the various experiments were so uniform that only one or two experiments of each class need be described. Section of the vagi.—The following experiment shows the usual effect upon the heart-beat of cutting the vagi when these are in a condition of tonic activity. Experiment A. Very small dog. Morphine and ether. Left carotid con- nected with Hiirthle’s manometer. Left vagus had been cut. Time. Duration in seconds of Time. Duration in seconds of Hrs. min. Systole. Diastole. | Hrs. min. sec. Systole. Diastole. 3) 50 0.175 0.495 0.165— = 0.165 0 495 3) 50 = = R. vagus cut. 0.175 0.365+- 0.155+ 0.260 0.165 0.365-+ _ 0.260 0.170— 0.330 0.150— = 0.165 0.305 0.145 = ELI at ars ea — 0.280+ 10 0.140 0 255 0.165— — 12 0.130+ 0.255 — — 14 0.120 0.255 1 In this and subsequent tables the dash (—) means that the curves were not counted out in full; the labor of counting these tracings to hundredths of seconds is very great. Acceleration of the Mammatan Freart. 437 These results are shown in the plotted curve of Fig. 6 better than in the table; the ordinates represent the duration of systole and diastole in 0.C5 of a second, the abscissa. five heart- beats. In Fig. 7 asmall part of the original tracing is repro- duced. ihe=chiet--et- fects upon the heart rate of cut- *L AMNDIY ‘SnSVA JYSII oY} Suyyno Jo 0.15 *‘AZIS [RUISTIO JY} SPAY} OMT, ting the vagi, as shown by the FIGURE6. Experiment A. Section above EXpPeti- of right vagus. The ordinates ment, are (1) the represent the duration of systole, very sudden and S, and of diastole, D, in 0.05 fa : seconds; the abscissz, 5 heart- Soe SETS beats. the duration of diastole, and (2) the much more slowly developed and relatively less marked effect upon the systole. The short- ening of diastole began in the heart-beat during which the vagus was cut, and had reached almost the maximum before the shortening of systole began. These results are in accord with the well-known fact that it is the diastole which is most easily and quickly affected when the heart rate is altered, and that the influence of the vagus upon diastole is greater than its in- fluence upon the systole. Results very similar to the above are ob- tained when the heart returns to its normal rate after it has been slowed by stimulation of the peripheral end of the vagus or when it has been slowed reflexly. Stimulation of the accelerators. — An experi- ment was described in the first part of this paper (p. 402) showing the effect upon the duration of the systole and diastole of cutting 0.10 *S[RAIOJUL PUODIS I PUL 10°O FO S[BAIIUL UT SUIT], ‘JYSII 0} JJ] WOIZ pvdI aq OF, JOJO MOYS O} LOJOWOULU SaTYJANFT YIM udyxV} pxooer jo weg “YW JuoWTIodxay 438 Reid Hunt. the accelerator nerves; the following table and curve (Fig. 8) show the effect of stimulating the accelerators in this experiment. Time. Hrs. 2 FiGuRE8. Experiment C. Stimulation of the right annulus The ordinates represent the duration of systole, 5S, and of diastole, D, in 0.05 seconds; the abscissx, 5 (2 10) 35) min. 3 R. ann. stim. ; coil 10 cm. Stim. off annulus. Duration of Systole. 0.285 0.300+- 0.285 0.265 0.300 0.280 0.265 0.240+ 0.235 0.215+ 0 230 0.195 0.180 0.175 Diastole. 0.310 0.325 0.305 0.330 0.330 0.305 0.265 0.275 0.260 0.245 0.240— 0.225 0.220+ 0.210+ 0.215+ 0.200 0.190+ 0.205 0.210+ 0.205+ 0.220 heart-beats. Heart-beats ii IO seconds. 164 (Every 5th beat counted.) 28+ The exception- ally long duration of the systole in this experiment was caused by the section of the ac- celerators. This experiment shows that stimula- tion of the accelera- tors causes a short- ening of systole as well as of diastole, and that the latent period of each is very long; in fact, the maximum shortening occurred after the cessation of the stimulation. Acceleration of the Mammalian Heart. 439 Curves very similar to the above are obtained when the accele- rators are stimulated during a long stimulation of the vagi, by which the heart is slowed. Occasionally, however, when the heart rate is very slow, either in conse- quence of the stimulation of the vagi,! or of the tonic activ- ity of these nerves, or from other causes, and the stimulus applied to the accelerators is very strong, the latent period is much shorter than in the above experiment,? and the diastole is much shortened be- fore the shortening of the sys- tole begins. In such cases the curve is intermediate in form FIGURE 9. Experiment E. Stimulation of beeween those resulting feont saphenous. (See above table.) The ordi- nates represent the duration of diastole, D, section of the vagi and those and of systole, S, in 0.05 seconds; the ab- usually following stimulation scisse represent 5 heart-beats. of the accelerators. Acceleration of the heart resulting from stimulation of a sensory nerve. — The following experiment illustrates the effect upon the heart rate of stimulating a sensory nerve. Lixperiment EF. Medium-sized dog. Morphine and ether; curare. The following table and curves (Figs. 9 and 10) show the effect upon the heart of stimulating the saphenous nerve. 1 Frangois-Franck (Travaux du laboratoire de Marey, 1878-79, p. 80) states ‘that the latent period is prolonged when the heart is under the influence of the vagus; I have found just the opposite to be the case. There is, moreover, the following difference: when the vagi have been divided, or when they are not in tonic activity, the latent period of the accelerators is found to be long in both systole and diastole, and the shortening of one does not begin before that of the other. If, however, the vagi are in activity, stimulation of the accelerators may cause a marked shortening of diastole before the duration of systole is at all affected. When, on the other hand, the vagus is stimulated, the diastole is always prolonged before the systole, z. e. the latent period of stimulation of the vagus applies especially to the systole. 2 Hiirthle (Archiv f. d. ges. Physiol., 1891, xlix, p. 89) describes an experiment on a very slowly beating heart in which the second diastole was shortened; I never have observed a shortening of any diastole before the fourth as a result of stimulating the vagus. 440 Reid Hunt. Time. Duration in seconds of Time. Duration in seconds of Hrs. min. Systole. Diastole. | Hrs. min. Systole. Diastole. 11 . 23 0.175 0.415 _— — 0.175 0.420 | == = R. saphenous stimu- = — lated for 10 secs. ; 0.145 0.265: coil 1] cm. _ _ 0.180— 0.350 = — 0.165 0.300 = ets = a 0.140 0.255 0.160 0.290 Stimulus off saphe- = = nous. = = 0.165 0.505+- Examination of the above table and curves shows that the short- ening of the diastole is very marked and the latent period very short; the effect upon the systole is less marked and is more slowly developed. The heart rate also returned very quickly to the normal. When the effects upon the heart rate of stimulating a sensory nerve are compared with those described above, resulting from cutting the vagi and from stimulating the accelerators, it is very evident that they resemble the former much more closely than they do the latter. When the heart is accelerated by section of the vagi, or by the stimu- lation of a sensory nerve, the diastole is shortened relatively much more than the systole, and the latent period is very short. When, however, the accelerators are stimulated directly, the systole as well as the diastole is much shortened, and the latent period is very long. Moreover, the after-effect upon the heart rate of stimulating the accelerators directly is often very different from that occurring in reflex acceleration; in the former case the heart continues beating at a rapid rate for some time, whereas in the latter it often returns very quickly to its previous rate or is slowed. Acceleration of the Mammatian Heart. As the results described above are by no means exceptional, but are the rule, I think they can be regarded as strong evidence for the view that in reflex acceleration of the heart diminution of the tonic activity of the vagi plays the chief rdle. These results are of a special interest, since they suggest that under certain circumstances the cause of any sudden increase in the heart rate, z. ¢. as to whether the increase is due to stimulation of the accelerators or to a diminution of the tonic activity of the vagi, can be determined from the cardiogram of the intact animal or of man. While in most cases the curves of direct and of reflex acceleration differ in the man- ner described above, there are exceptional cases in which the difference is not well marked. In some cases of reflex accelera- tion, for example, the latent period is com- paratively long; this occurs most frequently when the heart rate is already rapid and the acceleration relatively small. On the other hand, the latent period when the ac- celerators are stimulated may be very short; as already described, this occurs when the heart is beating very slowly. Further, the difference. mentioned above in the effect upon systole and diastole, in the two cases, is not always marked. Even in these ex- ceptional cases, however, the subsequent course of acceleration usually differs; the maximum shortening is reached much more quickly in reflex than in direct acceleration. Reflex acceleration after section of the ac- celerators. — Such an experiment as the fol- lowing shows that marked reflex acceleration of the heart may occur after the principal nerves containing accelerator fibres have been divided. ‘wo Z [109 Aie~puosas {aAiau snouaydes *S[VAIOJUT PUODIS O'I Puv 1O'0 UT OWT, 4 ‘4 SIL 0} JJO[ WOIJ Pvo1 aq OF Sujrypnwuiys Jo yoyo MOYS OF AsJOWOULUE JPYIANFYT OY YRIM usye} p1odeL Jo weg “Y JuawUadxy ‘OI ANNOY ‘QZIS [LUISIIO 9} Jey 9uUQ 441 442 Reid Hunt. Experiment 139. Small dog. Morphine and ether. Stellate ganglia and their branches exposed. Blood pressure from left femoral artery. Time. Heart-beats Time. Heart-beats Hrs. min. in To seconds. | Hrs. min. in ro seconds 1°88 ]4— aS. R. saphenous stim. for 10 104 sec.; coil 10 cm. 22— 403 103 132 R. saphenous stim. for 10 124+ | sec.; coil 14. 183 LA+ | 103— ik 30 10 to Accel. nerves cut. 94+ iL Se 103 1 39 145 51 it R. saphenous stim. for 10 R. saphenous stim. for 10 sec.; coil 10 cm. 193 sec.; coil 16 cm. 17+ 112 Al lly 10 103 Section of the vagi caused the heart rate to increase to 26 beats in 10 seconds. The accompanying curve (Fig. 11) shows the effect upon the heart rate of one stimulation of the saphenous nerve in the above experi- Perret call Sn MMU = > a Ficure 11. Two fifths the original size. Experiment 139. Acceleration of the heart resulting from stimulation of the saphenous nerve, S—S, after section of the accelera- tor nerves. Time in intervals of 10 seconds. Tracing to be read from left to right. ment after the accelerators were cut. A glance at this curve shows it to be very different from those obtained when the accelerators are stimulated directly; in the latter case the latent period is much longer, the maximum acceleration is much more slowly reached, and the heart rate returns much more slowly to its previous rate. The reflex acceleration in this experiment was slightly greater before than after the accelerators were cut; this feature, which frequently Acceleration of the Mammalian Fleart. 443 occurs, will be discussed below, but it evidently does not interfere in the least with the conclusion that in reflex acceleration diminu- tion of the tonicity of the vagi plays the chief rdle. Results similar to the above were secured in a large number of experiments. In fact whenever reflex acceleration was obtained with the accelerators intact, it was obtained also after these nerves had been divided, provided the tonicity of the vagus centre was not destroyed by the operation. The operation necessary to expose the accelerators and the section of these nerves tend to reduce or to abolish permanently the vagus tonicity; if this occurs, no reflex acceleration takes place.’ In order to get the best results it is well to proceed as in the above experiment; the stellate ganglia should be exposed with as little operating as possible, and then some time allowed for the animal to recover. The temperature is prevented from falling by keeping the animal on a zinc box filled with warm water, and the wounds are.carefully covered with towels wet with warm Saline solution. Finally the nerves are cut with a pair of very sharp scissors, and pulling or crushing of the nerves carefully avoided. All cases in which reflex acceleration occurred before but not after section of the accelerators could be explained by the loss of vagus tonicity resulting from the operation. On the other hand, I had never observed reflex acceleration to occur except when there was clear evidence that the vagi were in tonic activity.” Another point of interest in this connection (and the one which first led me to suspect that reflex acceleration is due to a diminution of the vagus tonicity) is that the rate reached by the heart during reflex acceleration is never greater than that following the section of the vagi; it may reach this rate, but never exceeds it. Certain objections may be raised to the conclusion that in such experiments as the above the acceleration was due to a reflex diminution of the tonic activity of the vagi. Thus the acceleration might be attributed to the rise of blood pressure which so often occurs at the same time. It is not at all uncommon, especially when 1 Tt is not improbable that the absence of reflex acceleration in the two experi- ments of Asp referred to above (p. 433), in which the stellate and inferior cervical ganglia had been removed, was due to the loss of tonicity of the vagi resulting from the operation. 2 Reflex acceleration also occurs in animals in which subsequent section and stimulation of the accelerator nerves show them to have been in a condition of maximum acceleration ; the reflex acceleration in such cases is obviously due to an inhibition of the vagus centre. A44 Rewd Flunt. the heart is beating very slowly, for stimulation of a sensory nerve to cause a rise of blood pressure and a considerable acceleration of the heart even after all the cardiac nerves are divided;? the same result may follow stimulation of the peripheral end of the splanchnic, both when the cardiac nerves are intact and when they have been divided. The course of the acceleration occurring in such cases as these, however, is very different from that which occurs when a sen- sory nerve is stimulated and the vagi are intact. In the latter case the acceleration begins with considerable suddenness; the second or third beat may be shortened and a very distinct acceleration occur before the blood pressure has begun to rise; in the former case the acceleration begins very slowly; I have never observed it to begin until after the nerve had been stimulated for at least 10 seconds, and the blood pressure had risen very considerably. Moreover, reflex acceleration frequently takes place when the change in the blood pressure is insignificant. Another possible cause of the acceleration occurring after the stellate ganglia and their branches have been extirpated remains to be considered, viz. a reflex stimulation of accelerator fibres which pass to the heart in the vagus or vago-sympathetic trunk. As is well known, the slowing of the heart caused by stimulation of the peripheral end of the vagus or of the vago-sympathetic in the dog is sometimes followed by an acceleration; if atropine has been given, acceleration alone may result. This acceleration at present is usually explained by supposing that there are certain accelerator fibres which reach the heart by this route, and the possibility of reflex accel- eration being produced by means of such fibres must be considered. Certain considerations, however, make it very improbable that these fibres play any important part in the production of reflex accelera- tion. In the first place, it is rather exceptional to find any evidence for the existence of accelerator fibres in the vago-sympathetic of the dog; reflex acceleration is very frequently obtained after removal of the stellate ganglia in animals in which no acceleration is observed when the vago-sympathetics are stimulated either before or after the administration of atropine. When stimulation of the vagus does cause acceleration after atropine, the curve closely resembles that observed when the other accelerators are stimulated, and is not at 1 The acceleration observed in such cases may not be due to the rise of blood pressure, but to the warm blood which is forced suddenly into the heart from the abdominal viscera. Cf. MARTIN: Physiological papers, 1895, p. 18. Acceleration of the Mammatan Fleart. 445 all like that obtained in reflex acceleration. Moreover, the accelera- tion caused by the direct stimulation of these nerves is seldom so great as that which is often obtained reflexly by the stimulation of sensory nerves. Stimulation of sensory nerves after section of the vagi.— The ques- tion, Does reflect acceleration occur after section of the vagi? may now be discussed. It may be said at once that in a large number of experiments stimulation of sensory nerves caused either no accelera- tion at all after section of the vagi, or the acceleration was so slight that it could be referred probably to changes in blood pressure; in no case was there evidence that the slight acceleration was due to stimulation of the accelerator nerves, for such changes in the heart rate occurred after these nerves as well as the vagi had been cut. No reflex acceleration took place after the vagi had been cut in cases in which all the conditions seemed very favorable, z.¢. in cases in which marked reflex acceleration had been observed before the vagi were cut, and in which, as subsequent examination showed, the accelerators were not in a condition of maximum activity and were very irritable. The question may be raised, if after the vagi were cut the heart was not already beating at so rapid a rate that the conditions were not favorable for the occurrence of reflex acceleration, although the accelerator centres may have been irritable. This rapid rate of the heart, however, could not account for the entire absence of reflex acceleration, for the maximum rate to which the heart can be ac- celerated is independent of the rate at which the heart beats before stimulation,’ and it is very rare for the heart to be in a condition of maximum acceleration after section of the vagi. Still, if the heart was beating slowly before reflex acceleration occurred, the relative increase would be greater, and hence more striking. Accordingly, in a number of experiments in which the heart rate had increased as a result of cutting the vagi, the peripheral end of one or of both of these nerves was stimulated with a current just sufficient to bring the heart back to the rate at which it was beating before the nerves were cut. Stimulation of sensory nerves in such cases never caused any acceleration, although direct stimulation of the accelerators caused a great increase in the rate. These experiments are of interest in connection with the work of Roy and Adami. These authors agree with me as to the absence of 1 BowpitTcH: Ber. d. sachs. Gesell. d. Wiss., math.-naturw. Cl., 1871, p. 266. 446 Red Flunt. reflex acceleration after section of the vagi,’ but give an entirely different explanation. Roy and Adami explain reflex (and also direct) acceleration of the heart as due to a diminution of the vagus tonus zz the heart resulting from the action of the accelerator nerves ; after section of the vagi, reflex or direct acceleration of the heart is impossible, since there is no vagus tonus in the heart to overcome. If this explanation were correct, it is impossible to see why reflex acceleration does not occur when the effect of the vagi upon the heart has been restored by the artificial stimulation of these nerves. A few experiments on the effect upon the heart rate of stimulating the cerebral cortex may be referred to here. The suggestion that the accelerator nerves may be thrown into activity by processes originating in the cerebrum is frequently made; hence it seemed possible that stimulation of the cerebral cortex might yield interest- ing results. Accordingly in a number of experiments upon dogs the motor areas and various parts of the frontal and occipital lobes were stimulated with the faradic current. Acceleration of the heart frequently occurred when the vagi were intact and in tonic activity, but no acceleration was obtained after section of the vagi, either when the heart was beating rapidly, or when it was slowed by stimulating the peripheral end of the vagus. Influence of the tonic activity of the accelerators upon reflex accelera- tion. — Although, as has been shown above, reflex acceleration is due to a diminution of the tonus of the vagi, and occurs after the acceler- ator nerves have been divided, yet these nerves, if they are in a condition of tonic activity, exert a modifying influence upon the course of the acceleration. The extent of the reflex acceleration, like the increase in the heart rate following section of the vagi, is in fact determined by two factors,—the cutting off of the influence of the tonic activity of the vagi, which of itself keeps the heart beating slowly, and the removal of the check to the tonic activity of the accelerators. This influence of the tonic activity of the accelerators is shown in three ways. In the first place, the rate to which the heart is accel- erated is, as a rule, greater when these nerves are intact than when they have been divided. Secondly, the course of the acceleration is, or may be, somewhat different; there may be, to begin with, a very sudden and marked acceleration, due to the inhibition of the tonic inhibitory impulses, and then an acceleration more slowly developed, 1 Roy and ADAMI: Philosophical transactions, 1892, 183 B, p. 267. Acceleration of the Mammatan Fleart. 