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

The effect on systemic haemodynamics of BQ‐123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on separate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nmol min −1 BQ‐123, each for 15 min, in a randomized, placebo‐controlled, double‐blind study. The response of forearm blood flow to brachial artery infusion of endothelin‐1 (ET‐1; 5 pmol min −1 for 90 min) was also studied using bilateral forearm plethysmography, after systemic pre‐treatment, on separate occasions, with one of two doses of BQ‐123 (300 and 1000 nmol min −1 for 15 min) or placebo. 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 300 nmol min −1 and P <0.01 for 1000 and 3000 nmol min −1 ) during the 60 min following infusion. There were concurrent increases in heart rate and cardiac index. BQ‐123, when infused systemically for 15 min, appeared to reach a maximum effect at 1000 nmol min −1 . Intra‐brachial ET‐1 infusion, after pre‐treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. This vasoconstriction was attenuated by pre‐treatment with BQ‐123 at 300 nmol min −1 and abolished by BQ‐123 at 1000 nmol min −1 ( P <0.01 vs placebo). 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 blockade. We conclude that ETA‐mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men.British Journal of Pharmacology (2001) 134 , 648–654; doi: 10.1038/sj.bjp.0704304