experimer,ts, and more particularly from the fact that adrenalin apnoea

Transcription

1 THE ACTION OF ADRENALIN ON THE CENTRAL NERVOUS SYSTEM. BYA. ST G. HUGGETT (Beit Memorial Research Fellow) AND J. MELLANBY. (From the Physiological Laboratory, St Thomas's Hospital, London.) IN a previous paper (1) we have considered the effects on adrenalin apneea of (1) visceral afferent impulses, (2) varying intracranial pressure, and (3) impulses from the mid brain and cerebrum. As a result of these experimer,ts, and more particularly from the fact that adrenalin apnoea is annulled by a previous intravenous injection of ergotoxin, we concluded that adrenalin apn.cea is due to a vaso-constriction of the blood vessels of the respiratory centre, a view which had been previously put forward by Roberts. On the other hand, Boruttau(2) and later Nice, Rock and Courtright(3) state that adrenalin apncea is due to a direct action of adrenalin on the cells of the respiratory centre, a view which does not demand the presence of local vaso-motor nerves to the cerebral blood vessels. In this paper we record a series of experiments on the action of adrenalin on various reflexes. The bulb contains not only the respiratory centre but also centres associated with the heart, blood vessels and alimentary canal. Therefore on the hypothesis that adrenalin produces constriction of the blood vessels supplying the respiratory centre, the vascular and alimentary reflexes should be effected to some degree simultaneously with the respiration. Further, on the hypothesis of localised vaso-motor innervation, there existed a possibility that the adrenalin would influence other cranial and spinal reflexes. We therefore investigated its action on the conjunctival reflex, the pupillo-motor reflex and the reflex mechanism associated with skeletal muscle. Finally, we determined the influence of afferent nerve stimulation on adrenalin apncea in order to analyse the ultimate mechanism in the causation of adrenalin apncea. Adrenalin on bulbar and midbrain reflexes. At the outset we carried out experiments which conclusively located the action of adrenalin in producing apncea to the bulb or mid brain. The cord of an ainesthetised cat was cut at the level of the 2nd cervical nerve, after which artificial respiration was used. When artificial respiration was suspended as the PH. LIX. 25

2 388 A. Si' G. HUGGETT AND J. MELLANBY. blood became more venous, the alae nasi showed marked respiratory contractions. The intravenous injection of adrenalin at once annulled the contraction of these accessory respiratory muscles. Similarly, we have observed that adrenalin apnoea is readily produced in the decerebrate cat. It is therefore evident that adrenalin apncea is due to the local action of adrenalin on the bulb or mid brain and is independent of the advent of nervous impulses to the respiratory centre either from the cerebrum or periphery. Cardio-inhibitory centre. In order to demonstrate the effect of adrenalin on depressor reflexes, the dose must be less than that required to produce a maximal adrenalin action. Otherwise the central depressor effects are obscured by the peripheral adrenalin action. The absence of effect of adrenalin on this centre is shown in the blood-pressure tracing (Fig. 1) obtained by a Gad manometer. This type of manometer was used to show cardiac effects rather than blood-pressure changes. 1 c.c. of *0033 p.c. adrenalin produced a rate of heart-beat of 212 per min. (A). The same dose of adrenalin immediately followed by central depressor stimulation resulted in a heart-beat of 128 per min. (B). Clearly then, adrenalin does not diminish the sensitivity of the cardio-inhibitory centre in depressor nerve stimulation. Vaso-motor centre. The vagi were cut to limit the lowering of bloodpressure produced by stimulation of the central end of the depressor to I I Fig. 1. Adrenalin on cardio-inhibitory centre. A, adrenalin alone. B, depressor stimulated after adrenalin. Fig. 2. Adrenalin on vaso-motor centre (rabbit). A, depressor stimulated. B, adrenalin injected. C, depressor stimulated after adrenalin.

