Rosenthal(4), Hill(5), Lumsden(6), J. F. and C. Heymans(l, Gesell(7m, C. F. Schmidt(s)). These facts are taken by several authors

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1 6I2.288:6II.I33 6I :577.I74.5 SINUS CALOTICUS AND RESPIRATORY REFLEXES. I. Cerebral blood flow and respiration. Adrenaline apnceal. BY C. HEYMANS AND JEAN J. BOUCKAERT. (From the Department of Pharmacology, University of Ghent.) IF the isolated head of a dog B is perfused from the vessels of a dog A, and the only connections between the head of B and the isolated heartlung preparation of B are the vagus-depressor nerves, one observes (1) that an increase or a decrease of the arterial blood-pressure in the cardioaortic vascular area of B produces respectively a reflex inhibition, a reflex apncea, or a reflex stimulation, a reflex hyperpncea, of the respiratory centre of head B. The vagus-depressor nerves are the centripetal paths of these respiratory reflexes, in relation with the cardio-aortic bloodpressure. It is known that the occlusion of the common carotid arteries stimulates and that an increase of blood-pressure, or blood flow, in the carotid cephalic circulation inhibits the activity of the respiratory centre (Magendies and Cooperv2), Kussmaul and Tenner(3), Rosenthal(4), Hill(5), Lumsden(6), J. F. and C. Heymans(l, Gesell(7m, C. F. Schmidt(s)). These facts are taken by several authors as evidence that " the respiratory centre is influenced directly by changes in the blood supply... respiration is depressed by an increase in cerebral blood flow, stimulated by a decrease no matter how produced" (C. F. Schmidt). However, as early as 1900, Siciliano(9 pointed out that the respiratory reactions are more marked after the occlusion of the carotids than after occlusion of the vertebral arteries, although the latter are more important for the blood supply of the circle of Willis, and Siciliano concludes in favour of respiratory reflexes of carotid origin. In 1912, Sollmann and Brown(lo) demonstrated that traction on the cephalic end of the common carotid produced respiratory reflexes. More recent investigations have shown that electric stimulation of the bifurcation of the common carotid (sinus caroticus) and the increase of 1 A preliminary account of these experiments was read before the Physiological Society in London on January 18th, 1930.

2 SINUS CAROTICUS AND RESPIRATION. 255 pressure in the sinus caroticus produce respectively a reflex stimulation and a reflex depression of the respiratory centre (H. E.. Hering(ll), Danielopolu and his collaborators(12), Moissejeff(l3), 0. Heymans(14), and E. Kocha(5)). In order to obtain more definite information on the relations between blood-pressure, cephalic blood flow, / \ and respiratory activity, we have s -tab.... CM performed the following 1. experiments. In dogs (Fig. 1) 'anaesthetized with chloralosane or uretliane, the two common carotid arteries 'are cut between ligatures. The thyroid vi arteries and the efferent branches of the sinus caroticus (external carotids, internal carotids, occipital, laryngeal and lingual arteries) are tied, care being taken not to sever the sinus innervation. The cephalic ends of the / common carotids are connected with 3 the Dale-Schuster(16) pump; outflow cannulas are placed in the Fig. 1. Showing the method of sinus efferent branches of the lingual perfusion of the two isolated sinus caroticus. arteries. By means of this technique, which is an adaptation of the method of perfusion of the isolated sinus caroticus which one of us described before (14, 17), the two isolated sinus caroticus (bifurcation of the common carotid and ganglion caroticum), connected with the animal only by the sinus innervation, are perfused under pulsating arterial pressure with defibrinated blood or Ringer solution of which one can modify the pressure, the flow, the pulsating rate and the physico-chemical properties. The dog's respiratory rate and volume, the heart frequency and femoral blood-pressure are registered. The two sinus caroticus being perfused at a low pressure of 60 mm. Hg (S.P. Fig. 2), the respiratory rate of the vagotomized dog is 28 movements per minute (R. Fig. 2). At t a, Fig. 2, a rise of the sinus perfusion pressure to 300 mm. Hg produces an immediate cessation of respiration, a reflex apncea, with a diminution of the general and cerebral arterial (vertebral arteries) blood-pressure from 260 to 120 mm. Hg. This apncea remains till the moment the sinus perfusion pressure is