447 due to the accelerator nerves; whereas after section of the acceler- ators reflex acceleration usually reaches its maximum very quickly, and is often followed by a partial return to the normal while the stimulation continues. In the third place, the after-effect of the stimulation is often different: when the accelerators are intact, the rate may continue rapid for some time after the stimulation ceases, and only slowly return to the normal, or give way to a secondary slowing. If, however, the accelerators have been divided, the rate after stim- ulation of a sen- sory nerve usually 0.60 returns quickly to the normal, or per- haps more fre- 0.50 quently is followed bya reflex slowing. yllthree of the © 0-40 above points are illustrated by the eunves tm is. 12 ; these results were ¢.95 obtained from an FiGuRE 12. Experiment H. Stimulation of the saphenous, experiment upona A, before, B, after, section of the accelerator nerves. The dog. stimulation continued 10 seconds in each case; the strength of the stimulating current was also the same. Or- dinates represent the duration of the heart-beat in 0.05 the saphenous in seconds ; the abscisse, 5 heart-beats. this case, when Stimulation of both vagi and accelerators were intact, caused the heart rate to increase from 224 to 31+ beats in 10 seconds. Section of the accelerators caused the heart rate to decrease to 19} in 10 seconds; stimulation of the saphenous now with the same strength of current as above caused the heart rate to be increased to but 24} beats in 10 seconds. Of course the objection may be made that the more rapid rate in the former case (z.¢. when the heart rate increased to 31) was due in part to a reflex stimulation of the accelerators, and not exclusively to a diminution of the tonic activity of the vagi. That, however, the latter factor alone is sufficient to account for the acceleration is shown by the following fact: before the saphenous nerve was stimulated or the accelerators cut, the conductivity of the vagi was suspended by ether vapor with the result that the heart rate increased to 34 in 10 seconds. 448 Reid Flunt. The rate 31 therefore does not represent the maximum acceleration which might have resulted from inhibition of the inhibitory impulses. The vagi were afterward cut with the result that the heart rate in- creased to 29 beats in 10 seconds. To summarize the results of this experiment and to show how completely the heart rate is determined at any given time by the interaction of the inhibitory and accelerator nerves, the following table may be given. Heart rate in Io seconds. Vagi and accelerators intact and in tonic activity. . . . ete re. 22 Activity of vagi suspended by ether vapor, the accelerators ene Intact. a4 Accelerators cut, vagi intact and in tonic activity. ........ 19 After section of accelerators and vagi. . . 6 6 So eee Reflex acceleration, accelerators and vagi beingintact. . .... . 31 Reflex acceleration after section of the accelerators. . . .. . . . 24 Stimulation of accelerators (weak current), vagi being intact . . . . 27 Stimulation of accelerators (current as before), vagicut . . . . . . 345 If, returning to the course of reflex acceleration, we compare the two curves given in Fig. 12, the following differences will be observed. When the accelerators were intact and the saphenous nerve stimu- lated, there was first a sudden marked shortening of the duration of the heart-beat; this was followed by a longer period in which the heart rate was very slowly increased. After cessation of the stimula- tion the acceleration of the heart continued for some little time. When, on the other hand, the saphenous was stimulated after section of the accelerators, there was also a sudden increase in the heart rate ; but this was soon followed by a slight slowing, and immediately after the stimulation there was a very marked slowing. The curves given above are intended only to illustrate the differ- ences which the section of the accelerators may make in a given experiment in the course of reflex acceleration; they are not intended to serve as types of the reflex acceleration occurring before and after section of the accelerators. No such types can be given, for the course of acceleration is seldom the same in any two experiments. Thus in one experiment the acceleration may be followed by reflex slowing, even during the stimulation of the sensory nerve, although the accelerators are intact and in tonic activity; whereas in another experiment reflex acceleration may continue long after the cessation of the stimulation, although the accelerators have been divided. In any one experiment, however, the section of the accelerators usually Acceleration of the Mammatan Fleart. AAQ has some such effect as that described in the above case, 7. e. the maximum acceleration is less and is more quickly developed and there is a greater tendency to a subsequent slowing. The parts taken by the inhibitory and accelerator nerves in causing reflex changes of the heart rate find a striking analogy in the relation of the oculo-motor and sympathetic nerves in reflex movements of the pupils. Thus, according to Braunstein,’ reflex dilatation of the pupil is due to an inhibition of the tonic activity of the oculo-motor centre, for it occurs after section of all the pupil-dilating fibres, if the oculo-motors are intact; on the other hand, no reflex dilatation of the pupil occurs after section of the oculo-motors although the pupil-dilating fibres are intact.2 Moreover, just as the tonic activity of the accelerator nerves modifies the course of reflex acceleration of the heart, so the tonic activity of the pupil-dilating fibres modifies the course of the reflex dilatation of the pupil; after section of these fibres the dilatation occurs more slowly, as some of the “dilating force’’ is lost. Some influences affecting the condition of the cardio-inhibitory centre. — With the exception of the respiratory centre there is perhaps no medullary centre in the cat and dog so easily influenced as that of the inhibitory nerves of the heart; Hering’s experiments on rabbits show that this, probably, is true for these animals also.* No attempt will here be made to discuss the influences affecting the condition of the cardio-inhibitory centre with any degree of fulness; only a few factors will be noted which it is necessary to take into consideration in connection with the question of reflex acceleration. Some influences increase, others decrease, the tonic activity of the cardio-inhibitory centre; among the former may be mentioned high blood pressure and deficient respiration, and among drugs morphine and, apparently, small doses of curare. Morphine causes slowing of the heart not only by its direct action upon the cardio-inhibitory centre, but also through its action upon the respiration. In animals 1 BRAUNSTEIN: Zur Lehre von der Innervation der Pupillenbewegung, p. 95; Wiesbaden, 1894. 2 In man, also, no reflex movements of the pupil are obtained after complete paralysis of the oculo-motor. The dilatation of the pupil resulting from stimulation of the cerebral cortex is also due, according to Braunstein (p. 116), to a diminution of the tonus of the oculo-motor centre. _ § HERING, H. E.: Archiv. f. d. ges. Physiol., 1895, 1x, p._429. 29 450 Reid Flunt. anesthetized by means of cerebral pressure the vagi are usually found to be in a condition of marked tonic activity. Ether and large doses of curare, and of chloroform, decrease or abolish the tonus of the vagus centre completely; * operations and loss of blood have the same effect, so that unless great care is taken in operating, the tonus of the vagi is completely lost. Not only does the extent of the tonus of the vagi vary widely in different animals of the same species, but the susceptibility of the centre to influences which increase or decrease the tonus also varies in different individuals. In most dogs, for example, morphine causes a very slow heart beat, but in some it has almost no effect upon the heart rate, although given in very large doses. The tonic activity of the vagi seems to be very slight in young animals, and to be very easily abolished in them. Influence of the condition of the cardio-inhibitory centre upon cardiac vefleres. It is obvious that no inhibition of a centre can occur unless the centre is in a condition of activity; but the question arises, Isa centre more easily inhibited the greater the activity, or is it more easily inhibited when influences are at work which tend, of them- selves, to weaken the activity? The results of my experiments upon the cardio-inhibitory centre indicate very clearly that the latter is the case; this was shown best, perhaps, in experiments on dogs narco- tized with morphine. In such animals the cardio-inhibitory centre is in a condition of marked activity, and stimulation of a sensory nerve often has at first no effect; if, however, some drug which of itself tends to destroy the tonus of the centre is given, the stimula- tion of a sensory nerve may cause a marked acceleration of the heart. Among the drugs which reduce the irritability of the cardio- inhibitory centre are ether and curare, as was mentioned above; if one of these is given to an animal under the influence of morphine, there may be an increase of the heart rate of short duration, and then the slow rate returns; stimulation of a sensory nerve now, however, may easily cause an inhibition of the centre and so an acceleration of the heart. Similar results are obtained in animals anzesthe- tized by cerebral pressure; in these animals the cardio-inhibitory centre is in a condition of strong activity, and stimulation of sensory 1 An irregular rhythm of the heart, probably due to the inhibitory nerves, is frequently made to disappear by the administration of ether or of curare, or by the stimulation of a sensory nerve, all of which cause a diminution of the vagus tonus. Acceleration of the Mammatian Fleart. A5I nerves may have no effect upon the heart or may cause a slowing. If, however, ether or curare is given, —although no visible change is produced, — stimulation of a sensory nerve usually will cause an inhibition of the centre. If both vagi are intact and in tonic activity, stimulation of a sensory nerve may have no effect upon the heart rate; but if one vagus be cut, — although this of itself may cause no increase in the heart rate, —stimulation of the same sensory nerve may cause a marked acceleration. Just the converse of the above holds good for reflex slowing of the heart. If the irritability of the cardio-inhibitory centre has been much reduced so that the heart is beating very rapidly, stimulation of a sensory nerve may have no effect upon it; if, however, the res- piration is diminished, or the blood pressure increased in some manner, or intravenous injections of warm normal saline solutions be made, — influences which tend to stimulate the centre, — then stimulation of a sensory nerve may cause a marked slowing of the heart. Such experiments as those briefly sketched above show that in order to obtain either reflex inhibition or reflex excitation of the cardio-inhibitory centre it is necessary that this centre be in a con- dition of unstable equilibrium; if the centre is in this condition, the result of stimulating a sensory nerve is determined in part (but only in part, as will be shown later) by the rate at which the heart is beating when the nerve is stimulated: if the heart is beating slowly, reflex acceleration results; if it is beating rapidly, reflex slow- ing occurs. Thus, in one of many experiments the heart rate was 24 in 10 seconds, and stimulation of the saphenous nerve caused the heart rate to decrease to 174. A small amount of warm normal saline solution was injected into the femoral vein, as a result of which the heart rate decreased to 18 in 10 seconds; stimulation of the saphenous now caused the rate to increase to 265 beats, but after the stimulation it returned to 18. Repeated stimulation, or sometimes a single stimulation of a sensory nerve, tends to cause permanent (7. e. permanent for the individual experiment) changes in the heart rate. Thus, if the heart is beating slowly, two or three stimulations of a sensory nerve may cause an acceleration of the heart which continues for hours, or as long as the experiment continues; simply ligating the sciatic nerve has caused a similar effect. If, on the other hand, the heart is beat- ' 452 Reid Flunt. ing rapidly, repeated stimulations may cause the rate to become and remain slow. These are further illustrations of the already mentioned tendency of the heart to reach and remain at a constant rate, whenever its rate has been changed. The afferent nerve fibres by which reflex acceleration is produced. — Attention has already been called to the part which the condition of the cardio-inhibitory centre plays in determining whether reflex acceleration or reflex slowing of the heart follows stimulation of afferent nerves: in this section some facts relating to the afferent nerve fibres themselves will be discussed. Aside from such nerves as the depressors and vagi, which are known to contain nerve fibres having special relations to the vaso- motor and respiratory centres, there is evidence that there are different kinds of afferent nerve fibres in other nerve trunks. In a previous paper, for example, I have collected evidence based on experiments of Howell and others and of my own which tends to show that in most mixed nerve trunks there are two varieties of nerve fibres which may influence the vasomotor centre, one causing a reflex rise, the other a reflex fall of blood pressure. These results suggest the question whether those nerve fibres, stimulation of which causes a reflex acceleration of the heart, will, under different circum- stances (when, for example, the condition of the cardio-inhibitory centre has been altered), cause a reflex slowing, or whether, in fact, there are two sets of nerve fibres, stimulation of one of which will always cause an acceleration, provided it has any effect at all upon the heart rate, while stimulation of the other set will cause a slowing. Further, what is the relation of the nerve fibres which cause reflex changes in the heart rate to those which cause changes in the blood pressure ? In the historical review given at the beginning of this part of the paper evidence was stated that stimulation of some nerves (e. g the trigeminus) nearly always causes a reflex slowing of the heart, whereas stimulation of certain other nerves (¢. ¢. the sciatic) more frequently causes an acceleration, or an acceleration first and then a slowing. I have observed in my own experiments that when the saphenous and the sciatic were stimulated in the same animal the former usually caused only an acceleration, while the latter frequently caused an acceleration followed by a slowing; moreover, slowing 1 Hunt: Journal of physiology, 1895, xviii, p. 381. Acceleration of the Mammalian Heart. 453 alone occurred more frequently from stimulation of the sciatic than of the saphenous. Since this difference of action of the various nerves was observed in experiments in which there was no reason for supposing that the condition of the cardio-inhibitory centre was different in one case from its condition in the other, the most prob- able explanation is that there are two varieties of nerve fibres in- volved, and that one variety occurs in larger number in some nerves than does the other variety. The fact also that stimulation of such a nerve as the sciatic has or may have a twofold action upon the heart, causing first a reflex acceleration and then a slowing,’ suggests that there are two sets of fibres involved, and that the action of one set becomes evident before that of the other.?, Such a double effect upon the heart is never, or only very rarely, observed when certain other nerves, such as the depressor or trigeminus, are stimulated. Working upon this supposition, many experiments were performed in the hope of finding a method by which the conductivity or irrita- bility of one set of fibres might be suspended while that of the other remained. The methods employed were in general the same as those which I employed to separate physiologically those nerve fibres which cause a reflex fall of blood pressure from those which cause a rise, and consisted essentially in subjecting the nerve trunks to influences which altered their conductivity or irritability, and then observing the effect upon the heart rate of stimulating them in various ways; of course precautions were taken to avoid causing, at the same time, changes in the cardio-inhibitory centre. Some of the methods employed, although giving evidence of the existence of two sets of fibres to the vasomotor centre, gave only negative results as to the afferent fibres to the cardio-inhibitory centre; one, however, the experiments on the regeneration of nerves, gave posi- tive results. Effect of stimulating the central end of a recently regenerated nerve. — Most of these experiments were performed upon the sciatic nerves of cats. One nerve was crushed by drawing a ligature tightly around 1 If, as is often the case, a rise of blood pressure also occurs from stimulation of the sciatic, this may be the cause, in part, of the slowing of the heart; the latter often occurs, however, when there is no change in the blood pressure, and also when there is a fall of blood pressure. 2 Cf. MELTZER: Archiv fiir Physiologie, 1892, p. 390 (afferent nerves to the respiratory centre); also my paper on afferent nerve fibres to the vasomotor centre, op. cit., p. 406. 454 Reid Hunt. it, high in the thigh; the wound was closed and the nerve allowed to regenerate. After a period of five or six weeks, or after signs of motion became apparent for some distance down the leg, the animals were anzesthetized (usually by cerebral compression), both sciatics exposed and divided, and the central ends stimulated with tetanizing currents of varying intensities. Six experiments were performed in this manner, and in all of them stimulation of the regenerated nerve produced a different effect upon the heart rate from that caused by stimulating the normal nerve. Stimulation of the former usually caused an acceleration of the heart ; in some cases no effect was produced, but in none was there a reflex slowing. Stimulation of the normal nerve in these animals caused in all cases a reflex slowing. One of these experiments was as follows. Experiment 32. Cat. Left sciatic crushed 42 days previously. Anzesthesia caused by cerebral pressure. Blood pressure 100 mm. of mercury. Stimula- tion of the left sciatic about 1} inches below point of injury, with currents of varying strength, caused a very slight acceleration of the heart; in one case, for example. the rate increased from 27 to 2g in ro seconds, the blood pressure remaining unchanged. Stimulation of the right (normal) nerve caused only reflex slowing ; during one stimulation, for example, the rate decreased from 274 to 20 in ro seconds, while the blood pressure fell 2 mm. of mercury. The results of the above experiment differ from those usually observed in that stimulation of the nerves in this case caused no change in the blood pressure, whereas stimulation of the normal nerve usually causes a rise, and stimulation of the regenerated nerve a fall, of blood pressure. The absence of any changes in the blood pressure in this experiment makes it improbable that blood pressure changes were the cause of the difference in the effect upon the heart rate in the other experiments; there is, moreover, other evidence for this view. Thus, if an unusually long interval be allowed to elapse between the crushing and the stimulation of the nerve, the power of a portion of the nerve near the point of injury to cause a reflex fall of blood pressure may be lost, while that to cause acceleration remains. Thus, in one experiment 48 days were allowed to elapse between the operation and the stimulation of the nerves; the result was that stimulation of the nerve at a certain distance from the point of injury caused a rise of blood pressure, while the heart rate was increased from 18 to 24 beats in 9g seconds. Also, on the other Acceleration of the Mammatan Fleart. 455 hand, stimulation of the normal nerve may occasionally cause a fall of blood pressure, although a reflex slowing of the heart occurs. I think the above considerations show sufficiently clearly that the changes in the heart rate are independent of the changes in the blood pressure. The most probable explanation of the result of these experiments is that in such mixed nerve trunks as the sciatic, there are two sets of afferent nerve fibres to the cardio-inhibitory centre, one of which causes inhibition, the other stimulation, of this centre, and that in a nerve which has been crushed the former regenerates more rapidly than do the latter. Of course it is not necessary to suppose that the only function of these nerve fibres is to affect the cardio-inhibitory centre; they are probably ordinary sensory nerve fibres which can cause other reflexes, only some of them are connected with the vagus centre in such a way that their stimulation inhibits, while that of the other excites, this centre. What little evidence there is to connect either of these varieties of nerve fibres with other varieties (those causing changes in the vasomotor centre, for example) will be given below. Liffect upon cardiac reflexes of cooling the afferent nerve.