THE EFFECT OF ADRENALINE ON VASOMOTOR REFLEXES.

Transcription

1 : THE EFFECT OF ADRENALINE ON VASOMOTOR REFLEXES. By LIANG-WEI CHU and FONG-YEN Hsu. From the Institute of Psychology, Academia Sinica, Nanking. (Received for publication 23rd October 1937.) IT is well known that when adrenaline, by its peripheral action, raises the general blood-pressure this effect in turn activates a compensatory reflex vasodilatation through the activity of pressure-sensitive zones of the vascular system [Heymans, Bouckaert, and Regniers, 1933; Heymans, Bouckaert, Farber, and Hsu, 1936]. This, however, seems not to be the only way in which adrenaline acts on the vasomotor mechanism, for reflex vasodilatation also takes place when adrenaline is introduced into the blood stream, without at the same time causing any appreciable arterial hypertension [Heymans, Bouckaert, and Wierzuchowski, 1937; Hsu and Chu, 1937]. An attempt to obtain a more complete understanding of the action of adrenaline led to the study of the effect of this substance on the excitability of the vasomotor system, the result of which will be reported here. Hoskins and Rowley [1915] have previously noticed that in anaesthetised dogs the infusion of adrenaline reduced both pressor and depressor responses such as are normally elicitable by nicotine injection or by afferent stimulation. The site of such reduction was thought to be both central and peripheral. EXPERIMENTAL. Method.-Dogs under sodium veronal or chloralose anoethesia were used. The trachea was cannulated and both vagi were usually cut. Vasomotor reflexes were elicited by faradic stimulation of the central end of a cut vagus, or by clamping and unclamping of the common carotid arteries. Occasionally either the "pressor area" on the floor of the fourth ventricle, or the carotid sinus nerve, was also stimulated. Arterial blood-pressure was taken from the femoral artery with a mercury manometer. Sometimes the volume changes of the spleen, perfused from another dog through vessel anastomosis, were also recorded. Slow and continuous infusion of adrenaline at a rate of about mg. per kg. per minute was made, when desired, into a cannulated external jugular vein, commercial synthetic adrenaline solution, diluted with normal saline, to a concentration of about 1/100,000 being used. VOL. XXVII., NO

2 308 Chu and Hsu I FIG. 1. Dog (R), 11 kg., c3, veronal. Spleen perfused by dog (P), 20 kg., 3, veronal. S.V., spleen volume, 1, 3, and 5, carotid sinus reflex activated by clamping and unclamping the common carotid arteries, 2, 4, and 6, central end of the cut right vagus was stimulated with a Harvard inductorium, coil distance 4 cm. At 3 and 4, adrenaline solution was infused at the rate of 0 01 mg. per min. At 7, the vagus was stimulated while the common carotid arteries were clamped. Arrow upwards =carotids clamped; arrow downwards =carotid released. _Em. FIG. 2. Dog (R), 13-5 kg., c, veronal. Right vagus cut. Spleen perfused by dog (P), 7.5 kg., Y. Left carotid sinus nerve stimulated at signals, coil distance 12 cm. At 2, continuous adrenaline infusion.

3 The Effect of Adrenaline on Vasomotor Reflexes 309 RESULTS. The Damping Action of Adrrenaline.-During adrenaline infusion the pressor as well as the depressor reflexes were greatly diminished or even abolished (figs. 1 and 2). When stimulation was directly applied to the "pressor area" of the medulla the usual pressor response was absent and was sometimes replaced by a depressor one (fig. 3). On the other hand, the respiratory inhibition which occurred during FIG. 3.-Dog, 14 kg., d', veronal. The pressor areas at the floor of fourth ventricle were exposed and stimulated. Coil distance, 9 cm. L and R =left and right areas respectively. At 2 and 5, continuous adrenaline infusion. Between 3 and 4, the carotid sinus nerves were severed. vagus stimulation was not affected by the presence of adrenaline in the blood stream. The site of the damping action was therefore not generalised. The reversal of response presented in fig. 3 further suggests that the damping action might be restricted to the vasoconstrictor centre, the excitation or further inhibition of which was thereby rendered more difficult, so that the spread of the stimulating current to the nearby "depressor point" [Ranson and Billingsley, 1916] directly excited a vasodilator response. That the effect in question was not of peripheral origin can be deduced from experiments in which the volume changes of the perfused spleen were also recorded. During adrenaline infusion this organ

