Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries

Abstract

Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK 1 receptor antagonist L-733060 (0.5 μM), the voltagesensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor N ω -nitro-Larginine methyl ester HCl (L-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K + channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM)+apamin (0.1 μM) and iberiotoxin (0.5 μM)+apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the abovementioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK 1 , NO, vanilloid receptors, voltage-sensitive calcium channels, K + channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.

Role of sensory C fibers in hypoxia/reoxygenation-impaired myogenic constriction of cerebral arteries

“…Although acute exposure to capsaicin activates sensory nerve C-fibers via TRPV1 to release neuropeptides, like calcitonin gene-related peptide and substance P, prolonged exposure to capsaicin, as the protocol applied in studies of our own and others, results in desensitization of the nerve ending to further activation17,18. Noticeably, capsaicin-sensitive nerves are widely distributed in the vasculature of humans and animals19,20. Our findings from cerebral arteries are consistent with the studies of Scotland et al 7.…”

Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception

“…TRPA1, like TRPV1, is expressed in neurons innervating blood vessels, and selective activation of TRPA1 can induce vasodilation via the release of CGRP (50,62). Proton-induced CGRP release has been shown to be exclusively mediated via TRPV1 activation (20,50,62). TRPV1 can release CGRP in response to ischemia-induced decrease in pH, however, the block of TRPA1 by protons could negatively modulate CGRP release.…”

Activation of TRPV1 by Dietary Capsaicin Improves Endothelium-Dependent Vasorelaxation and Prevents Hypertension

“…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). In addition, neonatal denervation of sensory nerves does not modify the NO release elicited by capsaicin, indicating that perivascular nerve fibers probably do not participate in capsaicin-induced relaxation (Rocha and Bendhack, 2009).…”

“…TRPV1, a polymodal nonselective cation channel, is expressed in sensory neurons and also present in nonneuronal tissues including blood vessels (Nilius, 2007; Pedersen et al, 2005; Vennekens et al, 2008). Apart from its role as a potent analgesic (Caterina et al, 2000), capsaicin exerts effects in the cardiovascular system (Gupta et al, 2007; Pacher et al, 2004). However, the effects of capsaicin on vascular tone and arterial pressure are a paradox.…”