The pulmonary vasculature of newborns with persistent pulmonary hypertension is characterized by active vasoconstriction and vascular remodeling. It has been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and growth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ET(A) receptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension and then treated for the remainder of the 14 d with an orally active, nonpeptidic ET(A) antagonist (TBC3711, 22 mg x kg(-1) x d(-1)). At the end of the exposure, Hb, pulmonary artery pressure, right ventricle to left ventricle plus septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SIN-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs were determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treatment. By 3 d of exposure to hypoxia, piglets had already developed significant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 +/- 1.3 mm Hg versus 14.2 +/- 3.4 mm Hg) and percentage wall thickness (26.6 +/- 5.9% versus 18.7 +/- 2.4% for vessels 0-30 microm). Whereas further exposure to hypoxia for 14 d did not enhance the increase in pulmonary artery pressure and percentage wall thickness, it did augment the right ventricle to left ventricle plus septum weight ratio (0.71 +/- 0.09 versus 0.35 +/- 0.01). ET-1 circulating levels were increased only when exposure to hypoxia was prolonged to 14 d (5.1 +/- 2.4 pg/mL versus 1.0 +/- 0.4 pg/mL). Treatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant reduction in the right ventricle to left ventricle plus septum weight ratio (0.60 +/- 0.06), pulmonary artery pressure (20.0 +/- 4.8 mm Hg), and percentage wall thickness (18.5 +/- 3.3%) and restored the dilator response to the NO donor SIN-1. Prolonged hypoxia markedly reduced exhaled NO concentrations (0.3 +/- 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 +/- 2.8 ppb) to the level of normoxic controls (4.9 +/- 3.0 ppb). Lastly, treatment with TBC3711 increased ET-1 circulating levels in both the normoxic (5.4 +/- 2.8 pg/mL) and hypoxic (13.0 +/- 6.3 pg/mL) groups. In conclusion, the specific ET(A) receptor antagonist, TBC3711, can significantly ameliorate the morphologic changes encountered in hypoxia-induced pulmonary hypertension in the newborn piglet and may improve the dilator response to NO.