Endothelin‐1 and Endothelin‐3 Regulate Endothelin Receptor Expression in Rat Coronary Arteries

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–ERK1/2 signalling pathway is involved in ET_B 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. 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.