Functional and biochemical evidence for capsaicin-induced neural endothelin release in isolated working rat heart
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.
References (36)
- et al.
In vitro effect of capsaicin: antiarrhythmic and antiischemic activity
Eur. J. Pharmacol.
(1995) - et al.
Endothelin as a putative sensory neuropeptide in the guinea pig: different properties in comparison with calcitonin gene-related peptide
Regul. Pept.
(1991) - et al.
Co-existence of substance P and calcitonin gene-related peptide-like immunoreactivities in sensory nerves in relation to cardiovascular and bronchoconstrictor effects of capsaicin
Eur. J. Pharmacol.
(1985) Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves
Prog. Neurobiol.
(1995)Endothelin receptor antagonism
Adv. Pharmacol.
(1995)- et al.
Interaction between capsaicin and nitrate tolerance in isolated guinea-pig heart
Eur. J. Pharmacol.
(1999) Capsaicin-sensitive sensory nerve terminals with local and systemic efferent functions: facts and scopes of an unorthodox neuroregulatory mechanism
Prog. Brain Res.
(1996)- et al.
Endothelin release by capsaicin in isolated working rat heart
Eur. J. Pharmacol.
(1999) - et al.
DMPO and reperfusion injury: arrhythmia, heart function, electron spin resonance, and nuclear magnetic resonance studies in isolated working guinea pig hearts
Am. Heart. J.
(1990) - et al.
Adenosine triphosphate-sensitive potassium channel blocking agent ameliorates, but the opening agent aggravates, ischemia/reperfusion-induced injury: heart function studies in nonfibrillating isolated hearts
J. Am. Coll. Cardiol.
(1994)
Capsaicin induces a depletion of CGRP-immunoreactive nerves in the cardiovascular system of the guinea pig and rat
J. Auton. Nerv. Syst.
Role of endothelin-A receptors in ischemic contracture and reperfusion injury
Circulation
Role of endothelin, nitric oxide and L-arginine release in ischemia/reperfusion injury of rat heart
Cardiovasc. Res.
The capsaicin receptor: a heat-activated ion channel in the pain pathway
Nature
Endothelin-1 inhibits L-type Ca2+ current enhanced by isoprenalin in rat atrial myocytes
J. Cardiovasc. Pharmacol.
Capsaicin-sensitive local sensory innervation is involved in pacing-induced preconditioning in rat hearts: role of nitric oxide and CGRP?
Naunyn-Schmiedeberg's Arch. Pharmacol.
Calcitonin gene-related peptide and tachykinins in relation to local sensory control of cardiac contractility and coronary vascular tone
Acta Physiol. Scand.
CGRP and capsaicin-induced stimulation of heart contractile force and rate
Naunyn-Schmiedeberg's Arch. Pharmacol.
Cited by (29)
Reversible Cerebral Vasoconstriction Syndrome Following Exposure to Oleoresin Capsicum “Pepper Spray”
2021, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :The vasoactive role of arterial injection of capsaicin has been demonstrated by the Bezold-Jarisch reflex through activation of these capsaicin receptors.16 Furthermore, capsaicin leads to a concentration-dependent constriction of the coronary arteries and decreased coronary flow by acting on Vanilloid Receptor1 (VR1) capsaicin receptors and by endothelin release from sensory nerve terminals as documented in an isolated beating rat's heart.17 It could be postulated that similar receptors may be present in intracranial vasculature.
Riot control agents
2020, Handbook of Toxicology of Chemical Warfare AgentsMechanisms underlying the hypertensive response induced by capsaicin
2010, International Journal of CardiologyCitation Excerpt :Thus, the hypertensive effect may be due to the direct action of capsaicin as discussed earlier [4]. Recently capsaicin is shown to release endothelin from sensory nerve terminals [3]. Endothelin, a peptide known to produce severe vasoconstriction thus can be a potential agent to mediate the capsaicin-induced hypertension.
Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension
2010, Cell MetabolismCitation Excerpt :Capsaicin may exert direct effects on the vasculature, relaxing coronary, mesenteric, hepatic, basilar, and meningeal arteries of pigs and rats (Bratz et al., 2008; Lo et al., 2003). However, it has also been reported that activation of TRPV1 can cause vasoconstriction in mesenteric (Scotland et al., 2004), coronary (Szolcsanyi et al., 2001), and skeletal muscle arteries (Kark et al., 2008) in rodents and canines. Furthermore, capsaicin-induced relaxation of human and porcine coronary arteries is likely to be attributed to a CGRP-independent mechanism (Gupta et al., 2007).
Endothelin Receptors and Pain
2009, Journal of PainCitation Excerpt :ET-1 is derived from various cells in skin: keratinocytes,244 vascular endothelial cells,262 immune cells,61,217 and mast cells.62 Sensory afferents themselves72,77,234 and satellite cells of DRG124 contain ET-1. Thus, both cells of the skin and those that innervate it may release ET-1 in normal and pathological conditions.
Capsaicin-induced nonneural vasoconstriction in canine mesenteric arteries
2002, European Journal of Pharmacology