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Reflexes arising from coronary receptors
352
SHORT COMMUNICATIONS
Reflexes arising from coronary receptors The coronary vessels and adjacent myocardium have a rich sensory innervation1,13,15,19 whose functional significance is only partially understood. Thus, coronary mechanoreceptors which respond to changes in coronary arterial pressure are connected to afferent fibers in the vagi. When coronary pressure is increased, these receptors initiate a depressor reflex associated with a reduction in cardiac sympathetic nervous discharge4, 5. Other afferent fibers6,7, 9,1s run with the cardiac sympathetic nerves which often are erroneously thought to contain only efferent fibers. The reflex connections of these afferent sympathetic fibers have been unknown until this time. We describe here a coronary-sympathetic reflex provoked by increased coronary arterial pressure which has its afferent limb in afferent cardiac sympathetic nerves, and is mediated by the spinal cord. This pressure-sensitive spinal reflex which is accompanied by an increase in cardiac sympathetic discharge is contrasted with the vagally-mediated coronary depressor reflex. These coronary reflexes may be the basis of the profound bradycardia and hypotension that often accompany posterior myocardial infarction due to coronary occlusionZ, 11 and the tachycardia and hypertension that follow the onset of angina pectoris 12. The method of perfusing the main left coronary artery, and recording afferent activity from the vagi and from afferent and efferent cardiac sympathetic nerve fibers in the cat, has been fully described4,5,8,9,14. In summary, blood was led from one common carotid artery to a constant flow pump (Holter, Inc.) and thence to a stainless steel cannula which was passed retrograde along the left subclavian artery to the mouth of the main left coronary artery where it was tied into place. Slips of nerve dissected from the cut peripheral end of either the vagus, inferior cardiac nerve, or third thoracic ramus communicans were used for afferent recording, and slips of nerve dissected from the cut central end of the latter two nerves were used for recording efferent activity. These nerves are known to innervate the heart3,14,16. In general, single units were sought but multifiber records of as many as 4-5 different fibers could be analyzed using a computer 17. The preparation showed no change in blood pressure or heart rate for 6-8 h. Changes in coronary flow produced changes in pressure restricted to the coronary vascular bed (Fig. 1), thereby localizing the pressure stimulus. Pressures in the right ventricle, left ventricle, aorta (Figs. 1 and 2), both atria and the pulmonary artery were unchanged. Ten sec after stopping coronary inflow, myocardial ischemia was produced 8. Depending upon collateral flow from the right coronary artery, another 30-60 sec were required before left ventricular end-diastolic pressure rose or systemic arterial blood pressure fell8, either of which indicated left ventricular failure. The effect of increased coronary arterial pressure on a quiescent afferent cardiac sympathetic fiber is shown in Fig. 2A. A burst of increased activity appeared immediately and persisted while the pressure was increased. Twelve other single units had the same response. An afterdischarge persisting for several seconds was often present. Three single fibers which were spontaneously active also showed a sustained increase of activity at higher pressures. The effective stimulus was either increased pressure or Brain Research, 24 (1970) 352-355
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20 SEC Fig. J. Effectof different levels of coronary flow on coronary arterial pressure (Cor. P), left ventric ular pressure (LVP), right ventricular pressure (RVP). The flow was 4, 8, 12, 16, 20, 0 and 20 ml/min at 1-7. Normal flow is about 6 ml/min. There was no change in any of the pressures other than coronary arterial pressure. Left atrial, pulmonary arterial and aortic pressures were also unaffected. At zero inflow, the mean coronary arterial pressure was 40 mm Hg partly because of good collateral flow from the right coronary artery.
