tone. The observations were taken to mean that sympathetic stimulation was

Transcription

1 289 J. Physiol. (1942) IOI, I74.5:6I AN ACTION OF ADRENALINE ON TRANSMISSION IN SYMPATHETIC GANGLIA, WHICH MAY PLAY A PART IN SHOCK BY EDITH BCLBRING AND J. H. BURN, From the Department of Pharmacology, Oxford (Received 11 April 1942) We have had two reasons for approaching this problem. One of us [Burn, 1932] showed that when the hindleg of a dog was perfused with defibrinated blood through a cannula tied in the abdominal aorta 34 cm. above the bifurcation, the vasoconstriction produced by stimulating the lumbar sympathetic chain was very small. When adrenaline was added to the perfusing blood, however, the effect of the same stimulation was greater, and this augmentation outlasted the effect of the added adrenaline on the vascular tone. The observations were taken to mean that sympathetic stimulation was effected by the liberation of adrenaline from the post-ganglionic endings, and that in the preparation used the necessary store of this adrenaline was depleted, until it was restored by addition of adrenaline to the blood. Thus, the augmentation of the effect of sympathetic stimulation was thought to be due to a change at the post-ganglionic terminations. Recently, Dr P. Glees called our attention to a paper by Stohr [1939] in which large-scale drawings of sympathetic ganglia showed the ganglion cells surrounded by what St6hr described as chromaffine tissue. Dr Glees himself obtained phlotographs showing similar small cells. Reflexion suggested that if chromaffine cells were present in sympathetic ganglia, they presumably exerted some function. What function could adrenaline have in sympathetic ganglia? The question recalled the observations which have just been described, in which the stimulation was applied to the preganglionic fibres of the sympathetic chain. It was clear that the augmentation of the effect of stimulation produced by adrenaline might have been due to a change in the ganglion whereby transmission was improved. Our second reason for studying this question was that we have recently [Biilbring & Burn, 1941] made observations on the transmission of impulses in the spinal cord, and have observed three effects of adrenaline. We found that adrenaline facilitated the action of small doses of acetylcholine in causing PH. CI. 20

2 290 E. BULBRING AND J. H. BURN a discharge of motor impulses from the spinal cord. We found that adrenaline, by an action on the spinal cord, augmented the size of the flexor reflex. Thirdly, we found that adrenaline modified the action of prostigmine on the flexor reflex; in the presence of adrenaline, prostigmine powerfully augmented the flexor reflex; in its absence prostigmine was without effect. Thinking it likely from the evidence we obtained that synaptic transmission in the spinal cord is, in part at least, by acetylcholine, and that these effects of adrenaline were modifications of such a transmissilon, we decided to examine other parts of the body, where impulses are transmitted by acetylcholine, for similar effects of adrenaline. We first studied the transmission at the neuromuscular junction in skeletal muscle, and looked to see whether adrenaline would modify the action of prostigmine. We found [Biilbring & Burn, 1942] that it did. When maximal single shocks are applied to the sciatic nerve, and the tension in the gastrocnemius is recorded, if the rate of stimulation is slow, the injection of prostigmine leads to an increase in the tension. We found that when adrenaline was injected this increase was much greater. On the other hand, when more rapid stimulation was used the increase in tension caused by prostigmine disappeared when adrenaline was injected. Thus, at the neuromuscular junction adrenaline augmented or diminished the action of prostigmine according to the rate of stimulation. The second site at which transmission is effected by acetylcholine is the sympathetic ganglia. What effect had adrenaline on transmission here? Marrazzi [1939 a, b] has published evidence that adrenaline causes depression and inhibition of ganglionic transmission. He recorded the action potentials in the post-ganglionic fibres coming from the superior cervical ganglion, and observed that when adrenaline was injected these action potentials were reduced. This reduction was observed when the dose of adrenaline was as small as 5p,g., and when adrenaline was not injected but liberated in the body by stimulation of the splanchnic nerve. Marrazzi showed that occlusion of the circulation to the ganglion for 2-3 min. produced no depression and, therefore, concluded that the adrenaline effect could not be due to diminution of the blood supply to the ganglion. RESULTS Perfusion experiments. We have made observations by three different methods, all of which have given similar results. Our main evidence has been obtained with a preparation we have already described in detail [Biilbring & Burn, 1941]. This consists of a perfusion scheme in which there are two circulations of defibrinated blood entirely separate from one another. For the purpose of these experiments the essential feature of the one circulation is that it supplies the sympathetic ganglia, while the other supplies the vessels in which the post-ganglionic fibres terminate. We were thus able to study the