— One of the simplest ways of separating physiologically the nerve fibres, stimulation of which causes a reflex rise of blood pressure from those which cause a fall, is to cool the nerve trunk and then stimulate it below the point of cooling; the reflex vaso-constrictors lose their conductivity at a higher temperature than do the reflex vaso- dilators. My experiments so far have failed to show any difference in the action of cold upon the fibres causing a reflex slowing and those causing a reflex acceleration of the heart. Cardiac reflexes, whether acceleration, slowing, or the two combined, as a rule have disappeared at about the temperature (10° C. or less) at which a reflex rise of blood pressure was no longer obtained; when the cool- ing was continued below this point stimulation of the nerve caused a fall of blood pressure but no effect upon the heart rate. Effect of varying the strength and rate of stimulation. — My obser- vations upon these points were confined almost exclusively to experi- ments upon the sciatic of the dog. When stimulation of this nerve causes a reflex acceleration, there is usually a certain strength of current, varying in different cases, which gives the maximum acceler- ation, that is, causes the greatest number of additional heart beats. If the strength of the current is reduced below this optimum degree, the 456 keeid Flunt. maximum acceleration reached during stimulation may not at first be decreased, but the acceleration does not continue so long after the stimulation ceases; if, however, the strength of the stimulus is still further reduced, the maximum acceleration becomes less. When, on the other hand, the strength of the current is increased beyond the optimum, there may be at first a slight increase in the maximum acceleration reached, but this is followed by a greater tendency to slowing. This tendency to slowing becomes, as a rule, more and more marked as the strength of the current is increased, and sometimes stimulation produces only slowing; the latter result, however, is rather infrequent. As a rule, if there has been an acceleration with a weak stimulus, there is an equally great or greater acceleration with a stronger stimulus; the tendency to subsequent slowing is greater in the latter case.1 As regards the strength of current necessary to cause reflex changes in the heart rate, as compared with the strength necessary to cause other reflex effects, it may be said that, in general, when the vagus is in tonic activity and the vasomotor centre is irritable, a stimulus too weak to affect the one is also usually without effect upon the other. Frequently neither the heart rate nor the blood pressure is influenced by a stimulus which causes respiratory and other reflex movements. The results of stimulating a sensory nerve with a succession of induction shocks slowly repeated do not differ materially from those obtained with tetanizing currents; the only difference is that with the former method the acceleration or slowing is more slowly developed. The above experiments and considerations seem to me to afford clear evidence for the view that there are two varieties of afferent nerve fibres to the cardio-inhibitory centre, one causing an excitation and the other an inhibition of this centre. The mere fact that in the same animal stimulation of one nerve may cause a reflex slowing and stimulation of another, a reflex acceleration of the heart, when the condition of the centre has undergone no change, is difficult to explain on any other hypothesis. Moreover, in the regeneration method we have a means of showing the presence of two sets of nerve fibres in the same nerve; when the nerve is crushed and i Simanowsky is quoted (Jahresbericht der Anatomie und Physiologie, 1881, x, p- 62) as having observed that stimulation of the brachial and sciatic plexuses with a weak stimulus caused an acceleration, while a strong stimulus caused a slowing of the heart. MacWilliam (Proceedings of the royal society London, 1893, lili, p. 471) obtained similar results. Acceleration of the Mammalian Fleart. 457 allowed to regenerate, those fibres causing an inhibition of the centre regenerate earlier than do those which cause an excitation. If the cardio-inhibitory centre underwent changes in irritability in the course of the experiment, it would be easy to see how stimula- tion of the same nerve fibres might in one case cause inhibition and in another excitation, just as the condition of the cerebral cortex or of the cardiac muscle is supposed to determine whether stimulation shall cause inhibition or augmentation; but in the above experiments changes in the centre were excluded. We have, further, no evidence that stimulation of the one set of fibres can ever under any circumstances cause any change but a reflex slowing, or stimulation of the other set anything but a reflex acceleration of the heart. Although, as was shown above, the condition of the cardio-inhibitory centre plays an important part in determining the manner in which this centre responds to the stimulation of a mixed nerve, such as the sciatic, yet this influence is limited to determining whether the centre responds to the impulses reaching it along the one or the other set of fibres; in other words, when both sets of fibres are stimulated inhibition or increased action will result according as the centre is more irritable to the one or the other set of impulses. The relation which these fibres to the cardio-inhibitory centre bear to other nerve fibres — those to the vasomotor centre, for example — is an interesting but very complex problem. The experiments on regenerating nerves suggested at first that the fibres which cause a reflex fall of blood pressure are identical with those causing a reflex acceleration of the heart. The experiments on the effect of cold upon the nerves, however, show that the two sets of fibres can- not be identified in this manner, for cold causes the fibres which produce reflex changes in the heart rate to lose their conductivity earlier than those which cause a fall of blood pressure. For a similar reason it seems impossible to identify the fibres which cause a rise in blood pressure with those which cause a slowing of the heart. Of course the relative irritability of the cardio-inhibitory and vaso- motor centres probably exerts an important influence in this matter, and a more thorough investigation may show the following view to be incorrect, but at present it is difficult to avoid the conclusion that we are dealing with four varieties of nerve fibres: (1) those causing a reflex rise of blood pressure, (2) those causing a reflex fall of blood 458 Reid Hunt. pressure, (3) those causing a reflex slowing of the heart, and (4) those causing a reflex acceleration of the heart. These four varieties of nerve fibres are very unequally distributed in different nerve trunks, some being entirely absent from certain of them. Thus there is no satisfactory evidence that there are fibres in the depressor which ever cause a reflex rise of blood pressure,’ or that the saphenous of the cat contains any fibres which can cause a fall;? as has already been pointed out, stimulation of the trigeminus, if it has any effect upon the heart, always causes a slowing, and v. Cyon® found only an acceleration to result from stimulation of the third root of the de- pressor. The glossopharyngeal usually causes a fall of blood pres- sure and a slowing of the heart, the infraorbital* a rise of blood pressure and a slowing of the heart, while stimulation of the sciatic may cause either a rise or a fall of blood pressure and either a slow- ing or an acceleration of the heart. PART ITI, GENERAL CONSIDERATION OF RESULTS. Functions of the accelerator nerves. — In speaking of the functions cf the accelerator nerves it is necessary to distinguish the effect which these nerves have upon the rate from their effect upon the force of the heart-beat. It is well known that these two effects have no constant relation to each other; in fact they seem almost always to occur separately. Thus in very few of my own experiments in which acceleration of the rate has been observed has there been any evidence that the force of the beats has been increased; a rise of blood pressure was exceptional, and when present bore absolutely no relation to the increase in the rate. Although the same observa- tion has been recorded by almost every one who has worked upon this subject, the statement is still frequently made that the increase in the heart rate leads to a rise of blood pressure. On the other hand, in those experiments in which increase in the force of the heart-beat has been found to follow stimulation of 1 See v. Cyon: Archiv f. d. ges. Physiol., 1898, lxx, p. 229. 2 Hunt: Journal of physiology, 1895, xviii, p. 386. 3 vy. Cyon: of. cit., p. 142. 4 KNOLL: Sitz.-Ber, d. kais. Akad. d. Wiss., math.-naturw. Cl., 1885, xcii, 3, Pp. 449. Acceleration of the Mammalian Heart. 459 the accelerators there has been as a rule little or no acceleration of the rate. Thus in my own experiments when arise of blood pressure occurred it usually resulted from stimulation of the accelerators of the left side, and as I have already shown these nerves have, as a rule, but little effect upon the heart rate. It is interesting that in the experiments which Roy and Adami,’ who studied the effect of the accelerators upon the force of the heart-beat very carefully, quote to show the effect of direct stimulation of these nerves upon the heart, there is a marked increase in the force of the heart while there is scarcely any change in the rate. Such facts as the above have led to the suggestion that there are really two kinds of nerve fibres in the accelerator nerves: one which causes increase in the rate, and another which causes an increase in the force of the beat. The former variety may be called the acceler- ator, the latter the augmentor nerve fibres. The function of the augmentor fibres is doubtless to cause a rise of general blood pressure, or, as Roy and Adami? put it, “ they sacrifice the heart in order to increase the output of the organ and enable the ventricles to pump out their contents against heightened arterial pressure.” The principal functions which can be ascribed to the nerve fibres which cause an increase in the rate of the heart with no effect upon the blood pressure have been referred to already when their tonic activity and relation to the vagi were discussed. From the experi- ments on the effects of cutting these nerves two conclusions may be drawn: (1) the normal rate of the heart is determined in part by the impulses constantly reaching it through these nerves, (2) in cases in which the irritability of the heart is low, the tonic activity of these nerves plays an important part in maintaining the regular rhythm of the heart. Attention was also called to the fact that the accelerator centres and nerves are very resistant to influences (low blood pres- sure, extreme asphyxia, certain drugs, etc.) which quickly depress other nerve centres and even affect the cardiac muscle itself; hence these nerves, in virtue of their tonic activity, are in a posi- 1 Roy and Apamr: Philosophical transactions, 1892, 183 B, p. 244, see curve 14, p. 239, stimulation of left annulus, and curve 15, p. 241. In most of the ex- periments upon which these authors base their views of the effect of the accel- erators upon the force and output of the heart acceleration was produced reflexly by the stimulation of a sensory nerve; as has been shown above it is very improb- able that the acceleration in such cases was due to the accelerator nerves at all. 2 Roy and ADAMI: of. cit¢., p. 296. 460 Reid Hunt. tion to supply an efficient stimulus to the heart when one is most needed. It was shown further that the tonic activity of these nerves limits the action of the vagi; when the heart is slowed by reflex stimula- tion of the vagus, not only do the accelerators limit the extent of the slowing, but they enable the heart to return more quickly to its normal rate. It is probable that this action of the accelerators is very important in counteracting influences which cause reflex slow- ing of the heart, such, for example, as injury to the abdominal viscera, and perhaps also in asphyxia. Nothing definite can be said as to the part the accelerators play when they are thrown into increased activity, as so little is known about the conditions under which this occurs; in fact, little can be added to the statements made by the brothers Cyon more than thirty years ago. These physiologists, who recognized that there is not necessarily an increase in the work done when these nerves are stimulated, suggested that their function consisted in diminishing the resistance which the vagi opposed to the development of the heart-beat. Although the total amount of work done by the heart when it is accelerated by stimulation of these nerves is not increased (the work being simply differently distributed in time, as the Cyons expressed it), yet, as has been already shown, this acceleration causes fatigue of the heart; perhaps this fatigue is due to the shortening of the periods during which the heart is at rest. In what manner either the heart itself, or the rest of the body, benefits by the more rapid rate (which of itself causes fatigue of the heart) is obscure. Possibly some clue to this problem is to be found in the work on the transfusion of blood through isolated organs. It has become the generally recognized view that in such experiments much better results are obtained when the stream of blood is supplied intermittently * than when it is supplied at a constant pressure. If the blood is sup- plied under constant pressure, cedema and other pathological changes appear in the organ under experiment,” and the circulation is soon slowed, or even arrested altogether; this is due in part to the cor- 1 Although Kronecker, in 1871, stated that less injury is done to the vessels of a muscle by high pressure if this is intermittent than when it is constant, Stevens and Lee (Studies from the biological laboratory, Johns Hopkins University, 1884, ili, p. 109) seem to have been the first actually to make use of an intermittent supply of nutrient fluid in transfusion experiments. 2 HAMEL: Zeitschrift fiir Biologie, 1889, xxv, p. 492. Acceleration of the Mammalian Fleart. 461 puscles adhering to the walls of the blood vessels and to each other,? and even a great increase in the pressure causes but a temporary improvement. If, however, the blood is supplied intermittently, the slight movement of the corpuscles at each pulsation and the conse- quent changes in the diameter of the blood vessels prevent this clumping together of the corpuscles, and the transfusion can be con- tinued for a much longer time at a comparatively low pressure.” I have been unable to find any statements as to the number of pulsations per minute which yield the best results in transfusion ex- periments; this number would probably be influenced by such factors as the nature of the blood-vessel walls, the length of the capillaries, etc., so that it is very probable that a rate which is suitable for one organ would not be adapted to another. Support for this supposition is found in v. Cyon’s work on the circulation through the thyroid gland: ® v. Cyon showed that when the heart was beating slowly, as a result of stimulating the vagus, a much greater amount of blood flowed from the thyroid vein than when the heart was beating more rapidly, although the blood pressure was the same and vasomotor changes in the gland were excluded; the outflow from the saphenous vein was also increased, but relatively to a much less degree than that from the thyroid vein. In the light of such experiments as the above it seems quite proba- ble that conditions may arise under which the circulation of an organ may be better provided for by a series of rapid heart-beats, each of which throws out a smaller quantity of blood, than by a slower rate with which the output at each beat is greater. In fact certain changes in the respiratory waves of the curve of blood pressure result- ing from the stimulation of the accelerator nerves seems to point to such anaction. One of the most constant effects upon the blood pres- sure curve of stimulating the accelerator nerves is a marked increase in the amplitude of the respiratory undulations; this occurs not only when the blood pressure rises or remains at the same level, but also when it falls; and further, it occurs in animals under curare and in which artificial respiration is maintained by a pump or pair of bellows which discharges with great regularity the same amount of 1 von Frey: Archiv fiir Physiologie, 1885, p. 538. Welch and Mall consider -that the absence of pulsation in an occluded artery plays an important part in the production of a hemorrhagic infarction. 2 JAcosr: Archiv f. exper. Pathol. u. Pharmakol., 1890, xxvi, p. 398. o Vet CVON2 Of: C72, Ps TOT 462 Red Hunt. air at each stroke. If changes in both the blood pressure and the volume of the respired air are excluded, as is the case in such experi- ments as these, then the increased amplitude of the respiratory waves seems to indicate that a larger volume of blood is passing through the lungs at any given time, and this, in turn, that a larger amount of blood is being returned to the right auricle through the systemic vessels. Of course the increased amplitude of these waves may have been due in part to the faults of the mercury manometer, that is, when the heart was beating more slowly the excursions of the column of mercury were increased so greatly by its inertia that the respiratory undulations were obscured, whereas with the more rapid rate the effects of the mercury’s inertia were less marked. But it does not seem probable that this change in the respiratory waves can be explained entirely in this manner, for not only are these waves often marked when the heart is beating slowly, but their amplitude is frequently increased by injecting a large amount of normal saline solution into the circulation, although no changes occur in the blood pressure and heart rate, or at least do not occur for some time after the changes in the respiratory waves. The increased amplitude of these waves after the injection of normal saline solution is almost certainly due to the larger amount of liquid in the vessels of the lungs; the same change occurring after stimulation of the accelera- tors is probably due to a similar cause. Finally the experiments of Stevens and Lee upon the action of intermittent pressure upon the blood vessels of the frog and terrapin suggest the possibility that the accelerators may, at times, play a part in maintaining the normal tone of the blood vessels. These authors found that ‘a rhythmically interrupted force applied to the blood vessels of the frog and terrapin through the medium of a circulating fluid exerts a special action upon them, in consequence of which a constriction of them takes place;” as a result of such action a much smaller amount of liquid supplied intermittently is needed to maintain a given arterial pressure than when the force is a constant one. No experiments were made to determine the number of interruptions which give the best results; it is probable, however, that this number would be found to differ in the case of the vessels of different organs, so that in some a rapid, in others a slow, rate would have the more marked effect. Rapid heart action of other than reflex origin. — There are many cases of rapid heart action of other than reflex origin upon which Acceleration of the Mammalian Fleart. 463 the experiments described in this paper may throw some light; a few such cases will be considered briefly. Voluntary acceleration of the heart. — The power which some persons have of voluntarily increasing the heart rate has been studied with especial care by Tarchanoff' and Pease,? and more recently by Van de Velde.’ Tarchanoff made a number of experiments in order to determine the cause of the acceleration, z. e. whether it is due to a diminution of the tonic activity of the vagi or to astimulation of the accelerators ; he reached the conclusion that the acceleration is due to a direct action upon the centres of the accelerator nerves. The grounds for this conclusion were three: (1) the manner in which the accelera- tion appeared and disappeared, (2) the changes in the form of the sphygmograms, and (3) the changes in the volume of the extremi- ties. Tarchanoff found that in the person upon whom he experi- mented, the maximum acceleration was reached only after one half to three quarters of a minute after the beginning of the effort to increase the heart rate; the return to the normal rate was also gradual. Comparing the slow development of the voluntary acceleration with the rapid development following the section of the vagi, Tar- chanoff drew the conclusion that the voluntary acceleration was due to the accelerator nerves. It does not seem to me that this argument is at all conclusive. It does not seem fair to compare the effect of section of the vagi, which causes an immediate effect on the heart rate, with the acceleration following a distinct effort of the will. It has also been shown above that under certain circumstances the diminution of the tonicity of the vagus caused by the stimulation of a sensory nerve may be very slowly developed and very slowly dis- appear. Moreover, in one of Van de Velde’s patients the maximum acceleration occurred in the first 10 seconds of the effort; whereas Bohm in experiments upon animals found from the examination of a large number of tracings that when the accelerators were stimulated directly the maximum acceleration occurred asa rule in the second 1 TARCHANOFF: Archiv f. d. ges. Physiol., 1885, xxxv, p. 109. 