Selective or nonselective endothelin antagonists in porcine hypoxic pulmonary hypertension?

We evaluated the hemodynamic effects of various endothelin (ET) receptor antagonists using selective and nonselective ETA and ETB receptor blockade in hypoxic pigs in vivo. BMS-182874 (10 mg/kg i.v.) TBC-1125lz (10 mg/kg i.v.), selective ETA receptor antagonists, attenuated hypoxia (Fi02 0.1)-evoked increase in pulmonary arterial pressure and pulmonary vascular resistance. Bosentan (10 mg/kg Lv.) a nonselective ETA and ETB receptor antagonist, cause essentially similar effects as ETA antagonism alone. No effects were observed after selective ETB blockade using BQ-788 (total dose 1 mg i.v.). The vasoconstrictor effect of exogenous ET was most effectively antagonized by TBC-11251z, followed by BMS-182874 and bosentan. The pulmonary vasodilator effect exerted by exogenous ET during hypoxia was reversed by BQ-788 and bosentan but not by TBC-11251z or BMS-182874. We can therefore conclude that ET contributes to hypoxic pulmonary vasoconstriction primarily through ETA receptor activation.