3 256 C. HEYMANS AND JEAN J. BOUCKAERT. lowered ( t b, Fig. 2) to 150 mm. Hg; the respiration comes back immediately, and this before the rise of general blood-pressure. Fig. 2. Dog. 23*5 kg., chloralosane, vagi-depressor nerves cut. Perfusion of the two isolated sinus caroticus. R., pneumogram. B.P., femoral arterial blood-pressure, mercury manometer. S.P., perfusion pressure of the sinus caroticus, mercury manometer. t a, increase of sinus perfusion pressure. Apncea and decrease of general blood-pressure. t b, decrease of sinus perfusion pressure. Respiration returns and increase of general blood-pressure. The two sinus caroticus being perfused at a pressure of 48 mm. Hg (S.P. Fig. 3) the respiratory rate is 16 movements per minute (R. Fig. 3).

4 SINUS CAROTICUS AND RESPIRATION. 257 At t a and t c, Fig. 3, the sinus pressure is increased to 220 mm. Hg; the respiration becomes immediately slower (R. Fig. 3) although the general and cerebral vertebral pressure decreases from 160 to 120 mm. Hg (B.P. Fig. 3). Fig. 3. Dog kg., chloralosane, vagi-depressor nerves cut. Perfusion of the two isolated sinus caroticus. R., pneumogram. B.P., femoral arterial blood-pressure, mercury manometer. S.P., perfusion pressure of the sinus caroticus, mercury manometer. f a and t c, increase of sinus perfusion pressure. Reflex inhibition of the respiratory centre and decrease of general blood-pressure. t b and t d, decrease of sinus perfusion pressure. Reflex stimulation of the respiratory centre and increase of general bloodpressure.

5 258 C. HEYMANS AND JEAN J. BOUCKAERT. At t b and t d, Fig. 3, the sinus perfusion pressure is lowered to 50 mm. Hg and the respiration of the animal becomes immediately faster (16 movements per minute). The general blood-pressure rises to 230 mm. Hg (B.P. Fig. 3). The respiratory reflex stimulation precedes the reflex changes of the general blood-pressure. Fig. 4. Dog. 17*5 kg., chloralosane, vagi-depressor nerves cut. Perfusion of the two isoiated sinus caroticus. R., pneumogram. B.P., femoral arterial blood-pressure, mercury manometer. S.P., perfusion pressure of the sinus caroticus, mercury manomqter. t a, increase of sinus perfusion pressure from 60 to 80 mm. Hg. Reflex inhibition of the respiratory centre, 18 to 14 respiratory movements per minute. t b, decrease of sinus perfusion pressure from 80 to 60 mm. Hg. Reflex stimulation of the respiratory centre, 14 to 18 respiratory movements per minute. With the perfusion pressure (S.P. Fig. 4) of the isolated sinus caroticus at the level of 60 mm. Hg, one observes that a slight increase of sinus pressure to 80 mm. Hg produces a reflex slowing of the respiration

6 SINUS CAROTICUS AND RESPIRATION. 259 (R. Fig. 4), whereas a slight decrease of the sinus pressure causes an acceleration of the respiratory movements. These experiments show that changes of arterial blood-pressure affecting only the isolated sinus caroticus reproduce the modifications of the activity of the respiratory centre which may be obtained by changing the blood-pressure in the cephalic circulation. The reflex stimulation of the respiratory centre, by a low bloodpressure in the isolated sinus caroticus, also occurs in a hyperventilated dog; the humoral apncea is neutralized by the reflex hyperpncea. In the same way we observed that a central humoral hyperpncea may be transformed into an apncea by raising the blood-pressure in the sinus caroticus only. In a previous paper(i) we have also demonstrated that a low blood-pressure in the cardio-aortic circulation only, may transform, by a reflex, the central apucea into an hyperpnmea. These observations may perhaps explain the facts described by Fraser, Ross and Dreyer(1s), Bald(19), Hertzmann and Gesell(2o) of hyperventilation produced by haemorrhage (low blood-pressure) although the blood is more alkaline. Before the discovery of the important and predominant part taken by the sinus caroticus in the reflex regulation of heart rate and vasomotor tonus, it was generally accepted that cerebral blood-pressure acted directly upon the centres regulating the heart rate and the vasomotor tonus. The experiments of H. E. Hering and his collaborators (Koch, Kisch, Mies and Nordmann), Florey, Marvin anddrury (21), and our own observations(14) have demonstrated that the changes of cephalic blood-pressure and blood flow determine modifications of heart rate and vasomotor tonus only by a reflex set up by the bloodpressure changes acting on the sensitivity of the sinus caroticus. Acute anaemia or asphyxia has a direct central action, but if a lowering of cephalic arterial pressure produces a reflex (sinus caroticus) acceleration of the heart, acute anaemia on the contrary produces a central heart slowing. The question arises: are the immediate modifications of respiration produced by the changes in cephalic blood-pressure or blood flow also only of reflex, sinus caroticus, origin or are they partly of direct central origin? The following experiments were performed in order to answer this question. In dogs, anaesthetized with chloralosane or urethane, all the efferent branches of the two sinus caroticus, except the lingual arteries, are ligatured, the depressor nerves are cut (method of E. Koch), threads

