Stimuli of sensory-motor nerves terminate arterial contractile effects of endothelin-1 by CGRP and dissociation of ET-1/ET(A)-receptor complexes

Merlijn J P M T Meens, Matthijs G Compeer, Tilman M Hackeng, Marc A van Zandvoort, Ben J A Janssen, Jo G R De Mey

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

BACKGROUND: Endothelin-1 (ET-1), a long-acting paracrine mediator, is implicated in cardiovascular diseases but clinical trials with ET-receptor antagonists were not successful in some areas. We tested whether the quasi-irreversible receptor-binding of ET-1 (i) limits reversing effects of the antagonists and (ii) can be selectively dissociated by an endogenous counterbalancing mechanism.

METHODOLOGY/PRINCIPAL FINDINGS: In isolated rat mesenteric resistance arteries, ET(A)-antagonists, endothelium-derived relaxing factors and synthetic vasodilators transiently reduced contractile effects of ET-1 but did not prevent persistent effects of the peptide. Stimuli of peri-vascular vasodilator sensory-motor nerves such as capsaicin not only reduced but also terminated long-lasting effects of ET-1. This was prevented by CGRP-receptor antagonists and was mimicked by exogenous calcitonin gene-related peptide (CGRP). Using 2-photon laser scanning microscopy in vital intact arteries, capsaicin and CGRP, but not ET(A)-antagonism, were observed to promote dissociation of pre-existing ET-1/ET(A)-receptor complexes.

CONCLUSIONS: Irreversible binding and activation of ET(A)-receptors by ET-1 (i) occur at an antagonist-insensitive site of the receptor and (ii) are selectively terminated by endogenously released CGRP. Hence, natural stimuli of sensory-motor nerves that stimulate release of endogenous CGRP can be considered for therapy of diseases involving ET-1.

OriginalsprogEngelsk
Artikelnummere10917
TidsskriftPLOS ONE
Vol/bind5
Udgave nummer6
ISSN1932-6203
DOI
StatusUdgivet - 2010
Udgivet eksterntJa

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