Endothelin Receptor Blockade Does Not Alter The Increase In Pulmonary Blood Flow Due To Oxygen Ventilation In Fetal Lambs

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs with oxygen. Both mechanical and humoral factors are involved, including the release of vasoactive substances such as prostacyclin and endothelium-derived nitric oxide (EDNO). However, the exact mechanisms remain unclear. Because endothelin-l (ET-1) produces potent pulmonary vasodilation in the fetus via EDNO release and ET-1 concentrations are increased at birth, we considered that ET-1 activity may participate in the pulmonary vasodilation that occurs with O-2 ventilation. Therefore, we studied and compared the changes in pulmonary hemodynamics associated with in utero O-2 ventilation with and without ET-1 receptor blockade induced by an infusion of Ro 47-0203 (Bosentan, a nonselective ET receptor antagonist), in 13 late-gestation fetal lambs:. In all fetal lambs, prostaglandin synthesis was prevented by an infusion of meclofenamate, and ductus arteriosus constriction was prevented by prior formalin infiltration. The infusion of Ro 47-0203 blocked the decrease in pulmonary vascular resistance induced by injections of either ET-1 (-0.985 versus +0.012 mm Hg/mL/min/100 g of lung, p < 0.05) or 4-Ala-ET-1 (an ET(b) receptor agonist) (-0.717 versus -0.052 mm Hg/mL/min/100 g of lung, p < 0.05). However, ET receptor blockade did not change the increase in pulmonary blood flow or decrease in pulmonary vascular resistance associated with in utero O-2 ventilation. This study suggests that endogenous ET-1 activity does not play an important role in the vasodilatory response to ventilation with O-2 in utero.