7 260 C. HEYMANS AND JEAN J. BOUCKAERT. are placed, but not tied, under the vertebral arteries. The pneumogram and the arterial femoral blood-pressure are registered. The clamping (t a, Fig. 5) of the two common carotids brings about r~~~~~~~~trt F~ig. 5. Dog. 11*9 kg., urethane, depressor nerves; cut. The efferent arteries of the two sinus caroticus, except the lingual arteries, are tied. R., pneumogram. B.P., femoral arterial blood-pressure, mercury manometer. t a, common. carotid arteries are clamped. Reflex stimulation of the respiratory centre (24 to 40 respiratory movements per minute) and increase of the general blood-pressure. t b, common carotid arteries are opened. Reflex inhibition of the respiratory centre and decrease of general bloodpressure. t~ c to t~d, vertebral arteries clamped, no changes in respiratory activity and blood-pressure. a diminution of blood-pressure in the sinus caroticus only, the general blood-pressure of the dog rises from 165 mm. Hg to 220 mm. Hg; the respiratory centre is stimulated, the respiratory rate changing from 24 to 40 movements per minute. When the clamps on the common carotids are removed the respiratory rate slows down immediately to the previous rate of 24 movements per minute. The occlusion ( t c to t- d, Fig. 5) of the two vertebral arteries does not produce any change in the activity of the respiratory centre. In other experiments the efferent arteries of the sinus caroticus were not ligatured. The occlusion of the common carotid arteries (1- a, Fig. 6, A) produces the normal acceleration of respiration (R?., Fig. 6) and the respiration slows down immediately when the carotids are opened again ( t b, Fig. 6, A). The two sinus caroticus are then denervated between A and B, Fig. 6, and one observes that, although the general blood-pressure and cerebral blood flow are increased, the respiratory centre is not depressed but stimulated, and that the occlusion and

8 SINUS CAROTICUS AND RESPIRATION. 261 opening of the common carotids ( t c, t d, Fig. 6, B) no longer produce modifications in the activty of the respiratory centre. Fig. 6. Dog kg., chloralosane, depressor nerves cut. R., pneumogram. B.P., femoral arterial blood-pressure, mercury manometer. t a, common carotid arteries are clamped. Stimulation of the respiratory centre and increase of general blood-pressure with heart acceleration. t b, common carotid arteries are opened. Immediate inhibition of the respiratory activity and decrease of general blood-pressure with heart slowing. The two sinus caroticus nerves are then cut between A and B; this produces an increase of general blood-pressure (190 to 280 mm. Hg), heart acceleration and increase of rate and amplitude of respiration. t c, common carotid arteries are clamped. No changes in the activity of the respiratory centre, slight mechanical increase of general blood-pressure. 4 d, common carotid arteries are opened. No changes in the activity of the respiratory centre, slight mechanical drop of genera blood-pressure. These experiments furnish evidence that the immediate respiratory responses to changes in cephalic blood-pressure and blood flow are due

