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...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2879375?pdf=render |
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| author | 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 |
| author_facet | 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 |
| author_sort | Merlijn J P M T Meens |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T21:35:26Z |
| format | Article |
| id | doaj.art-362b3f3584494c208b7774510d6e5d4f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T21:35:26Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-362b3f3584494c208b7774510d6e5d4f2022-12-22T03:15:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0156e1091710.1371/journal.pone.0010917Stimuli 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 MeensMatthijs G CompeerTilman M HackengMarc A van ZandvoortBen J A JanssenJo G R De MeyBACKGROUND: 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.http://europepmc.org/articles/PMC2879375?pdf=render |
| spellingShingle | 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 Stimuli of sensory-motor nerves terminate arterial contractile effects of endothelin-1 by CGRP and dissociation of ET-1/ET(A)-receptor complexes. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC2879375?pdf=render |
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