Vasoconstriction to Endogenous Endothelin-1 Is Increased in the Peripheral Circulation of Patients With Essential Hypertension

Abstract

Background —In humans, endothelin (ET)-1 could be implicated in the pathophysiology of several cardiovascular diseases, including essential hypertension. We therefore evaluated the role of ET-1 in control of vascular tone in essential hypertension. Methods and Results —We used strain-gauge venous plethysmography to test changes in forearm blood flow induced by intrabrachial infusion of TAK-044 (10, 30, and 100 μg · 100 mL −1 · min −1 ), an ET A /ET B receptor antagonist, or sodium nitroprusside (1 and 2 μg · 100 mL −1 · min −1 ), a vasodilator that acts 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 -monomethyl- l -arginine, (L-NMMA; 10, 30, and 100 μg · 100 mL −1 · min −1 ), an NO synthase inhibitor, and norepinephrine (3, 9, and 30 ng · 100 mL −1 · min −1 ) as control. Immunoreactive plasma ET-1 was measured by radioimmunoassay. In hypertensive patients, TAK-044 caused a vasodilation that was significantly ( P <0.01) increased compared with normotensive subjects. Moreover, vasoconstriction to L-NMMA was significantly ( P <0.01) decreased in hypertensive patients compared with controls. In contrast, the vascular responses to sodium nitroprusside and norepinephrine, as well as levels of immunoreactive plasma ET-1, were similar in hypertensive patients and controls. In the study population, vasodilation to TAK-044 and vasoconstriction to L-NMMA showed 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 compared with normotensive subjects, an alteration associated with decreased tonic NO release.