stretching of the coronary arteries rather than the increased flow since greater bursts of activity were always produced when the coronary sinus was occluded at the same time as the inflow was increased. This procedure reduces flow through the coronary bed but increases pressure or stretch therein. A total of 16 single units were stimulated by increased coronary arterial pressure. Each was also activated by moving the tip of the coronary cannula and five were further localized by direct probing over the main left coronary artery and adjacent ventricle. Five multifiber preparations showed increased discharge when coronary arterial pressure was elevated. Myocardial ischemia also excited afferent cardiac sympathetic fibers 6,7,1s although the latency of 10 sec or more was very much greater than that of the pressuresensitive receptors. The response to ischemia could be easily distinguished in this way. In spinal vagotomized cats, increased coronary arterial pressure provoked a reflex increase o f activity in preganglionic sympathetic fibers of the third thoracic ramus communicans and in postganglionic fibers of the inferior cardiac nerve (Fig. 2B). The increased activity appeared in quiescent or spontaneously active fibers, was transient or persisted for the duration of stimulus application, and was prevented by prior section of the cardiac sympathetic nerves. The patterns of reflex discharge observed were identical to the various patterns described for afferent fibers. ManipulaBrain Research, 24 (1970) 352-355
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Fig. 2. A, Effectof increasedcoronary arterial pressure (Cor. P.) on a single afferent unit dissected from the third thoracic ramus communicans (T3) (top trace). B, Effect of increased coronary arterial pressure on a single efferent unit dissected from T3 (top trace). Ao.P. is aortic pressure, which was unchanged.
tion of the tip of the coronary cannula also elicited increased discharge in such fibers. Eight single units and 12 multifiber preparations showed increased activity when coronary pressure was elevated. Pressure-sensitive receptors in or near the coronary arteries also send fibers to the brain via the vagi 4. Elevated coronary pressures excite such vagal mechanoreceptors which then initiate a depressor reflex associated with a reduction of activity in the inferior cardiac nerveL The same stimulus, namely increased coronary arterial pressure, excites one group of receptors whose fibers run in the cardiac sympathetic nerves and another group whose fibers run in the vagP. The reflex response mediated by the vagi in intact brain cats4, .~ is accompanied by a reduction in efferent cardiac sympathetic discharge, whereas the response mediated by afferent cardiac fibers running with the sympathetics in spinal vagotomized cats shows an increase in efferent discharge. One explanation could be that two completely different populations of efferent fibers were sampled in the two sets of experiments and the two patterns of response were reflexly initiated by the same stimulus. Another possibility is that the same population was sampled but two completely different reflexes were evoked by the stimulus. This would require either a common interneuronal pathway or a common preganglionic neuronal pool. Ordinarily the depressor or inhibitory effect prevails4, 5 but when the vagi are cut, the excitatory effect becomes manifest; other excitatory spinal sympathetic reflexes are known to be inhibited by the brain stem TM. Brain Research, 24 (1970) 352-355
SHORT COMMUNICATIONS
355
This work was s u p p o r t e d by G r a n t s No. H E 5166025 a n d I T H E 5875-01 from the U.S. Public Health Service a n d U t a h H e a r t Association. A. M. was Visiting Professor o f Cardiology on leave from the Universit~t di Milano. A M B is a n Established Investigator o f the A m e r i c a n H e a r t Association. Departments of Physiology and Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84112 (U.S.A.)
A. MALLIANI* A. M. BROWN
1 /~BRAH,~M,A., Die Nervenversorgung der Kranzgeffisse des Herzens, Arch. int. Pharmacodyn., 139 (1962) 17-27. 2 ADGEY,A., GEDDES,J., MULHOLLAND,I-I., KEEGAN,D., AND PARTRIDGE,J., Incidence, significance and management of early bradyarrhythmia complicating acute myocardial infarction, Lancet, 2 (1968) 1097-1101. 3 BRONK,D. W., FERGUSON,L. K., MARGARIA,R., ANDSOLANDT,D. Y., The activity of the cardiac sympathetic centers, Amer. J. Physiol., 117 (1936) 237-249. 4 BROWN, A. M., Mechanoreceptors in or near the coronary arteries, J. Physiol. (Lond.), 177 (1965) 203-214. 5 BROWN, A. M., The depressor reflex arising from the left coronary artery of the cat, J. Physiol. (Lond.), 184 (1966) 825-836. 6 BROWN,A. M., Excitation of afferent cardiac sympathetic nerve fibres during myocardial ischaemia, J. Physiol. (Lond.), 190 (1967) 35-53. 7 BROWN A. M., Cardiac sympathetic adrenergic pathways in which synaptic transmission was blocked by atropine sulphate, J. Physiol. (Lond.), 191 (1967) 271-288. 