Endothelin in atherosclerosis: Importance of risk factors and therapeutic implications

Endothelin (ET)-1, a potent vasoconstrictor peptide, is primarily released abluminally from endothelial cells and exerts its biological effect through the activation of specific ET receptors. Endothelin subtype A receptors (E TA) are involved in constriction and proliferation of vascular smooth muscl e cells, whereas endothelin subtype B receptors (ETB) on endothelial cells mediate the formation of nitric oxide, which acts as vasodilator and inhibi ts platelet aggregation. Cardiovascular risk factors such as hypertension a nd aging, as well as hypercholesterolemia, which are precursors of atherosc lerosis, and elevated ET-1 levels are found. The best approach to determine the contribution of endogenous ET to vascular structural and functional al terations can be achieved by chronic inhibition of ET receptors with ET rec eptor antagonists. Recent studies showed favourable effects of selective ET A - antagonists on vascular alterations in different experimental models of hypertension, hypercholesterolemia and atherosclerosis, suggesting that ac tivation of the local ET system importantly contributes to endothelial dysf unction and vascular remodeling, mainly through ETA receptors. Chronic bloc kade of ETA receptors may be a new therapeutic approach for the treatment o f atherosclerosis and its risk factors.