Vasoconstriction to endogenous endothelin-1 is increased in the peripheralcirculation of patients with essential hypertension

Background-In humans, endothelin (ET)-1 could be implicated in the pathophy siology of several cardiovascular diseases, including essential hypertensio n. We therefore evaluated the role of ET-1 in control of vascular tone in e ssential hypertension. Methods and Results-We used strain-gauge venous plethysmography to test cha nges in forearm blood Row induced by intrabrachial infusion of TAK-044 (10, 30, and 100 mu g.100 mL(-1).min(-1)), an ETA/ETB receptor antagonist, or s odium nitroprusside (1 and 2 mu g.100 mL(-1).min(-1)), a vasodilator that a cts on smooth muscle cells, in hypertensive patients and healthy controls ( n=10 in each group). The NO pathway was also evaluated by infusion of N-G-m onomethyl-L-arginine, (L-NMMA; 10, 30, and 100 mu g.100 mL(-1) min(-1)), an NO synthase inhibitor, and nonpinephrine (3, 9, and 30 ng.100 mL(-1).min(- 1)) as control. Immunoreactive plasma ET-I was measured by radioimmunoassay . In hypertensive patients, TAK-044 caused a vasodilation that was signific antly (P<0.01) increased compared with normotensive subjects. Moreover, vas oconstriction to L-NMMA was significantly (P<0.01) decreased in hypertensiv e patients compared with controls. In contrast, the vascular responses to s odium nitroprusside and norepinephrine, as well as levels of immunoreactive plasma ET-1, were similar in hypertensive patients and controls. In the st udy population, vasodilation to TAK-044 and vasoconstriction to L-NMMA show ed an inverse correlation (r = -0.56, P<0.05). Conclusions-These results indicate that TAK-044 caused a greater degree of vasodilation in the forearm vessels of essential hypertensive patients comp ared with normotensive subjects, an alteration associated with decreased to nic NO release.