Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries |
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Authors: | Saurabh Gupta Jair Lozano-Cuenca Carlos M Villalón René de Vries Ingrid M Garrelds Cees J J Avezaat Jorge P van Kats Pramod R Saxena Antoinette MaassenVanDenBrink |
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Institution: | (1) Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands;(2) Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, C.P. 14330 Mexico D.F., Mexico;(3) Department of Neurosurgery, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands;(4) Thoracic Surgery and Heart Valve Bank, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands |
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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 NK1 receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor
antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor N
ω-nitro-l-arginine 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 above-mentioned 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, NK1, 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. |
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Keywords: | Capsaicin CGRP Human coronary artery Human meningeal artery Porcine coronary artery |
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