8 BROWN A. M., Motor innervation of the coronary arteries of the cat, J. Physiol. (Lond.), 1 98 (1968) 311-328. 9 BROWN, A. U., AND MALLIANI, A., Spinal sympathetic reflexes initiated by coronary receptors, J. Physiol. (Lond.), (1970) in press. 10 COOTE,J., DOWNMAN,C., AND WEBER, V. F., Reflex discharges into thoracic white rami elicited by somatic and visceral afferent excitation, J. Physiol. (Lond.), 202 (1969) 147-159. 11 COSTANTIN, L., Extracardiac factors contributing to hypotension during coronary occlusion, Amer. J. Cardiol., 11 (1963)205-217. 12 FRIEDBERG,C. K., Diseases of the Heart, Saunders, Philadelphia, Pa., 1956, p. 448. 13 HIRSCH, E. F., AND BORGHARD-ERDLE,A. M., The innervation of the human heart. I. The coronary arteries and the myocardium, Arch. Path., 71 (1961) 384-407. 14 MALLIANI,A., SCHWARTZ, P., AND ZANCHETTI,A., A sympathetic reflex elicited by experimental coronary occlusion, Amer. J. Physiol., 217 (1969) 703-709. 15 NETTLESHIP,W. A., Experimental studies on the afferent innervation of the cat's heart, J. comp. Neurol., 64 (1936) 115-131. 16 RANDALL,W., MCNALLY,H., COWAN,J., CALIGUIRI,L., AND ROHSE,W., Functional analysis of the cardioaugmentor and cardioaccelerator pathways in the dog, Amer. J. Physiol., 191 (1957) 213-217. 17 SCHMITTROTH,L., in BEssotr, P., AND PERL, E. R., The response of cutaneous sensory units with unmyelinated fibers to noxious stimuli, J. NeurophysioL, 32 (1969) 1025-1043. 18 UEDA, H., UCHIDA,Y., AND KAMISAKA,K., Distribution and responses of cardiac sympathetic receptors to mechanically induced circulatory changes, Jap. Heart J., 10 (1969) 70-81. 19 WOOLLARD,H. H., The innervation of the heart, J. Anat. (Lond.), 60 (1926) 345-373. (Accepted September 30th, 1970)
* Present address: Istituto di Ricerche Cardiovascolari, Universit~t di Milano, Milan, Italy. Brain Research, 24 (1970) 352-355
SHORT COMMUNICATIONS
Reflexes arising from coronary receptors The coronary vessels and adjacent myocardium have a rich sensory innervation1,13,15,19 whose functional significance is only partially understood. Thus, coronary mechanoreceptors which respond to changes in coronary arterial pressure are connected to afferent fibers in the vagi. When coronary pressure is increased, these receptors initiate a depressor reflex associated with a reduction in cardiac sympathetic nervous discharge4, 5. Other afferent fibers6,7, 9,1s run with the cardiac sympathetic nerves which often are erroneously thought to contain only efferent fibers. The reflex connections of these afferent sympathetic fibers have been unknown until this time. We describe here a coronary-sympathetic reflex provoked by increased coronary arterial pressure which has its afferent limb in afferent cardiac sympathetic nerves, and is mediated by the spinal cord. This pressure-sensitive spinal reflex which is accompanied by an increase in cardiac sympathetic discharge is contrasted with the vagally-mediated coronary depressor reflex. These coronary reflexes may be the basis of the profound bradycardia and hypotension that often accompany posterior myocardial infarction due to coronary occlusionZ, 11 and the tachycardia and hypertension that follow the onset of angina pectoris 12. The method of perfusing the main left coronary artery, and recording afferent activity from the vagi and from afferent and efferent cardiac sympathetic nerve fibers in the cat, has been fully described4,5,8,9,14. In summary, blood was led from one common carotid artery to a constant flow pump (Holter, Inc.) and thence to a stainless steel cannula which was passed retrograde along the left subclavian artery to the mouth of the main left coronary artery where it was tied into place. Slips of nerve dissected from the cut peripheral end of either the vagus, inferior cardiac nerve, or third thoracic ramus communicans were used for afferent recording, and slips of nerve dissected from the cut central end of the latter two nerves were used for recording efferent activity. These nerves are known to innervate the heart3,14,16. In general, single units were sought but multifiber records of as many as 4-5 different fibers could be analyzed using a computer 17. The preparation showed no change in blood pressure or heart rate for 6-8 h. Changes in coronary flow produced changes in pressure restricted to the coronary vascular bed (Fig. 1), thereby localizing the pressure stimulus. Pressures in the right ventricle, left ventricle, aorta (Figs. 1 and 2), both atria and the pulmonary artery were unchanged. Ten sec after stopping coronary inflow, myocardial ischemia was produced 8. Depending upon collateral flow from the right coronary artery, another 30-60 sec were required before left ventricular end-diastolic pressure rose or systemic arterial blood pressure fell8, either of which indicated left ventricular failure. The effect of increased coronary arterial pressure on a quiescent afferent cardiac sympathetic fiber is shown in Fig. 2A. A burst of increased activity appeared immediately and persisted while the pressure was increased. Twelve other single units had the same response. An afterdischarge persisting for several seconds was often present. Three single fibers which were spontaneously active also showed a sustained increase of activity at higher pressures. The effective stimulus was either increased pressure or Brain Research, 24 (1970) 352-355