2 PEASE: Boston medical and surgical journal, 1889, cxx, p. 526. 8 VAN DE VELDE: Archiv f. d. ges., Physiol., 1897, Ixvi, p. 232. 4 Van de Velde compares the effort necessary to cause acceleration to the feeling experienced when a person attempts to perform some unusual muscular movement, such, for example, as contracting the muscles of the ear, or flexing indepen- dently the last phalanx of the finger. 464 Red Hunt. 10 seconds of the stimulation. In the experiments of Pease also the latent period seems to have been very short; thus in some of the tracings given the first beat after the effort was made seems to have been shortened and the greatest acceleration to have occurred in the first two or three seconds, the entire effort continuing but five seconds. We certainly have no reason to suppose that the accelera- tors can be thrown into activity by an act of the will more quickly than when they are stimulated directly by the electric current. It is also worthy of note that in the case of Salomé, upon whom most of Tarchanoff’s experiments were made, acceleration of the heart easily resulted from slight external causes, —a fact which, judg- ing from experiments upon animals, points to an unstable condition of the cardio-inhibitory centre. The second argument which Tarchanoff brings forward in support of his view — the changes in the form of the sphygmogram — seems to me to be still less conclusive, owing to the difficulty of interpret- ing these curves; in fact the changes which Tarchanoff adduces as evidence that the increase in the heart rate was due to the action of the accelerators are very nearly the same as those which Nothnagel brought forward to show that in some cases of rapid heart action the increase comes from a diminution of the vagus tonus. The third argument of Tarchanoff in support of the above view is that when the heart rate increased, the volume of the foot, as deter- mined by the plethysmograph, was not increased, although, accord- ing to Tarchanoff, an increased volume would necessarily have occurred as a result of the augmented blood pressure if the accel- eration in rate had been due to a diminution of vagus tonus; it is however, by no means uncommon for section of the vagi to cause acceleration of the heart without any increase in the blood pres- sure occurring — in fact there is sometimes a fall of general blood pressure. In the light of these considerations it seems to me that the evi- dence for the view that voluntary acceleration is due to the action of the accelerator nerves is entirely inconclusive; in fact I am inclined to think that the weight of evidence is rather in favor of the view that it is due to a diminution of the tonus of the vagi. Acceleration of the heart during muscular exercise. — The influence of the cardiac nerves on the increase in the heart rate during muscu- lar exercise has been most carefully studied by Hering! This author 1 HERING, H. E.: Archiv f. d. ges., Physiol., 1895, 1x, p. 429. Acceleration of the Mammatan Ffeart. 465 reaches the conclusion that the acceleration is due in part to an in- creased activity of the accelerator nerves, perhaps of reflex origin, and in part to a diminution of the tonic activity of the vagi caused by the increased respiratory movements. It seems to me that a careful examination of Hering’s experiments shows that the diminution of the tonic activity of the vagi is sufficient to explain his results, and that there is no clear evidence for believing in any increased action of the accelerators; the tonic activity of the latter nerves plays, however, a very important part here, as in the acceleration following stimulation of sensory nerves. Without going into too many details, the following observation on Hering’s experi- ments may be made. The average rate of the heart reached during muscular exercise in a number of experiments was 320 beats per minute, whereas the average rate during rest after section of the vagi was 321. Moreover, in one half of these experiments (see table p- 440) the maximum rate reached during exercise was less than or just the same as the rate in rest after the vagi were cut; in the other half of these experiments the maximum acceleration in exercise after the vagi were cut-was less than 7 per cent. This acceleration of 7 per cent may have been due to a stimulation of the accelerator nerves, but it should be observed (1) that in other experiments (p. 476) in which both the vagi and accelerators had been cut a much greater acceleration (33 per cent and more) — due probably to changes in the respiration and blood pressure — was observed, and (2) that direct stimulation of the accelerators after section of the vagi may cause a much greater increase in the heart rate; the Cyons, for example, obtained an acceleration of over 50 per cent in such experiments. On the other hand Hering’s results show very clearly that the acceleration of the heart rate in exercise was much less after section of the accelerators; the average acceleration was but two-fifths as creat as when they were intact. I think, however, that this difference can be attributed entirely to the removal of the tonic impulses of the accelerators. That the accelerators were in tonic activity in these experiments is made almost certain by the fact that when the vagi were cut after section of the accelerators there was but a slight increase in the heart rate; the greatest increase was 60 and the average 31 beats per minute, whereas in another series of experi- ments in which the vagi alone were cut the average increase was 122 beats and the smallest increase (and this was a very exceptional case) 30 J 466 Reid Hunt. was 68.1 Itseems to me that these results, so far as the influence of the cardiac nerves is concerned, can be explained in exactly the same way as the acceleration following stimulation of a sensory nerve, namely, the essential factor in the acceleration is a diminution of the activity of the cardio-inhibitory centre; if the accelerator nerves are intact and in tonic activity the maximum rate reached is greater than when they are not in activity, but there seems to be no sufficient evidence for supposing that these nerves are thrown into increased action in muscular exercise. Athanasiu and Carvallo? have also recently studied this question, and reached the conclusion that the essential factor in the accelera- tion is the reflex diminution of the activity of the cardio-inhibitory centre; their tracings also show that the latent period of the acceler- ation in muscular exercise is very short. MacWilliam,? who believes the acceleration to be of vagus origin, has called attention to the fact that in those animals which are capable of long continued muscular exercise (such as the horse, dog, and hare) the vagi are in a condition of marked tonic activity, while in such an animal as the rabbit, which is not capable of so prolonged exertions, the tonic activity of the vagi is not so marked. Acceleration following compression of the carotids. — Cooper and Magendie stated that acceleration of the heart results from the com- pression of the carotid; this subject has been studied with especial care by Francois-Franck,* who considered acceleration to be due to a stimulation of the accelerator nerves. Examination of the curves and the descriptions of the experiments of Francois-Franck show that in most cases the vagi were intact; in other cases nothing is said about the vagi. The curves published by this author are strikingly like the curves of reflex acceleration obtained by stimu- lating a sensory nerve after section of the accelerators; the second, and in some cases the first, heart-beat after compression of the carotid was shortened, and after the compression ceased the heart returned instantly to its previous rate or was slowed, the very first beat being 1 Hering commented on the slight increase in the heart rate following section of the vagi after previous section of the accelerators, and recognized that the integ- rity of these nerves is an important factor in the acceleration following section of the vagi, but he seemed to hesitate to interpret his results as evidence for the tonic activity of the accelerators. (See also note on p. 397.) 2 ATHANASIU and CARVALLO: Archives de physiologie, 1898, p. 561. 3 MACWILLIAM: Proceedings of the royal society, London, 1893, liii, p. 476. 4 FRANCOIS-FRANCK: Travaux du laboratoire de Marey, 1878-79, p. 74. Acceleration of the Mammalian Frleart. 467 either of the normal length or prolonged. Francois-Franck noted the very short latent period as compared with the latent period when the accelerator nerves are stimulated electrically, and suggested that the difference may be due to the normal stimulus from the central nervous system acting differently from direct electrical stimulation ; but there seems to be no evidence for this supposition. It is true that Francois-Franck states that no acceleration occurred after extir- pation of the inferior cervical and first thoracic ganglia; but such an operation, unless performed with great care, destroys the tonicity of the vagus centre. Many more cases of acceleration of the heart in which diminution of the tone of the vagi is probably the chief factor might be cited. Thus the acceleration accompanying each act of deglutition in man,’ that occurring during each inspiration,? and the increase in the heart rate when the lungs are inflated by a pair of bellows,’ all seem to be due to a diminution of the tonic activity of the vagi. The cause of the rapid heart rate observed in certain diseases,* and after the admin- 1 MELTZER: Archiv fiir Physiologie, 1883, p. 223. 2 FREDERICQ: Archives de biologie, 1882, iii, p. 86. 3 HERING: Sitz.-Ber. d. kais. Akad. d. Wiss., math.-naturw. Cl, 1871, lxvi, 2, p. 248. See also H. E. HER1ING: Archiv f. d. ges. Physiol., 1895, lx, p. 461. 4 The rapid heart action in paroxysmal tachycardia is sometimes referred to a diminution of the tonus of the vagus, sometimes to a stimulation of the accelerators ; there seems to be little unanimity of opinion among those who have described this condition. The above experiments upon animals seem adapted to throw some light upon this subject. Unless we assume that the accelerator nerves of man are very different physiologically from those of the lower animals, it seems impossible to accept the view that in some cases of tachycardia the rapid rate of the heart is due to a stimulation of the accelerator nerves. Thus there are cases reported (by H. C. Wood, e. g. University medical magazine, 1890-91, ili, p. 273, and by Hochhaus, Deutsches Archiv fiir klinische Medicin, 1893, li, p. 19) in which the rapid action of the heart ended instantaneously, the rate decreasing in one case from 184 to 78 per minute; experiments on animals show that stimulation of the accelerators is always followed by a long after-effect upon the heart. Again, the rapid action of the heart in these cases may continue for days, the heart beating continuously at double or more than double its normal rate; such an acceleration in animals can be maintained for but a very short time by powerful electrical stimulation of the accelerators. On the other hand, many of these cases can be easily explained by the diminu- tion of the tonus of the inhibitory nerves. I have shown above how easy it is to get the cardio-inhibitory centre into a condition of unstable equilibrium by the action of drugs, changes in blood pressure, respiration, etc. ; I have also called attention to the fact that there are great individual variations, the centre being inhibited in some animals with ease, in others of the same species with difficulty. When the cardio-inhibitory centre is in such a condition of unstable equilibrium, very slight 468 Reid Hunt. istration of drugs, is in many cases obscure; but there seems as yet to be no evidence inconsistent with the view that in these cases the action is, as a rule, either a direct one upon the heart itself or upon the cardio-inhibitory centre. Unusual difficulties are met with in investigating the effect of psychical influences upon the heart rate, but there seems to be no reason for supposing that the acceleration in such cases is different in origin from that in the cases which have been discussed above. Leaving out of consideration the cases in which the cause of the acceleration is doubtful, and admitting that in some of those dis- cussed above the acceleration is due in part to a direct action of the accelerator nerves, it must still be granted that decrease of the tone of the cardio-inhibitory centre is the most usual cause of an increase in the heart rate. When it is remembered what an important part inhibition in one form or another plays in other functions of the body, — how, for ex- ample, it seems to occur in every act of respiration,’ in every move- ment of a limb,? how important it is in movements of the pupil,’ the regulation of the flow of the blood, the movements of the intestine, causes —a little ether or curare, weak stimulation of a nerve, a little operating, etc. — are sufficient to cause a marked acceleration of the heart; this acceleration may con- tinue foralong time. If we assume that in the patients who suffer from paroxysmal tachycardia the cardio-inhibitory centre is in an unstable condition (usually as an individual peculiarity, though this condition seems to be exaggerated at times by such influences as recent illness. excessive use of alcohol, coffee, etc.), it is easy to see how some slight change might bring on an attack. Among the exciting causes mentioned (see Prébsting, Deutsches Archiv fiir klinische Medicin, 1882, xxxi, p- 349, and Herringham, Edinburgh medical journal, 1897, i, p. 367) are sudden exertions or injuries, digestive and uterine disturbances — influences which might readily cause a reflex inhibition of the vagus centre. In some cases pathological changes of the pericardium and of the myocardium are described ; in the light of the experiments of Knoll upon the reflexes from the heart it is not improbable that such changes can cause a reflex inhibition of the cardio-inhibitory centre. That diminution of the tonic influence of the vagi is sufficient to account for the rapid heart observed in most cases of tachycardia follows from the effects of injuries to the trunk of the vagi; Edinger says that a heart rate of 240 per minute and more has resulted in man from such injuries—a rate which is not often exceeded in paroxysmal tachycardia. 1 MELTZER: Archiv fiir Physiologie, 1892, p. 340. 2? HERING and SHERRINGTON: Archiv f. d. ges. Physiol., 1897, Ixviii, p. 222. SHERRINGTON : Journal of physiology, 1899, xxiii, suppl., p. 26. 8 BRAUNSTEIN: Zur Lehre von der Innervation der Pupillenbewegung, 1894, Pp. 95: Acceleration of the Mammalan Heart. 469 etc.,) it is not surprising that the body should make use of it in regulating the rate of the heart-beat. Not only can an increase in the heart rate be caused more quickly by an inhibition of the cardio- inhibitory centre than by a stimulation of the accelerator centre, but it probably involves a smaller expenditure of energy. Although the accelerator nerves take no direct part in the production of a more rapid heart-beat (z. ¢. they are not thrown into increased activity), yet it is largely in virtue of their tonic activity that inhibition of the vagus centre leads to such prompt results. Whether an inhibition of the accelerators leading to a slowing of the heart ever occurs is not known. It is not improbable, however, that changes in the tonicity of the accelerator centre occur, the tonicity being at one time increased and at another decreased, but there seems to be no evidence that such changes are ever produced suddenly, for example, as a result of a reflex act. SUMMARY OF RESULTS. The chief facts brought out in this paper may be summarized as follows : — ¥ (1) The accelerator nerves of the dog, cat, and rabbit, and prob- ably of other mammals, are almost always in tonic activity; the tonic activity of the accelerators is not impaired by influences which abolish not only the tonic activity but also the irritability of many other nerve €entres: (2) Under some circumstances the tonic activity of the accelerators is an important factor in maintaining the normal rhythm of the heart, and stimulation of them will sometimes cause an irregular heart to become regular; this action of the accelerator seems to be most marked in cases in which the irritability of the cardiac muscle has been reduced in some manner. (3) Stimulation of the accelerators, if excessive, will decrease the rate of beat, and make the heart more irritable to impulses reaching it through the vagi. Even death may result from the excessive stim- ulation of these nerves. These facts indicate that the stimulation of the accelerators can cause real fatigue of the cardiac muscle. (4) New evidence is afforded for the view that the inhibitory and accelerator nerves are strictly antagonistic ; this antagonism applies to 1 For other illustrations of inhibition, see MELTzER: Archiv fiir Physiologie, 1883, pp. 225-235. 470 Reid Hunt. both systole and diastole, but with the same strength of current the systole is more easily influenced by stimulation of the accelerators, and the diastole by stimulation of the inhibitory nerves. (5) The tonic activity of the accelerators limits the tonic activity of the inhibitory nerves, and vice versa ,; the normal heart rate, so far as this is governed by the extra-cardiac nerves, is determined by the impulses reaching it simultaneously through these two channels. (6) The inhibitory nerves exert a protective influence over the heart; not only do they restrain the action of the accelerators, but their stimulation seems to improve the condition of the heart. (7) The view that reflex acceleration is caused by inhibition of the cardio-inhibitory centre is confirmed; no evidence could be found that the accelerator nerves are ever thrown into action reflexly. (8) The tonic activity of the accelerator nerves exerts a modifying influence over reflex acceleration; the maximum acceleration is greater, and is longer continued, and there is less tendency to a subsequent slowing when these nerves are intact. (9) There are probably in most nerve trunks two varieties of nerve fibres to the cardio-inhibitory centre; one variety causes an inhibition, the other an excitation of this centre. When a nerve is crushed the former variety regenerates earlier than the latter. (10) The most important functions of the accelerators seem to be connected with their tonic activity; aside from this their functions are obscure, but it is not improbable that by altering the rate of the heart-beat they exercise an important influence upon the circula- tion through certain organs. (11) It is very probable that almost all cases of rapid heart action are due to a diminution of the tonic activity of the cardio-inhibitory centre. fae PHYSIOLOGICAL ACTION OF EXTRACTS: OF THE SYMPAPRHETIC GANGEFA By ALLEN CLEGHORN. [From the Laboratory of Physiology in the Harvard Medical School.] HE presence of peculiar polygonal cells which stain deeply in chromic acid or its salts in the medulla of the suprarenal bodies and in the sympathetic ganglia of the higher vertebrates has been recently pointed out by Stilling,* Kose,? and Kohn.? Many embryologists are of opinion that the medulla of the adrenals is developed in connection with the sympathetic nervous system and from the same Anlage. The first to notice this connection were Bergmann * and Remak.? Leydig® showed the intimate connections between the sympathetic and the paired suprarenal glands of Elasmobranchs. Balfour’ confirmed this and described in Elasmobranch fishes a series of paired bodies derived from the sympathetic Anlage and an unpaired body of mesoblastic origin — the mesoblastic portion represents the cortical part of the matured suprarenal body, while the paired bodies from the sympathetic Anlage form the medulla. Brun * has established the development of the medullary cells from the sympathetic nerve cells in Reptilia also. Mitsukuri? confirms the above observations of Balfour on the separate origin of the two portions of the adrenals in Elasmobranchs and shows further that in mammals the medullary 1 STILLING: Anatomischer Anzeiger, 1898, xv, p. 229. 2 KosE: Sitz.-Ber. des deutschen naturw.-medicin. Ver. f. Béhmen, “Lotos ” 1898, Nr. 6. I have found no difficulty in recognizing these cells in preparations made by Kose’s method. 3 KOHN: Prager medicinische Wochenschrift, 1898, xxiii, Nr. 17. 4 BERGMANN: Dissertatio de glandulis suprarenalibus, G6ttingen, 1839. 5 REMAK: Untersuchungen tiber die Entwickelung der Wirbeltiere, Berlin, 1855. 6 LreypiGc: Beitrage zur mikroskopischen Anatomie, etc., der Rochen und Haie, Leipzig, 1852. 7 BALFouR: A monograph on the development of Elasmobranch Fishes, London, 1878; also Text-book of comparative embryology, 1881, ii, p. 459. 8 Brun: Arbeiten aus der zoologischen-zootomischen Institut, Wiirzburg, 1879, v, pp. 1-30, Table iii. 9 MITSUKURI: Quarterly journal of microscopical science, xxii, pp. 17-29. 