SYSTEMIC ENDOTHELIN RECEPTOR BLOCKADE DECREASES PERIPHERAL VASCULAR-RESISTANCE AND BLOOD-PRESSURE IN HUMANS

Background Although local inhibition of the generation or actions of e ndotholin-1 has been shown to cause forearm vasodilatation, the system ic effects of endothelin receptor blockade in healthy humans are unkno wn. We therefore investigated the cardiovascular effects of a potent p eptide endothelin ET(A/B) receptor antagonist, TAK-044, in healthy men . Methods and Results Two randomized, placebo-controlled, crossover st udies were performed. In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodi latation and hypotension. Four hours after infusion of the highest dos e (1000 mg), there were decreases in mean arterial pressure of 18 mm H g and total peripheral resistance of 665 AU and increases in heart rat e of 8 bpm and cardiac index of 0.9 L . min(-1). m(-2) compared with p lacebo. TAK-044 caused a rapid. dose-dependent increase in plasma immu noreactive endothelin (from 3.3 to 35.7 pg/mL within 30 minutes after 1000 mg). In a second study in eight subjects, intravenous administrat ion of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstr iction to brachial artery infusion of endothelin-1. Brachial artery in fusion of TAK-044 caused local forearm vasodilatation. Conclusions The endothelin ET(A/B), receptor antagonist TAK-044 decreases peripheral vascular resistance and, to a lesser extent, blood pressure; increases circulating endothelin concentrations; and blocks forearm vasoconstri ction to exogenous endothelin-1. These results suggest that endogenous generation of endothelin-1 plays a fundamental physiological role in maintenance of peripheral vascular tone and blood pressure. The vasodi lator properties of endothelin receptor antagonists may prove valuable therapeutically.