3 ADRENALINE ACTION ON GANGLIA 291 effect of adrenaline on the transmission of impulses through the ganglia, while excluding any change at the post-ganglionic terminations. The actual observations were made in the lower half of the body of a dog from which the viscera were removed. The one circulation passed through a stretch of aorta from the bifurcation to just above the renal arteries (which were tied), and supplied the sympathetic chain through the spinal arteries; the second circulation supplied the vessels of the left hindleg. All vascular connexions between the two circulations were tied, while the nervous connexions remained untouched. The arterial pressures were recorded with a mercury manometer from each arterial cannula. Changes in the arterial pressure in the ganglion circuit were modified by an artificial resistance, tied in the upper end of the aorta, acting as a shunt to prevent any excessive rise of pressure in a relatively small circulation. By means of this shunt it was possible to alter the adrenaline content of the blood without greatly changing the perfusion pressure and consequently the blood supply to the ganglia. Effect of adrenaline. The course of an experiment may be followed in Fig. 1. The upper record shows the changes in the venous outflow from the leg vessels, while the middle record shows the corresponding changes in arterial resistance in these vessels. The lower record shows the arterial resistance in the circuit supplying the ganglia. The first four sections (a, b, c, d) show the effect of a steady addition of adrenaline at the rate of mg., later mg./min. to the reservoir supplying blood for the leg. At the points marked by the signal the sympathetic chain was stimulated at the level of the kidney from an induction coil for periods of 10 sec., 32 break shocks being applied per sec. The vasoconstrictor effect of this stimulation in the hindleg is seen to increase with the rise in vascular tone produced by the adrenaline. During this stage of the experiment no adrenaline was added to the blood passing through the sympathetic ganglia, although a concentration of 0 05 mg./l. had been added before the perfusion began, and in the 40 min. elapsing between Fig. l(a) and (e) was slowly disappearing. The effect of this disappearance first showed itself in Fig. 1 (e) where, although the tone in the leg vessels was still higher than in (d), the effect of sympathetic stimulation was much reduced. Between (e) and (f) over a period of 30 min., adrenaline 0'003 mg./min. was added to the reservoir supplying blood to the ganglia. Stimulation of the sympathetic chain then produced a greatly augmented effect in the leg (f). The addition of adrenaline to the blood circulating through the ganglia was then stopped, while that to the blood for the hindleg was maintained, and 15 min. later in (g), the smaller response to stimulation wao recorded once more. In Fig. 2 the same influence of a varying concentration of adrenaline in the blood supplying the ganglia is shown. Throughout the period covered by the figure adrenaline was added to the blood for the hindleg at a constant rate (0-006 mg./min. to a volume of 600 c.c.). In (a) adrenaline was added at the 20-2

4 BtJLBRING AND J. H. BURN r Pr I- IT r o a.1 Fig. 1. Dog, double perfusion. Records frbm above downwards: Venous outflow in leg circuit; arterial resistance in leg circuit; arterial resistance in ganglion circuit. At signals stimulation of sympathetic chain, coil 15, 10 sec. The vasoconstrictor effeots in the leg are shown, (a)-(e), when adrenaline was added to the leg circuit while it disappeared from the ganglion circuit. The response was augmented when adrenaline was added to the ganglion circuit (f), and became small again (g) when the adrenaline was stopped.

