We previously demonstrated that rats exposed to hypoxis exhibit selective enhancement of endothelin-1 (ET 1) and ETA receptor mRNA levels in lung and increased pulmonary artery pressure (PAP). The current study tested the hypothesis that TBC11251. a novel ET, receptor antagonist (IC50 =2.1nM, [125IJ-ET binding; ETA/ETB=6000) prevents and reverses the pulmonary hypertension (PH) due to acute hypoxia. Nine wk old, male Sprague-Dawley rats were instrumented with femoral venous and pulmonary arterial cannulae. Grp 1 received vehicle, Grp 2 received 15mg/kg (p.o., 2 hrs) and Grp 3 received 5mg/kg (i.V., 20 mm) of TBC11251 prior to 90 min hypoxic exposure (10% O2, 1 atm). Grp 4 received 5mg/kg (i.v.) of TBC11251 45 min after the hypoxic exposure (reversal study). Mean PAP (mmHg) were monitored in conscious, unrestrained rats. Results are: Time after 10%02 -20min 0 min 15min 30min 45min 60min 90mîn Grp 1, control, n=12 18±1 18±2 21±1 22±1 24±1 26±1 26±1 Grp 2, p.o., n=4 16±1 16±1 14±115±014±014±0" 15+1Grp 3, i.V., n=5 18±1 18±1 19±1 19±118±118±117±1Grp 4, i.V., n=5 18±1 18±0 22±1 22±1 24±1 22±118±1p<0.05, compared to respective values of Grp 1. Data are means±SEM. Pretreatment (p.o. or i.v.) with TBC11251 completely blocked the acute hypoxia-induced PH. Administration of TBC11251 45min after hypoxic exposure significantly reversed acute PH. These findings indicate that ET-1, acting by a paracrine mechanism on ETA receptors in the pulmonary vasculature, plays a major role in the pathogenesis of hypoxia-induced PH.