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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 antago...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879375/ https://www.ncbi.nlm.nih.gov/pubmed/20532232 http://dx.doi.org/10.1371/journal.pone.0010917 |
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author | Meens, Merlijn J. P. M. T. Compeer, Matthijs G. Hackeng, Tilman M. van Zandvoort, Marc A. Janssen, Ben J. A. De Mey, Jo G. R. |
author_facet | Meens, Merlijn J. P. M. T. Compeer, Matthijs G. Hackeng, Tilman M. van Zandvoort, Marc A. Janssen, Ben J. A. De Mey, Jo G. R. |
author_sort | Meens, Merlijn J. P. M. T. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2879375 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28793752010-06-07 Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ET(A)-Receptor Complexes Meens, Merlijn J. P. M. T. Compeer, Matthijs G. Hackeng, Tilman M. van Zandvoort, Marc A. Janssen, Ben J. A. De Mey, Jo G. R. PLoS One Research Article 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. Public Library of Science 2010-06-01 /pmc/articles/PMC2879375/ /pubmed/20532232 http://dx.doi.org/10.1371/journal.pone.0010917 Text en Meens et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Meens, Merlijn J. P. M. T. Compeer, Matthijs G. Hackeng, Tilman M. van Zandvoort, Marc A. Janssen, Ben J. A. De Mey, Jo G. R. Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ET(A)-Receptor Complexes |
title | Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ET(A)-Receptor Complexes |
title_full | Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ET(A)-Receptor Complexes |
title_fullStr | Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ET(A)-Receptor Complexes |
title_full_unstemmed | Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ET(A)-Receptor Complexes |
title_short | Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ET(A)-Receptor Complexes |
title_sort | stimuli of sensory-motor nerves terminate arterial contractile effects of endothelin-1 by cgrp and dissociation of et-1/et(a)-receptor complexes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879375/ https://www.ncbi.nlm.nih.gov/pubmed/20532232 http://dx.doi.org/10.1371/journal.pone.0010917 |
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