SHORT
353
COMMUNICATIONS
-20
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LVP
COR.P
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;9
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20 SEC Fig. J. Effectof different levels of coronary flow on coronary arterial pressure (Cor. P), left ventric ular pressure (LVP), right ventricular pressure (RVP). The flow was 4, 8, 12, 16, 20, 0 and 20 ml/min at 1-7. Normal flow is about 6 ml/min. There was no change in any of the pressures other than coronary arterial pressure. Left atrial, pulmonary arterial and aortic pressures were also unaffected. At zero inflow, the mean coronary arterial pressure was 40 mm Hg partly because of good collateral flow from the right coronary artery.
stretching of the coronary arteries rather than the increased flow since greater bursts of activity were always produced when the coronary sinus was occluded at the same time as the inflow was increased. This procedure reduces flow through the coronary bed but increases pressure or stretch therein. A total of 16 single units were stimulated by increased coronary arterial pressure. Each was also activated by moving the tip of the coronary cannula and five were further localized by direct probing over the main left coronary artery and adjacent ventricle. Five multifiber preparations showed increased discharge when coronary arterial pressure was elevated. Myocardial ischemia also excited afferent cardiac sympathetic fibers 6,7,1s although the latency of 10 sec or more was very much greater than that of the pressuresensitive receptors. The response to ischemia could be easily distinguished in this way. In spinal vagotomized cats, increased coronary arterial pressure provoked a reflex increase o f activity in preganglionic sympathetic fibers of the third thoracic ramus communicans and in postganglionic fibers of the inferior cardiac nerve (Fig. 2B). The increased activity appeared in quiescent or spontaneously active fibers, was transient or persisted for the duration of stimulus application, and was prevented by prior section of the cardiac sympathetic nerves. The patterns of reflex discharge observed were identical to the various patterns described for afferent fibers. ManipulaBrain Research, 24 (1970) 352-355
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Fig. 2. A, Effectof increasedcoronary arterial pressure (Cor. P.) on a single afferent unit dissected from the third thoracic ramus communicans (T3) (top trace). B, Effect of increased coronary arterial pressure on a single efferent unit dissected from T3 (top trace). Ao.P. is aortic pressure, which was unchanged.
tion of the tip of the coronary cannula also elicited increased discharge in such fibers. Eight single units and 12 multifiber preparations showed increased activity when coronary pressure was elevated. Pressure-sensitive receptors in or near the coronary arteries also send fibers to the brain via the vagi 4. Elevated coronary pressures excite such vagal mechanoreceptors which then initiate a depressor reflex associated with a reduction of activity in the inferior cardiac nerveL The same stimulus, namely increased coronary arterial pressure, excites one group of receptors whose fibers run in the cardiac sympathetic nerves and another group whose fibers run in the vagP. The reflex response mediated by the vagi in intact brain cats4, .~ is accompanied by a reduction in efferent cardiac sympathetic discharge, whereas the response mediated by afferent cardiac fibers running with the sympathetics in spinal vagotomized cats shows an increase in efferent discharge. One explanation could be that two completely different populations of efferent fibers were sampled in the two sets of experiments and the two patterns of response were reflexly initiated by the same stimulus. Another possibility is that the same population was sampled but two completely different reflexes were evoked by the stimulus. This would require either a common interneuronal pathway or a common preganglionic neuronal pool. Ordinarily the depressor or inhibitory effect prevails4, 5 but when the vagi are cut, the excitatory effect becomes manifest; other excitatory spinal sympathetic reflexes are known to be inhibited by the brain stem TM. Brain Research, 24 (1970) 352-355
SHORT COMMUNICATIONS
355
This work was s u p p o r t e d by G r a n t s No. H E 5166025 a n d I T H E 5875-01 from the U.S. Public Health Service a n d U t a h H e a r t Association. A. M. was Visiting Professor o f Cardiology on leave from the Universit~t di Milano. A M B is a n Established Investigator o f the A m e r i c a n H e a r t Association. Departments of Physiology and Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84112 (U.S.A.)