3 ADRBNALIN ON REFLEXES. 389 an effect on the vaso-motor system only. Fig. 2 A shows the fall of blood-presure produced by central stimulation of the left depressor. Fig. 2 B shows the rise of blood-pressure produced by 1 c.c. of *001 p.c. adrenalin. Fig. 2 C shows first the fall of blood-pressure produced by depressor stimulation of the same strength as A, and, at the depth of the depressor fall, the rise of blood-pressure due to the injection of adren,alin of the same strength as produced the rise B. The rise produced by the adrenalin is approximately equal to the depressor fall. From the point of view which we are investigating, the adrenalin rise of bloodpressure may be a resultant of (a) stimulation of the peripheral vasomotor nerve endings, and (b) the central inhibition of the vaso-motor centre in a maer comparable to that observed with the respiratory centre. But, since the adrenalin rise of blood-pressure during depressor nerve stimulation (i.e. during the period in which the vaso-motor centre is inhibited) is of the same height as when the depressor nerve is not stimulated it is evident that the adrlin rise of blood-pressure is not the resultant of a central and peripheral effect but solely to the peripheral action of adrenalin on the nerve endings in the periphery. The experiments with the depressor nerve clearly demonstrate that adrenalin has no action on the cardio-inhibitory centre nor on the vaso-motor centre. Presor nerve stimulation shows precisely the same facts. The central end of the cut right femoral nerve of a cat was stimulated during the rise of pressure produced by the intravenous injection of *01 mgrm. of adrenalin (Fig. 3). The adrenalin rise of blood-pressure (A) was markedly Fig. 3. Adalin on vaso-motor centre (cat). A, adrenalin injected. B, combined adrenalin injection and stimulation of femoral nerve. increased by a simultaneous stimulation of the central end of the right femoral nerve (B), indicating that the bulbar pressor mechanism was unaffected by the adrenalin. Swallowing centre. The experiments were made on a cat decerebrated

4 390 A. ST G. HUGGETT AND J. MELLANBY. by Sherrington's method and on a cat ansesthetised by urethane. The stimulus to swallow was obtained either by placing a drop of alcohol on the fauces or back of the tongue, or by electrical stimulation of the central end of the superior laryngeal nerve. A graphic record was obtained by fixing a hook to the hyoid bone and attaching it to a recording lever. Fig. 4 shows the effect of an intravenous injection of.~~~ Fig. 4. Adrenalin on swallowing centre (cat). Large excursions =swallowing. Small excursions= respiratory. adrenalin on the swallowing reflex provoked by rhythmic stimulation of the central end of the superior laryngeal nerve. The small waves record respiratory movements, the large waves, swallowing movements. It may be observed that the adrenalin produced no effect on the swallowing reflex but almost abolished the respiratory efforts. After the apnoea passed off the tracing shows the usual hyperpncea. Pupillo-motor reflex. The dilatation of the pupil produced by adrenalin might be due in part to central inhibition of the nucleus of the 3rd nerve, and this possibility was investigated. An anesthetised cat was taken into a room with a dim light. The resting size of the pupil was approximately three-quarters of full dilatation and the pupil when illuminated by electrical torch diminished to one-third dilatation. The intravenous injection of 2 c.c. of -004 p.c. adrenalin dilated the pupil from a resting value of three-quarters to five-sixths of full dilatation. This adrenalin pupil when illuminated contracted rapidly from five-sixths to two-thirds dilatation. It is evident, therefore, that the pupil under the influence of adrenalin acts as effectively to the light stimulus as the pupil ofthe normal cat. The light stimulus acts through the nucleus of the 3rd nerve. Consequently the results prove that adrenalin does not diminish the activity of the 3rd nerve nucleus.

5 ADRENALIN ON REFLEXES. 391 Conjunctival reflex. This reflex was tested by lightly touching the corner of the eye under the same conditions as those described for the pupillo-motor reflex. There was no evidence that it was diminished by the intravenous injection of adrenalin. The absence of any demonstrable effect of adrenalin on the bulbar and mid brain centres in general, apart from the respiratory centre, offers strong evidence against the vaso-motor hypothesis of adrenalin apncea. The general association both from an anatomical and physiological point of view, of the bulbar centres renders it very improbable that the blood vessels to one centre should be affected by a substance with so extensive an action as adrenalin, without the blood supply to the adjacent centres being affected. Spinal reflexes. The foregoing experiments show that the respiratory centre is the only cranial centre influenced by the intravenous injection of adrenalin. We therefore investigated the action of adrenalin on spinal reflexes associated with voluntary muscles, to determine whether adrenalin had an action on the cord similar to that observed with the respiratory centre. Knee jerk. A record of the knee jerk was obtained by supporting the knee joint of a cat and attaching the foot to a writing lever. The patellar tendon was mechanically stimulated by light taps at 2 second intervals, and during this stimulation 1 c.c. of *02 p.c. adrenalin was intravenously injected. The record showed that the knee jerk was not influenced by adrenalin. (Crureus muscles. The reflex contractions of the left crureus muscles in a spinal cat were elicited by stimulating the central end of the ipsilateral sciatic nerve, the anterior crural (femoral) nerve being left intact. Tetanic stimuli lasting for 2 seconds repeated at 12 second intervals were used. During the regular series of reflex contractions 1 c.c. of *01 p.c. adrenalin was given intravenously. The tracing showed that the contractions were not effected. The tone of muscles. A spinal cat was prepared and a record was obtained of the tone of the quadriceps extensor before, during and after the injection'of a massive dose of,adrenalin (.05 mgrm.). There was no indication of any change in the tone of the muscles during the general action of adrenalin in the animal. Similar results were obtained from an examination of the effect of adrenalin on the exaggerated postural tonus of the decerebrated cat.

