Cambridge. University of Cambridge.) (From the Physiological Laboratory, abnormally low blood-pressure to a normal height, that is to say the

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1 THE EFFECT OF ADRENALIN UPON RESPIRATION. BY FF. ROBERTS, M.D., M.R.C.P., Fellow of Clare College, Cambridge. (From the Physiological Laboratory, University of Cambridge.) IT has long been known that adrenalin, when it is injected into an animal, induces a profound change in respiration. In 1895, Oliver and Sc haf er (1) mentioned that extract of the suprarenal gland caused sometimes an arrest but more commonly a shallowing of respiration and that the effect was greater in the rabbit than in the dog. Four years later, Boruttau(2) described a progressive shortening of the inspiratory phase and a gradual prolongation of the expiratory phase, breathing coming to temporary standstill in full expiration. The effect was not altered by division of the vagi and on this account he believed that it was due to the direct action of adrenalin upon the medulla. Boruttau also showed that the change in respiration was produced when adrenalin raised an abnormally low blood-pressure to a normal height, that is to say the respiratory effect was not due to an abnormally high blood-pressure. In 1901, Langley(3) confirmed the observations of Oliver and Schafer and noted that the effect wore off upon repeated injections. Salvioli and Pezzolini(4) found that while in both the rabbit and the dog the respiratory movements became shallower, in the rabbit they became at the same time more rapid but in the dog less rapid. Kahn(5), like Boruttau, found the change to consist in a gradual shortening of the inspiratory and prolongation of the expiratory phase. With large doses short expiratory pauses occurred. He further found that adrenalin intensified apncea produced in other ways, as for instance by stimulating the central end of the vagus. He suggested that the effect might possibly be due to centripetal impulses in sympathetic nerves set up in the abdominal viscera or in the heart and aorta, by the peripheral action of adrenalin. Nice, Rock and Courtright(6) compared the changes in blood-pressure caused by adrenalin with the changes in respiration. They found that both the fall of blood-pressure caused by a small dose of adrenalin and the rise of blood-pressure caused by a larger dose were

2 ADRENALIN ON RESPIRATION. 347 accompanied by a synchronous increase in respiration, sometimes preceded by a decrease. From these and other observations they concluded that the action of adrenalin was direct on the nerve-centres. The observations, however, do not distinguish between a direct action and an indirect action either by centripetal impulses or by changes in blood supply. From the preceding account it will be seen that no serious attempt has been made to determine the cause of the respiratory variations produced by adrenalin. The common supposition that it has a direct action on the respiratory centre is purely hypothetical. My experiments were made to determine more exactly the method of action. Methods. The animals used were rabbits and cats. They were given a preliminary dose of urethane except in one experiment the object of which was to show that the presence of this drug was in no way responsible for the result. C.E. mixture was used to complete anaesthesia. Respiration was recorded by connecting one limb of the Y-shaped trachea-tube to a thin rubber tambour, the other limb being open to the air. The advantage of this method is that it causes the least disturbance to the nornial respiratory process. It does not record the duration of the inspiratory and expiratory contractions but this is of no importance for the object of my experiments. The blood-pressure cannula was tied into one of the carotid or femoral arteries. The injections were made through cannulse tied into the left or right jugular vein and sometimes into the distal end of the carotid or vertebral artery. It may be thought that when one carotid artery and one jugular vein are ligatured a disturbance of the circulation apparently so gross would show itself in a modification of the medullary functions. This, however, is not so, although the vein above the ligature becomes much distended with blood. Nor when one carotid artery is connected to the manometer is respiration influenced by clamping the carotid artery of the other side. All that happens is a slight rise in bloodpressure of mechanical origin. When the second artery is unclamped there is sometimes a slight transient increase in the depth of respiration which may possibly be due to stimulation of the medulla by blood which has stagnated in the part of the artery below the clamp. The stock adrenalin used was the Parke-Davis 0.1 p.c. solution. The dose most commonly employed was 1 c.c. of *01 p.c. adrenalin, sometimes 1 c.c. of *005 p.c. or of 1 p.c. One further point requires mention. In my experience, contrary to that of MacWilliam(7), Ringer's solution to which sodium citrate has been added has itself an effect upon respiration. Respiration is deepened

