Functional and biochemical evidence for capsaicin-induced neural endothelin release in isolated working rat heart

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Abstract

In isolated working rat heart, capsaicin elicited a concentration-dependent constriction of coronary arteries accompanied by decline of all cardiac parameters recorded (heart rate, coronary and aortic flow, left ventricular developed pressure, and first derivative of left ventricular developed pressure). The following evidence suggests that capsaicin-induced changes are mediated by endothelin of neural origin: (1) the capsaicin (10 nM)-evoked decrease in coronary flow resulting in deterioration of cardiac functions was mimicked by endothelin (0.1 nM); (2) the selective endothelin ETA receptor antagonist, cyclo (d-α-aspartyl-l-propyl-d-valyl-l-leucyl-d-tryptophyl) (1 μM), abolished the cardiac effects provoked by capsaicin (10 nM); (3) reduction of extracellular Ca2+ concentration from 2.4 to 1.2 or 0.6 mM inhibited the cardiac effects of capsaicin (10 nM) but not those induced by endothelin (0.1 nM); (4) perfusion of the heart with 0.1% (v/v) Triton X-100 damaged the endothelium and reversed the enhancement of coronary flow evoked by bethanechol (1 μM), decreased the basal flow, but was without effect on capsaicin-induced coronary constriction; (5) in response to capsaicin challenge (10–100 nM), the endothelin concentration measured in coronary effluent by means of radioimmunoassay increased up to sevenfold but remained unchanged in the presence of 0.6 mM Ca2+; (6) no reduction of coronary flow was induced by capsaicin (100 nM) applied to the heart of rats which were desensitised by capsaicin (150 mg/kg). It is concluded that, in the rat heart, capsaicin acting on VR1 capsaicin receptors elicits a release of endothelin from the sensory nerve terminals.

Introduction

Capsaicin, the pungent principle of red pepper due to its selective site of action on a subset of primary afferent neurones Holzer, 1991, Szolcsányi, 1993, Maggi, 1995, Caterina et al., 1997, has become a valuable tool to reveal the function of the afferents. Activation of capsaicin-sensitive nociceptive, heat-sensitive and chemoceptive nerve endings (Szolcsányi, 1993) results in release of a variety of sensory neuropeptides, particularly tachykinins and calcitonin gene-related peptide (CGRP) which elicit various local tissue responses Holzer, 1991, Maggi, 1995, Lundberg, 1996, Szolcsányi, 1996. The myocardium and coronary vessels are richly innervated by sensory neuropeptide-containing primary afferent neurones sensitive to capsaicin Lundberg et al., 1985, Saito et al., 1986, Wharton et al., 1986, Maggi, 1995, Lundberg, 1996. Although the neuropeptide-releasing effects of capsaicin have been studied and well characterised in a wide variety of tissues, our knowledge concerning the capsaicin-elicited responses in the heart and coronary vessels is relatively sparse. The acute effects of capsaicin have been analysed in detail for the guinea-pig isolated perfused heart Franco-Cereceda, 1988, Franco-Cereceda and Lundberg, 1985, Franco-Cereceda et al., 1991a, Oroszi et al., 1999 or the guinea-pig isolated atria Fukuda and Fujiwara, 1969, Molnar et al., 1969, Franco-Cereceda, 1988, Maggi, 1995, Lundberg, 1996. Surprisingly, regarding rat heart, few data are available for the acute effects of capsaicin although studies on isolated perfused heart obtained from capsaicin-pretreated rats raised the issue of an important adaptive role in cardioprotection for CGRP and nitric oxide (NO) released from capsaicin-sensitive afferents Ferdinandy et al., 1997, Song et al., 1999. In the rat, positive inotropic and chronotropic effects of capsaicin were described in the isolated atrial preparation similar to those seen with hearts from the guinea-pig and have been attributed to the release of sensory neuropeptide CGRP Franco-Cereceda, 1988, Maggi, 1995, Lundberg, 1996. Recently, however, we observed that capsaicin applied to the isolated working rat heart induced a decrease in coronary and aortic flow with negative inotropic effects resembling the action of endothelin (Szolcsányi et al., 1999). The present aim was to shed light on the mechanism of capsaicin action on the isolated working rat heart. Particular emphasis was put on providing evidence for the hypothesis that capsaicin induced a release of endothelin from sensory nerve endings. It seemed to be important since, in spite of some histochemical data indicating the existence of endothelin in perivascular nerve fibres Giaid et al., 1989, Franco-Cereceda et al., 1991b, Loesch et al., 1998, the presence of endothelin in capsaicin-sensitive sensory neurones or its release from sensory nerve endings in general has not yet been shown Holzer, 1991, Maggi, 1995, Szolcsányi, 1996, Lundberg, 1996.

Section snippets

Animals

Male Sprague–Dawley rats (320–350 g body weight) were used for the experiments. The experimental protocols applied conformed to the European Community guiding principles for the care and use of laboratory animals and were approved by the local ethical committee of the University of Pecs, Hungary.

Isolated working heart preparation

Rats were anaesthetised with diethyl ether and then intravenous heparin (500 IU/kg) was given. After thoracotomy, the heart was excised and placed in ice-cold perfusion buffer. Immediately after

Effects of reduced extracellular Ca2+ concentration on cardiac responses evoked by capsaicin or endothelin

In these studies, the extracellular Ca2+ concentration was reduced from its control value of 2.4–1.2 or 0.6 mM in the presence of 10 nM capsaicin. The capsaicin concentration was selected according to the dose–response curve from the previous experiments. These alterations in extracellular Ca2+ concentrations did not produce any significant change in baseline heart rate, coronary flow, aortic flow, left ventricular developed pressure and first derivative of left ventricular developed pressure

Discussion

The present findings confirm our previous results (Szolcsányi et al., 1999) that capsaicin at nanomolar concentrations markedly diminishes coronary flow, resulting in deterioration of all cardiac functions in the isolated working rat heart. The following experimental data support the concept that the effects observed are due to release of endothelin. (1) Direct radioimmunoassay determination revealed that capsaicin perfusion at low concentrations (10–100 nM) increased the endothelin level in

Acknowledgements

This work was supported by Hungarian Grants: OTKA: T-030766, T-029428, T-032002 and T-032008; ETT: T-04032/99, T-03031/99, T-03011/99 and T-04367/2000; AKP: 98-523.2; the Hungarian Academy of Sciences, and the Volkswagen Stiftung, Berlin, Germany. We thank Mrs. Csilla Zador for expert technical assistance.

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