J. C. G. Coleridge

Search for a cardiac nociceptor: stimulation by bradykinin of sympathetic afferent nerve endings in the heart of the cat.

1. We have examined the effect of bradykinin on impulse traffic in sympathetic afferent fibres from the heart, great vessels and pleura, and have attempted to identify cardiac nociceptors that on the basis of their functional characteristics might have a role in the initiation of cardiac pain. 2. In anaesthetized cats, we recorded afferent impulses from ‘single‐fibre’ slips of the left 2nd‐‐5th thoracic rami communicantes and associated chain, and selected fibres arising from endings in the heart, great vessels, pericardium and pleura. We applied bradykinin solution (0 . 1‐‐1 . 0 microgram/ml.) locally to the site of the ending; we also injected bradykinin (0 . 3‐‐1 . 0 microgram/kg) into the left atrium. 3. Afferent endings excited by bradykinin (159 of 191 tested) were of two types. The larger group (140) were primarily mechanoreceptors with A delta of C fibres (mean conduction velocity, 7 . 5 +/‐ 0 . 6 m/sec). They were very sensitive to light touch. Those located in the heart, great vessels or overlying pleura had a cardiac rhythm of discharge and were stimulated by an increase in blood pressure or cardiac volume. 4. Bradykinin increased mechanoreceptor firing from 0 . 7 +/‐ to 5 . 0 +/‐ 0 . 3 (mean +/‐ S.E. of mean) impulses/sec. Some endings appeared to be stimulated directly by bradykinin, others sensitized by it so that they responded more vigorously to the pulsatile mechanical stimulation associated with the cardiac cycle. 5. The smaller group of eighteen endings, of which ten were in the left ventricle, were primarily chemosensitive. Most had C fibres, a few had A delta fibres (mean conduction velocity, 2 . 3 +/‐ 0 . 7 m/sec). They were insensitive to light touch. With one exception they never fired with a cardiac rhythm, and even large increases in aortic or left ventricular pressure had little effect on impulse frequency. 6. Chemosensitive endings were stimulated by bradykinin, impulse activity increasing from 0 . 6 to 15 . 6 +/‐ 1 . 3 impulses/sec and remaining above the control level for 1‐3 min. The evoked discharge, which was either continuous or occurred in irregular bursts, was not secondary to mechanical changes in the heart and great vessels. 7. Tachyphylaxis occurred when the interval between successive applications of bradykinin was 20 min or less. It was a feature of the response of both mechanosensitive and chemosensitive endings. 8. Because of their responsiveness to changes in pressure and their sensitivity to light touch, the mechanosensitive endings appear to be unlikely to subserve a primarily nociceptive function, although they may be responsible for evoking some of the components of the pseudoaffective response. By contrast, the chemosensitive endings appear well fitted to act as cardiac nociceptors.

CARDIAC RECEPTORS IN THE DOG, WITH PARTICULAR REFERENCE TO TWO TYPES OF AFFERENT ENDING IN THE VENTRICULAR WALL.

A great deal is known about afferent endings in the atrial walls of the heart. Histological studies have yielded descriptions of their appearance and distribution, and electrophysiological investigations have enabled their impulse activity to be extensively described (reviewed by Paintal, 1963). Less is known about receptors in the ventricles. A variety of afferent endings have been demonstrated histologically in the ventricular wall (see Discussion) but without any clearly defined pattern of distribution such as Nonidez (1937) found in the atrium. The impulse activity of ventricular fibres has been described in detail in cats (Paintal, 1955) and in frogs (Kolatat, Kramer & Miihl, 1957) but there has so far been no detailed account of these fibres in the dog. This is surprising in view of the many attempts made in this animal to evoke reflex effects by distending the ventricle (e.g. Salisbury, Cross & Rieben, 1960). The present paper describes experiments in which impulses were recorded in dogs from ventricular fibres with a cardiac rhythm of discharge, similar to those described by Paintal (1955) in the cat. In addition, other fibres were encountered with an irregular type of discharge and whose afferent endings were near the epicardial surface of the ventricles. Some further observations were also made on the distribution and nerve connexions of receptors in the atria.

Pulmonary afferent fibres of small diameter stimulated by capsaicin and by hyperinflation of the lungs.