472 Allen Cleghorn. portion insinuates itself gradually into the cortical organ, although at first separate from and outside it, but continues to retain its intimate connection with the neighboring sympathetic ganglia. Recently Swale Vincent! has described in the medullary organs of Elasmo- branchs a peculiar cell which he believes to be a transition form between a nerve cell and a medullary cell. This form is found also in amphibians, reptiles, and birds. The same observer” noted further the presence of cells apparently identical with those of the suprarenal medulla in the sympathetic ganglia of Salamandra macu- losa. Other embryologists® point out that in man and certain other. mammals, if not in all, both the cortex and medulla of the adult gland are formed from mesenchymal cells. The very general belief in the similarity in structure and origin of the sympathetic cells and the cells of the medulla of the adrenals suggested to me that an extract prepared from sympathetic ganglia, intravenously injected, might have the same powerful action on the blood pressure that Oliver and Schafer* have taught us to expect from extracts of the medulla of the suprarenal bodies. I therefore have made many intravenous injections of the extract of sympathetic ganglia and have found indeed that a very decided change in the blood pressure always takes place, but in the opposite direction to that expected; for suprarenal extract causes the pressure to rise, but an extract of sympathetic ganglia causes invariably a marked fall. Starting from this point the action of the extract on the peripheral and central vasomotor mechanisms, skeletal and cardiac muscle, and on the isolated heart, has been studied, with the results set forth in the following pages. The making of the extracts. — The extracts employed in this research were prepared from fresh sympathetic ganglia of the ox, sheep, pig, 1 VINCENT: Internationale Monatschrift fiir Anatomie und Physiologie, xv, p. 288. 2 VINCENT: loc. ciz., XV, Pp. 298. 8 See MInoT: Human embryology, 1892, p. 488. * OLIVER and SCHAFER: Journal of physiology, 1895, xviii, p. 230. ° The embryological studies mentioned above suggest that the substance which causes such a marked fall in the blood pressure may yet be found in the medulla of the suprarenals. Its presence there in minute quantities might well be masked by the epinephrin isolated by Dr. Abel (The Johns Hopkins hospital bulletin, No. 76, July, 1897), a body which causes a great increase in blood pressure. It should be remembered that Dr. Abel, while separating epinephrin, did indeed find in the medulla a substance lowering the blood pressure. Action of Extracts of the Sympathetic Ganglia. 473 dog, and cat." In the first three animals only ganglionic masses from the solar plexus were used. In the dog and cat separate extracts were made from several sympathetic ganglia, namely, superior cervical, inferior cervical, stellate, and semilunar ganglia. Each of these several extracts, when injected into the veins, possesses the power of lowering the blood pressure. Three methods were used to prepare the extracts: (1) the ganglia were cleaned of adherent fat, etc., cut into small pieces, placed in a glass vessel, and covered with chemically pure glycerine. The vessel was now put into a thermostat and the contents allowed to macerate for several days at a temperature of 37° C. When about to be used a small quantity of 0.8 per cent sodium chloride solution was added, and after trituration in a mortar the whole was filtered under pressure. (2) The ganglia were finely divided, triturated in a mortar with a small quantity of clean white sand and a few cubic centimetres of the saline solution, warmed in a test tube, and then filtered. This warming of the extract was several times carried past the boiling point without affecting the activity of the extract. (3) The ganglia were placed in a desiccator over concentrated sulphuric acid and, after being thoroughly dried zz vacuo, were powdered, mixed with saline solution, and filtered. Of these three methods the first was the one most commonly employed, as it furnished a stock which could be kept for any length of time and used as desired by the simple addition of the saline solution and filtration. In the prepara- tion of these extracts the glycerine or the saline solution was added in the proportion of I c.c. to I gram of ganglia. The extracts were administered by direct injection into either the external jugular or the femoral vein. The fall in blood pressure took place immediately. Control experiments were done with the glycerine and saline solutions employed in the research, and with extracts prepared from brain substance, spinal cord, spinal ganglia, nerve (sciatic and vagus), and abdominal tissue — peritoneum, fat, etc. From none of these was a fall in blood pressure obtained. In all experiments in which a tracing of the blood pressure was taken the animals were anesthetized with a small dose of morphia and ether. The cannula leading to the manometer was inserted in one of the common carotid arteries — usually the left. The manom- 1 One experiment was done with an extract prepared from the semilunar gan- glion of a Brazilian monkey, with results similar to those produced by the other extracts. 474 Allen Cleghorn. eter used was the common U-shaped mercury form. The tubes between the manometer and the carotid were filled with a 30 per cent solution of magnesium sulphate. ACTION ON THE CIRCULATION. General blood pressure. —In more than sixty injections, made on sixteen cats and five dogs, the extract of sympathetic ganglia invariably lowered the general iia i yA a blood pressure from 10 to 50 mm. aa Hg according to the dose admin- : istered. In the cat 1 c.c. would usually cause a fall of 20 to 30 mm. Hg. The pressure change is almost immediate; indeed when the injection is made very slowly the fall begins before the injection FIGURE 1. One third the original size. js finished. The characteristic re- The uppermost curve shows the fall in . : . He rs nue sult is shown in Figure 1. The the blood pressure in the carotid artery of the cat, on the injection of sympa- Pressure falls rapidly, and before thetic extract into the jugular vein. The long returns slowly to the original middle line is atmospheric pressure. height. The experiment may be The heavy black band marks the dura- : tion of the injection. The lowest line repeated a number of times on gives the time in seconds. the same animal. In only one instance did the extract appear to have a prolonged effect. Here the return to the normal was extremely slow. In two animals a slight rise preceded the fall in pressure. In several experiments an endeavor was made to neutralize the depressant action of the extract by injecting with it an extract pre- pared from the medulla of the suprarenal capsules. The results varied according to the proportion of the extracts; when suprarenal was in excess a rise took place, when sympathetic a fall. In two cases a balance was nearly struck and an interesting tracing was the result, the blood pressure rising quickly for an instant and then as quickly falling again to slightly below the normal, where it remained for a few seconds. This was repeated several times until at last the oscillations ceased and the rise caused by the suprarenal ex- tract remained comparatively steady. In two experiments on cats the cannula of one syringe was tied in the external jugular vein and that of another fastened in the femoral. The former was filled with Action of Extracts of the Sympathetic Gangha. 475 an extract prepared from the sympathetic and the latter with supra- renal extract. It was found that the fall produced by injecting sym- pathetic extract could be checked or counteracted by the immediate injection of suprarenal extract. This experiment was reversed by - injecting suprarenal extract and checking the consequent rise with sympathetic extract. The rabbit’s ear. — Injections were made into the jugular vein of two white rabbits and the animals’ ears held between the observer and the light. A dilatation of the vessels of the ear could be plainly seen; small vessels which were invisible before stood out clearly. The extraordinary fall in blood pressure which we have seen to follow the injection of the extract of sympathetic ganglia may be the consequence of the action of the extract directly on the vasomotor centres, the sympathetic vasomotor neurons, or the blood vessels themselves, or finally, on any two or perhaps on all three of these structures. Experiments to answer these questions, in part at least, were now made. The first question to be determined is whether the extract dilates the blood vessels through the agency of the vaso- motor centre in the bulb. Perfusion of the bulb. — A cat was anzesthetized with ether and tracheo- tomized. The subclavian arteries and the two vertebral arteries were tied close to their origin and a ligature was passed round the superior vena cava. In the cardiac end of the left carotid was inserted a cannula connected with a mercury manometer recording the systemic blood pressure on a smoked drum. In the cranial end of the same artery was placed a cannula connected with the perfusion apparatus, arranged to supply at will normal defibrinated blood mix- ture, or blood mixture containing sympathetic extract. The right carotid artery was laid bare but was left free to supply the bulb with normal blood until perfusion actually began. Both vagi were divided. The ligature about the superior vena cava was drawn tight. The jugular veins were now opened freely, the right carotid artery clamped, and the brain perfused with defibri- nated blood at 100 mm. Hg pressure. ‘The blood reached the brain through the cannula in the left carotid artery —the only cerebral artery remaining open —and escaped through the severed jugular veins. None of the brain blood could reach the heart, because the superior vena cava was tied. ‘Thus the blood-supply of the brain was separated entirely from that of the rest of the animal, which continued to be nourished in the normal way. On _ the addition of sympathetic extract to the blood passing through the brain no fall in the systemic blood pressure took place. That the vasomotor centre was in an active condition was shown by the fact that the systemic 476 Allen Cleghorn. blood pressure rose considerably when the circulation to the brain was shut off (asphyxia. ) Similar experiments were done on two other cats. It follows from these perfusions that the fall in blood pressure is not a bulbar action. It will now be demonstrated that the fall is pos- sible in the absence of the bulb. Exclusion of vasomotor centre in bulb. — In this experiment the vessels going to and coming from the head were ligated in a manner similar to that de- scribed in the preceding experiment. The cannula of a syringe filled with sympathetic extract was tied into the femoral vein and the systemic blood pressure was taken from the left carotid artery. Both vagi were divided. The posterior arches of the second and third cervical vertebrae were removed and the spinal cord cut immediately below the bulb. ‘The blood pressure at once fell from 105 to 40 mm. Hg. The distal end of the cord was now stimulated with rapidly repeated induction shocks in order to bring the blood pressure once more to a level at which the lowering action of the extract might be evident ; the blood pressure rose to 80 mm. Hg and remained constant at this level. The sympathetic extract was injected into the femoral vein during the stimulation of the cord. At once a decided fall (between 20 and 30 mm. Hg) in the blood pressure took place. Six injections were made in this same animal and all gave similar results. Having thus excluded the bulbar centre, we must next inquire whether the extract secures its results by means of the spinal vaso- motor centres. To answer this question perfusions were made in tis- sues and organs isolated entirely from the central nervous system. Perfusion of the isolated kidney.— A small dog was anesthetized with morphia and ether and the abdomen opened in the median line. The renal artery and vein were then ligated separately close to their respective origins and a glass cannula filled with 0.8 per cent sodium chloride solution inserted in each. The kidney was carefully freed from its bed and placed in a Roy j oncometer which was connected with an Ellis ? piston recorder writing on the smoked surface of a revolving drum. The cannula in the renal artery was connected with the perfusion apparatus and the normal perfusion fluid con- sisting of defibrinated dog’s blood diluted one half with o.8 per cent sodium chloride solution was forced through the kidney at a constant pressure of 115 mm. Hg. An assistant held the two cannulas in position, maintaining them in a straight line with the vessels and so avoided any possibility of the 1 Roy and CoHNHEIM: Untersuchungen iiber die Circulation in den Nieren, Berlin, 1883. 2 Exxis: Journal of physiology, 1886, iv, p. 309. Action of Extracts of the Sympathetic Ganglia. 477 vessels twisting or kinking and consequently impeding the blood flow through the organ. The perfusion apparatus was so arranged that blood containing sympathetic ganglia extract could be passed from a second reservoir through the kidney as desired in place of the normal perfusion fluid. This change could be effected without altering the pressure in the perfusion tubes. The perfusion fluids were maintained at a constant temperature (37.5°C.). A rte EEE ETEE AEE HEE 60 “TER Ge Caninpamet 7) a OO Ea PA Peet ve eg Pee ae —- soos sae FIGURE 2. Curve showing the increased outflow from the renal vein in consequence of the perfusion of sympathetic extract. During the breaks in the curve the outflow was too rapid to be counted. The heavy black lines mark the duration of the perfusion. The ordinates give the number of drops; the abscissz, intervals of 30 seconds. 40 10 glass tube conveyed the blood from the cannula in the renal vein to a beaker. and here the outflow was measured by counting the number of drops falling from the tube in successive periods of thirty seconds. That the perfusion of blood containing the sympathetic extract markedly increased the flow from the renal vein can readily be seen by studying Figure 2. So great was this increase that in three of the thirty second periods the blood flowed from the renal vein in a stream and counting became impossible. The curve in Figure 2 is therefore interrupted, blank spaces representing the period during which the outflow was too rapid to be counted. 478 Allen Cleghorn. Further evidence was obtained by the perfusion of the submaxillary gland. Perfusion of submaxillary gland.— A medium size dog was anesthetized with morphia and ether, tracheotomized, and the artery and veins of the sub- maxillary gland laid bare. A glass cannula was then placed in the duct of the gland, another in the facial artery just before it gives off the submaxillary branch, and another in the external jugular vein. The facial artery was ligated above and below the origin of the branch to the gland; all tributaries of the external jugular vein were also ligated except those coming direct from the gland, and a small artery which enters the gland on its dorsal margin was tied. Thus the gland was isolated entirely from the systemic circulation. It will be noticed that the nerves going to the gland were left intact. The cannula in the facial artery was now connected with a perfusion apparatus and defibrinated dog’s blood at body temperature was passed through the gland at a pressure of roo mm. Hg. In three experiments the amount of blood issuing from the cannula in the jugular vein was measured during successive periods of two minutes, while the gland was being perfused with normal blood, and with blood containing sym- pathetic extract. When the gland was perfused with blood containing the sympathetic extract, the outflow was increased 21.4 per cent, 25 per cent, and 71.4 per cent in the three experiments respectively. ‘lwo other dogs gave a similar result. Perfusion of hind limb. —A dog received a small dose of morphia, and was then kept fully under the influence of ether. The superficial femoral artery and vein of the right hind limb were exposed. The artery was ligated above the origin of the profunda femoris and the vein above the similar venous branch. Glass cannulas were inserted into the artery and vein below the pro- funda artery and vein. ‘This was done in order to abolish the free anastomosis existing through these vessels between the superior and inferior regions of the thigh, through which channels blood perfused into the limb might escape into the general circulation. ‘The perfusion of the limb was carried out in a manner similar to that already described for the kidney experiments. A blood tracing from the carotid artery was recorded on a drum. It was found that the out- flow from the femoral vein (75 c.c.) during four minutes’ perfusion with the sympathetic extract was exactly double the amount issuing from the vein during the perfusion of normal blood in the same length of time. No change took place in the systemic blood pressure. It appears from these several experiments that marked dilatation of the blood vessels follows the perfusion of parts isolated from the central nervous system and hence cut off from communication with the vasomotor centres. The dilatation is so great as to make it Action of Extracts of the Sympathetic Gangha. 479 probable that the action of the extract is chiefly on the sympathetic vasomotor neurons or on the blood vessels themselves. The follow- ing experiments strengthen the latter opinion by showing that the extract does indeed affect the contractility of muscle. Cardiac muscle; the “apex” of the dog’s heart. — The technique and apparatus employed in this experiment I have described at length in a former publication. A cannula was tied in one of the apical divisions of the ramus descendens of the left coronary artery and the part of the apical half of the ventricle sup- plied through the arterial branch cut out (Porter’s method).* The excised apex was placed in a wide glass tube inserted in a large tank of water kept at a constant temperature of about 36.5° C. The cannula was con- nected to perfusion flasks also immersed in the tank, and the preparation perfused at a con- stant pressure of about 100 mm. Hg with defibrinated dog’s blood diluted with an equal volume of o.8 per cent sodium chloride solution. The con- tractions were registered by means of a fine wire leading from a hook in the apex to an FIGURE 3. Original size. Curve drawn by lever = : “c , 9 nel : be ordinary muscle. lever magnify- attached to “apex of perfused dog’s heart. Magnification X 7. Time in periods of 5 sec- ing seven times. Three dog ; me 8s onds. During the interval marked by the white were used and two apex prep- band, blood containing sympathetic extract was arations were made from each substituted for the normal perfusion blood. heart. In all six cases the re- sults were identical. When the normal blood passing through the apex was replaced by blood containing the extract of sympathetic ganglia there was at once a great difference in the character of the contractions. Strong doses of the extract (20 per cent) slowed the contractions and diminished their force while at the same time a very considerable fall in tonus was produced. Smaller doses — from 5 to ro per cent — did not seem to affect the rate of the beat but increased considerably the héight of the contractions 1 CLEGHORN : This journal, 1899, ii, p. 273. 2 PORTER: Journal of experimental medicine, 1897, ii. p. 3901. 480 Allen Cleghorn. and caused a marked fall in tonus. The fall in tonus compensated for the in- creased contraction, that is to say although the amplitude of the beats was in- creased the fall in tonus was sufficient to prevent the top of the contraction curve from rising above the normal. Skeletal muscle. — The action of the extract on skeletal muscle was tested on the gastrocnemius muscle of frogs in which from r to 2 c.c. had been in- jected into the dorsal lymph-sac. About ten minutes after the injection the animal showed signs of distress and the respiration became labored and quickened. In fifteen or twenty minutes the hind legs were extended. Frequently the animal would be found in this state on its back, from which position it could only recover itself with FIGURE 4. Two thirds the original size. Curves drawn by gastrocnemii muscles, 4, normal; 2, poisoned by the injection of sympathetic extract into the dorsal lymph- sac. The rise in the middle line indicates stimulation with maximum break shock. The lowest curve gives the time in ;4, seconds. The levers magnified 9 times. difficulty. When placed on the floor and stimulated to jump the frog could not jump straight but always turned more to one side or the other, and the jump at best appeared jerky although strong. In two cases the frogs were found dead twenty minutes after the injection. Both were in the dorsal posi- tion with their hind legs powerfully extended. In the four remaining frogs the effect passed off in about forty-five minutes. A preparation of the sciatic nerve and gastrocnemius muscle was made from each of six poisoned frogs and from the same number of normal animals and the contractions of the several muscles in response to maximum break shocks were recorded on a Baltzar drum revolving at arapid speed. A great difference in the character of the contractions may be noticed (see Fig. 4). The latent period of the poisoned muscle is half again as long as in the normal muscle preparation. The actual contraction or shortening of the muscle is also pro- longed while the period of relaxation is extended to such a degree as to resemble greatly the curve of a muscle poisoned with veratrine. Action of Extracts of the Sympathetic Ganglia. 