Endothelin and cardiovascular regulation

Endothelin-1 is a potent vasoconstrictor, pressor and growth promoting peptide produced by vascular endothelial cells by the action of a unique metalloprotease, endothelin converting enzyme (ECE), on its precursor big endothelin-1. In humans, local infusion studies in the forearm and hand veins have shown that endothelin-1 can act on ETA and ETB receptors in vascular smooth muscle to cause vasoconstriction and venoconstriction, and on ETB receptors in endothelial cells to modulate constriction through generation of endothelial dilators, including prostacyclin and nitric oxide. Studies with the ETA receptor antagonist, BQ-123, and the ECE inhibitor, phosphoramidon, show that ECE is present in forearm but not hand veins, and that endothelin-1 plays a crucial role in regulation of basal tone in resistance vessels. Systemic studies with endothelin receptor antagonists in healthy subjects confirm these findings, showing that endothelin-1 acts to maintain peripheral vascular resistance and blood pressure. Endothelin-1 mediated venoconstriction is greater in patients with essential hypertension than in matched controls, and sympathetically mediated venoconstriction is enhanced by endothelin-1 in hypertensive but not control subjects. Recent studies with ETA receptor antagonists show that they are effective vasodilators in patients with untreated hypertension, and diuretic and ACE inhibitor treated heart failure. However, antagonists at both ETA and ETB receptors may be needed to fully block the vasoconstriction to endothelin-1. These novel drugs show much promise in the treatment of hypertension