Effects of the endothelin ETA receptor antagonist, TA-0201, on pulmonary arteries isolated from hypoxic rats

To investigate the roles of endothelin-1 in the pathogenesis of hypoxic pul monary hypertension, we studied the effects of a selective endothelin ETA r eceptor antagonist, TA-0201 (N-(6-(2-(5-Bromopyrimidin-2-yloxy) ethoxy)-5-( 4-methylphenyl) pyrimidin-4-yl)-4-(2-hydroxy-1,1-dimethylethyl) benzensulfo namide sodium salt sesquihydrate), on helical strips of pulmonary arteries isolated from hypoxia-induced pulmonary hypertensive rats as compared with those of normoxic rats. Endothelin-l-induced maximum contractions were sign ificantly inhibited by exposure to hypoxia in the pulmonary arterial strips , but not in the mesenteric arterial strips. The hypoxia also induced right ventricular hypertrophy in rats. Addition of TA-0201 to the bath inhibited the endothelin-1-induced contraction of pulmonary arterial strips isolated from hypoxic rats more effectively than in those of normoxic rats. Oral ad ministration of TA-0201 to hypoxic rats inhibited the hypoxia-induced right ventricular hypertrophy, and decreased the maximum contractile response to endothelin-1 in pulmonary arterial strips isolated from these rats. Those inhibitory effects induced by the oral administration of TA-0201 were not o bserved in the pulmonary arteries from normoxic rats or in the mesenteric a rteries from both hypoxic and normoxic rats. These results suggest that end othelin-1 has important pathophysiological roles in hypoxia-induced pulmona ry hypertension, and that TA-0201 may inhibit the endothelin-1-induced cont raction through a change in the function of endothelin ETA receptor as well as competitive inhibition for endothelin ETA receptor. (C) 1999 Elsevier S cience B.V. All rights reserved.