3 348 FF. ROBERTS. and sometimes quickened. On this account it has been necessary to fill the tube connecting the artery and manometer with pure Ringer. Clotting is of course more liable to occur. In the rabbit, when doses of adrenalin of the order of 1 c.c. of a *01 p.c. solution are injected intravenously the changes in respiration are three in kind. 1. There is invariably a rapid diminution in deptb usually proceeding to a pause of about 20 seconds duration. This pause occurs in expiration Fig. 1. Rabbit. Adrenalin 1 c.c. of 0.1 p.c. intravenously. Respiration arrested then resumed at a faster rate. Fig. 2. Rabbit. Adrenalin, same dose. Cheyne-Stokes respiration. The speed of the drum was changed during the record; rate of respiration is not altered. Fig. 3. Cat. Adrenalin, same dose. Respiration much diminished in depth and frequency. as is obvious from an inspection of the animal; as stated above, it is not shown in tracings by the method used. 2. The pause may be followed by typical Cheyne-Stokes respiration which gradually merges into respiration of regular type. The tendency to Cheyne-Stokes respiration seems to be largely a matter of individual susceptibility and it is more prone to occur with an already high bloodpressure and with large doses of adrenalin. 3. There is a well-marked tendency to change in the rate of respiration. It is not that respiration becomes progressively altered in rate as it diminishes in depth though such a change mav occur. It is that when

4 ADRENALIN ON RESPIRATION. 349 respiration is resumed after the pause it is resumed at a rate quite different from the original, usually faster. If a second pause occurs in the course of Cheyne-Stokes respiration the rate after this pause may be again different. Usually the original rate is restored. Typical examples of these three modifications are shown in Figs. 1 and 2. In the cat the results are more or less the same. With doses which are too small to produce the full effect respiration is diminished in depth and also in rate (see Fig. 3). This agrees with what Salvioli and Pezzolini found in the dog. Cheyne-Stokes respiration can also be induced but a larger dose is required than in the rabbit. A curious form Fig. 4. Cat. Adrenalin 1 c.c. of *01 p.c. intravenously. (a), (b) and (c) are continuous. Fig. 5. Stimulation of central end of splanchlnic nerve. of such breathing is shown in Fig. 4. Towards the end of each period of respiration one deep breath is taken. The first six of these breaths are almost exactly equidistant from one another. Further, each period of respiration tends to be itself multiple. The same tracing also shows how the rate of respiration is changed. There are three possible ways in which adrenalin may conceivably cause this diminution and temporary arrest of respiration. They have been investigated as follows: Afferent impulses. If afferent impulses exist we should expect to find them arising from the two regions suggested by Kahn; the splanchnic

5 350 FF. ROBERTS. area, since it is here that adrenalin is most potent in other respects, and the heart and aorta since these organs seem to be put passively to the greatest strain. I have tested this hypothesis in two ways. In the first the central end of the splanchnic has been stimulated. When any effect at all is produced it has been in the direction of augmentation not diminution of respiration (see Fig. 5). In the second method the abdominal aorta has been ligatured above the origin of the coeliac axis and adrenalin injected below the ligature. This procedure has practically no effect upon respiration. As regards the heart and aorta my experiments are in agreement with those of previous observers in that the effect is not lessened by division of the vagi. I have found that in the rabbit this applies also to the depressors. 1_~~~~~~~~~~1- Fig. 6. Fig. 7. Fig. 6. Rabbit. Abdominal aorta compressed. but not altered in rate. Respiration is slightly decreased in depth, Fig. 7. Cat. The same operation. Respiration is decreased in depth and in rate. We may therefore conclude that adrenalin does not either directly or indirectly inhibit the respiratory centre by nervous impulses from the periphery. Blood-pressure. Frequently, but by no means always, the change in respiration occurs concurrently and in a corresponding degree with the change in blood-pressure. This is particularly the case in regard to the recovery of the normal depth of respiration which usually occurs pari passu with the return to the normal in blood-pressure. But even if such a relation were invariable it would not follow that tbe change in respiration was due to the change in blood-pressure, since effects upon the medulla and upon the arterioles in the rest of the body, though independent, would be likely to take approximately the same time to develop, become established and die away. Such correspondence would be still more