This paper describes experiments in which impulses have been recorded from afferent vagal fibres whose endings were located in the lung. These fibres differed from the pulmonary stretch fibres described by Adrian (1933) and subsequent workers in that their spontaneous activity was sparse and irregular and showed no respiratory modulation at normal ventilation volumes. The fibres were stimulated, however, by inflating the lungs with larger volumes. The fibres appeared to be of small diameter, having a mean conduction velocity of 16 m/sec and a blocking temperature of 1-6° C. These slowly conducting fibres were identified in the following way. Capsaicin, a decylenic acid amide of vanillylamine, injected intravenously produces bradyeardia, systemic hypotension and apnoea (Toh, Lee & Kiang, 1955; Porsz6asz, Such & Porszasz-Gibiszer, 1957). Porsztasz et al. (1957) suggested that this triad of effects was evoked reflexly by stimulation of baroreceptors in the extrapulmonary parts of the pulmonary artery. Subsequently, Coleridge, Coleridge & Kidd (1964) found that although pulmonary arterial baroreceptors undoubtedly played a part in mediating the reflex effects, some other afferent endings within the vascular bed of the lung itself were probably involved. A search was therefore made for intrapulmonary receptors which were stimulated by capsaicin. The afferent fibres described in the present paper were encountered in the course of this work. They were the only pulmonary fibres consistently stimulated by capsaicin, the drug having little or no effect on the activity of pulmonary stretch fibres of the type described by Adrian (1933).

Impulses in Slowly Conducting Vagal Fibers from Afferent Endings in the Veins, Atria, and Arteries of Dogs and Cats

Afferent impulses in 61 fine myelinated or unmyelinated vagal fibers arising from endings in large blood vessels (“vascular endings”) were recorded in anesthetized dogs and cats. The endings had a sparse, irregular spontaneous discharge, or they were quiescent. They were stimulated by capsaicin, phenyl diguanide, or veratridine injected into the bloodstream but not by sodium cyanide or hypoxia. Unlike arterial baroreceptors and atrial receptors, which are concentrated in localized areas, vascular endings were widely distributed in the thoracic aorta, the pulmonary artery, the brachiocephalic artery, the splenic artery, the atriovenous junctions, the atrial appendages, the inferior vena cava, and the hepatic vein. Conduction velocity in 28 fibers ranged from 0.8 to 11.0 m/sec (mean 3.1 m/sec), and in 19 of these fibers the velocity was less than 2.5 m/sec (i.e., the fibers were C-fibers). Vascular endings were stimulated by distending the vessels with balloons. Endings in the pulmonary artery and the aorta did not respond to pressures within the physiological range, but they were stimulated by abnormally high pressures (pulmonary artery 60–110 mm Hg, aorta 200–215 mm Hg). The physiological role of the vascular endings is unknown.

Stimulation of pulmonary vagal afferent C-fibers by lung edema in dogs.

In anesthetized, open-chest dogs we examined the effect of pulmonary edema on the firing frequency of afferent vagal fibers arising from the lung. We recorded impulses from slips of the cervical vagus nerves and infused isotonic Krebs-Henseleit solution (20% of body weight) intravenously to increase net filtration pressure in the lung microvasculature. Measurement of extravascular lung water (6.0 ± 0.4 g/g dry lung), and morphological examination of lung tissue (revealing various degrees of perivascular and peribronchial cuffing) confirmed that edema was present. At the end of the infusion when the lungs were congested (lung microvascular pressure, 37 cm water) and edematous, the impulse frequency of pulmonary and bronchial C-fibers and rapidly adapting receptors had increased 5–6 times. The only significant change in slowly adapting receptor activity was an increase during deflation. When lung water was still elevated but lung microvascular pressure had been restored to control by withdrawal of blood, impulse activity of rapidly and slowly adapting receptors reverted to or below control. Pulmonary C-fiber activity, although less than during congestion, remained significantly above control, several C-fibers being stimulated by interstitial edema in the absence of alveolar edema. Bronchial C-fibers were stimulated in severely edematous lung showing pronounced peribronchial cuffing and alveolar edema, but were not stimulated in milder grades of edema. Our results support the hypothesis (Paintal, 1969) that pulmonary C-fibers (J-receptors) are stimulated by an increase in interstitial pressure secondary to edema.

Afferent pathways involved in reflex regulation of airway smooth muscle

Our purpose in the present review is to give an account of the various sensory regions from which reflex effects on airway smooth muscle are known to arise, with some reference to the nature of the sensory structures involved, where this is known. We deal first with intrinsic afferent inputs-intrinsic in the sense that they arise from the airways themselves, although for convenience the term has been extended to include the upper airways that do not contain airway smooth muscle-and then with extrinsic afferent inputs that arise from regions remote from the airways and lungs.

Operational sensitivity and acute resetting of aortic baroreceptors in dogs.

