The Role of Endothelin in Congestive Heart Failure

Endothelin (ET) is an endothelium-derived peptide that produces sustained contraction of arterial and venous vascular smooth muscle in vitro [1, a]. The endothelins which are comprised of three distinct isoforms, ET-1, ET-2, and ET-3 are widely distributed and mediate their biological actions by interacting with at least two receptors which have been cloned and well characterized [3, 4]. The endothelin-A (ETA) receptor which is widely distributed and preferentially expressed in vascular smooth muscle cells mediates potent vasoconstrictor actions and binds preferentially the ET-1 isoform [5]. The endothelin-B (ETB) receptor which is preferentially expressed in vascular endothelial cells and binds all three identified endothelin isoforms, ET-1, ET-2, and ET-3, and when activated releases nitric oxide and prostacyclin [5]. Studies have also demonstrated in vitro that ET may enhance smooth muscle and cardiac cell growth supporting a role for ET in cell hypertrophy [6, 7]. In vivo investigations have repeatedly established that pharmacologic concentrations of ET result in potent coronary, renal and systemic vasoconstriction associated with activation of the renin-angiotensin-aldosterone system (RAAS) [8, 9]. Such actions are consistent with a role for ET as an important cardiovascular regulatory peptide of endothelial origin.