6 ADRENALIN ON RESPIRATION. likely if the action upon the respiratory 'centre were the result of constriction of the blood vessels in the medulla. That, apart from the injection of adrenalin, a relation exists between respiration and blood-pressure has been shown by G uth rie and Pike(s). These observers have found that when the blood-pressure in the carotid artery is raised by occluding the dorsal or abdominal aorta respiration is slightly quickened but diminished in amplitude. As regards the change in amplitude, I am in agreement with Guthrie and Pike. Fig. 6 shows that when in the rabbit the abdominal aorta is kinked by pulling upon a loop of string tied loosely round it, respiration is definitely diminished. There is, however, no change in rate. When the same procedure is applied to the cat (Fig. 7) the diminution in the depth of respiration is more striking and is accompanied by considerable diminution in rate. It is clear therefore that the rise in blood-pressure itself is at least a contributory cause of the change in respiration which occurs when adrenalin is injected. The first question is whether it is the sole cause. Comparison of Figs. 3 and 7 which are taken from the same animal suggests AD that for an approximately similar rise in pressure a greater change in respiration is produced by injection of adrenalin than by occlusion of the abdominal aorta. Experiments were then made to determine what A: changes adrenalin produces when there is \ little or no rise of blood-pressure. In order to eliminate as far as possible any change in blood-pressure I have made use of the :1 compensator shown in Fig. 8. It is essentially a modification of the mercury valve described by Bayliss. A glass T- 351 piece C connects with an upright glasstube A of about 2 metres length, with a bottle B, the height of which can be adjusted, and with a coil of tubing the other end of which is connected with the abdominal aorta. The coil of tubing is inserted in a basin of water at body temperature. The passages are clamped as Fig. 8. Blood-pressure shown at E, F and G. The clamp G being compensator. closed and E and F open the height of the fluid in the tube A is adjusted

7 352 FF. ROBERTS. at a level above the cannuli in the abdominal aorta corresponding approximately to the pressure as indicated in the mercury manometer which is inserted into the carotid artery. E is then closed, F and G opened and the clamp released from the artery. The column of fluid in A having adjusted itself, the bottle B is. raised or lowered so that the fluid in it is at the same level as the fluid in A. The clamp E is then opened. When adrenalin or any other pressor substance is injected the resulting rise of blood-pressure drives blood into the apparatus, and since the area of surface of the bottle B is comparatively large there is practically no change in blood-pressure. As the effect of the adrenalin which remains in the circulation wears off the blood returns into the body. Fig. 9 shows the effect of injecting 1 c.c. of *01 p.c. adrenalin. The rise in bloodpressure is very slight and soon passes off. The change in respiration, though it may be not quite so intense as it is without the compensator, Fig. 9. Rabbit. Adrenalin 1 d.c. *01 p.c. intravenously with the compensator described in the text. is nevertheless very marked and it is always much more prolonged. It is less intense because so much of the adrenalin escapes temporarily from the body. It is more prolonged because adrenalin is returning to the body with the returning blood. It is therefore proved that the rise in blood-pressure, though it may under normal circumstances contribute to the change in respiration, plays no large part in its production. Direct action on the medulla. By a process of exclusion then we are driven to the view that adrenalin produces its effect upon respiration by a direct action upon the medulla. With the object of confirming this conclusion I have injected adrenalin into the peripheral end of the car6tid and vertebral artery. A typical result is shown in Fig. 10. It will be seen that respirition begins to be diminished very definitely before the blood-pressure begins to rise. It must be admitted, however, that the change in respiration does not set in as early as nmight be expected.