5 ADRENALINE ACTION ON GANGLIA 293 same rate to the blood for the ganglia, but between (a) and (b) this addition was stopped. During (b), (c) and (d) we recorded a diminishing response to U. SQ,~~~~~ Fig. 2. Dog, double perfusion. Records as in Fig. 1. The vasoconstriction in the leg produced by sympathetic stimulation, coil 17, 10 sec., became less and disappeared when adrenaline disappeared from the ganglion circuit, (ahd), although maintained throughout at mg./ min. in the leg circuit. On adding adrenaline to the ganglion circuit, (e)-(g), the vasoconstrictor response in the leg reappeared. sympathetic stimulation, which in (e) disappeared altogether. Adrenaline was then added to the blood for the ganglia once more, and, as shown in (f) and (g), the response to the sympathetic stimulation returned to its original height. The time elapsing between (a) and (g) was 1 hr.

6 294 E. BUYLBRING AND J. H. BURN Effect of larger amounts of adrenaline. The foregoing results indicated that adrenaline improved the transmission of impulses through the sympathetic ganglia. We obtained evidence, however, that when the amount of adrenaline was large, the opposite effect was obtained. This depression of transmission is illustrated in Fig. 3. Throughout this experiment the adrenaline addition to the leg circuit was kept constant at a rate of mg./min., and the perfusion pressure remained steady. To the blood supplying the ganglia during the period from which (a) is taken, adrenaline was added at a rate of mg./min. This rate was increased to 0.01 mg./min. between (a) and (b) and kept there for 30 mi. from (b) to (d), after which it was stopped. The pressor response in the leg to stimulation of the sympathetic chain in (a) was 40 mm., but with the trebled adrenaline concentration in the blood to the ganglia, the response in (b), (c) and (d) fell to 30, 20 and finally 8 mm. As the concentration of adrenaline declined in (e), (f) and (g), the response increased again to 24, 35 and 64 mm. Effect of adrenaline on the stimulating action of acetylcholine on sympathetic ganglia and the suprarenal medluua. We have carried out experiments to see if the above observations could be confirmed in the whole animal, and have used two different methodsw It is well known that in the fully atropinized animal, the injection of large doses of acetylcholine causes a rise of blood pressure, which is due to stimulation of the sympathetic ganglia and the suprarenal medulla. In atropinized spinal cats the pressor effect of a given dose of acetylcholine, injected intravenously at regular intervals of min., was found to be approximately constant. When a smau dose of adrenaline was interposed between two injections of acetylcholine, the pressor effect of the acetylcholine was increased. Moreover, when successive doses of acetylcholine were given at shorter intervals of 3-S5 min., their pressor effect steadily increased, and it appeared likely that this was due to the action of adrenaline liberated by one injection on the next. In Fig. 4A the increased pressor effect of 0-4 mg. acetylcholine is seen after mg. adrenaline, the increase persisting for more than 20 mi. The effect in this experiment was unusually well-marked, in most cats it was smaller, and in one it was not seen at all. The increase of the pressor effect of acetylcholine was only seen in animals with the suprarenal glands intact. It appeared immediately after the pressor effect of a small dose of adrenaline ( mg.) had passed off and persisted for 20 min. After slightly larger doses (0 01 mg.) there was at fint a period during which the pressor effect of acetylcholine was decreased and the augmentation appeared only after 20 mn. The depression of the ganglionic effect of acetylcholine by large doses of adrenaline was observed with regularity both in animals in which the suprarenal glands were intact and in which they were removed. Fig. 4B, taken from the same experiment as Fig. 4A, illustrates this effect, when 0 03 mg. adrena-

7 ADRENALINE ACTION ON GANGLIA 295 line depressed the action of 0-6 mg. acetylcholine for 40 min. Still larger doses of adrenaline, especially when given by slow infusion, almost abolished the action of acetylcholine, injected after the infusion was stopped and when the presor effect of the adrenaline had disappeared Fig. 3. Dog, double perfusion. Records as in Fig. 1. The vasoconstriction in the leg due to stimulation of the sympathetic chain is shown in (a) when adrenaline was infusd, mg./min. into the leg circuit and 0003 mg./min. into the ganglion circuit. When the amount of adren. aiine in the ganglion circuit was excessive, 0.01 mg./min., (bhd) a gradual diminution of the sympathetic effects was observed, which inereased again (e)h(g) as the adrenaline tone was allowed to pas off. During a slow infusion of adrenaline the pressor effect of acetylcholine was always either depressed or abolished. In the experiment illustrated in Fig. 5, adrenaline was infused into a spinal cat in which the suprarenals were excluded; the rate of infusion was 0*004 mg./min. and the blood pressure was maintained

