Endothelin-1 and Vascular Tone in Subjects With Atherogenic Risk Factors

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor that increases vascular tone in the resistance vessels of subjects with hypertension. It is unclear whether endogenous ET-1 affects resistance-vessel function equally in patients with other cardiovascular risk factors. Vasoconstriction to ET-1 is mediated principally via the endothelin-A (ET A ) receptor on vascular smooth muscle cells. Accordingly, we used an ET A -specific antagonist, BQ-123, to test the hypothesis that endogenous ET-1 increases vascular resistance selectively in subjects with hypertension compared with other risk factors. BQ-123 was infused at 100 nmol/min for 80 minutes into the brachial artery of 10 subjects with hypertension (mean±SEM arterial pressure, 106±5 mm Hg), 12 subjects with hypercholesterolemia (mean±SEM total cholesterol, 7.1±0.2 mmol/L), 10 active smokers (mean±SEM, 42±11 pack-years), and 11 healthy, age-matched individuals. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. BQ-123 dilated resistance arterioles in hypertensive subjects, with FBF’s increasing by 46±7% from baseline ( P <0.001). BQ-123 increased FBF to a lesser extent in hypercholesterolemic (24±5%, P <0.001) and healthy (20±8%, P =0.007) individuals but did not affect FBF significantly in smokers (10±8%, P =0.185). The vasodilator response in hypertensive subjects, but not in hypercholesterolemic patients or smokers, was significantly greater than that in healthy individuals ( P =0.012). Endogenous ET-1, acting via the ET A receptor, increases resistance-vessel tone in subjects with hypertension more than in subjects with hypercholesterolemia or in smokers. These results indicate that ET-1 contributes more to the pathophysiology of hypertension than of other risk factors in subjects without overt atherosclerosis.