A comparison of bradykinin‐ and capsaicin‐induced myocardial and coronary effects in isolated perfused heart of guinea‐pig: involvement of substance P and calcitonin gene‐related peptide release

Abstract

1 Bradykinin and capsaicin were compared for their ability to elicit functional effects and to release sensory neuropeptides from guinea-pig isolated perfused hearts. 2 Both bradykinin (1O/M) and capsaicin (1 pM) produced a marked increase in coronary flow, a large positive chronotropic effect and a significant reduction in contractile strength. These actions were associated with a marked release of substance P-like immunoreactivity (SP-LI) and calcitonin gene-related-like immunoreactivity (CGRP-LI). The percentage of the tissue content of SP-LI and CGRP-LI released by each agent was similar, although bradykinin was less effective than capsaicin. The ratio of SP-LI/CGRP-LI released by both agents was similar to that present in cardiac tissue. 3 Neuropeptide release could be evoked only once with capsaicin but at least four times with bradykinin. Also, functional responses to capsaicin underwent desensitization. After either in vitro or systemic capsaicin pretreatment, the release of SP-LI and CGRP-LI by bradykinin was reduced and the positive chronotropic effect of bradykinin was significantly reduced, while the increase in coronary flow and negative inotropic responses remained unchanged. 4 Pretreatment with indomethacin (10/M) strongly antagonized the release of SP-LI and CGRP-LI by bradykinin and reduced the increase in heart rate. 5 These findings suggest that activation by bradykinin (probably through indirect mechanisms) of capsaicin-sensitive sensory nerves in the heart, leads to a local release of sensory neuropeptides. These neuropeptides, in turn, could participate in determining the complex functional effects of this kinin on cardiac performance.

TRPV1 Gene Knockout Impairs Postischemic Recovery in Isolated Perfused Heart in Mice

“…We and others have previously shown that chronic afferent denervation induced by neonatal capsaicin treatment results in sensory nerve degeneration, which entails not only downregulation of the TRPV1 receptors but also depletion of sensory neuropeptides including CGRP and SP. 2,5,9,13,21,27,28 Thus, for any given changes resulting from capsaicin treatment, it is unknown whether the changes are caused by reduced release of sensory neuropeptides or decreased expression of the TRPV1 channels. In fact, sensory nerve degeneration induced by capsaicin is a quite nonspecific change that involves loss of an array of receptors, channels, and neuropeptides expressed in these nerves.…”

“…Given that the SP release was not directly measured from the perfusate because of technical difficulties and that the small number of samples per group was used because of the limited supply of TRPV1 Ϫ/Ϫ mice, however, the precise relationship of TRPV1 and SP release needs to be confirmed when more sophisticated 32 It is known that TRPV1 activation leads to release of neuropeptides such as SP, CGRP, and other neurokinins from sensory nerve terminals. 8,9,30,31 Among these sensory neuropeptides, CGRP exerts marked cardiostimulatory and coronary vasodilatory effects in pig and guinea pig hearts, 9,33 whereas SP appears to cause primarily coronary vasodilatation. 9,34 Our findings that exogenous CGRP and SP improve recovery after ischemia/reperfusion injury in WT and TRPV1…”

Effect of bradykinin and prostaglandins on the release of calcitonin gene‐related peptide‐like immunoreactivity from the rat spinal cord in vitro

“…On the other hand, the B2-receptor antagonist, Hoel40 (Hock et al, 1991) inhibited the action of bradykinin, indicating that the facilitation of CGRP-LI release is mediated by B2-receptors, as are all of the hitherto reported actions of bradykinin on sensory neurones (see Steranka et al, 1988;Dray et al, 1988;Burgess et al, 1989a;Dunn & Rang, 1990 (Juan & Lembeck, 1974;Weinreich, 1986;Manzini et al, 1989;Geppetti et al, 1990a;1991) and that bradykinin, acting via B2-receptors, evoked the release of prostaglandins from various tissues and cell lines (Lembeck et al, 1976;Sametz & Juan, 1982;Bareis et al, 1983;Gammon et al, 1989). The effect of indomethacin in our studies, and the ability of various prostaglandins to mimic the action of bradykinin, suggests that the effect of bradykinin was secondary to prostaglandin release.…”

Arachidonic acid‐induced bronchomotor responses are partially mediated by release of sensory neuropeptides from capsaicin‐sensitive structures

“…In some tissues prostanoids have been shown to stimulate capsaicin-sensitive-structures (Yanagisawa et al, 1986;Longhurst & Dittman, 1987;Manzini et al, 1989) and Stewart et al (1984) showed that leukotriene D4 enhances histamine-induced bronchoconstriction through a mechanism involving capsaicin-sensitive afferent fibres. Eicosanoid (mainly leukotrienes)-mediated bronchomotor responses can be elicited by exogenous administration of arachidonic acid (AA) (Burka, 1985).…”

“…Superfusates were collected every 3 min in tubes containing enough acetic acid to give a final concentration of 2N. Calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) was assayed as previously described (Manzini et al, 1989 In isolated bronchi, AA (1 mM) produced at most, weak bronchomotor effects (n = 8). However, in the presence of the cyclo-oxygenase inhibitor indomethacin (10gM), AA consistently elicited a sustained contraction the amplitude of which, at steady state, was 316 + 26mg (n = 18).…”