Endothelin receptor antagonists in congestive heart failure: A new therapeutic principle for the future?

Congestive heart failure (CHF) is characterized by impaired left ventricula r function, increased peripheral and pulmonary vascular resistance acid red uced exercise tolerance and dyspnea. Thus, mediators involved in the contro l of myocardial function and vascular tune may be involved in its pathophys iology. The family of endothelins (ET) consists of four closely related pep tides, ET-1, ET-2, ET-3 and ET-4, which cause vasoconstriction, cell prolif eration and myocardial effects through activation of ETA receptors. In cont rast, endothelial ETB receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ETB receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ETA-rec eptor antagonist into the brachial artery in healthy humans leads to vasodi lation, whereas infusion of an ETB-receptor antagonist causes vasoconstrict ion. Endothelin-1 plasma levels are elevated in CHF and correlate both with hemodynamic severity and symptoms. Plasma levels of ET-1 and its precursor , big ET-1, are strong independent predictors of death after myocardial inf arction as well as in CHF. Endothelin-1 contributes to increased systemic a nd pulmonary vascular resistance, vascular dysfunction, myocardial ischemia and renal impairment in CHF. Selective ETA, as well as combined ETA/B-rece ptor antagonists, have been studied in patients with CHF, and their use has shown impressive hemodynamic improvement (i.e., reduced peripheral vascula r and pulmonary resistance as well as increased cardiac output). These resu lts indicate that ET-receptor antagonists, indeed, have a potential to impr ove hemodynamics, symptoms and, potentially, prognosis in patients with CHF , which still carries a high mortality. (J Am Coll Cardiol 2001;37:1493-505 ) (C) 2001 by the American College of Cardiology.