Myocardial effects of endothelin-1

Abstract

Endothelin (ET)-1 was originally identified in 1988 as a vasoconstrictor peptide produced by vascular endothelial cells. It is now known that ET-1 can be produced by vascular and endocardial endothelium and by myocardial cells. Activation of endothelin receptors modulates a wide variety of biological processes including vascular tone, growth and myocardial contractile function. In mammals, ET-1's effects are mediated through binding to two types of receptors, ET(A) and ET(B). ET(A) receptor activation elicits vasoconstriction, positive inotropism and mitogenesis, and acutely increases myocardial distensibility. ET(B) receptor stimulation generally promotes vasodilatation, mediated by release of nitric oxide and prostacyclins, growth-inhibitory effects and clearance of ET-1 from the circulation. ET(B) receptors can be further subdivided into ET(B1), located in endothelial cells and responsible for vasodilatation and negative inotropic effects, and ET(B2), located in smooth muscle and myocardial cells and responsible for vasoconstriction and positive inotropic effects. Increased levels of cardiac and circulating ET-1 have been linked to development of cardiac dysfunction and severity of heart failure. This has fueled research into the development of endothelin antagonists (ET receptor and converting enzyme inhibitors) in view of the potential benefits that might derive from their use in clinical practice. The present review will focus on current understanding of the mechanisms mediating the myocardial actions of ET-1.