481 It is evident from the experiments recorded in this study of the action of the extract of sympathetic ganglia on the circulation that the fall in blood pressure is chiefly, or wholly, peripheral; in other words is dependent on either the sympathetic vasomotor cells, or the direct dilation of the vessels themselves, or, possibly, on both these mechan- isms. Evidence has been adduced which makes it somewhat probable that the extract acts on the blood vessels without the mediation of the sympathetic system, but this at present must not be affirmed with too much confidence. ACTION ON THE ISOLATED HEART, AND ON THE PUPIL. The isolated heart. — The tortoise heart was perfused with defibrina- ted cat’s blood, diluted one half with 0.8 per cent sodium chloride solu- tion, through the ventricular coronary system in the manner described by Gaskell." Three preparations were used. The circulation was so slow — even with 100 mm. Hg pressure — that the results do not stand out with the distinctness noticed in the dog’s apex. In all the experiments however the extract produced a slowing of the rate and a slight lessening in the force of the contraction and in the tonus. In three experiments the heart of the frog was removed from normal animals, with all its vessels ligated, and its contractions recorded by means of a light lever attached to the apex. Injections of sympathetic extract were made into the bulbus arteriosus by means of a hypodermic syringe with a very fine needle. In all cases the heart stopped beating and a very slight fall in tonus took place. After a few minutes recovery as a rule occurred. Injection of normal saline solution as a control experiment stimulated the heart, causing an accelerated and more powerful action. Pupil. — In no experiment was any alteration in the. pupil noticed either when the extract was intravenously injected or applied to the conjunctive directly. In conclusion I desire to acknowledge with thanks the valuable assistance of Prof. W. T. Porter, and also to thank Dr. Albert P. Mathews for his kind aid in the operations on the submaxillary gland. SUMMARY. 1. The injection of glycerine or aqueous extract of the semilunar ganglia of the ox, sheep, and pig, and of the superior and inferior ' GASKELL: Journal of physiology, 1883, iv, p. 43. 31 482 Allen Cleghorn. cervical, stellate, and semilunar ganglia of the dog and cat causes almost immediately a marked temporary lowering in blood pressure. 2. The fall in blood pressure caused by ‘“‘ sympathetic extract” can a be checked or counteracted by the injection of extract of the supra- renal bodies, and wéce versa. 3. The lowering of the blood pressure is not brought about through the vasomotor centres but by the action of the extract on the blood vessels themselves, or possibly on their sympathetic vasomotor neurons. 4. Perfusion with the extract lowers the tonus of the heart muscle. 5. The latent period and the phase of relaxation of skeletal muscle is lengthened. 6. No action on the pupil was observed. 4 fe DLASFATIC ACTION OF PANCREATIC JUICE. By B. kK, RACHFORD.: N recent years many observers have devoted much time and labor to the study of the action of unorganized ferments on food stuffs. In this study amylopsin, the diastatic ferment of the pan- creas, has been almost wholly neglected. In fact, as far as I am aware no systematic study of the action of amylopsin on starch under the various conditions herein described has ever been made with pure pancreatic juice.1 Chittenden, Langley and Eves, and others have given us most valuable information on the diastatic action of saliva as modified by various conditions, suggested by the conditions under which diastatic ferments are supposed to act in the digestive tract; and in the absence of experimental work to determine the diastatic action of pancreatic juice, under such varying conditions, we have for the most part been forced to formulate our knowledge of the action of amy- lopsin from the experimental work done with ptyalin and other dias- tatic ferments. It may be that the diastatic action of the pancreatic juice will under all conditions be the same as that of saliva; yet, however this may be, there can be no doubt that it would be more desirable to have our knowledge of the diastatic action of pancreatic juice based upon experiments made with the juice itself rather than be forced to infer the extent of its action under diverse conditions from the action of other diastatic ferments under similar conditions. In this statement I do not wish to appear to underrate the value of these studies or to insist that the principles of starch digestion, as obtained from the study of the diastatic action of saliva and malt, shall not be applied in explaining the diastatic action of pancreatic juice in the small intestine, but it goes without saying that confirma- tory experiments made with pure pancreatic juice would substitute certainty for inference and place our knowledge of the intestinal digestion of starches on a much more satisfactory footing. The work of pancreatic juice in carrying on the intestinal digestion of starchy foods is recognized as a digestive function second in importance to none. That experimenters have neglected this field of 1 See the criticism of HAMBURGER: Archiv f. d. ges. Physiol., 1895, lx, p. 558. 484 B. KE. Rachford. work is not therefore due to its unimportance, but rather to the difficulties in the way of obtaining pure pancreatic juice in quantities sufficient to carry on a systematic research. The purpose therefore of this paper is not only to record some experiments, which I recently have made, but also and more especially to call attention to a method of obtaining pure pancreatic juice from the rabbit in suffi- cient quantity for experimental purposes. Operation for temporary pancreatic fistula in the rabbit. — The opera- tion for making a temporary pancreatic fistula in the rabbit was first described by me in the Journal of physiology, 1891, xii, p. 80. The operation given here in detail is an improvement on the original and makes it possible for any observer to obtain sufficient pancreatic juice for research. Experience has taught me that it is a waste of time to use any but the largest and strongest rabbits. With such animals the operation for temporary pancreatic fistula is easily and quickly done as follows. After removing the hair make an abdominal incision in the linea alba, on a level with the lower ribs, three centimetres long. Find the duodenum, which is easily reached high up in the right hypochondriac region lying close against the abdominal wall, and bring it through this opening. Run down the gut to a point where the peritoneum binds it so closely that it will not come through the opening without tearing the mesenteric attach- ment, and just at this point will be found the pancreatic duct as it passes through a leaf of the pancreas to enter the intestinal canal. Gently separate the mesenteric attachment of the gut so as to bring the latter through the abdominal opening without tearing blood vessels and producing unnecessary hemorrhage. By holding the gut to the light the pancreatic duct can readily be observed and two points chosen, one on either side about two centimetres from the papilla, for applying ligatures to the intestine. These points should be selectéd with an eye to the vascular distribution to the intestine, so that the blood-supply shall be disturbed as little as possible. The ligatures are tied at this point so as to occlude the lumen of the intestine; the ends are then passed around the body of the animal and tied in that position. If it be preferred small clamps, resembling prepuce clamps, may be used instead of ligatures. All of the intes- tines except that portion included between the clamps or ligatures is returned to the abdominal cavity wzthout section. This arrange- ment will maintain the relative position of the parts, so that the portion of the mesentery holding the pancreatic duct cannot be dis- The Diastatic Action of Pancreatic Juice. 485 arranged by peristaltic contractions or by the subsequent move- ments of the animal. If a large abdominal wound is made it is sometimes necessary to close it partially by stitches, so that the intestine cannot be forced through the opening and in that way disarrange the parts. Care must be taken however that the abdomi- nal wound be sufficiently open to permit the free passage of the mesentery carrying the pancreatic duct. The portion of the intes- tine included between the clamps or ligatures is now laid open oppo- site its mesenteric attachment and spread out on the abdominal wall. The lateral margins are packed with absorbent cotton to prevent bleeding. The pancreatic papilla can be observed on the exposed mucous membrane. In a short time it will open and pancreatic juice will exude. Into this papilla is inserted a small glass cannula to which has been attached an inch or two of rubber tubing. The cannula being in position, the exposed mucous membrane is covered with absorbent cotton, which may if necessary be saturated from time to time with warm physiological salt solution. The flow of juice may begin at once, or it may not commence for an hour after the insertion of the tube. When the pancreatic juice commences to flow it continues from five to eight hours. During this time the juice is collected by emptying the filled cannula from time to time and rein- serting it. In this manner may be obtained from three to five c.c. of pancreatic juice uniform and powerful in physiological action. It is my custom to have two rabbits under operation at the same time, and in this way I never fail to obtain juice sufficient for an experi- ment. The pancreatic juice collected from both rabbits is mixed together in a single tube and afterward divided equally between the tubes containing the digestive mixtures. In this way one is sure that all the tubes of a single experiment contain pancreatic juice uniform in physiological action. Influence of bile and hydrochloric acid on the diastatic action of pancreatic juice. — In the starch experiments here recorded the bile used was obtained from the same rabbits that furnished the pancreatic juice. The method used in determining the rate of diastatic action was the one described by Pavy’ under the title ‘“ Quantitative determination of sugar by the ammoniated cupric test.” The time of each experiment was 45 minutes. When the diastatic action was stopped by boiling the mixtures, the total volume of liquid 1 Pavy, F. W.: Physiology of the carbohydrates, London, 1894. 486 B.K. Rachford. in each tube was 60 c.c. One gram of wheat starch boiled in a definite quantity of water was used in each. The hydrochloric acid used in these experiments was in the form of a O.I per cent solution. I made a number of tests to determine the amount of this acid solution necessary to neutralize a given quantity of pancreatic juice and the results of these tests are noted elsewhere in this paper. Determinations were also made by Dr. W. H. Crane, who was given 5 minims of pure pancreatic juice and a sample of the 0.1 per cent hydrochloric acid solution used in the experiments, with the request that he estimate the amount of the acid solution necessary to neutralize the 5 minims of juice. Dr. Crane diluted the pancreatic juice with 5 c.c. of distilled water and added a drop of 0.5 per cent alcoholic solution of dimethyl amido azo-benzol. Tenc.c. of 0.1 per cent hydrochloric acid were diluted to 100 c.c., placed in a burette, and added drop by drop to the pan- creatic juice. Neutralization was obtained with 4.5 c.c. of the 0.01 per cent hydrochloric acid. Thus 5 minims of pancreatic juice re- quired 045 c.c. of 0.1 per cent hydrochloric acid for neutralization. It may here also be noted that all the hydrochloric acid tubes, in the above or in subsequent experiments, contained from 2 to 10 c.c. of the hydrochloric acid solution in excess of the amount required to neutralize the pancreatic juice, and that the subsequent addition of bile or albumin was not sufficient to neutralize this excess of free acid. All hydrochloric acid tubes therefore in the following experi- ments except those to which sodium carbonate was added contained free acid. I submitted to Dr. Crane a fluid containing the following in- gredients: pancreatic juice 10 minims, 0.1 per cent hydrochloric acid solution 3 c.c., starch I gram, water 25 c.c., with the request that he determine whether or not the fluid contained free acid, and if acid how much bile would be required to neutralize the acid. Dr. Crane found 27.4 c.c. of fluid in the test tube. It was acid to dimethyl amido azo-benzol. Of the starchy fluid 13.7 c.c. were placed in a beaker and bile (0.9 c.c. of which had been diluted to 9.0 c.c. with water) introduced from a graduated pipette. Neutralization required 6.2 c.c. Thus 27.4 c.c. of the fluid are neutralized by 1.24 G.c. pile: I would call attention to the fact that the mixture upon which the above report was made was taken as a sample of the hydrochloric acid tubes in the experiments on page 487. It must be noted, however, The Diastatic Action of Pancreatic Juice. 487 a = rd € 3 2 62 Experiment. se Water. ae Bile. Starch. =o 5= a ae _ S is) I minims. C.c. c.c. minims. gram. Per cent. 1 10 60 0 4 1 30 2 10 57 3 4 1 27 3 10 57 3 0 1 23 + 10 60 0 0 1 30 II 1 10 60 0 8 1 50 Z 10 57 33 8 1 50 3 10 Sy] 3 0) 1 37 4 10 60 0 0 1 40 III 1 10 60 0 6 1 32 2 10 By 3 6 1 32 3 10 57 3 0 1 20 4 10 60 0 0 1 25 IV 1 7 60 0 5 1 25 2 7 57 3 5 1 dH 3 7 57 3 0 1 24 4 7 60 0 0 1 26 Vv 1 10 60 0 5 1 34 2 10 57 3 5 1 36 3 10 57 3 0 il 30 + 10 60 0 0 1 34+ VI 1 10 60 0 8 1 oe 2 10 57 3 8 1 36 3 10 57 3 0 1 24 4 10 60 0 G ] 28 j 488 B. BK. Rachford. that this mixture contained the minimum amount of acid used in any of the digestive mixtures, and that this mixture was found to require 1.24 c.c. of bile to neutralize it; a much larger amount of bile than was used in any of the tubes, except tubes 1 and 2 of Experi- ment VII. In these tubes, however, it will be noted that the 8 and 10 c.c. of the hydrochloric acid solution which these tubes respectively contained was sufficient to give to them an acid reaction. Studying the above experiments it is plain that bile slightly ex- pedites the diastatic action of pancreatic juice. The expediting influence of the bile, however, is here shown to be so slight that the manner of its action scarcely merits discussion. It is important to observe that the bile does not exert an unfavorable influence on the diastatic action of pancreatic juice. But it is of much more im- portance to note that the 0.1 per cent hydrochloric acid solution used in these experiments had only a slight retarding influence on the dia- static action of the ferment. A slight retardation is, however, seen in every case. Tube 3 in each of the above experiments contains 3 c.c. of a O.1 per cent solution of hydrochloric acid, which gave to the contents a decided acid reaction. In experiments made to determine the amount of the hydrochloric acid solution necessary to neutralize pancreatic juice, it was found that 12 to 15 minims of the hydro- chloric acid solution would destroy the alkalinity of 10 minims of pancreatic juice and that 15 to 18 minims would give to it an acid reaction. Hence the amount of hydrochloric acid solution in these tubes was more than 2 c.c. in excess of the amount required to neutralize the alkalinity of the pancreatic juice, and yet in the presence of this excess of free hydrochloric acid the pancreatic juice had al- most as much diastatic action as it had when acting alone in the pres- ence of its own alkaline salts. Of yet greater interest are the tubes marked 2 in the above expe- riments. Each of these tubes contained not only 3 c.c. of the hy- drochloric acid solution, but also a certain amount of bile. A study of these tubes shows us that the bile not only neutralized the slight retarding influence of the free hydrochloric acid but also furnished the conditions in the presence of this acid for pancreatic juice to do its most rapid diastatic work. The tubes containing both bile and pancreatic juice, in every experiment except one, lead in the amount of diastatic work done. In the experiment in which the bile and hy- drochloric acid tube fails to do the most work, the failure is probably The Diastatic Action of Pancreatic Jutce. 489 due to the small amount of bile used. Whatever may be the expla- nation, it is an important physiological fact that bile, when added to pancreatic juice acting in the presence of a small quantity of free hy- drochloric acid, will not only neutralize the retarding influence which the free acid has on the diastatic action of pancreatic juice, but will in doing so furnish the most favorable conditions for the action of this ferment. And it is also important to note that bile will accom- plish this result without neutralizing the acid completely, thus show- ing that the favorable influence of the bile on the diastatic action of pancreatic juice is not simply one of acid neutralization. The following experiment shows even more clearly the value of bile when pancreatic juice is acting in the presence of free hydro- EXPERIMENT VIL. Starch S 7 starch reduced. Pancreatic ELGI. 0.1 per cent | minims. ae 1: | minims. Per cent. poe ese | 20 30 0 chloric acid. Here the retarding influence of 8 and 12c.c. of ao.I per cent hydrochloric acid solution is very marked, but in tube 1, containing 8c.c. of the hydrochloric acid solution, twenty minims of bile not only neutralizes the retarding action of the hydrochloric acid but also enables the pancreatic juice to do even more diastatic work than is done in tube 5, where the pancreatic juice is acting apart from the influence of either hydrochloric acid or bile. In tube 2, 30 minims of bile enables 12 minims of pancreatic juice acting in the presence of 12c.c. of hydrochloric acid solution to digest 24 per cent of starch instead of 12 per cent, the amount digested in tube 3 in which the same quantity of pancreatic juice acted in the presence of 12c.c. of the hydrochloric acid solution without the assistance of the bile. 490 LB. KE. Rachford. In Experiment VIII, even more graphically than in any that has preceded it, is shown the retarding influence of free hydro- chloric acid on the diastatic action of pancreatic juice and the value of bile in neutralizing this retarding action. Here 12 c.c. of the hydrochloric acid solution almost destroys the diastatic action of 15 minims of pancreatic juice, and 8c.c. of the acid solu- tion greatly retards its action, while 7 minims of bile is sufficient to neutralize entirely the retarding influence of 8 c.c. of the acid solution. EXPERIMENT VIII. Starch S 3 tarch reduced. Water. o.I per cent minims. “Cs ie minims. gram. Per cent. 15 0 0 1 25 0 1 14 0 1 2 / 7 The preceding experiments clearly establish the fact that bile is not necessary to the diastatic action of pancreatic juice acting alone uninfluenced by hydrochloric acid, but that bile may be of the great- est assistance to pancreatic juice, indeed almost necessary to its full diastatic action, when the former is acting in the presence of free hydrochloric acid, and that bile can serve this purpose without neu- tralizing all of the free acid present. The influence of acid albumin on diastatic action of pancreatic juice. — In Experiment IX, the egg albumin was mixed with the hydro- chloric acid solution before the pancreatic juice was added to the tube, and here it will be seen that 0.3 gram of egg albumin exer- Lhe Diastatic Action of Pancreatic Jutce. 4QI EXPERIMENT IX. Starch reduced. Egg Water. albumin. Starch. Pancreatic O.I per cent HCl minims. ics Ce gram. minims. Per cent. 10 | 0 10 10 10 0 0 0 0 10 10 | 5 10 10 ‘ 8 : 10 10 Q 10 cised very much the same influence on pancreatic juice acting in the presence of free hydrochloric acid that the bile did in the previous experiments. Tubes 2, 4, and 6 demonstrate that acid albumin very materially expedites the diastatic action of pancreatic juice. Tubes 6, 7, and 8 of this experiment contain each 10 minims of bile. In tube 6 the presence of the bile seems to add little to the diastatic action of the pancreatic juice since almost the same percentage of starch is digested in tubes 2 and 4, which do not contain bile, but in other respects resemble tube 6. In tube 7, however, we learn by comparison with tubes 3 and 5 that the 10 minims of bile had a very decided influence in increasing the diastatic action of the pancreatic juice in the conditions under which it is acting. In tube 7 of this experiment 0.3 gram of egg albumin was not sufficient to neutralize fully the retarding action of 8c.c. of the hydrochloric acid solution; the addition of 10 minims of bile, however, accomplished this. The failure of bile to increase further the diastatic action of pancreatic juice in tube 6 is due to the fact that the 0.3 gram of egg albumin is almost if not quite sufficient to neutralize the 4 c.c. of hydrochloric acid solution, and for this reason the further addition of bile or egg albumin would not materially increase the action of the pancreatic juice. 492 B. K. Rachford. Influence of sodium carbonate on the diastatic action of pancreatic juice. — Experiment X was planned for the purpose of studying the influence of sodium carbonate on the diastatic action of pancreatic juice acting under various conditions. A one per cent solution of sodium carbonate was used. Tubes 2 and 3 of this experiment show that 2 and 5c.c. of the sodium carbonate solution almost entirely destroy the diastatic action of 5 minims of pancreatic juice; while tubes 4 and 5 show that 5 minims of bile have a decided influence in neutralizing the retarding influence which the soda solution has upon the diastatic action of pancreatic juice. Tubes 6 and 7 indicate that the 0.6 gram of egg albumin also had some influence in neutral- izing the retarding action of the soda. EXPERIMENT X. 3: Starch Egg reduced. | albumin. Pancreatic I per cent Na,CO 0.1 per cent HCl Per cent. minims. | aC: .c. |minims.