4 310 Chu and Hsu dilated and did not respond to afferent stimulation, although this organ itself was not in contact with the infused adrenaline. Moreover, the vasomotor damping was not due to any condition resulting from arterial hypertension during the infusion, for it was absent when hypertension was achieved by other means, e.g. clamping of the common carotid arteries (fig. 1 (7)). Neither was it due to the action of chloretone usually employed as preservative for the commercial I'IG. 4. Dog (R), 10 5 kg., S, chloralose, spleen perfuised by dog (P), 20 kg., S. Between arrows 0-2 mg. of adrenaline was injected into the internal carotid artery. At signals the central end of the vagus was stimulated, coil distance at 6 cm. adrenaline solution, for control experiments with this substance gave negative results. Ephedrine was inactive too. The Vasomotor Centre.-The next question is whether the damping action of adrenaline is exerted directly on the vasomotor centre or indirectly through some mediators. To examine the first possibility, adrenaline solution was injected into the circle of Willis via the internal carotid artery, the carotid sinuses having been previously denervated. It can be seen from fig. 4 that no reduction of the pressor reflex was observed even when the dose was big enough to raise the general blood-pressure. Experiments on the Carotid Sinus. In search of the mediators for chemical effects, the well-known chemically sensitive vascular zones

5 The Effect of Adrenaline on Vasomotor Reflexes 311 deserve first consideration. As the vago-depressors have been cut, the carotid sinus waas the remaining possibility. It can be seen from fig. 5 that after destroying both carotid sinuses the damping action of adrenaline on the pressor reflex was much reduced even with doses of adrenaline much higher than before. Here the magnitude of contraction of the perfused spleen in response to afferent vagus stimulation shonwed a sharp contrast to that before sinus destruction. FIG. 5. Same experiment as in fig. 4. At signals the central end of the right vagus of (R) was stimulated, coil distance 6 cm. At 2 and 5, continious adrenaline infusion, abouit 001 mg. per ruin.; at, 6, the rate was increased to about mg. The caroti(d sinuses were cruished between 3 and 4. Similarly after denervation of the carotid sinuses the response from stimulating the pressor area was not converted from a pressor to a depressor one by adrenaline as was previously the case (fig. 3 (5)). On the other hand, when adrenaline was present only in the blood circulating through the carotid sinus, vasomotor damping could also be demonstrated. As can be seen from fig. 6, the carotid sinuses of one dog were perfused by another according to the technique described by Heymans et al. [1933]. During the infusion of adrenaline into the donor dog, afferent vagus stimulation in the recipient dog elicited a much smaller vasomotor response than it norinally did or even causedl reversal (fig. 6 (5)). Such experiments suggest, therefore, that at least a great part of the recorded phenomenon was due to afferent impulses from the region of the carotid sinus exerting some inhibitory influence on the vasomotor centre and rendering it refractory to reflex stimulation. It remains to know in what wa,y adrenaline acts on the carotid

6 312 Chu and Hsu sinus. There are two possibilities: 1, adrenaline may sensitise the pressure receptors of the carotid sinus, so that they are more effective in damping down blood-pressure changes brought about by afferent stimulation; 2, adrenaline may stimulate the chemical receptors of the sinus giving rise to inhibitory impulses [Bettencourt, 1935]. The first possibility was borne out by experiments on the perfused carotid sinus, in which the glomus circulation was excluded, using the technique I FIG. 6. Dog (R), 20 kg., X, veronal. Carotid sinuses perfused by dog (P), 11 kg., 3, veronal. Vagi of both dogs were cut. R, respiratory movement of dog (R). At signals the central end of the left vagus of (R) was stimulated. From 1 to 3, coil distance at 6 cm.; from 4 to 6, coil distance at 7 cm. At 2 and 5, adrenaline solution was continuously inftused into dog (P). previously described by one of us [Hsu, 1937]. When a small quantity of adrenaline was slowly injected into the perfusion tube, the depressor response to pressure stimulation was perceptibly enhanced (fig. 7). Sensitisation alone, however, does not explain the whole effect, for in the experiment described above, the pressor response elicitable by reducing the pressure in the common carotid arteries to zero, instead of being enhanced, as the sensitisation hypothesis would demand, was actually reduced in the presence of adrenaline. Experiments were next designed to study the action of adrenaline on the chemical receptors with the intrasinusal pressure kept nearly constant. A cul-de-sac was made of the sinus by ligating all the

