Intrapulmonary injections of prostaglandin D2(PGD2) reduce pulmonary arterial pressure and resistance in fetal and hypoxic neonatal lambs without affecting systemic arterial pressure. This apparently specific pulmonary effect of PGD2could be explained by inactivation of the agent during passage through the pulmonary capillary bed. We therefore studied the effects of both pulmonary and systemic infusions of PGD2on the acute vascular response to a 1-min episode of hypoxia in newborn lambs. Since PGD2has been reported to be a pulmonary vasoconstrictor in normoxic lambs, we also evaluated its effects during normoxemia. Pulmonary vascular pressures were not affected by either 1- or 10-μg.kg-1.min-1infusions into the left atrium or inferior vena cava during normoxia. Infusion of 1 μg.kg-1.min-1PGD2into the inferior vena cava decreased pulmonary vascular resistance and increased systemic arterial pressure. These two parameters were unchanged with the other three infusion regimens. Mean pulmonary vascular resistance rose 83% with hypoxia and no PGD2. PGD2prevented any change in pulmonary vascular resistance with hypoxia, while systemic arterial pressure increased (1-μg.kg-1.min-1doses) or was unchanged. Thus PGD2specifically prevents hypoxic pulmonary vasoconstriction while maintaining systemic pressures, regardless of infusion site. PGD2may be indicated in treatment of persistent pulmonary hypertension of the newborn and other pulmonary hypertensive disorders.