8 B. BtLBRING AND J. H. BURN 296 at 120 mm. The injection of 2 mg. acetylcholine produced no appreciable rise, and indeed there was a slight fall despite the injection of 2 mg. atropine just A B Fig. 4. Spinal cat, atropine. (A) Pressor effects of 0*4 mg. acetylcholine injected at 20 mm. intervals. Just before (c) 0005 mg. adrenaline was injected and augmented the effect of the acetylcholine. (B) Same experiment as (A), pressor effects of 0x6 mg. acetylcholine injected at '10 min. intervals. Between (b) and (c) 0-03 mg. adrenaline' was injected and depressed the effect of the acetylcholine. before. The infusion of adrenaline was then stopped, and after an interval the blood pressure. was raised to the same level by infusing pituitary (posterior lobe) extract at the rate of 0-2 unit/min. The injection of 2 mg. acetylcholine then caused a sharp rise of blood pressure of 76 mm., showing that in the presence of pituitary extract the ganglionic stimulation was vigorous. Effect of adrenaline on the pressor effect of splanchnic stimulation. The third method of studying the action of adrenaline was to stimulate the preganglionic splanchnic fibres in spinal cats in which the suprarenal glands were excluded. The splanchnic nerves were cut where they left the sympathetic chain in the thorax, and dissected up to the semilunar ganglia. The right splanchnic nerve was brought to the left side underneath the Fig. 5. Spinal cat, suprarenals aorta, so that both splanchnics could be stimulated excluded,atropine. The effect of aorta,~~~ thtbt.pacnc ~.3 cudb tiuae injecting mg. acetylcholine is side by side. The mid-lne incision through which shown in 2(a) m during gac ancineuis infusion the operation had been done was then sewn up to of adrenaline, mg./min.; prevent exposure of the intestines, and a fresh and in (b) during an infusion of lateral incision just above the left kidney was made pituitary posterior lobe extract, to allow access to the splanchnics. These were laid 2 unt/mm. on a shielded silver plate 6 mm. wide acting as a unipolar electrode, the second

9 ADRENALINE ACTION ON GANGLIA 297 electrode being placed under the skin nearby. The intestines were protected from exposure at this incision by careful packing with cotton wool. The nerves were stimulated at regular intervals, for sec., by condenser discharges at rates which varied in different experiments from 8 to 48 per sec., and care was taken to see that the stimulation was maximal. Unlike the pressor effect of acetylcholine which was augmented by adrenaline only when the vascular effect of the adrenaline had disappeared, the pressor effect of splanchnic stimulation was readily augmented during a continuous adrenaline infusion. Thus, in the presence of adrenaline, the same stimulus applied to the preganglionic fibres produced a much larger effect than before, Fig. 6. Spinal cat; suprarenals excluded. The effect of stimulating both splanchnic nerves (48 per seo., for 10 sec.) is seen in (a) before; in (b) during an infusion of adrenaline mg./min.; in (c) during an infusion of pituitary posterior lobe extract 0-12 unit/min.; in (d) 37 mi. later when the pituitary tone had disappeared; and in (e) once more during an infusion of adrenaline mg./min. or than that produced in the presence of pituitary extract at the same height of blood pressure. In Fig. 6 adrenaline was infused at about mg./min. into the femoral vein and the effect of splanchnic stimulation was almost doubled, as shown by comparing the rise of pressure in (a) with that in (b). The adrenaline infusion was stopped, and an infusion of pituitary extract at a rate of 0-12 unit/min. was begun instead. When the blood pressure was about the same height as in (b), stimulation of the splanchnic nerves produced a rise in pressure (c) only a little greater than that in (a). The pituitary infusion was stopped, and when the blood pressure declined to the level in (a), the stimulation in (d) caused the same rise as in (a). Adrenaline was infused again at a higher rate of mg./min., and repetition of the stimulation (e) once more was followed by a much larger rise,

