THE ETA RECEPTOR ANTAGONIST, BMS-182874, REDUCES ACUTE HYPOXIC PULMONARY-HYPERTENSION IN PIGS IN-VIVO

Objective: Elevated levels of the potent vasoactive peptide endothelin (ET), have been found in pathophysiological conditions associated wit h pulmonary hypertension. In this study, we have investigated the effe cts of the ETA receptor antagonist, BMS-182874, on hypoxic pulmonary h ypertension in pigs. Methods: Pigs were subjected to acute, intermitte nt 15-min periods of hypoxia (FiO(2) 0.1). Following a first hypoxia e stablishing hypoxic baseline values, vehicle or EMS-182874 (10 or 30 m g/kg) was administered i.v. before a second hypoxic period. In separat e groups of animals, the effects of the nitric oxide synthase inhibito r N-omega-nitro-L-arginine (L-NNA) in combination with EMS-182874 (10 mg) during repeated hypoxia were investigated. The ET-1-blocking prope rties of EMS-182874 were studied in vivo by infusion of ET-1 during no rmoxia and in vitro using isolated porcine pulmonary arteries. Results : The hypoxia-evoked increase in mean pulmonary artery pressure was re duced by administration of EMS-182874 (10 mg/kg i.v.; from 42 +/- 8 to 34 +/- 4 mmHg, P < 0.05 and 30 mg/kg i.v.; from 38 +/- 4 to 30 +/- 5 mmHg, P < 0.05). In addition, EMS-182874 at 30 mg/kg reduced the pulmo nary vascular resistance during hypoxia (from 7.4 +/- 1.5 to 5.3 +/- 1 .1 mmHg.min.l(-1) P < 0.05). The hemodynamic response to repeated hypo xia was reproducible in control animals and unaffected by the cyclo-ox ygenase inhibitor diclophenac (3 mg/kg). Infusion of L-NNA alone resul ted in an augmented pulmonary vasoconstriction during hypoxia: pulmona ry arterial pressure from 35 +/- 6 to 43 +/- 9 mmHg; P < 0.05 and vasc ular resistance from 7.2 +/- 1.1 to 9.9 +/- 1.8 mmHg.min.l(-1); P < 0. 05. L-NNA in combination with BMS-182874 (10 mg/kg) resulted in a hypo xic pulmonary vasoconstriction of similar magnitude as hypoxic baselin e. In addition, EMS-182874 reduced the hemodynamic response to ET-1 in normoxic pigs and competitively antagonized the vasoconstrictor effec t of ET-1 in isolated porcine pulmonary arteries. Conclusions: The non -peptide, selective ETA receptor antagonist, BMS-182874, reduces hypox ic pulmonary vasoconstriction in pigs. The reduction in pulmonary vasc ular response to hypoxia following BMS-182874 is at least partly indep endent of nitric oxide. (C) 1998 Elsevier Science B.V.