PROSTAGLANDINS, ANGIOTENSIN, NUCLEOTIDES IN PREGNANCY

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The long-term objective is to elucidate the mechanisms which regulate maternal renal and cardiovascular adaptation to pregnancy. Such knowledge will strengthen our understanding of normal gestation, and most likely contribute to unravelling the pathogenesis of preeclampsia. The studies proposed herein should yield new and important information, largely because of the dual nature of our experimental approach. First, utilization of an animal model of human gestation developed by us, the chronically instrumented, conscious pregnant rat, provides not only reliable observations of maternal adaptation to pregnancy, but also enables investigation of potential mechanisms by using pharmacologic inhibitors of hormonal systems. Second, techniques recently acquired by the P.I. will facilitate research of alterations of hormone biosynthesis and receptors, and of cellular biology, which may mediate maternal adaptation to pregnancy. The specific aims are: (1) To test the hypothesis that gravid rats subjected to "stress", e.g., sodium depletion (volume contraction), recruit vasodilatory prostaglandins (PGs) to a greater degree than do sodium-depleted virgin animals, in order to offset vasoconstrictor stimuli. That is, it is postulated that with dietary sodium restriction: (a) inhibition of PG synthesis will produce a more precipitous decline of renal hemodynamics in pregnant than in virgin rats, (b) the attenuated renal and systemic pressor response to exogenous vasoconstrictors observed during pregnancy will develop PG-dependency, and (c) in vitro biosynthesis of PGs will be greater in glomeruli and aortic segments isolated from gravid, than virgin animals. (2) To test the hypothesis that a major source of enhanced urinary excretion of the PGE2 and PGF2Alpha observed during gestation is the renal medulla/papilla. (3) To ascertain whether or not urinary excretion of 2,3 dinor6keto-PGF1Alpha, which reflects systemic synthesis of prostacyclin, is enhanced during rat pregnancy. (4) To test the hypothesis that angiotensin II receptor density of isolated glomeruli and mesenteric artery is decreased during rat gestation. (5) To test the hypothesis that sex steroid(s) attenuate the contractile capacity of renal mesangial cells in culture. (6) To determine whether or not cyclic AMP and cyclic GMP, compounds implicated in mediating the action of many vasodilatory hormones, are differentially stimulated by pharmacologic as well as receptor-coupled means in freshly isolated renal and vascular tissues from gravid and virgin rats. In summary, this proposal addresses the potential role of prostaglandins, angiotensin II, and cyclic nucleotides in maternal renal and cardiovascular adaptation to pregnancy.