Endothelin (ET)-1 is a potent vasoconstrictor peptide that modulates basal pulmonary vascular resistance (PVR) in the normal ovine fetus and contributes to high PVR after chronic intrauterine pulmonary hypertension. Although high PVR is present in premature lambs with severe hyaline membrane disease (HMD), whether ET-1 plays a role in the pathophysiology of experimental HMD is unknown. To test the hypothesis that ET-1 activity contributes to high PVR in the premature lamb with HMD, we studied the hemodynamic effects of a selective ET(A) receptor antagonist, BQ 123, in 10 animals (gestational age 125 d; 147 d=term). After baseline measurements, animals were intubated, treated with surfactant (Infasurf), and mechanically ventilated with a fraction of inspired oxygen of 1.00 for 8 h. Animals were treated with continuous infusions of either BQ 123 (1 mg/h; treatment group, n=5) or 1% DMSO (control; n=5). Plasma ET-1 levels progressively increased during prolonged ventilation with hyperoxia (0.8+/-0.1 pg/mL, baseline to 6.8+/-2.5 pg/mL, 8 h, p < 0.05). In comparison with control lambs, BQ 123 treatment caused a sustained reduction in pulmonary vascular resistance (0.55+/-0.04 mm Hg mL-(-1) min(-1), control versus 0.18+/-0.04 mm Hg mL(-1) min(-1), BQ 123, p < 0.05), increased left pulmonary artery blood flow (70+/-12 mL/min, control versus 194+/-28 mL/min, BQ 123, p < 0.05), and increased arterial PaO2 (53+/-14 mm Hg, control versus 174+/-71 mm Hg, BQ 123, p < 0.05) 8 h after the onset of ventilation. We conclude that circulating levels of ET-1 increase after delivery of premature lambs with severe HMD, and that selective ET(A) receptor blockade causes sustained improvement in hemodynamics in severe experimental HMD. These studies suggest that ET-1 contributes to the hemodynamic abnormalities in this model of pulmonary hypertension and severe HMD.