10 298 E. BULBRING AND J. H. BURN In view of the results with acetylcholine we were expecting that when the rate of adrenaline infusion was raised above 0{005 mg./min. we would find that the response to splanchnic stimulation would be depresed. This, however, did not happen, and indeed in the experiment from which Fig. 6 is taken there was no diminution of the response during 40 mi. infusion at a rate of mg./min. The response remained increased about min. in height as in Fig. 6 (e). We found, however, that whenever the adrenaline infusion was stopped, and the blood pressure fell, the response to splanchnic stimulation became very small, e.g. 20 mm. While an adrenaline infusion regularly increased the response to splanchnic stimulation, it scarcely altered the effect of a given dose of adrenaline. In FIg. 7. Spinal cat, suprarenas excluded. S8 astmulation of both splanchnio nerves (16 per Sec for- 15 sec.). The pressor effect of mg. adeaieis compared with that of splanchnic stimulation (a) before, (c) after, and (b) during an infusion of mg. adrenaline/min. Fig. 7 (a) the pressor effect due to splanchnic stimulation was about half the size of that produced by 0*007 mg. adrenaline; in (b), while adrenaline mg./mi. was infused, the splanchnic effect was more than doubled whereas the adrenaline effect was increased by -only 10 %. When the adrenaline infusion was stopped (c) the splanchnic effect became less than its initial size, the adrenaline effect was still increased. In another experiment, the pressor effect of splanchnic stimulation, which was the same as; that of mg. adrenaline, was augmented during an adrenaline tone to the size of that produced by 0.01 mg. adrenaline. Increases of the pressor effect of adrenaline by % have been observed during an adrenaline infusion; these were, however, always much smaller than the increa'ses of the pressor response to sjplanchnic stimulation which ranged from 100 to 500 %. To study the depressant action of larger amounts of adrenaline, we did not infuse it, but injected single dosesi, comparing the effect of stimulation when

11 ADRENALINE ACTION ON GANGLIA 299 the pressor action of the dose had passed off with that before it was given. The depression was regularly observed after 0{04 mg. or more. Whatever the size of the dose, the response was usually smallest min. after the adrenaline pressor effect had disappeared, and it returned to its original height Fig. 8. Spinal cat, suprarenals excluded. Pressor effects of stimulating both splanchnic nerves are shown before and after the injection of 0-08 mg. adrenaline. a J ffo If I Fig. 9. S-pinal cat, suprarenails excluded. (a) The pressor response to stimulation (S) of both splncbiic Dnerves (16 per sec. for 15 sec.)-equals that of 0.01 mg. adene; (b) 10 mi. after 0*15 mg. adrenaline the splanchnic effect is reduqed to half the size; after 20 mi. (c) it equals mg. adrenaline; after 30 min., (d) it equals mg. adrenalne. after periods which were longer the larger the dose; thus after 0 04 mg. the period was min.; after 0.15 mg. the depression sometimes lasted over an hour or never recovered. In Fig. 8 the response of splanchnic stimulation is reduced to about half its former size after the injection of 0 08 mg. adrenaline. In order to see whether, after such an excessive vasoconstriction, the blood vessels failed to constrict or whether the ganglia failed to transmit the impulse, the pressor response to splanchnic stimulation was matched with that of a dose of adrenaline. In Fig. 9 (a) splanchnic stimulation produced the same