7 The Effect of Adrenaline on Vasomotor Reflexes 313 F 80 0i FIG. 7.-Dog, 16 kg., 9, veronal. Right carotid sinus denervated, left vagus cut and left sinus perfused with Ringer solution. Between arrows 005 mg. adrenaline was injected into the perfusion fluid. B.P., blood-pressure; P.P., perfusion pressure. FIG. 8.-Dog, 17 kg., S, veronal, left vagus cut. Right sinus made a cul-de-sac. At 1 and 4, central end of the vagus stimulated, coil distance 4 cm. At 2, 0.1 c.c. saline introduced into the sinus. At 3, 0*05 mg. adrenaline in 0.15 c.c. saline to the same.

8 314 Chu and Hsu efferent branches as far from the sinus as possible, leaving the nerves intact. The common carotid artery was also tied below the origin of the thyroid artery, and the blood in the sinus emptied. The introduction of a small amount of saline into the sinus called forth very little vasomotor response. However, when the saline was replaced by adrenaline solution, a profound and long-lasting fall of bloodpressure was observed (fig. 8). The vasomotor response to vagus stimulation was also somewhat diminished, though not very marked. Such experiments therefore demonstrate the chemical sensitivity of the carotid sinus towards adrenaline. They are in agreement with those of Palme [1936; quoted by Schweitzer and Wright, 1937], who noted a long-lasting depressor effect after painting the exterior of the sinus with adrenaline. Experiment8 on the Perfu8ed Inte8tine and Hind Leg.-In order to see whether adrenaline has any action on the other peripheral bloodvessels, similar to that which it has on the carotid sinus, a few experiments have been arranged for the perfusion of the small intestine and hind leg, the technique of which has been described previously [Hsu and Chu, 1937]. The intestine was perfused with defibrinated blood by means of a Dale-Schuster pump while the leg was perfused from another dog. Our previous experiments have shown that when the perfusion pressure was suddenly raised in the perfused organs a small and transient depressor effect could be observed in the general circulation. That such effects might be accentuated by the presence of adrenaline in the perfusion circuit is suggested in the experiments presented in figs. 9 and 10. In the perfused intestine the local hypertension caused by adrenaline injection into the perfusion blood was able to call forth a bigger general depressor effect than that caused by increasing the output of the pump (fig. 9). In the perfused leg a local rise of pressure caused by a brief clamping of the femoral vein was able to elicit a general depressor response. With adrenaline in the perfusion blood the reflex sensitivity was increased so that the hypertension caused by the removal of a clamp from the femoral artery was also effective (fig. 10). We were unfortunately not able to follow out these experiments as completely as we could have wished. Discu88ion.-The experiments reported above have demonstrated that the depressive action of adrenaline on vasomotor reflexes is largely a function of the carotid sinus and possibly of other homologous structures. It is the afferent impulses from such regions that make the vasomotor centre, especially the constrictor centre, more or less refractory to other incoming impulses. It is interesting to correlate these results with the findings of Malm6jac et al. [Malmejac and Donnet, 1935; Malmejac, Donnet, and Desanti, 1935], who found that the secretion of adrenal glands was inhibited by intravenous

