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


RESULTS
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.
Meens
Merlijn J P M T
MJ
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Compeer
Matthijs G
MG
Hackeng
Tilman M
TM
van Zandvoort
Marc A
MA
Janssen
Ben J A
BJ
De Mey
Jo G R
JG
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects*
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D015740:Calcitonin Gene-Related Peptide