Endothelin and Its Receptor Antagonists in Cardiovascular Disease.

Chronic heart failure is characterized by the failure of the cardiac pump function and activation of a neurohumoral axis. Endothelin appears to play a pivotal role in the pathophysiology of chronic heart failure. Plasma levels of endothelin-1, and its precursor big endothelin-1, are elevated in patients with chronic heart failure, and correlate with the clinical and hemodynamic severity of the disease. Endothelin-1, modulated by stress, catecholamines, angiotensin, and cytokines, induces vascular smooth cells and myocardial hypertrophy, increases pulmonary and peripheral resistance, and decreases renal sodium secretion. Two types of endothelin receptors, A and B, have been described. Activation of endothelin type A induces vasoconstriction, smooth muscle and myocardial cell proliferation, and platelet aggregation, whereas activation of endothelin type B receptors produces mainly vasodilation by stimulating the release of nitric oxide and prostacyclin by endothelial cells. Clinical trials showed marked hemodynamic, symptomatic, and prognostic amelioration with selective endothelin type A as well as mixed endothelin type A/endothelin type B receptor blockades when combined with conventional drugs. Endothelin receptor blockers may constitute a new option in the treatment of chronic heart failure. [ABSTRACT FROM AUTHOR]