9 2622C. HEYMANS AND JEAN J. BOUCKAERT. only to reflexes from the sinus caroticus. The nerves of the sinus caroticus exert an inhibitory respiratory tonus which is maintained by the normal blood-pressure acting on the nerve endings of the sinus caroticus. Adrenaline apncea. It is a well-known fact since the first experiments of Oliver and Schafer(22) that an intravenous injection of adrenaline produces a diminution in the rate and depth of respiration, sometimes a cessation of respiration, an adrenaline apncea. In previous papers (1) we have shown that, in accordance with the conclusion of Voegtlin and Wiggers(23), the direct action of adrenaline on the respiratory centre is not to depress but to stimulate it. Evidence was also presented' that adrenaline hypertension confined to the somatic circulation of a dog B produces a reflex (vagus-depressor) inhibition, an apncea, of the respiratory centre of the isolated head of dog B, with its head perfused by means of a dog A. This reflex adrenaline apncea is due to the increase of bloodpressure in the heart and aortic arch; if one prevents the rise of somatic blood-pressure no reflex apncea of the isolated head occurs. We have concluded from these observations that the adrenaline apncea is due essentially to a reflex (vagus-depressor) inhibition of the respiratory centre by the high blood-pressure. This conclusion was recently contradicted by C. F. S ch midt(24); for this worker "reflex inhibition appears to be a factor, but by far the most important cause is increase in blood supply of the centre." This conclusion is based upon the fact that "adrenaline is never made completely ineffective by vagotomy" and that "the brain of a cat was perfused via the vertebral arteries, addition of adrenaline to the perfusing blood caused marked rise in systemic pressure, but perfusion pressure was not raised and respiration was only very slightly depressed. However, when the carotids were opened, typical adrenaline apncea occurred at once. The results demonstrate the dependence of adrenaline apncea upon passive changes in cerebral blood flow and its independence of reflexes or of direct action upon the respiratory centre." But the experiments that we have described above indicate that the conclusions of Schmidt ought to be re-examined. In Schmidt's experiments, indeed, the adrenaline rise in blood-pressure does only produce a very slight respiratory depression (vagus depressor reflex) because the common carotid arteries were clamped, and this sets up a reflex (sinus caroticus) respiratory stimulation. However, when the carotids were opened, apnea occurred at once, because the high systemic blood-pressure is acting on the nerve endings of the sinus caroticus. In

10 SINUS CAROTICUS AND RESPIRATION. 263 our experiments adrenaline hypertension, acting only on the two isolated sinus caroticus and with no increase but decrease in the cerebral blood flow, reproduces the same apncea, which consequently is a reflex. This conclusion is also supported by the following experiments. In dogs anesthetized with urethane or chloralosane, the two depressor and sinus nerves are cut. Pneumogram (R., Fig. 7) and femoral Fig. 7. Dog. 119 kg., urethane, depressor and sinus caroticus nerves cut. R., pneumogram. B.P., arterial femoral blood-pressure, mercury manometer. j, intravenous injection of 0 3 mg. adrenaline. Hypertension but no changes in respiratory activity. blood-pressure (B.P., Fig. 7) are registered. The intravenous injection ( A, Fig. 7) of 03 mg. adrenaline does not produce the slightest changes in respiratory rate or amplitude. These experiments demonstrate that after section of the cardioaortic nerves and sinus caroticus nerves, the adrenaline hypertension brings about neither inhibition nor cessation of respiratory activity, nor a slowing of the heart, although the cerebral blood flow and bloodpressure are increased.

11 Fig. 8. Dog. 16 kg., chloralosane. Depressor nerves cut. B., pneumogram. B.P., femoral blood-pressure, tonometer. I, t a, intravenous injection of 0-2 mg. adrenaline. Hypertension; heart slowing and respiratory inhibition (apncea). Between I and II the two sinus caroticus are denervated. II, t b, intravenous injection of 02 mg. adrenaline. Hypertension; no heart slowing (vagi intact), slight inhibition of re spiration followed by respiratory stimulation.

