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, and a number of endothelin receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ET(A) receptor is undisputed, the role of the ET(B) receptor remains unclear. Hemodynamic effects of systemic doses of the ET(B)-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 of BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placebo-corrected, 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 big 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% at 40 minutes; P<0.0001). The selective ET(B) receptor antagonist BQ- 788 causes peripheral vasoconstriction in healthy volunteers, suggesting that the overall balance of effects of endogenous ET-1 at the vascular ET(B) receptor favors vasodilatation. Further investigation is now clearly required to address whether selective ET(A) or combined ET(A)/ET(B) receptor blockade will be more effective in the clinical setting.