Franklin, 1933; Waterman, 1933]; indeed, the only negative findings, [Waterman, 1933]. Inasmuch, then, as Donegan was misled with

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1 381 6I2.I34:6I2.893 THE CONSTRICTOR RESPONSE OF THE INFERIOR VENA CAVA TO STIMULATION OF THE SPLANCHNIC NERVE BY K. J. FRANKLIN AND A. D. McLACHLIN (From the University Department of Pharmacology, Oxford) (Received January 31, 1936) DO N E G A N [1921], in the first extensive study of the innervation of veins, was unable to record any response to electrical excitation on the part of the inferior vena cava, though he stimulated the lumbar and dorsal sympathetic cord, and the distal portion of the cut cervical cord. He obtained equally negative results with adrenaline, even in very high concentration. His findings with the drug are thus opposed to those of most other workers, both before and after him [Gunn and Chavasse, 1913; Edmunds, 1915; Bricker, 1924; Franklin, 1925; Maloff, 1931; Franklin, 1933; Waterman, 1933]; indeed, the only negative findings, apart from Donegan's, are some few in Bricker's and Waterman's series. The species, in which positive results have been obtained, are the rabbit, cat, dog, and man; in the first three of these reactions have been recorded in situ [Franklin, 1933], as well as with isolated preparations; the lowest effective concentration of adrenaline has been 1 in 140 million [Waterman, 1933]. Inasmuch, then, as Donegan was misled with regard to adrenaline, doubt must also arise about his results with nerve stimulation, the more so as Michelazzi [1933] has described a copious nerve supply to the inferior vena cava in man, the dog, and the rabbit. The fibres are more numerous in the walls of this vein than they are in those of the aorta, and they are particularly abundant in two places, namely, distal to the liver and proximal to the iliac bifurcation. Michelazzi's anatomical findings, however, have not yet received physiological confirmation; the experiments recorded in this paper were, therefore, a natural next step, though their actual conception dates from some observations made by one of us (K. J. F.) in 1928.

2 382 K. J. FRANKLIN AND A. D. McLACHLIN METHOD AND RESULTS It seemed to us most probable that the splanchnic nerve would carry constrictor impulses for the inferior vena cava, and our idea has been amply justified so far as the portion of the vein between the iliac and renal tributary entries is concerned. The first experiments were performed upon cats, anaesthetized with ether and chloroform. In each case the abdomen was opened throughout its length by a mid-line incision, and the bladder, abdominal portion of the alimentary canal, and spleen removed. In the first cat the circulation was arrested by an overdose of anaesthetic, and the inferior vena cava was found to respond by contraction to direct faradization of its walls. Search was then made for postganglionic nerve fibres, and about half-way between the right iliac and renal veins there was found a small nerve twig, which gave a number of fine branches to the vena cava. Distal faradic stimulation of the cut nerve resulted in a rather slow, localized diminution of about one-third in the calibre of the vein. The stimulation was repeated twice with similar results. A right-angled glass tube was tied in the vena cava caudal to the renal veins, and the nerve again stimulated; during stimulation there was a slight rise of fluid in the tube and after cessation of the stimulus a fall. Another nerve twig was found somewhat nearer the renal veins, and stimulation of its distal end gave results similar in sign, though less in degree; the least time for complete relaxation was 10 sec. In the second cat the distal portion of the cut right splanchnic nerve was stimulated for 1 min. Before the stimulus was applied, the calibre of the vein at a selected point was 3-9 mm., 30 sec. after stimulation it was 2*9 mm., 90 and 150 sec. after stimulation 3-5 mm. In the third cat the adrenal veins were tied off, and thereafter a first stimulation of the distal end of the right splanchnic nerve gave the following results. The initial calibre of the vein was 3*6 mm.; stimulation lasted 1 min.; 35 and 60 sec. later the calibre was respectively 2-9 and 3-2 mm. An arterial pressure tracing, taken after this, showed that the adrenal glands had been effectively excluded from the circulation. In a fourth cat all the tributaries to a portion of the vena cava were ligatured, and a glass tube tied into the vein. The tube-vein system was then filled with Ringer's solution to an appropriate height. Subsequent stimulation of the distal right splanchnic nerve caused a rise of fluid in the tube, and cessation of the stimulus a fall. It was noted in all the experiments that the reactivity of the vein

