Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men

1 The effect on systemic haemodynamics of BQ-123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on se parate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nm ol min(-1) BQ-123, each for 15 min, in a randomized, placebo-controlled, do uble-blind study. The response of forearm blood flow to brachial artery inf usion of endothelin-1 (ET-1; 5 pmol min(-1) for 90 min) was also studied us ing bilateral forearm plethysmography, after systemic pre-treatment, on sep arate occasions, with one of two doses of BQ-123 (300 and 1000 nmol min(-1) for 15 min) or placebo. 2 Systemic BQ-123 dose-dependently decreased systemic vascular resistance ( P <0.01 for all doses vs placebo) and mean arterial pressure (P <0.05 for 3 00 nmol min(-1) and P <0.01 for 1000 and 3000 nmol min(-1)) during the 60 m in following infusion. There were concurrent increases in heart rate and ca rdiac index. BQ-123, when infused systemically for 15 min, appeared to reac h a maximum effect at 1000 nmol min(-1). 3 Intra-brachial ET-1 infusion, after pre-treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. T his vasoconstriction was attenuated by pretreatment with BQ-123 at 300 nmol min(-1) and abolished by BQ-123 at 1000 nmol min(-1) (P <0.01 vs placebo). 4 These effects occurred at concentrations of BQ-123 in the plasma (510 +/- 64 nmol l(-1)) that were ETA receptor selective, and were not accompanied by an increase in plasma ET-1 that would have indicated ETB receptor blocka de. 5 We conclude that ETA-mediated vascular tone contributes to the maintenanc e of basal systemic vascular resistance and blood pressure in healthy men.