12 SINUS CAROTICUS AND RESPIRATION. 265 These facts should also be compared with the observations of McDowall(2s) that "adrenaline apnoea is produced in a manner similar to and coincident with the vagal inhibition of the heart caused by adrenaline," since we know that the heart slowing and respiratory inhibition produced by an increase of blood-pressure are reflexes of cardio-aortic and sinus caroticus origin. In some experiments (Fig. 8) one may observe that, in dogs with sinus and depressor nerves cut, the sudden increase of blood-pressure may produce a very slight depression of respiration; this inhibition of short duration is followed by increase of respiratory activity and also appears after adrenaline injection in dogs with carotid and vertebral arteries clamped and depressor and sinus nerves cut, therefore this slight inhibition must be a medullary afferent respiratory reflex. SUMMARY AND CONCLUSIONS. 1. A method of perfusion, with the Dale-Schuster pump, of the two isolated sinus caroticus, with nerve supply intact, is described. 2. The increase of blood-pressure in the isolated sinus caroticus circulation as well as in the cardio-aortic circulation produces a reflex inhibition of the respiration, a reflex apncea. 3. A decrease of blood-pressure in the same vascular areas produces a reflex stimulation of respiratory activity, a reflex hyperpncea. 4. Evidence is presented that the immediate changes in the activity of the respiratory centre, as well as the changes in heart rate and vasomotor tonus produced by modifications of blood-pressure and blood flow in the cephalic circulation, are due to reflexes arising in the sinus caroticus and not to modifications in the central blood supply. After denervation of the two sinus caroticus, occlusion of the carotids no longer produces respiratory reactions. 5. A humoral central apncea or hyperpncea may be transformed into a reflex hyperpncea or into a reflex apncea by lowering or increasing the blood-pressure only in the sinus caroticus or in the heart and aortic arch. 6. Adrenaline apncea is due to a reflex inhibition of the respiratory centre produced by the increase of blood-pressure in the cardio-aortic and sinus caroticus circulatory areas and not to changes in the central blood supply. 7. The afferent nerves for these respiratory reflexes are the vagusdepressor nerves and the sinus caroticus nerves. In normal circulatory

13 266 C. HEYMANS AND JEAN J. BOUCKAERT. conditions these nerves exert an inhibitory tonus on the activity of the respiratory centre. The expense of these researches was largely defrayed by a grant from the Ella Sachs Plotz Foundation and the Belgian National Fund for Scientific Research. REFERENCES. 1. Heymans, J. F. and C. C. R. Soc. Biol. Paris, 93. p p Arch. int. Pharmacodyn. 32. p p Heymans, C. Verh. Ges. f. Kreislauff. I. Tag. p Heymans, C. and Bouckaert, J. J. C. R. Soc. Biol. Paris, 103. p Magendies and Cooper, A. B. Guy's Hosp. Reports, 1. p Kussmaul, A. and Tenner, A. Moleschott's Untersuch. z. Natur. 3. p Rosenthal. Hermann's Handb. der Physiol. 4, 2. p Hill, L. The Cerebral Circulation, p London, Lumsden, T. This Journ. 57. pp. 153, p Gesell. Ergebn. Physiol. 28. p Schmidt, C. F. Amer; J. Physiol. 84. p Siciliano. Arch. ital. Biol. Napoli, 33. p Sollmann and Brown. Amer. J. Physiol. 30. p Hering, H. E. Die Karotissinusreflexe auf Herz u. Gefisse. Dresden u. Leipzig, Danielopolu, Aslon, Marcu, Proca and Manescu. Pr. med. p Moissejeff. Z. ges. exp. Med. 53. p Heymans, C. Amer. J. Physiol. 85. p Arch. int. Pharmacodyn. 35. p Ergebn. Physiol. 28. p Le sinus carotidien et les autres zones vasosensibles reflexogenes. Monographie. Paris, Presses Universitaires. London, Lewis and Co Koch, E. Ergebn. ges. Med. 13. p Z. f. Kreislauff. p Dale and Schuster. This Journ. 64. p Heymans, C. C. R. Soc. Biol. Paris, 100. p Fraser, Ross and Dreyer. Quart. J. Med. 15. p Bald. Amer. J. Physiol. 81. p Hertzmann and Gesell. Ibid. 81. p Florey, Marvin and Drury. This Journ. 65. p Oliver and Schafer. Ibid. 18. p Voegtlin and Wiggers. J. Pharmacol. 11. p Schmidt, C. F. Ibid. 35. p McDowall, R. J. S. Quart. J. Exper. Physiol. 18. p