Stimulus-response curves of aortic baroreceptors constructed by alternately increasing and decreasing pressure from a normal baseline or set-point differ from curves constructed by varying pressure in one direction only from an abnormally high or low pressure. In anesthetized dogs we recorded impulses from aortic baroreceptors with myelinated fibers, using a pressurized reservoir to control mean aortic blood pressure (MABP). After setting MABP to a baseline of 100 mm Hg (normal MABP in unanesthetized dogs), we constructed baroreceptor response curves by alternately decreasing MABP from 100 to 30 mm Hg, and increasing it from 100 to 180 mm Hg, in each case returning MABP to the baseline to obtain hysteresis loops. All baroreceptors were active at 100 mm Hg, their discharge averaging 15–16 impulses/sec. At all pressures above threshold, baroreceptors fired more when pressure was increasing than when pressure was decreasing. This hysteresis caused the steepest part of the response curve constructed in this manner to span the baseline value, demonstrating that, contrary to previous views, aortic baroreceptors signal decreases in pressure below the normal level, as well as increases above it. We also constructed response curves after holding MABP at a “hyperten- sive” baseline of 125 mm Hg for 20 minutes. “Hypertensive” curves demonstrated reversible resetting, shifting significantly to the right of “normotensive” curves so that baroreceptor threshold increased on average by 7 mm Hg (P < 0.01). Both hysteresis and short-term resetting probably result from the viscoelastic behavior of wall elements with which baroreceptors are coupled.

Stimulation by bradykinin of afferent vagal C-fibers with chemosensitive endings in the heart and aorta of the dog.

Bradykinin applied directly to the epicardium evokes a reflex increase in blood pressure by stimulating sympathetic afferent nerve endings in the heart, but injected into the coronary artery it evokes vagally mediated reflex decreases in heart rate and blood pressure. The afferents initiating these latter depressor effects have not been identified. We have attempted to determine which vagal sensory nerve endings in the heart are stimulated by bradykinin. In anesthetized dogs, we recorded impulses from afferent vagal fibers with endings in the heart and aorta and injected bradykinin (0.3-1.0 /ig/kg) into the left atrium. Neither Anor C-fiber mechanoreceptors nor aortic body chemoreceptors were stimulated directly by bradykinin, any changes in firing of a trial or ventricular mechanoreceptors, or of aortic baroreceptors or chemoreceptors, being secondary to the cardiovascular effects of bradykinin. However, 16 of 20 irregularly discharging vagal C-fibers with chemosensitive endings in the left ventricle, left atrium, and aorta were stimulated by bradykinin; firing increased from 0.2 ± 0.1 to 7.8 ± 1.4 (mean ± SE) impulses/sec and usually remained above control for about 30 seconds. These chemosensitive endings were not stimulated by ventilating the lungs with 5% O2 in N2, but they were stimulated by injecting capsaicin or phenyl diguanide into the left atrium. Four chemosensitive endings in the ventricular epicardium were also stimulated by dripping bradykinin (1 pg/ml) onto the heart. We suggest that these chemosensitive vagal C-fibers are responsible for the reflex decreases in heart rate and blood pressure elicited by bradykinin. Circ Res 46: 476-484, 1980

Role of the pulmonary arterial baroreceptors in the effects produced by capsaicin in the dog

Capsaicin, a decylenic acid amide of vanillylamine, is the active principle in paprika (Cap8icum annuum) (Fig. 1). Although opinions differ about the effects produced by injection of capsaicin at different points in the systemic arterial circulation, there is general agreement that intravenous administration of capsaicin is followed by bradyeardia, hypotension and apnoea (P6rszasz, Gyorgy & Porszasz-Gibiszer, 1955; Toh, Lee & Kiang, 1955; Porszasz, Such & P6rszasz-Gibiszer, 1957; Bevan, 1962). While all these authors are agreed that these effects are produced reflexly via afferent vagal pathways, the particular sensory endings stimulated by

Comparison of the Effects of Histamine and Prostaglandin on Afferent C-Fiber Endings and Irritant Receptors in the Intrapulmonary Airways

Afferent vagal endings with non-myelinated axons are widely distributed in the lungs, where they are considerably more umerous than the endings of myelinated fibers. Until recently this group of C-fibers has been thought of as a single, functionally homogeneous afferent input. Action potential studies in both dogsl and cats2 indicated that chemicals injected into the bloodstream gained access to the endings through the pulmonary circulation, and Paintal2 obtained good evidence that they were situated near the pulmonary capillaires; he, therefore, named them “juxtapulmonary capillary receptors (type J receptors)”. When stimulated by chemicals, these endings give rise to the pulmonary chemoreflex triad of bradycardia, systemic vasodilatation and apnea.