9 The Effect of Adrenaline on Vasomotor Reflexes 315 infusion of adrenaline, with a dose smaller than ours, but that this inhibition disappeared after cutting the aortic and carotid sinus depressor nerves. As vasoconstriction and adrenaline secretion are both under the control of the sympathetic centre situated in the medulla [Chen, Lim, WVang, and Yi, 1937], it is probable that the latter is inhibited by adrenaline. That the neighbouring centres are probably not involved has already been alluded to. In so far as adrenaline is bi FIG. 9. Dog, 12 kg., (, chloralose, small intestine perfused with defibrinate(1 blood. R., respiration; B.P., bloocl-pressure; P.P., perfusion pressure. At 1, perfuision pressuire was increasedl by increasing the ouitput of the ptump. At 2, 0-02 Illg. adrenialine was iinjectedi irnto the perfusion tube. being considered as the mediator of sympathetic impulses, this autoregulation of sympathetic functions through the carotid sinus is rather interesting, in spite of the fact that the concentration of adrenaline in blood in our experiments may have been too high to be physiological. With regard to the question whether adrenaline has any direct action on the vasomotor centre, the experimental evidence obtained hitherto agrees with that of others [Nowak and Samaan, 1935] in pointing to a negative answer, at least as regards the medullary centres. However, in view of the work of Schweitzer and Wright [1937], who

10 316 Chu and Hsu found that adrenaline inhibits the knee jerk reflex by acting on the spinal centres, the possibility that this substance may exert a similar effect on the spinal vasomotor centres suggests itself. However, the inhibition, if any, must be comparatively small, as experiments after destroying the carotid sinus have shown (fig. 5). Lastly, the experiments on the perfused leg and intestine suggest that adrenaline has on the diffuse vasostatic apparatus an action S *1 ii.q S A FiG. 10. Dog (R), 13 kg., c, veronal, with vagi cut and carotid arteries tied. Left hind leg perfused by dog (P), 16 kg., Y, veronal. Signals 1 and 2, clamping and unclamping of the femoral artery; 3 and 4, clamping and unclamping of the femoral vein. Continuous adrenaline inftusion at a rate of about 0.01 mg. per min. was made into dog (P) at (B). B.P. (R) and B.P. (P) general arterial pressures of recipient and donor respectively. similar to, though smaller than, that which it has on the carotid sinus, in that it sensitises the vascular wall to pressure stimulation. Such hypothesis may be justifiable in view of the experimental findings presented previously [Hsu and Chu, 1937] that the diffuse vasotatic reflex was more intense when the hypertension was attained by adrenaline than when produced by saline injection. SUMMARY. In anaesthetised vagotomised dogs continuous infusion of adrenaline solution depresses vasomotor activity. This depression is largely due B

11 The Effect of Adrenaline on Vasomnotor Reflexes 317 to afferent impulses from the carotid sinus, with the chemical receptors playing a major r6le. The depression seems to be localised in the constrictor centre. It seems that a diffuse vasotatic reflex is also accentuated by the presence of adrenaline in the perfusion blood. REFERENCES. BETTENCOURT, J. M. DE (1935). C.R. Soc. Biol. 120, 541. CHEN, M. P., LIM, R. K. S., WANG, S. C., and Yi, C. L. (1937). Chineese J. Physiol. 11, 367. HEYMANS, C., BOUCKAERT, J. J., FARBER, S., and Hsu, F. Y. (1936). Amer. J. PPhysiol. 117, 619. HEYMANS, C., BOUCKAERT, J. J., and REGNIERS, P. (1933). Le sinus carotidien et la zone homologue cardioaortique, G. Doin, Paris. HEYMANS, C., BOUCKAERT, J. J., and WIERZUCHOWSKI, M. (1937). Arch. int. Pharmacodyn. 55, 233. HOSKINs, R. G., and ROWLEY, WV. N. (1915). Amer. J. Physiol. 37, 471. Hsu, F. Y. (1937). Chinese J. Physiol. 11, 343. HsU, F. Y., and CHUT, L. WX. (1937). Ibid. 12, 37. MALM.JAC, J., and DONNET, V. (1935). C.R. Soc. Biol. 119, 734. MALMEJAC, J., DONNET, V., and DESANTI, E. (1935). Ibid. 119, 1152, NOWAK, S. J. G., and SAMAAN, A. (1935). Arch. int. Pharmacodyn. 51, 463. RANSON, S. WV., and BILLINGSLEY, P. R. (1916). Amer. J. Physiol. 41, 85. SCHWEITZER, A., and WRIGHT, S. (1937). J. Physiol. 88, 476.