Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men

Endothelin-1 (ET-1) is an important mediator of vascular tone in humans, an d a number of endothelin receptor antagonists are currently in clinical dev elopment as vasodilator agents. While the vasoconstrictor role of the ETA r eceptor is undisputed, the role of the ETB receptor remains unclear. Hemody namic effects of systemic doses of the ETB-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placebo-controlled, four-way crossover study. After a 15-minute infusion o f BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blo od pressure, heart rare, cardiac index, and stroke index were measured. Tot al peripheral vascular resistance was calculated from cardiac index and mea n arterial pressure. Hemodynamic data are expressed as maximum, placebo-cor rected, percentage change from baseline following BQ-788 (300 nmol/min) and were examined by ANOVA. Plasma ET-1 increased by 3.7+/-1.2 pg/mL (maximum at 15 minutes, P=0.02), whereas there was no significant change in plasma b ig ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13+/-7% at 50 minutes; P=0.002), cardiac index (17+/-5% at 40 minutes; P<0.0001), and stroke index (8+/-4% at 40 minutes; P=0.002) and an increase in total peripheral vascular resistance (24+/-5% a t 40 minutes; P<0.0001). The selective ETB receptor antagonist BQ-788 cause s peripheral vasoconstriction in healthy volunteers, suggesting that the ov erall balance of effects of endogenous ET-1 at the vascular ETB receptor fa vors vasodilatation. Further investigation is now clearly required to addre ss whether selective ETA or combined ETA/ETB receptor blockade will be more effective in the clinical setting.