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Endothelin-1 and Endothelin-3 Regulate Endothelin Receptor Expression in Rat Coronary Arteries.

Authors :
Skovsted GF
Kilic S
Edvinsson L
Source :
Basic & clinical pharmacology & toxicology [Basic Clin Pharmacol Toxicol] 2015 Nov; Vol. 117 (5), pp. 297-305. Date of Electronic Publication: 2015 May 18.
Publication Year :
2015

Abstract

In ischaemic hearts, endothelin (ET) levels are increased, and vasoconstrictor responses to ET-1 are greatly enhanced. We previously reported that ETB receptors are up-regulated in the smooth muscle layer of coronary arteries after myocardial ischaemia-reperfusion and that the MEK-ERK1/2 signalling pathway is involved in ETB receptor up-regulation. Whether ETs are directly involved in receptor regulation has not been determined. We suggest that ET-1 and ET-3 alter the expression/activity of ET receptors in coronary vascular smooth muscle cells. Vasoconstrictor responses were studied in endothelium-denuded coronary artery segments from rats that were subjected to experimental ischaemia-reperfusion or in organ-cultured segments. Post-ischaemic and cultured coronary arteries exhibited similar increased sensitivity to ET-3. ETA receptor-mediated vasoconstriction was dominant in fresh and non-ischaemic arteries. Organ culture significantly up-regulated ETB receptors and down-regulated ETA receptor expression. Co-incubation with ET-1 (1 nM) or ET-3 (100 nM) induced further down-regulation of the ETA receptor mRNA, while the function and protein level of ETA remained unchanged. ET-3 (100 nM) further up-regulated ETB receptor mRNA and proteins but abolished ETB receptor-mediated vasoconstriction, suggesting a desensitization of ETB receptors that was not observed with ET-3 (1 nM). In conclusion, ET-1, which is the most prevalent isoform in the cardiovascular system, induces down-regulation of ETA receptor expression without changing ETA or ETB receptor function or protein levels. Intermediate concentrations of ET-3 had an effect that was similar to that of ET-1, such that high concentrations of ET-3 (100 nM) up-regulated the ETB receptor at the gene and protein levels but switched off the function of the ETB receptors via desensitization.<br /> (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Details

Language :
English
ISSN :
1742-7843
Volume :
117
Issue :
5
Database :
MEDLINE
Journal :
Basic & clinical pharmacology & toxicology
Publication Type :
Academic Journal
Accession number :
25891848
Full Text :
https://doi.org/10.1111/bcpt.12407