| gram. 0 0 0 0 0 Sour ne, KO. MO kOe sows If hydrochloric acid be added to a mixture in which pancreatic juice is acting on starch in the presence of sodium carbonate the acid will neutralize the retarding influence of the alkali. This is shown in tube 8. This action may be simply one of chemical neutralization, but whatever the explanation, the observation is inter- esting as showing that the diastatic power of pancreatic juice ina strongly alkaline mixture may be increased by the addition of a small quantity of hydrochloric acid. Lhe Diastatic Action of Pancreatic Juice. 493 EXPERIMENT XI. g Bos 8 v : oo ‘ Starch et Water. os Bile. Starch. | »cquced. a ae minims, Cic; C.G: minims. gram. Per cent. 1 4h 60 0 0 1 50 2 4 58 2 0 1 5 S 4 55 5 0 a 3 4} 4 58 2 4h 1 1] 5 4 55 5 4 1 | 13 6 60 0 4 1 8 7 60 0 4 1 8 Experiment XI again demonstrates the destructive action of sodium carbonate on the diastatic action of pancreatic juice, and also shows the value of bile in neutralizing this retarding influence. In tubes 6 and 7 it is shown that bile itself has some diastatic power. CONCLUSIONS. (1) A small quantity of free hydrochloric acid has little or no retarding influence on the diastatic action of pancreatic juice. (2) Larger quantities of free hydrochloric acid very materially retard the diastatic action of pancreatic juice; in one experiment 12 c.c. of a O.1 per cent solution of hydrochloric acid almost de- stroyed the diastatic action of 15 minims of pancreatic juice acting in a mixture of sixty cubic centimetres volume; in another experi- ment the same quantity of acid reduced by two thirds the diastatic action of 12 minims of pancreatic juice. The facts that different specimens of pancreatic juice vary in their degree of alkalinity and in their diastatic power make it impossible to formulate precise statements concerning the influence which definite quantities of acid will have on definite quantities of pancreatic juice. (3) Acid proteids in small quantities slightly increase the diastatic action of pancreatic juice. Neutral proteids therefore when added to pancreatic juice acting in the presence of free hydrochloric acid 494 B. K. Rachford. will not only neutralize the retarding action of the acid on the diastatic action of the juice, but they will also by the formation of acid albumin assist materially the pancreatic juice in its work. (4) Sodium carbonate has a very destructive influence on the diastatic action of pancreatic juice. Two cubic centimetres of a one per cent solution of sodium carbonate almost totally destroys the diastatic action of 5 minims of pancreatic juice acting in a mixture of sixty cubic centimetres volume. (5) Bile has no retarding influence on the diastatic action of pancreatic juice; in fact it slightly expedites its action. (6) Bile not only neutralizes the retarding influence which free hydrochloric acid has upon the diastatic action of pancreatic juice, but in the presence of free hydrochloric acid it very materially expe- dites the action of the juice. Here again it is impossible to formu- late rules as to the exact amount of bile necessary to neutralize the retarding influence of a definite quantity of hydrochloric acid, and thus give to a definite quantity of pancreatic juice its greatest diastatic power. In the above experiments, however, it will be seen that four to eight minims of bile were sufficient to neutralize the retarding influence of from four to eight cubic centimetres of a O.1 per cent hydrochloric acid solution without destroying the acid reaction of the mixture and thus to give to pancreatic juice its great- est diastatic power. (7) Bile has a marked influence in diminishing the retarding influ- ence which sodium carbonate has upon the diastatic action of pan- creatic juice. (8) Bile itself has some diastatic power. Not the least interesting point in these conclusions is the sugges- tion that bile may play a not unimportant part in the intestinal digestion of starches. If there be any free acid in the food, as it is discharged from the stomach into the duodenum, the bile will neutralize this acid and thereby assist the acid proteids discharged with the starches through the pylorus, in furnishing the most favor- able conditions for the diastatic action of pancreatic juice. And possibly of even more importance is the fact that bile will limit the destructive action of sodium carbonate on the diastatic action of amylopsin. In this connection it is interesting to note that in herbivorous or starch-eating animals! the bile as a rule is poured 1 RACHFORD: Comparative anatomy of bile and pancreatic ducts, Medicine, 1895, p. 520. The Diastatic Action of Pancreatic Juice. 495 into the duodenum far below the point where the pancreatic duct enters. This arrangement would give to the bile the most favorable opportunities for neutralizing any retarding influence which the sodium carbonate of the intestinal juice might exert on the diastatic action of pancreatic juice. In conclusion I wish to express my thanks to Dr. Frank South- gate, who has assisted me very greatly in the arduous details of these experiments. ited, oe afedir =? PROCEEDINGS, OF THE AMERICAN PHYSIO=— LOGICA sO C HEY. ELEVENTH 2NNGAL MEETING. NEw YORK, DECEMBER 28, 29, and 30, 1898. PROCEEDINGS OF THE AMERICAN PHYSIOLOGICAL SOCIETY. ON EPINEPHRIN, THE ACTIVE CONSTITUENT OF THE SUPRARENAL CAPSULE AND ITS COMPOUNDS. By JOHN J. ABEL. ACTING on Hyrtl’s suggestion that epfzmephris would be the best name for the suprarenal capsule, the author has given the name Epinephrin to the active principle as isolated by him. Aside from the chemical and physiological interest attaching to this substance it is believed that its careful study will throw light on the symptoms of Addison’s disease. When the benzoate of epinephrin is decomposed in the autoclave at pressures varying from 8 to 12 atmospheres, the resulting solu- tion contains epinephrin; it no longer gives a rose-red color with iodine water and ammonia, but gives instead the fine emerald green which is always seen when ferric salts are added. All other reactions of epinephrin described in previous articles’ are retained. The salts of epinephrin secured in this way possess but little physiological activity owing to some slight change, perhaps the gain or loss of a molecule of water, or some shifting of atomic groups in the molecule. The analytical results for the free base and for some of its salts are given below in abstract. These results have led to the adoption of the formula Ci;H:;NO, as expressing the composition of the new alkaloid. Found Theory for found Theory for LEpinephrin Cy,Hy5NO4 Epinephrin Diacetate. Cy,Hy;NO4(CH3.COOH), Cy,Hy;NO,4 requires C,,H;NO4(CH; . COOH), requires CS Csile C = 68.68 C= Sse €— 16043 jl Ss Sy: He 5.05 JelS= ey Ei 5-51 N= 5.00 Riss 417A = 504: Nino -50 The salt lost acetic acid on drying and showed signs of decom- posing. 1 ABEL: Johns Hopkins hospital bulletin, July, 1897, and September—October, 1898. lv Proceedings of the American Physiological Society. LE pinephrin Theory for Lpinephrin Theory for Benzoate Cy, Hy4NOq. Picrate C,,H,;NO,.C,H,. Cy,HyyNOq. CO.C,H; Cy,Hy;NO,4. CgH. (NOg)3 .OH CO.C,H; requires (NO,)3.OH requires C7204: CG = Wiley C= 52729. CS 5247 Ee) 554 lal Gey H= 4.03 e342. N= 7340 NGS, N = 10.54 N = 10.65 Theory for Epinephrin sulphate Lpinephrin sulphate Cy,Hy;NO,4 . H2SO,4 C,,Hy;NO, . H2SO, requires Sulphuric acid found == 24.80% H.SO,4 = 24.78% The sulphate was made from the picrate, which had been made in turn from the free base. Both the sulphate and picrate are micro- crystalline compounds, and like the benzoate they leave no ash when incinerated. ON THE FORMATION AND COMPOSITION OF HIGHLY ACTIVE SALTS OF EPINEPHRIN. By JOHN J. ABEL. WHEN the benzoate prepared directly from aqueous extracts of the glands is decomposed in the autoclave in the presence of a I or 2 per cent solution of sulphuric acid and at pressures varying from 3 to 5 atmospheres, intensely active solutions of epinephrin are obtained. Such solutions also retain the property common to aqueous extracts of the gland, of giving a rose-red color when treated with iodine water and ammonia. If epinephrin is precipi- tated out of such solutions, immediately dissolved in dilute acids and tested on animals, it is found to possess considerable physiological activity. Nevertheless the chemical operations involved in the for- mation of salts from the free base, such as prolonged washing with water and exposure to air, so greatly reduce their physiological activity that it was determined to form the picrate by direct precipi- tation with sodium picrate immediately after removing the hydrolyzed benzoate from the autoclave. The picrate obtained in this way was highly active, although somewhat contaminated with a picrate of unknown composition and of a very high nitrogen content. This active picrate and the sulphate made from it give the rose-red color Eleventh Annual Meeting. Vv with iodine water already mentioned. The active but impure picrate has the following composition : — C= HOS rip 4:02 N = 13.02 A sulphate [A], also not quite pure, but highly active, yielded on analysis 22.20 per cent sulphuric acid. A second sulphate [B] equally active yielded 22.88 per cent sulphuric acid. For C,,;Hi;NO4.H2SO, theory requires 24.78 per cent H,SQ,. Of sulphate [A] it required 0.00013 gram to raise the arterial pressure about 14 mm. Hg in a small dog. This quantity of the sulphate corresponds to 0.00009 gram of the free base. Of a third sulphate it required only 0.00011 gram to elevate the blood pressure 16 mm. Hg in a dog weighing 6.08 kilos. In other words a very distinct physiological effect is produced by so small a quantity of the sulphate as 0.000018 gram per kilogramme of body weight, or 0.000013 gram per kilogramme of the free base. A maximal and prolonged rise of arterial pressure followed on the injection of five or six times this amount. There can be but little doubt that the active sulphate either has the same composition as the inactive sulphate described and analysed, or that it differs only very little from it. On drying the highly active sulphate in the hot air bath at 110°C. for some hours its activity is almost destroyed. An account was also given of the behavior of epinephrin toward alkaloidal reagents, toward fusion with alkalis, etc., and valid reasons were advanced for classing it with the alkaloids. tHe ACTION OF SUPRARENAL EXTRACT ON THE MAMMALIAN HEART. By GEO. B. WALLACE anp W. A. MOGK. TRACINGS were taken directly from the dog’s heart by a modified Roy and Adami myocardiograph. It was found that the suprarenal extract stimulates the vagus centre, thus inhibiting the heart. It produces also a direct stimulation of the heart muscle, resulting, when the vagus influence is removed, in an increase in the force and number of contractions. Accompanying the change in the heart action there occurs a rise in the systemic blood pressure, due to a contraction of the arterioles. The pressure in the pulmonary arteries, however, is not raised. vi Proceedings of the American Physiological Soczety. THE CHEMISTRY OF THE MELANINES. By WALTER JONES, Pu. D. THE black hair of the horse’s tail was allowed to stand several weeks in contact with concentrated hydrochloric acid, and from the product pigment-granules were isolated and purified. On fusing these granules with caustic potash a substance was obtained which had apparently lost none of the characters of a melaninic acid but was found on analysis to contain no sulphur. The failure of sulphur in the composition of the substance might suggest that an artificial choroid pigment had been made. This supposition however is untenable, for when the choroid pigment is similarly treated with caustic potash it loses all of its nitrogen while the melaninic acid in question contains 13 per cent of this element. A study was also made of the action of oxidation agents on the sulphur-free melaninic acid. The results show very conclusively that when the oxidation occurs in an alkaline medium the pigment is easily decomposed, giving rise to carbon dioxide and ammonia. Intermediate products, however, can be obtained when the oxidation is carried on in an acid medium. Under these conditions a substance is formed which has the odor, volatility, and basic character of putrescine, but differs from this compound in the ease with which it is decomposed when heated with alkalies. The oxidation in an acid medium also gives rise to a light yellow insoluble substance which becomes darker when warmed with water until it finally changes to a pigment which is in outward appearance indistinguishable from the original melaninic acid. Its analysis, however, shows that it is a decomposition product of the latter, and that it can be represented by so simple a formula as C,s;Hy,Ns5O4p. ON THE SOLUTION OF MERCURY IN THE BODY-JUICES. By A. S. CHITTENDEN. (Read by JOHN J. ABEL.) GENERALLY speaking, metallic mercury cannot as such pass through the intact epithelium of any part of the body. In mercurial ointments some of the mercury is present in the form of salts of the fatty acids, and when such ointments are rubbed into the skin, con- Eleventh Annual Meeting. Vil ditions favorable to the solution of more of the mercury are met in chemical constituents of the secretion of the sebaceous glands. The oxygen of the air is no doubt a necessary accessory to these changes in the mercury. Even in the lungs the secretions of the bronchial surfaces must induce the solution of the mercury condensed on them. Such reasoning has led many investigators to doubt that the body is capable of oxidizing mercury when it is introduced as such into the blood. To determine this point particles of pure mercury smaller than a red corpuscle were prepared by reducing alcoholic solutions of mercuric chloride with stannous chloride, and approx- imately 0.25 gram was injected into the femoral artery of four dogs, a solution of sodium chloride, 0.65 per cent, being used to keep the mercury in suspension. The injection was made by means of a fine hypodermic needle directly into the artery, which was clamped centrally during the operation, and the wound securely closed. The urine and faeces were collected during six weeks. The acidu- lated urine was passed over coils of reduced copper gauze and the mercury determined according to the directions of Winternitz. Glob- ules of mercury were found condensed in the receiving bulb and amalgamated with the gold foil which was placed beyond the bulb. The faeces contained no mercury. It is therefore proved that the body juices can dissolve mercury when this element is introduced directly into the circulation by a method which entirely excludes the presence of a soluble salt of the metal. Sections of the paw of one of the animals failed to show any emboli. When sections of the lymph glands were submitted to Prof. William H. Welch he found in them numerous large megalo- karyocytes, a condition suggesting parenchymatous embolism of the bone marrow. ‘These cells most probably entered the circulation from the bone marrow and were then filtered out by the lymph glands. vill Proceedings of the American Physiological Soczety. ON THE PRESENCE OF CHOLIN AND NEURIN IN THE INTESTINAL CANAL DURING ITS COMPLETE OBSTRUCTION. By BEATTIE NESBITT, M. D. A FOOD rich in lecithin (yolks of eggs) was fed to four dogs for two or three days, then the intestines were closed, and after two or three days more the animals were killed. The platinum double salt of cholin was prepared from the intestinal contents and purified. On analysis 0.1457 gram of this salt gave 0.0463 gram of platinum, or 31.77 per cent, whereas theory requires that this salt contain 31.64 per cent. The presence of cholin was therefore proved. From the intestinal contents of one dog, neurin was also obtained, though not enough for analysis. The presence of this highly toxic substance was proved by the solubilities of its platinum double salt and the crystalline character of this compound, and also by the be- havior of the solutions of cholin toward the alkaloidal reagents when these solutions contained neurin. The author also isolated a ptomaine which accompanied the cho- lin and neurin. The hydrochloride of this ptomaine is very solu- ble in water and in alcohol, and crystallizes in fine needles. The free base has a penetrating sweetish odor and is easily oxidized when exposed to the air. Both the platinum and gold salts are unstable and easily reduced compounds. The amount of this ptomaine which could be isolated did not suffice to establish its identity. These experiments lead the author to believe that complete occlu- sion of the small intestine at its lower end will give rise to the occurrence of cholin, neurin, and perhaps other bases provided the food taken contains any considerable quantity of lecithin. While cholin would have to be absorbed in relatively large amounts to exert a marked toxic action on human beings, it is otherwise with neurin, which is many times more toxic in its action, and must be classed with the exceedingly active poisons. It has been shown both by the experiments of Schmidt and Weiss and also by those recorded in this abstract that the poisonous neurin may be formed from cholin by bacteria. In its physiological action neurin agrees closely with muscarin; especially to be noted here is its paralytic action on the heart and its power to increase the intestinal move- ments to such an extent that continual evacuations occur. Eleventh Annual Meeting. 1X DIRECT AND REFLEX ACCELERATION OF THE MAMMALIAN HEART. By REID HUNT. THE experiments were performed upon dogs, cats, and rabbits ; most of them, however, upon dogs. The accelerators were found almost always in a condition of tonic activity, — a tonus much more constant than that of the inhibitory nerves to the heart. The centres of the accelerators show greater resistance to the action of drugs, changes in blood pressure, etc., than do the cardio-inhibitory or even the vasomotor centres. Section of the accelerator nerves causes a prolongation of both systole and diastole; and at times, especially in cases in which the vigor of the heart is not great, cardiac irregularity. The latter seems to be due to the ventricles failing to follow all the beats of the auricles. fatigue.— When the accelerators are stimulated with an electrical current causing a maximum acceleration, the heart soon returns partially to its previous rate. At first there is a rapid decrease in the rate; then a much longer period, during which the rate remains almost unchanged or decreases very slowly. The duration of these periods depends upon the condition of the heart and nerves and upon the character and strength of the stimulus employed. The cause of the decrease in the heart rate or fatigue is a local loss of irritability of the nerve at the point stimulated; and a genuine fatigue in the heart itself. The fatigue is shown by (1) the fact that with repeated stimulations of the accelerators the heart rate becomes slower; (2) the effect upon the heart of stimulating the accelerators becomes less; (3) the effect of the vagi upon the heart becomes greater; (4) by the action of certain drugs in hastening fatigue. As drugs act upon muscle or the endings of nerves before they affect the nerve fibres, it seems probable that the very rapid decrease in the heart rate from stimulating the accelerators after certain drugs is due to their effect upon the heart rather than to their effect upon the nerve fibres. Death frequently results from repeated and long con- tinued stimulation of the accelerators. If the vagi are in tonic activity or if they are stimulated simultaneously with the accelera- tors, the latter cause less fatigue of the heart; z.¢., the vagi havea protective influence on the heart. x Proceedings of the American Physiological Soczety. Reflex acceleration.