The physiologic role of endothelin-1 (ET-1) and its receptors in regulating fetal pulmonary vascular tone is unknown. We therefore investigated the role of ET-1 and its receptors in the regulation of fetal pulmonary vascular tone using BQ 123 (an ETa receptor antagonist) and 4 Ala ET-1 (an ETb receptor agonist). In six fetal sheep in utero, we found that injections of ET-1 (250 ng/kg fetal weight) into the left pulmonary artery increased left pulmonary blood flow (21.0 +/- 17.5 to 74.7 +/- 32.9 mL/kg/min, p < 0.05) and decreased left pulmonary vascular resistance (6.02 +/- 7.00 to 0.84 +/- 0.48 mm Hg/kg/min/mL, p < 0.05). BQ 123 (5 mg) increased pulmonary blood flow (24.6 +/- 28.7 to 47.7 +/- 27.4 mL/kg/min, p < 0.05) and decreased pulmonary vascular resistance (8.84 +/- 10.32 to 1.43 +/- 0.80 mm Hg/kg/min/mL, p < 0.05); 4 Ala ET-1 (1725 ng/kg) markedly increased pulmonary blood flow (8.6 +/- 6.8 to 69.4 +/- 23.1 mL/kg/min, p < 0.05) and decreased pulmonary vascular resistance (12.02 +/- 10.2 to 0.78 +/- 0.44 mm Hg/kg/min/mL, p < 0.05). The absolute increase in pulmonary blood flow produced by ET-1 was attenuated by glibenclamide (an ATP-dependent potassium channel blocker) (flow increase of 73.4 +/- 34.1 versus 49.3 +/- 16.8 mL/kg/min, p < 0.05). This study demonstrates that ETa receptor activation has a small role in maintaining basal fetal pulmonary vascular tone, and that specific ETb receptor activation produces marked pulmonary vasodilation. The increase in pulmonary flow produced by ET-1 in fetuses is partly mediated by ATP-dependent potassium channels.