Pathophysiological Roles of Endothelin Receptors in Cardiovascular Diseases

Abstract

Endothelin (ET)-1 derived from endothelial cells has a much more important role in cardiovascular system regulation than the ET-2 and ET-3 isoforms. Numerous lines of evidence indicate that ET-1 possesses a number of biological activities leading to cardiovascular diseases (CVD) including hypertension and atherosclerosis. Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ET_A- and ET_B-receptor subtypes. Both subtypes on vascular smooth muscle cells mediate vasoconstriction, whereas the ET_B-receptor subtype on endothelial cells contributes to vasodilatation and ET-1 clearance. Although selective ET_A- or nonselective ET_A/ET_B-receptor antagonisms have been assumed as potential strategies for the treatment of several CVD based on clinical and animal experiments, it remains unclear which antagonisms are suitable for individuals with CVD because upregulation of the nitric oxide system via the ET_B receptor is responsible for vasoprotective effects such as vasodilatation and anti-cell proliferation. In this review, we have summarized the current understanding regarding the role of ET receptors, especially the ET_B receptor, in CVD.