12 300 E. BtJLBRING AND J. H. BURN pressor effect as 0-01 mg. adrenaline. Ten mi. after the injection of 0415 mg. adrenaline (b), the splanchnic effect was much reduced but the adrenaline effect was unchanged. Ten min. later (c), the splanchnic response showed a partial recovery and a rise of blood pressure equal to that of 0007 mg. adrenaline was observed; but another 10 min. later (d) the splanchnic effect only equalled that of 0*004 mg. adrenaline; it did not return to its initial size. It was the rule to see this sequence of events when large doses of adrenaline were injected: after an initial depression the splanchnic response would show a partial recovery and then decline again. At the same time, the pressor effect Oy ~y 'Y I20y Min. Fig. 10, Spinal cat, suprarenals excluded. The diagram shows the effect of five different doses of adrenaline on the response to splanchnic stimulation. Ordinates are pressor effects in mm. Hg of stimulating both splanchnic nerves. Abscissae are minutes after the adrenaline rise of blood pressure had disappeared. of adrenaline was sometimes increased at first, then remained unchanged over a long period, and only in the final stages when the blood pressure became very low it was reduced by 10 or 20 %. The adrenaline response was never affected to such a degree as the response to splanchnic stimulation, which, after large doses of adrenaline, was regularly reduced to a quarter of its original size. It may be questioned whether this later depression was the result of the injection, but when large doses of adrenaline were not injected we never observed this decline of the vasoconstrictor response. Moreover, the depression was always accompanied by a fall in general blood pressure, presumably due to a depression at the sympathetic ganglia of the impulses proceeding to the muscles and the skin, a parallel depression to that we recorded when we stimulated the splanchnic nerves.

13 ADRENALINE ACTION ON GANGLIA 301 The course of the changes in the vasoconstrictor response is shown in Fig. 10, which represents the observations made in one experiment, in which adrenaline was injected in five different doses. Each point represents the actual rise in blood pressure produced by splanchnic stimulation. The injection of 0-02 mg. adrenaline increased the effect, whereas 0-04 mg. and 0-08 mg. depressed it. When 0-12 mg. was injected the response never returned to its former height, and a further lasting depression followed the injection of 0 3 mg. It should be added that similar results were obtained in cats anaesthetized with chloralose, though more adrenaline was needed to depress permanently the response to stimulation. DISCUSSION It has been shown by three methods that the transmission of impulses through sympathetic ganglia is facilitated by small doses of adrenaline, but depressed by large ones. The facilitation by small doses is of interest since Stohr has described chromaffine cells in sympathetic ganglia, and because it suggests a co-operation between adrenaline and acetylcholine at another site of cholinergic transmission. It was our observation of such a co-operation in the spinal cord which led us to look for it and to find it first at the neuromuscular junction in skeletal muscle and then in the sympathetic ganglion. In two of the methods, electrical stimulation was applied to the preganglionic fibres, and the augmentation of the effect by small doses of adrenaline might have been due to a lowering of the threshold in the preganglionic fibres rather than to an effect on the ganglion. Builbring & Whitteridge [1941] have observed that adrenaline lowers the threshold of the sciatic nerve to submaximal stimuli, and not to maximal stimuli. In the perfusion experiments submaximal stimuli were used, but in the experiments on spinal cats we applied maximal stimuli, s0 that changes in the preganglionic fibres were not involved. Moreover, when acetylcholine was used as a chemical stimulus to the ganglion, a similar augmentation by adrenaline was observed. Marrazzi [1939a] showed that adrenaline depressed impulses through sympathetic ganglia, but he saw no augmentation. His failure to observe the augmentation may be due to the time after the adrenaline injection at which he took his records. Some of our results suggest that if he had made his observations over longer periods he would have seen augmentation following the depression. After the adrenaline injection we had to wait until its pressor action had subsided before recording the response to ganglionic stimulation. With doses from 0* mg. adrenaline we saw first a depression of the ganglionic response followed by an augmentation, the depression being present from 5 to 15 min. after the injection, and the augmentation appearing after 20 min. It is probable that this sequence occurs also after smaller doses but at shorter intervals after the injection. It should be mentioned that, while in our experiments with acetylcholine we regularly observed the depressing action