A. MALLIANI* A. M. BROWN
1 /~BRAH,~M,A., Die Nervenversorgung der Kranzgeffisse des Herzens, Arch. int. Pharmacodyn., 139 (1962) 17-27. 2 ADGEY,A., GEDDES,J., MULHOLLAND,I-I., KEEGAN,D., AND PARTRIDGE,J., Incidence, significance and management of early bradyarrhythmia complicating acute myocardial infarction, Lancet, 2 (1968) 1097-1101. 3 BRONK,D. W., FERGUSON,L. K., MARGARIA,R., ANDSOLANDT,D. Y., The activity of the cardiac sympathetic centers, Amer. J. Physiol., 117 (1936) 237-249. 4 BROWN, A. M., Mechanoreceptors in or near the coronary arteries, J. Physiol. (Lond.), 177 (1965) 203-214. 5 BROWN, A. M., The depressor reflex arising from the left coronary artery of the cat, J. Physiol. (Lond.), 184 (1966) 825-836. 6 BROWN,A. M., Excitation of afferent cardiac sympathetic nerve fibres during myocardial ischaemia, J. Physiol. (Lond.), 190 (1967) 35-53. 7 BROWN A. M., Cardiac sympathetic adrenergic pathways in which synaptic transmission was blocked by atropine sulphate, J. Physiol. (Lond.), 191 (1967) 271-288. 8 BROWN A. M., Motor innervation of the coronary arteries of the cat, J. Physiol. (Lond.), 1 98 (1968) 311-328. 9 BROWN, A. U., AND MALLIANI, A., Spinal sympathetic reflexes initiated by coronary receptors, J. Physiol. (Lond.), (1970) in press. 10 COOTE,J., DOWNMAN,C., AND WEBER, V. F., Reflex discharges into thoracic white rami elicited by somatic and visceral afferent excitation, J. Physiol. (Lond.), 202 (1969) 147-159. 11 COSTANTIN, L., Extracardiac factors contributing to hypotension during coronary occlusion, Amer. J. Cardiol., 11 (1963)205-217. 12 FRIEDBERG,C. K., Diseases of the Heart, Saunders, Philadelphia, Pa., 1956, p. 448. 13 HIRSCH, E. F., AND BORGHARD-ERDLE,A. M., The innervation of the human heart. I. The coronary arteries and the myocardium, Arch. Path., 71 (1961) 384-407. 14 MALLIANI,A., SCHWARTZ, P., AND ZANCHETTI,A., A sympathetic reflex elicited by experimental coronary occlusion, Amer. J. Physiol., 217 (1969) 703-709. 15 NETTLESHIP,W. A., Experimental studies on the afferent innervation of the cat's heart, J. comp. Neurol., 64 (1936) 115-131. 16 RANDALL,W., MCNALLY,H., COWAN,J., CALIGUIRI,L., AND ROHSE,W., Functional analysis of the cardioaugmentor and cardioaccelerator pathways in the dog, Amer. J. Physiol., 191 (1957) 213-217. 17 SCHMITTROTH,L., in BEssotr, P., AND PERL, E. R., The response of cutaneous sensory units with unmyelinated fibers to noxious stimuli, J. NeurophysioL, 32 (1969) 1025-1043. 18 UEDA, H., UCHIDA,Y., AND KAMISAKA,K., Distribution and responses of cardiac sympathetic receptors to mechanically induced circulatory changes, Jap. Heart J., 10 (1969) 70-81. 19 WOOLLARD,H. H., The innervation of the heart, J. Anat. (Lond.), 60 (1926) 345-373. (Accepted September 30th, 1970)
* Present address: Istituto di Ricerche Cardiovascolari, Universit~t di Milano, Milan, Italy. Brain Research, 24 (1970) 352-355