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Endothelin‐1 and Endothelin‐3 Regulate Endothelin Receptor Expression in Rat Coronary Arteries
Author(s) -
Skovsted Gry Freja,
Kilic Semsi,
Edvinsson Lars
Publication year - 2015
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12407
Subject(s) - endothelin receptor , receptor , vasoconstriction , medicine , endocrinology , endothelin 1 , vascular smooth muscle , coronary arteries , endothelium , biology , chemistry , artery , smooth muscle
In ischaemic hearts, endothelin ( ET ) levels are increased, and vasoconstrictor responses to ET ‐1 are greatly enhanced. We previously reported that ET B receptors are up‐regulated in the smooth muscle layer of coronary arteries after myocardial ischaemia–reperfusion and that the MEK – ERK 1/2 signalling pathway is involved in ET B receptor up‐regulation. Whether ET s 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. ET A receptor‐mediated vasoconstriction was dominant in fresh and non‐ischaemic arteries. Organ culture significantly up‐regulated ET B receptors and down‐regulated ET A receptor expression. Co‐incubation with ET ‐1 (1 nM) or ET ‐3 (100 nM) induced further down‐regulation of the ET A receptor mRNA , while the function and protein level of ET A remained unchanged. ET ‐3 (100 nM) further up‐regulated ET B receptor mRNA and proteins but abolished ET B receptor‐mediated vasoconstriction, suggesting a desensitization of ET B 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 ET A receptor expression without changing ET A or ET B 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 ET B receptor at the gene and protein levels but switched off the function of the ET B receptors via desensitization.

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