— Reflex acceleration might be caused either by increasing the activity of the accelerators or by inhibiting the tonic activity of the vagi. The latter was found to be the usual if not the exclusive method. The evidence for this is as follows: (1) When the heart is accelerated by the stimulation of a sensory nerve, the course of acceleration is much more like that resulting from the section of the vagi than that observed when the accelera- tors are stimulated directly; that is, the latent period is very short, the maximum acceleration is very quickly reached, and the shorten- ing occurs mostly in diastole, whereas when the accelerators are stimulated, the latent period is long, the acceleration is slowly developed, and both systole and diastole are shortened; (2) reflex acceleration occurs just as readily after all the accelerators are divided as when they are intact; (3) in these experiments reflex acceleration was never obtained after section of the vagi. There is some evidence for the view that there are, in most sensory nerves, two sets of fibres, stimulation of one of which causes increased activity of the cardio-inhibitory centre and so reflex slow- ing, while stimulation of the other set causes inhibition of this centre and so reflex acceleration. A SIMPLE ETHERIZING BOTTLE. By C. C. STEWART. Two glass tubes pass through the stopper of the bottle, and by means of two T-tubes the arrangement illustrated in the diagram is pro- cured. If the tube A be connected with the cannula in the trachea, then on clamping at B fumes of ether are inhaled; while if the clamp is placed at C, pure air may be breathed. The advantage of the arrangement is that the ad- ministration of the anesthetic may be controlled with one hand, during either normal or artificial respiration, by changing a single clamp. Eleventh Annual Meeting. x1 THE NATURE OF MUSCLE FATIGUE. By FREDERIC S. LEE. EXPERIMENTS on the frog, the turtle, and the cat show that our previous knowledge of fatigue, limited largely to the frog, is incom- plete. The essential element in the course of fatigue, common to all three species, is a decrease of lifting power. Slowing of the phase of contraction, while slight in the frog, is great in the turtle, and apparently wanting altogether in the white muscle of the cat. Slow- ing of the phase of relaxation, while great in the two first-named species, is also practically wanting in the white muscle of the cat. In seeking the cause of muscle fatigue the muscles of fasting animals were compared with those in good nutritive condition but poisoned with lactic acid, potassium lactate, or sodium lactate. The contraction curve of a muscle of a fasting animal is a normal, not a fatigue, curve. That of a muscle poisoned by the substances men- tioned approximates, if it is not identical with, a normal fatigue curve. The chief cause of muscle fatigue thus appears to be poison- ing by fatigue substances, and not a consumption of contractile substance. Fatigue is a state intermediate between the fresh and the exhausted states. The latter state is due to the consumption of contractile material and is a serious condition, not easily recovered from. Fatigue is not serious, can readily be done away with, and appears to be a protective phenomenon, preventing the oncoming of exhaustion. Fatigued muscle-cells would hardly be expected to exhibit histo- logical characteristics different from those of fresh cells. Studies of such cells under the direction of the author, and by recent cytologi- cal methods, show no visible evidences of fatigue. xi Proceedings of the American Physiological Soctety. OBSERVATIONS ON THE INNERVATION OF THE INTRACRANIAL VESSELS. By G. CARL HUBER. THE Ehrlich methylene-blue method was employed on dogs, cats, and rabbits. In the pia mater of the dog, cat, and rabbit two kinds of nerves were found, — sensory nerves and vasomotor nerves. The sensory nerves accompany the larger vessels of the circle of Willis in bundles, containing from 15 to 20 large medullated nerve fibres. These bundles of medullated nerves, in suitable preparations, may be traced in company with the arterial branches proceeding from the circle of Willis to all parts of the pia mater, of the cerebrum and cere- bellum, until the arterial branches are reduced in size to vessels pos- sessing a media consisting of two layers of muscle cells. The vessels of the choroid plexus form an exception to this statement; these medullated sensory nerves terminate, after repeated branching, in an end-brush, situated for the main part in the adventitia of the pial arteries and in the surrounding connective tissue. This end-brush consists of numerous fine, varicose fibrils, which may often be traced for relatively long distances before terminating. The vasomotor nerves were found in the form of a perivascular plexus of non-medullated nerve fibres. This plexus was observed on all the vessels of the circle of Willis and on the arteries of the pia, vary- ing in size from the largest found to vessels with a media composed of two layers of muscle cells. That these varicose, non-medullated nerves terminate in the muscular coat of the arteries of the pia, and may therefore be looked upon as vasomotor nerves, was determined in tissue stained in methylene blue, fixed in ammonium molybdate, sectioned, and counterstained in alum carmine, after recognizing in the unfixed tissue—under the microscope —the non-medullated, perivascular nerves above mentioned. In the cranial dura mater, nerves similar to those above de- scribed for the pia mater were observed. Eleventh Annual Meeting. xiii POSSIBLE AMCEBOID MOVEMENTS OF THE DENDRITIC PROCESSES OF CORTICAL NERVE CELLS. By C. F. HODGE (with H. H. GODDARD). A NUMBER of modern neurologists attempt to explain varying psychic conditions by the extension and retraction of the cortical dendrites and their contact granules. In case the dendrites move in amoeboid fashion it should be possible by preparing the brain quickly enough to catch them in the retracted and expanded state. The method adopted consisted in cutting off the head of a young animal with a single blow of a large, thin knife, and having the parts fall instantly into large dishes of Cox’s solution warmed to 39° C. Three experiments have been made on pigeons, three upon hens (one experiment in each of these sets being made to compare effects of hypnotism), two on white rats, three on kittens, and three on puppies. The material from the kittens and from one of the experiments on puppies is not yet ready for study. That from the rats and from two of the experiments on puppies has yielded uniform and definite results, which confirm Demoor’s and Berkley’s work, and extend the former’s results to include normal physiological fatigue. The preparations from the birds do not contradict the above results but did not stain so well and were not cut in such wise as to make rigid comparison possible. In the case of two puppies (sisters from the same litter) one killed at 4 P.M., awake, showed the cortical dendrites varicose in 31.1 per cent of the cells. The other, after sleeping an hour and ten minutes, 8.15 P.M., showed varicosity in but 8.5 per cent of the cells, but in nearly eight per cent it was only very slight; while in the waking puppy 16 per cent were markedly varicose. In the next experiment with puppies the first was killed at 7 A.m., on waking, the other at 5.45 P.M., after being kept awake all day. This gave much more definite results. Not all parts of the cortex appeared equally affected, a point on which we hope to gain some evidence in succeeding experiments, but through large areas in this tired puppy practically all the cells showed marked varicosity of dendrites. No such areas have been found in the rested animal, the dendrites being uniformly expanded and the contact granules distinct. xiv Proceedings of the American Physiological Society. A NEW CHRONOSCOPE. By G2 WwW. FIDZ: THIS piece of apparatus is the result of an attempt to devise a chronoscope of simple form. It consists essentially of a tube resem- bling a burette tube, which is entered by one short glass tube at the top and another near the bottom; the latter connects with a water reservoir for filling the apparatus, while the upper tube serves as an overflow and determines the zero level of the water column. Con- nected with the lower end of the tube by a short piece of rubber tubing is a valve operated by two electro-magnets, one throwing it open, the other closing it. The valve was taken from an automatic electric gas-lighting burner. The circuits are arranged so that the opening magnet is connected with the signal key of an ordinary reaction apparatus, and the closing magnet is connected by a third wire with the response key. When the signal is given, the valve is opened and the column of water falls until arrested by the closure of the valve in response to the signal. The tube is graduated by means of a falling weight so that the interval in hundredths of a second is read off at the top of the water column. ‘This apparatus has been found to give uniform results, and thus stands as a cheap, simple form of chronoscope. It is possible to arrange the valve to work mechanically, making a still cheaper form in which the chief expense will be for the valve itself and the time of graduation. This any one can do by means of a falling weight arranged to give stated time intervals. ON THE MAXIMUM PRODUCTION OF HIPPURIC ACID IN RABBITS. By GRAHAM LUSK (For F. H. PARKER). IF a quantity of benzoic acid (as a lithium salt) be fed to fasting rabbits in quantity sufficient to unite with the glycocoll formed in the animal, but not sufficient to produce toxic symptoms, a fixed ratio will exist between the hippuric acid nitrogen and the total nitro- gen of the urine. This ratio, which is about 1: 20, would indicate that 5 per cent of the nitrogen of proteid may be eliminated in the form of glycocoll. The ratio is not increased after feeding carbohydrates, nor altered after ingestion of gelatin. Gycocoll is probably a cleavage product of proteid in metabolism to the extent indicated above. Eleventh Annual Meeting. XV IODINE IN THE TISSUES AFTER THE ADMINISTRATION OF POTASSIUM IODIDE. ispig 1s TNS JEW ADINY DS DURING the last few years there have been found in various organ- isms a number of normal tissue constituents containing iodine, as iodocarnein, iodokeratin, iodospongin, iodoproteid, iodofat. Some of these bodies can be obtained synthetically without great difficulty. It was the aim of the author to investigate the tissues of the higher animals as to their power of binding iodine intramolecularly. For this study hens were employed, since in them the chemical changes of at least one tissue could be followed from day to day. The eggs were examined from time to time during ten weeks, at the end of which period the other tissues were analysed. During the first three weeks, the author found iodine only in the form of potas- sium or sodium iodide. Beginning with the fourth week the iodine appeared as an organic compound, apparently as iodofat. Of the other tissues or organs, the following were examined: nervous tissues, muscular tissues, grandular organs, gastro-intestinal tract, skin, and adipose tissue. In none of them could any appreciable amount of organic iodine be detected with the exception of the bones, where a noticeable quantity of iodofat was present. Comparing these results with all that is known on the subject, the author comes to the conclusion that only certain keratins, such as that of the hair, are capable of binding iodine in the organ- ism; only certain proteids, such as that of the thyroid gland, have the same faculty; and only certain fats act in the same way. Whether this result depends on the peculiar chemical composition of those compounds or on a peculiar activity of the different organs or organ- isms the author will endeavor to solve. CORRELATION OF THE FUNCTIONAL AND ANATOMICAL DEVELOPMENT OF THE CEREBRUM. By WESLEY MILLS. HISTOLOGICAL observations in progress on the brains of very young animals will probably show that in all cases of early functional negativity, disappearing later, there is a corresponding immaturity of both the cortex and the white matter beneath it. xv1_ Proceedings of the American Physiological Society. A NOTE ON SENSORY NERVE-ENDINGS IN THE EXTRINSIC EYE MUSCLES OF THE RABBIT— ATYPICAL ~ MOTOR-ENDINGS OF RETZIUS. By G. CARL HUBER. IN his third volume of the ‘‘ Biologische Untersuchungen” Retzius gives an account of observations made with the Golgi and methylene- blue methods on motor-endings in striated muscle tissue, and here draws attention to an “atypical motor-ending ” found in the extrinsic eye muscles of the rabbit. The nerve-endings thus described have been repeatedly observed by me in the course of an investigation, now in progress, on the ending of sensory nerves in the eye muscles of vertebrates. That the ‘atypical motor-endings” of Retzius are sensory and not motor nerve-endings may, I believe, be argued from the following data: (1) the nerve-endings in question are found mainly in the anterior third of the recti muscles of the eye, while typical motor-endings are found in the middle third; (2) the nerves terminating in this ending present near their termination short internodal segments, branch frequently, and are surrounded by a thin sheath of Henle; agreeing in these respects with sensory nerves in other parts of the body; (3) the ending is found in the connective tissue, immediately outside of the sarcolemma of the muscle fibres between which they terminate, while the motor nerves end under the sarcolemma of the muscle fibres; (4) no other sensory nerve- endings have been found in the extrinsic eye muscles of the rabbit, while in other mammals studied such endings may readily be found. ON THE PATHS OF ABSORPTION FROM THE PERITONEAL CAV IEY: By LAFAYETTE B. MENDEL. IN a number of experiments regarding the paths by which colored fluids are absorbed from the peritoneal cavity, it was observed under a variety of conditions that in every case the colored substance (indigo-carmine) appeared in the urine considerably earlier than in the lymph flowing from the thoracic duct. The conditions of the experiments were carefully regulated to avoid the deficiencies of previous investigators, and the author is inclined to the blood-vessel theory of absorption, as suggested by Starling. Eleventh Annual Meeting. Xvil PRELIMINARY COMMUNICATION ON THE ABSORPTION OF PROTEIDS. By P. A. LEVENE anp J. LEVIN. IT has always been the accepted theory, though based on imperfect experimental testimony, that proteid material is absorbed from the gastro-intestinal tract by the blood system. Recently, however, Asher and Barbéra have subjected the question to a new trial, and obtained results that lead them to conclusions contradictory to the generally accepted view. The great difficulty of solving the problem with exactness lies in the fact that any injected proteid once past the barrier of the intesti- nal wall cannot be distinguished from the tissue proteids. It was, therefore, the aim of the authors to study the path of absorption of iodoproteids, as the latter could easily be identified in any tissue or organ. A ten per cent solution of iodoproteid was injected into a previously cleaned and ligated loop of the colon and rectum, and the proteid was searched for in the lymph of the thoracic duct. The results of three experiments are negative. Hence these results tend to corroborate the old theory and contradict the view taken by Asher and Barbera. The questions the authors are now endeavoring to answer are: what component of the blood (leucocytes or plasma) carries the proteids from the intestinal wall; and in what organ or organs is the iodoproteid decomposed before being assimilated (if it is assimilated at all). THE BEHAVIOR OF INULIN IN THE GASTRO-INTESTINAL Ae E. By hehe Crile Ni EN A SERIES of experiments on the behavior of inulin in the gastro- intestinal tract carried out in the writer’s laboratory by Arthur B. Siviter has led to the following conclusions. The ordinary amylolytic enzymes, such as the ptyalin of saliva, the amylopsin of pancreatic juice, vegetable diastase, and ‘ Taka”’ diastase are without action on inulin. Dilute hydrochloric acid (0.05 —o.2 per cent) at 40° C. inverts inulin to levulose. Combined hydrochloric acid (combined with xvil Proceedings of the American Physiological Soczety. proteids) likewise inverts inulin to levulose, but more slowly than corresponding strengths of free acid. Organic acids, such as oxalic, lactic, and salicylic, also transform inulin to levulose. The value of inulin as a food is probably due to the fact that the hydrochloric acid of the gastric juice may invert inulin to levulose, the latter being absorbed and utilized in increasing the store of glycogen in the liver. THE PRODUCTION OF FLUORESCENT PIGMENT BY BACTERIA. By EDWIN O. JORDAN. THE outcome of experiments made with six different cultures of “fluorescent bacteria” was as follows: 1. The presence of both phosphorus and sulphur is essential to the formation of the fluorescent pigment. 2. The nature of the base associated with the phosphorus and sulphur is not important. 3. The conclusions that may be drawn regarding the dependence ’ of the fluorescent ‘‘ function” upon the molecular constitution of the ammonium salts may be best appreciated through an examination of the constitutional formula of the organic acids whose salts were employed. The list is arranged as far as possible in order of fluorescigenic value. i; Asparagin. .. = COOH ..CH,..\CH(NH,)). COMEe 2, ,suecimiGacid —. “COOH 4 CH. CH, . COOH, 3. veactic acid’. 2 -CHy CHO. COOH. 4. (Cine acids «> « COO. C(OH).(GH-COOEns 5. Tartaricacid . COOH .CHOH.CHOH. COOH: 6. Uric acid: ~- . NH.CO..NH.COC =C.: NB .C@aniee Vawexceucacid .. Chive, COOH. 8. Oxalic acid . . COOH.COOH. Oy Mormic acid@ sa. ot COOH: The fluorescence is not intimately bound up with the bibasicity of the acid, and the existence in the molecule of at least two groups of CH. (as Lepierre asserts). The difference between acetic acid on the one hand and oxalic and formic acids on the other is certainly Eleventh Annual Meeting. xe significant, but that neither the carboxyl (COOH) nor the methylene (CH2) grouping is essential to pigment production is shown by the availability of urate. The difference between tartrate and succinate, as well as that between formate and acetate, does, however, clearly indicate that, other things being equal, the presence of the methy! or methylene group is coincident with superior nutritive value and fluorescigenic power. 4. The presence of acid in the medium not merely conceals the existence of the substance to which the color is due, but interferes with those vital activities of the bacilli which, in an alkaline solution, lead to the production of that substance. 5. Diffuse daylight is unfavorable to pigment production. 6. If chemical substances that prove, when in certain proportions, favorable to growth and to the production of pigment be present in excess of a certain quantity, the production of pigment will be checked, although growth may be more abundant than before. A NEW BRAIN MICROTOME. By €. F. HODGE (witH H. HH. (GODDARD): IN the new microtome the upper surface of the knife is level, and, being hollow ground, the knife thus carries the pool of liquid into which the section floats. This does away with the dripping bottle. The knife blade proper being only 2} inches wide the surface is widened to 8 inches by a simple pan of zinc screwed to the back of the blade and sealed on with melted paraffine. The pool of liquid on the blade is about + inch deep. In order to give a sufficient obliquity of cut a long blade is required. The blade in question is 36 inches in length, and since it would be difficult to support such a blade at one end and would require a very heavy sledge to hold it firmly, it was proposed (Mr. Goddard’s contribution of special value to the problem) to support the knife firmly at both ends. This has made it necessary to have the specimen move against the edge of the stationary knife. No difficulty was encountered, however, on this account, the brain being mounted on a case which slides upon a heavy iron track running obliquely underneath the knife. This case, a hollow box of cast iron, slides smoothly in an outer case of similar xx Proceedings of the American Physiological Society. construction, and the micrometer screw is fastened to the bottom of - the outer case and nutted through the bottom of the inner case so, that the inner case may be moved up or down within the outer.. The outer case is provided with projections which support it on the track, and the whole is moved from one end of the track to the other. easily and smoothly by means of a rack and pinion. A single notch. on the screw head gives a section 12} micra thick. The knife is made of a soft iron body into which an edge of very. hard razor steel is welded. This has obviated the warping and, twisting attendant on high tempering of solid steel blades and has resulted in a razor with a perfectly true edge. The framework of the microtome is made of cast iron, rigidly braced. The cost of constructing the machine was about $150.00. SOME Facts RELATING TO THE MELANINS. By R. H. CHITTENDEN. See this Journal, vol. i, p. 291. ON THE CAUSES OF THE ORDERLY PROGRESS OF THE PERISTALTIC MOvE- MENTS IN THE CiésopHaGus. By S. J. MELTZER. See this Journal, vol. ii, p. 266. EXPERIMENTS ON THE MAMMALIAN Heart. By W. T. Porter. See this Journal, vol. ii, p. 127. A CONVENIENT FoRM oF NON-POLARIZABLE ELECTRODE. By W. H. HOWELL. New Lasorarory Apparatus. By E. W. ScrIiprure. AN ImpRovep Form oF ELLis’s PistoN RECORDER. By W. P. Lomparp. A SIMPLE ONCOMETER. By FREDERIC S. LEE. DEMONSTRATION: METHYLENE BLUE PREPARATION OF SENSORY NERVE-END- INGS IN TENDON — Go.ci’s TENDON CorpuscLes. By G. C. Huser. A NEw ReEsprRraTION APPARATUS. By FREDERIC S. LEE. DEMONSTRATION: THE CO-ORDINATION OF THE VENTRICLES. By W. T. PORTER. EXHIBITION OF INSTRUMENTS FOR THE STUDY OF MOVEMENT AND FArIGUE. By qothick. (Carrerr. THE PxystotocicaL Basis or Mentat Lire. By H. MUNSTERBERG. CONFUSION OF TasTEs AND Opors. By G. T. W. PAarRICck. METHODS OF DEMONSTRATING THE PuystoLoGy AND PsycHOLOGY OF Cotor. By E. W. Scrirrure. ON THE FLICKER PHOTOMETER. By O. N. Roop. A CONVENIENT Form or SpHyGmMocrarH. By R. H. CHirrenDeEN. Eleventh Annual Meeting. Xx1 A CHEMICO-PHYSIOLOGICAL STUDY OF CERTAIN DERIVATIVES OF THE PRO- Tes. By R. H. CHIrrenDen. See this Journal, vol. ii, p. 142. EXPERIMENTS ON THE MOLECULAR CONCENTRATION AND ELECTRICAL CON-— DUCTIVITY OF CERTAIN ANIMAL Liqguips. By G. N. STewarr. THE CHOLESTERIN-ESTERS OF Brrps’ BLoop. By E. W. Brown (presented by L. B. MENDEL). See this Journal, vol. ii. p. 306. INFLUENCE OF MASSAGE UPON THE NUMBER OF BLOOD GLOBULES IN THE CIRCULATING BLoop. By J. K. Mircuett (read by H. P. BownpitTcn). Aw INSTRUMENT FOR’ MEasuRING Muscular Tonicity In Man. By L. J. J. MUSKENS. 7 i ite A, mr i i ne 4 : a in a? 4 hes ee 9 : : i ol Ve ae ae +e ‘ * . ? i, t ebige t ( -, bolt wy if < SpA By Re miles ¥ alt way ” 7, . come % 4 en = Bh. ete BINDING SECT. MAR4 1966 QP American Journal of Physiology 1 A5 Ved Hl COPec \S Biological & Medical | Serials PLEASE DO NOT REMOVE CARDS OR SLIPS FROM THIS POCKET oo eee UNIVERSITY OF TORONTO LIBRARY STORAGE ’ ’ ‘ ‘ rn we ‘ i i (ictting crak . ' Taba leks ot , ‘ ie in pad areree * . Shyu bn rerieer ts Proper OOF re tee resked® cas Vibege ' oreye bik i Ids Srey pgear eth MEA atthe oe ae Ne - + " rue ie ails tantuentess feyee trargest Hen Ly ire HPht ee et g is Fra weieateey EPA corre Vee Menten Wpui he? rier i. ig “me a 4 7 wn Hote ' eytates H 71 ean Nea as peeeaesees , ue Abe