Vascular effects of endothelin-1 in essential hypertension: Relationship with cyclooxygenase-derived endothelium-dependent contracting factors and nitric oxide

Endothelium plays a primary role in the local modulation of vascular functi on and structure by the production and release of several substances includ ing nitric oxide and endothelins (ET). Nitric oxide is a labile substance p roduced from the catabolism of L-arginine and not only causes vessel relaxa tion, but also inhibits platelet aggregation, smooth muscle cell proliferat ion, monocyte adhesion, adhesion molecules expression and endothelin-1 (ET- 1) production. Endothelium-derived ET-1 is a potent vasoconstrictor and has inotropic and mitogenic properties. ET-1 acts through smooth muscle ETA an d ETB receptors, which mainly mediate vasoconstriction, and endothelial ETB receptors, which oppose ETA- and ETB-mediated vasoconstriction by stimulat ing nitric oxide formation. Both nitric oxide and ET-1 play a crucial role in the cardiovascular physiology and an alteration of these systems can be a promoter of or be associated with most cardiovascular diseases. Essential hypertension is a pathological condition characterized by endothelial dysf unction. In hypertensive patients nitric oxide availability is impaired bec ause of the production of cyclooxygenase-derived vasoconstrictor substances . The latter may also mediate the vasoconstrictor response to exogenous ET- 1 because in forearm circulation of essential hypertensives, but not of nor motensive controls, the ET-l-induced vasoconstriction is significantly blun ted by intrabrachial indomethacin. Therefore, in normotensive subjects and essential hypertensives the vasoconstrictor effect of ET-1 seems to be depe ndent on different mechanisms. Moreover, in the peripheral circulation of n ormotensive subjects, where tonic nitric oxide production is preserved, uns elective ETA/B receptor blockade by TAK-044 causes a very modest degree of vasodilation. In contrast in essential hypertensives, where the tonic nitri c oxide production is reduced, the vasodilating effect of TAK-044 is more e vident, indicating that the predominant vascular effect of endogenous ET-1 is the vasoconstriction. A possible explanation for this finding, in additi on to an increased production of the peptide, could be related to a reduced ETB receptor-mediated nitric oxide activation. These peculiar aspects of t he role of ET-1 in essential hypertension could have physiopathological rel evance.