Endothelins - clinical perspectives

Endothelins (ET) are a group of endogenous peptides, which have a strong and long-lasting vasocon-strictive effect. Three isoforms of endothelins coded by three different genes have been identified to date. Endothelin-1 (ET-1) is the most potent vasoconstrictive agent currently identified, and it was originally isolated and characterized from the culture media of aortic endothelial cells. Two other iso-forms, named endothelin-2 (ET-2) and endothelin-3 (ET-3), were subsequently identified, along with structural homologues isolated from the venom of Actractapis engaddensis known as the sarafotoxins. The biological effects of endothelin production are determined via activation of one or two G-protein coupled receptors, endothelin receptors A (ETRA) and B (ETRB1 and ETRB2). Recently endothelin receptor C (ETRC) was discovered, however, its functions and distribution still remain unclear. The effects mediated by ET-1 via ETRA are vasoconstriction, bronchoconstriction and secretion of aldosterone. Agonists related to the ETRB1 activation cause vasodilatation by stimu-lating NO, PGI2 and endothelium-derived hyperpolarizing factor (EDHF). In contrast, coupling to ETRB2 causes vasoconstriction. Involvement of ET has been demonstrated in the pathophysiology of certain disorders. In this review, we discuss the physiological and pathophysiological role of endothe-lium-derived ET-1, the pharmacology of its two receptors, focusing on the role of ET-1 in the develo-pment of some pathophysiological conditions