and Specific Aims.) The fetal lung undergoes a complex series of changes at birth which include a decrease in pulmonary vascular resistance and ninefold increase in pulmonary blood flow. These changes occur primarily in response to an increase in fetal PaO2 at birth. This response to oxygen increases as fetus approaches term gestation. Failure of this adaptation often results in persistent pulmonary hypertension of the newborn, a condition associated with high mortality and morbidity. However, the mechanism by which oxygen causes pulmonary vasodilation is not known. The proposed studies will investigate the hypotheses that 1) pulmonary vasodilation occurring at birth is caused by increased production and release of purine nucleotides by the fetal lung in response to increase in fetal PaO2; 2) purine nucleotides then cause pulmonary vasodilation by stimulation of release of endothelium derived nitric oxide (EDNO); and 3) the increase in response of pulmonary vessels to oxygen with maturation is caused by augmentation of release of nucleotides in response to oxygen and/or increased sensitivity of receptors to vasodilator effects of nucleotides, with gestation.
The Specific Aims are to investigate 1) the independent effects of ventilation alone and ventilation with oxygenation on plasma nucleotide levels in pulmonary artery and pulmonary vein in near term fetal lambs; 2) the effects of 8-phenyltheophylline (a P1 receptor antagonist) and cibacron blue (a P2 receptor antagonist) on the response of fetal pulmonary circulation to ventilation with 3% O2, 5% CO2 and 92% N2, and ventilation with room air; 3) the effects of indomethacin, an inhibitor of PGI2 production, nitro-L-arginine, an inhibitor of EDRF synthesis, methylene blue, an inhibitor of guanylate cyclase and glybenclamide, an inhibitor of ATP-sensitive potassium channels, on pulmonary vascular effects of adenosine and ATP; 4) the effects of adenosine, ATP, acetylcholine, bradykinin and nitroprusside on the pulmonary vascular resistance in fetal lambs at 110, 120 and 132 days of gestation; and 5) plasma concentrations of adenosine and ATP in pulmonary artery and pulmonary vein at 110, 120 and 132 days of gestation. These studies may provide new information about the mechanisms of oxygen induced pulmonary vasodilation at birth.