3 INNERVATION OF VENA CAVA 383 decreased markedly with the passage of time. During all the observed contractions the vein remained cylindrical. The later experiments were performed upon two rabbits, anwesthetized with ether. In the first animal the circulation was arrested by an overdose of anaesthetic, the abdomen freely opened by a mid-line incision, and the abdominal viscera pushed over to the left side so as to expose the inferior vena cava. The right splanchnic nerve was ligatured and cut proximal to the ligature. The diameter of the vein at a selected point between the iliac and renal veins was 4-4 mm.; after 30 sec. stimulation of the distal end of the splanchnic nerve it was 3-2 mm.; 60, 135, and 210 sec. after cessation of the stimulus it was respectively 2-5, 1-3, and 2-5 mm. It had previously been found, in another rabbit, that the contracted vein could not be dilated by pressure on the column of blood in the wide portion proximal to the renal vein entries; tapping of the constricted portion with a forefinger, however, had caused immediate relaxationthe rate of tapping was about two taps per second. Such mechanical stimulation, applied in the case under consideration, had a similar result. A repetition of the experiment gave the following figures. The diameter of the vein was 4*0 mm., and the nerve was stimulated for 1 min. Immediately after the stimulation the calibre was 3x3 mm.; 45, 75, 120, 180, 270, 300, and 330 sec. later it was respectively 2-7, 2-5, 1-8, 1-4, 1 1, 1.0, and 1-4 mm. The constriction seemed to spread proximally from the distal portion of the vein. Tapping again resulted in rapid and complete relaxation. A fresh length of the nerve was exposed and stimulated for 1 min. The initial calibre of the vein was 4-3 mm.; after stimulation it was 3*9 mm., 75 sec. later 2-6 mm., 75 sec. again later 3-6 mm.; tapping dilated it to 4 0 mm. In the second rabbit the preliminary procedure was similar, but the circulation was not arrested. The nerve was stimulated for 1 min.; within 135 sec. from the cessation of the stimulus the calibre of the vein had fallen from its original 5-0 to 3 0 mm.; 5 min. later it was 4-1 mm., and tapping thereafter increased it to 4-9 mm. To exclude effects of adrenal medulla secretion, the glandular vessels were ligatured, and the, nerve was then stimulated again for a minute. The initial calibre of the vein, 4-9 mm., was reduced in 165 sec. to 2-4 mm.; at 315 sec. it was 3*2 mm., and thereafter further dilatation ensued on tapping. To make certain that the adrenal vessels had been effectively tied off, the whole of the two glands was removed, and it was found that no bleeding occurred. To exclude any arterial effects, the aorta was tied high up in the abdomen; another splanchnic stimulation caused, under these conditions, a decrease

4 384 K. J. FRANKLIN AND A. D. McLACHLIN in calibre of the vein from 4-8 to 2-1 mm., followed subsequently by relaxation to 2-5 mm. The vein in both rabbits remained cylindrical during its contractions and relaxations. DIscUSSION The diminution in cross-section of the vena cava, calculated from the experimental results, was 56 and 23 p.c. in the first cat, 45 p.c. in the second cat, and 35 p.c. in the third cat. In the first rabbit it was 91, 94, and 63 p.c., in the second rabbit 64, 76, and 81 p.c. The nerves stimulated included preganglionic and postganglionic, and contraction occurred with the circulation arrested or continuing, and with and without arterial and adrenal influences excluded. In all cases, some degree of relaxation occurred after contraction, but it was never complete during the relatively short period of our observations. Stimulation of the distal right splanchnic nerve caused a constriction of the whole vein as far as the renal vein entries; stimulation of the small postganglionic twigs, on the other hand, resulted in a more localized contraction. The dilatation produced by tapping was more or less confined to the part tapped. The technique was suggested by the " Klopfversuch ", and it was of interest to find that it was as effective upon the vena cava in our experiments as it was upon the splanchnic vessels in those of Go l t z [1864]. A more detailed study of this reaction is to be made in the near future, and further work is to be done upon other aspects of the innervation of the vena cava. It is very difficult, in view of our results, to account for Donegan's negative findings. The only explanations which we can offer are that his operative technique damaged the delicate periadventitial nerve fibres, that he took too long over his experiments, that the temperature of his Ringer's solution (400 C.) was too high, or that the vena cava lost its reactivity very rapidly through perfusion with such solution. The effects which we have described were confined to that portion of the vena cava which lies between the iliac and renal veins, i.e. the ascending portion in the commonest posture of the animal [Franklin, 1932]. That the effects were not due to current spread has been shown by non-electrical stimulation of the distal splanchnic nerve. Though the results described were all obtained with the right splanchnic nerve, contractions of the same order of magnitude have also been obtained by stimulation of the left splanchnic nerve.

5 INNERVATION OF VENA CAVA 385 SUMMARY Faradic stimulation of the distal end of the cut splanchnic nerve produces, in the cat and in the rabbit, a contraction of the inferior vena cava between the iliac and renal vein entries. REFERENCES Bricker, F. M. (1924). Z. ges. exp. Med. 42, 434. Donegan, J. F. (1921). J. Physiol. 55, 226. Edmunds, C. W. (1915). J. Pharmacol., Baltimore, 6, 569. Franklin, K. J. (1925). Ibid. 26, 215. Franklin, K. J. (1932). J. Anat., Lond., 66, 602. Franklin, K. J. (1933). J. Physiol. 77, 174. Goltz, F. (1864). Virchows Arch. path. Anat. 29, 394. Gunn, J. A. and Chavasse, F. B. (1913). Proc. Roy. Soc. 86, 192. Maloff, G. (1931). Pftilger8 Arch. 229, 38. Michelazzi, A. M. (1933). Cuore e Circol. N.S. 17, 121. Waterman, M. L. (1933). Algemeene en bijzondere Physiologie der Aderen, Amsterdam (Electrische Drukkerij "Trio"). PH. LXXXVI. 25