14 302 B. BULBRING AND J. H. BURN of adrenaline, we had much more difficulty in observing the augmenting action. This was not so when we stimulated the splanchnic nerves. A steady infusion of adrenaline had no depressant action, even though the amounts were as large as 0'008 mg./kg./min., as long as the infusion continued. Depression was, however, observed when such an infusion was stopped or after the injection of a single large dose. The depression of ganglionic transmission by adrenaline has been discussed by Marrazzi [1939b] as a mechanism having a beneficial effect, whereby adrenaline can check excessive sympathetic activity. He says: 'Adrenaline liberated by the augmented splanchnic impulses prolongs and greatly enhances sympathetic activity. If this tends to become excessive, thereby partially defeating its purpose, the concentration of adrenaline in the blood rises to a level sufficient to produce ganglionic inhibition, and thus decreases the sympathetic discharge by obstructing the passage of impulses from the pre- to the post-ganglionic neurones.' It may be that in certain circumstances this effect is beneficial, as Marrazzi thinks, but there is also another possibility. We believe that it may play a part, in the production of shock. Freeman, Freedman & Miller [1941] have shown that the infusion of adrenaline into dogs caused a steady decline of blood pressure, which continued after the infusion was stopped, and led to death. According to our results, the doses they used were certainly great enough to cause ganglionic depression after the infusion was discontinued, and we think that this depression must have been partly if not wholly responsible for the fatal fall in blood pressure. Probably there are many workers who have observed, as we have, that when an adrenaline infusion is stopped the blood pressure falls below the initial level, and may not return. It is of course a well-known observation that after a large single dose, the pressor effect is followed by a temporary fall. The view that excessive sympathetic activity is a cause of shock has many opponents, who quote the evidence of Prohaska, Harms & Dragstedt [1937] that continuous adrenaline infusion of amounts up to mg./kg./min. into dogs did not cause death from shock. These amounts were sufficient to cause hypertension, though they were not so great as those used by Freeman et al. which were from to mg./kg./min. Our own experiments suggest that the sudden liberation of large amounts of adrenaline is more likely to produce permanent circulatory damage than the steady infusion of smaller amounts. Under the influence of an overwhelming sensory stimulus, there can be no doubt that a liberation of a large amount of adrenaline occurs. After some accidents clinicians describe an early stage of collapse with low blood pressure, and then, after a period of recovery, a later stage in which the blood pressure falls again. When a large dose of adrenaline has been injected we have observed changes in the response to splanchnic stimulation which correspond with this chain of events as shown in Figs

15 ADRENALINE ACTION ON GANGLIA 303 SUMMARY 1. Evidence has been obtained by three different methods that adrenaline in small amounts augments the transmission of impulses in sympathetic ganglia, and in large amounts depresses it. This action of adrenaline has been observed in dogs in which the sympathetic ganglia were perfused by one circulation and the responding organ, the vessels of the hindleg, by a second. 2. In atropinized spinal cats adrenaline affects the ganglionic action of acetyleholine, the pressor effect of which is augmented by small doses and depressed by large doses of adrenaline. 3. When adrenaline is infused at constant rate into a spinal cat the pressor response to splanchnic stimulation is increased; the injection of single large doses however depresses the response. This depressant action, which may be permanent and is accompanied by a fall in general blood pressure, is discussed in its'possible relation to shock. We wish to express our thanks to Mr H. W. Ling for his assistanoe with the perfusion experiments. REFERENCES Btilbring, E. & Burn, J. H. [1941]. J. Physiol. ioo, 336. Btilbring, E. & Bun, J. H. [1942]. J. Physiol. 101, 224. Btilbring, E. & Whitteridge, D. [1941]. J. Phys;a. 99, 201. Burn,-J. H. [1932]. J. Phyasiol. 75, 144. Freeman, N. E., Freedman, H. & Miller, C. C. [1941]. Ame. J. Phyrio. 131, 545. Marrazzi, A. S. [1939a]. J. Pharmacol. exp. Ther. 65, 395. Marrazzi, A. S. [1939b]. Science, 90, 251. Prohaska, J. v., Harms, H. P. & Dragstedt, L. R. [1937]. Ann. Surg. 106, 857. St6hr, P. [1939]. Z. ZeUfor8ch. 29, 569.