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 function and structure by the production and release of several substances including nitric oxide and endothelins (ET). Nitric oxide is a labile substance produced from the catabolism of L-arginine and not only causes vessel relaxation, but also inhibits platelet aggregation, smooth muscle cell proliferation, 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 ET(A) and ET(B) receptors, which mainly mediate vasoconstriction, and endothelial ET(B) receptors, which oppose ET(A)- and ET(B)-mediated vasoconstriction by stimulating 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 dysfunction. In hypertensive patients nitric oxide availability is impaired because 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 normotensive controls, the ET-1-induced vasoconstriction is significantly blunted by intrabrachial indomethacin. Therefore, in normotensive subjects and essential hypertensives the vasoconstrictor effect of ET-1 seems to be dependent on different mechanisms. Moreover, in the peripheral circulation of normotensive subjects, where tonic nitric oxide production is preserved, unselective ET(A/B), receptor blockade by TAK-044 causes a very modest degree of vasodilation. In contrast in essential hypertensives, where the tonic nitric oxide production is reduced, the vasodilating effect of TAK-044 is more evident, indicating that the predominant vascular effect of endogenous ET-1 is the vasoconstriction. A possible explanation for this finding, in addition to an increased production of the peptide, could be related to a reduced ET(B) receptor-mediated nitric oxide activation. These peculiar aspects of the role of ET-1 in essential hypertension could have physiopathological relevance.
Taddei
S
S
Cattedra di Medicina Interna, Department of Internal Medicine, University of Pisa, Italy.
Virdis
A
A
Ghiadoni
L
L
Salvetti
A
A
D000818:Animals; D019332:Endothelin-1 / Q000502:physiology*; D016232:Endothelins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology*
D019332:Endothelin-1; D016232:Endothelins; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D011451:Prostaglandin-Endoperoxide Synthases