6 392 A. ST G. HUGGETT AND J. MELLANBY. The antagonistic action of adrenalin and afferent nerve stimulation on the respiratory centre. Afferent nerve stimulation produces an exaggerated discharge of the respiratory centre resulting in hyperpnoea. This hyperpuoea may be diminished or annulled by adrenalin. Fig. 5 shows the hyperpnoea produced by faradic stimulation of the central end of the right femoral Fig. 5. Adrenalin on hyperpnuea produced by afferent nerve. F, femoral nerve stimulated. A, adrenalin injected. Fig. 6. Afferent nerve stimulation in adrenalin apncea. A, adrenalin injected. B, femoral nerve stimulated with increasing strength of currents. nerve and the marked diminution in respiratory movements produced during nerve stimulation by the intravenous injection, *02 mgrm. of adrenalin. The contrary effect may be demonstrated with equal certainty. Fig. 6 A shows the apncea produced by *01 mgrm. of adrenalin. At B a faradic current was applied to the central end of the cut femoral nerve with the secondary coil at 12-no effect was produced; at B the secondary coil was moved up to 10 with a resultant return to normal respiration; at C the secondary coil was placed at 8 with a production of hyperpncea.

7 ADRENALIN ON REFLEXES. 393 DISCUSSION. From the foregoing experiments it is evident that adrenalin effects the respiratory centre only and has no action on other bulbar centres or on parts of the brain concerned with the eye reflexes. These facts render the hypothesis of localised vaso-constrictor nerves to the cerebral vesels improbable. On the other hand, no evidence has been obtained from a study of muscle tone and limb reflexes that adrenalin has a direct action on the cells of the brain or the spinal cord. Therefore we must asume that adrenalin acts directly on the cells of the respiratory centre and apparently on the cells of the respiratory centre only. This hypothesis is supported by the mutual antagonistic actions of adrenalin and afferent nerve stimulation on the activity of the respiratory centre. Afferent nerve hyperpncea may be diminished by adrenalin, or adrenalin apncea may be annulled by afferent nerve stimulation. Since afferent nerve hyperpncea is due to impulses affecting the cells of the respiratory centre it follows that the antagonistic action of adrenalin must be also due to an action of adrenalin on the same cells. In a previous paper it has been indicated that the facts of adrenalin apncea form an apparent contradiction to the generalisation that adrenalin acts as a defence mechanism in the body. The mutual antagonistic action of adrenalin and afferent nerve stimuli on the respiratory mechanism clears up this apparent difficulty. On the occurrence of danger afferent impulses tend to discharge the respiratory centre, and the resultant hyperpncea, if not controlled would lead to a depletion of C02 from the blood with a production of acapnia. But the simultaneous output of adrenalin diminishes the sensitivity to these stimuli and hyperpncea is produced only when the C02 of the blood has accumulated to a sufficient degree to overcome this diminished sensitivity. The facts of adrenalin apncea does not favour the hypothesis of Lumsden(4) that respiration is controlled by four distinct centres. These centres of different function, localisation and development should be effected in varying degrees by adrenalin and corresponding variations in respiration be produced. In point of fact, adrenalin only diminishes to a greater or less degree the movements of respiration-inspiratory apncea or gasping never being produced. This uniformity of adrenalin apncea, and the absence of adrenalin action on any other nerve cell in the mid brain, bulb, or spinal cord indicate the existence of one centre only for the nervous control of the respiratory mechanism.

8 394 A. ST G. HUGGETT AND J. MELLANBY. SUMMARY. (1) Adrenalin apncea is not accompanied by any change in the activity of the cardio-inhibitory centre, the vaso-motor centre or the swallowing centre. It is improbable, therefore, that adrenalin produces local vaso-constriction of the blood vessels to the bulb. (2) Adrenalin does not influence the normal tone of muscles, the exaggerated tonus of decerebrate rigidity, the pupillo-motor reflex, the conjunctival reflex, or the reflex movements of the limbs. (3) These experiments indicate that adrenalin effects respiratory movements by a specific action on the cells of the respitatory centre. REFERENCES. (1) Mellanby and Huggett. This Journ. 57. p (2) Boruttau. Pfliiger's Arch. p (3) Nice, Rock and Courtright. Amer. Journ. Physiol. 34. p (4) Lumsden. This Joum. 57. p Errata. Nos. 2 and 38 Vol. 59. p The Figure inscribed 'coil 6 cm.' is8 Fig. 5 (not Fig. 4), and that inscribed 'coil 6.75' iu Fig. 4 (not Fig. 5) in accordance with the description in the text. p. 248, line 20 from top. For '.1 to 2 mg.' read '41 to *2 mg.'