Studies in vitro have established that human uterus, fetal membranes and umbilical vasculature are potent sources of prostacyclin, a cyclooxygenase product of arachidonic acid. The suggestion that prostacyclin biosynthesis may increase in normal pregnancy, contributing to the fall in blood pressure and increase in plasma renin activity, has been difficult to confirm due to a lack of reliable indices of endogenous prostacyclin release. We have developed specific, sensitive, mass spectrometric methods for detection of 2 urinary prostacyclin metabolites and of 6-keto-PGF1Alpha the hydrolysis product of prostacyclin, in plasma. We wish to confirm prospectively our cross-sectional study suggesting prostacyclin biosynthesis increases in normal pregnancy. Prostacyclin deficiency may contribute to the development of pregnancy induced hypertension (PIH) or reflect impaired uteroplacental function. We shall also quantitate prostacyclin synthesis prospectively during pregnancies in which PIH develops and in normotensive pregnancies with evidence of chronic placental insufficiency. Insensitivity to the pressor effect of infused Angiotensin II (AII) develops in normal pregnancy, perhaps due to a prostaglandin dependent mechanism, as this phenomenon is blocked by pretreatment with aspirin. The pressor response to AII is restored in PIH and often preceeds the elevation in blood pressure. We will compare the predictive value of urinary prostacyclin metabolite determination with the AII Sensitivity Test (AST) in the diagnosis of PIH. We shall further determine whether infused AII evokes prostacyclin release which inversely relates to the pressor response and whether low dose infusions of prostacyclin restore insensitivity to AII in patients with PIH. Finally, platelet activation is common in PIH and may compromise fetal blood flow. Thromboxane A2 (TxA2), a platelet aggregating, vasoconstrictor substance, is the major prostaglandin product in platelets but is also produced by uteroplacental tissues in vitro. We shall determine whether thromboxane generation is altered in PIH and relate these changes to alterations in prostacyclin synthesis and platelet function. Development of an assay for urinary Tx metabolite permits noninvasive estimation of Tx generation from both platelet and extraplatelet sources. This will be compared with the release of Tx during activation of platelets ex vivo during normal pregnancy and pregnancy complicated by PIH.
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