The broad long-term objectives of the application are elucidation of mechanisms of local regulation of fetal blood flow in human term placenta and effects of parturition and complications of pregnancy on these mechanisms. Arachidonate metabolites, particularly 5-lipoxygenase products, and purities may contribute directly and/or indirectly to local regulation of fetoplacental vascular resistance. Their contributions will be investigated using in vitro preparations of human term placenta and cord blood. The dual-perfused placental cotyledon will be used to study release of leukotrienes and thromboxane associated with the increase in fetoplacental vascular resistance elicited by hypoxic maternal perfusion, examining actions of leukotriene and thromboxane synthesis inhibitors and receptor antagonists on release and the hypoxic pressor response, using HPLC and RIA to measure released autacoids. The contribution of adenosine to fetoplacental vasoconstriction elicited by maternal ischemia in the perfused cotyledon will be investigated, examining effects of pharmacologic modulation of intraluminal adenosine and adenosine receptor blockers on the ischemic pressor response and concomitant release of adenosine, measuring adenosine via fluorescence HPLC. The fetoplacental adenosine receptor type will be determined via dose response curves and relative potencies of adenosine analogues selective for A1 and A2 receptors. The contribution of endothelium to purine- (adenosine, ATP, ADP) and leukotriene-mediated pressor responses and to hypoxia will be investigated in isolated chorionic and stem vessel strips, measuring relaxation or contraction elicited by the autacoids in the presence and absence of endothelium and in the presence of inhibitors of endothelium-derived relaxing factor. Leukotriene synthesis by placental vessels segments under control and hypoxic conditions will be analyzed by HPLC and RIA. Purine levels in umbilical artery and vein plasma from patients with normal and complicated pregnancies will be determined by HPLC and correlated with clinical indices such as antepartum fetal testing, Doppler flow studies, progress of labor, acute or chronic fetal distress, scalp pH, cord blood pH and neonatal outcome. It is expected that this integrated approach of assessing both vascular and biochemical responses of the placenta in vitro and relating cord blood purities to clinical parameters will lead to a better understanding of the local control mechanisms regulating fetoplacental blood flow in normal and abnormal conditions and provide information pertinent to understanding intrauterine growth retardation and preeclampsia.
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