8 ADRENALIN ON RESPIRATION. 353 When we consider how adrenalin stops respiration by an action on the medulla two possibilities present themselves; first that it causes profound vaso-constriction of the blood vessels of the medulla which leads to paralysis of the centres owing to oxygen want or accumulation of metabolites; secondly that it exerts a specific paralysing action upon the cells-composing the respiratory centre. In order to test the first possibility, I bave tried the effect upon respiration of sudden anwemia of the medulla:produced in other ways. 1. The animal is bled rapidly by opening the dorsal aorta. The result is shown in Fig. 11. Accompanying the sudden fall in blood-pressure Fi. 10. Fig. 11. Fig. 10. Rabbit. Adrenalin, 1 c.c p.c. injected into the distal end of the carotid artery. Respiration diminishes before blood-pressure rises. Fig. 11. Rabbit. Sudden bleeding from th'e abdomin,al aorta. there is an immediate stoppage of respiration, which lasts until the final spasms set in. At first sight, 'this fact seems to be contradictory to the statement made above that respiration is diminished by rise and increased by fall in blood-pressure. The two cases are, however, not really comparable for while there we were dealing with a partial and relatively slow change in pressure, we are here concerned with a complete and abrupt fall which must result in a complet6 and sudden anwmria of the brain. '2. A similar effect upon respiration can be produced by clamping the two carotid and two subclavian arteries (the latter below the origin of the vertebrals). A typical result is showna in Fig. 12. This experiment PH. LV. 23

9 354 FF. ROBERTS. has, of course, been performed by numerous workers in the past all of whom have found that ligature of all four vessels stops respiration. But the point which I want to emphasise is that the apnoea is sudden in onset. It may therefore be concluded that the apncea produced by adrenalin can be sufficiently explained by assuming that the substance causes a well-marked vaso-constriction of the vessels of the medulla. The centre is paralysed by want of oxygen or accumulation of metabolites. This does not preclude the possibility of a specific action upon the nervecells, but it renders such an explanation unnecessary. Further experiments are in progress with the view to determining whether respiration can be modified by sympathetic stimulation. Fig. 12. Rabbit. Clamping in succesion the carotid and vertebral arteries. CONCLUSIONS. 1. In aniesthetised cats and rabbits, adrenalin in large doses besides causing diminution and temporary arrest of respiration, causes alteration in rate and may cause Cheyne-Stokes respiration. 2. The diminutiont and arrest occur when there is no change in blood-pressure and are mainly central in origin. 3. They are caused by sudden anaemia of the respiratory centre due to vaso-constriction. 4. There is no evidence that adrenalin causes afferent nervous impulses from the periphery. I wish to thank Prof. Langley, Mr Barcroft and Dr Dixon for their kindly interest and helpful suggestions.

10 ADRENALIN ON RESPIRATION. 355 REFERENCES. (1) Oliver and Schafer. Journ. of Physiol. 17. p (2) Boruttau. Pfluiger's Arch. 78. p (3) Langley. Journ. of Physiol. 27. p (4) Salvioli and Pezzolini. Arch. Ital. de Biol. 37. pp. 380 and (5) Kahn. Arch. f. (Anat. u.) PhysioL p (6) Nice, Rock and Courtright. Amer. Journ. of PhysioL 34. p (7) MacWilliam, Mackie and Murray. Journ. of Physiol. 30. p (8) Guthrie and Pike. Amer. Journ. of Physiol. 16. p (The expenses of the above research have been partly defrayed by a grant from the Royal Society, Government Grant Committee.) 23-2