PROSTAGLANDINS, ANGIOTENSIN, NUCLEOTIDES IN PREGNANCY

其长期目标是阐明调控机制 孕妇的肾脏和心血管对怀孕的适应。这样的知识 将加强我们对正常妊娠的理解，而且很可能 有助于揭开先兆子痫的发病机制。这些研究 在这里提出的应该产生新的和重要的信息，主要是因为 我们实验方法的两面性。第一，网络的利用率 我们开发的人类妊娠动物模型，长期 仪器化，清醒的怀孕大鼠，不仅提供可靠的 观察孕妇对怀孕的适应，但也使 应用药物抑制剂研究血管紧张素转换酶潜在机制 荷尔蒙系统。其次，私家侦探最近获得的技术将 促进激素生物合成和受体变化的研究， 以及细胞生物学，这可能介导母体适应 怀孕了。其具体目的是：(1)检验怀孕的假设 承受“压力”的大鼠，例如钠耗竭(体积收缩)， 血管扩张性前列腺素(PG)的募集比 钠耗竭的处女动物，以抵消血管收缩药 刺激物。也就是说，据推测，在限制饮食钠的情况下： (A)抑制PG合成将导致更急剧的下降 妊娠大鼠的肾脏血流动力学比处女大鼠的肾血流动力学，(B)减弱 观察肾脏和全身对外源性血管紧张剂的升压反应 在怀孕期间会发展成PG依赖，以及(C)体外生物合成 在分离的肾小球和主动脉节段中PG的比例将更大 怀孕，而不是处女动物。(2)检验一个重大事件的假设 观察到PGE2和PGF2Alpha尿液排泄增加的来源 在妊娠期间是肾髓质/乳头。(3)确定是否或 而不是2，3-二酮或6-酮-前列腺素F1α的尿液排泄，这反映了系统性 在大鼠怀孕期间，前列环素的合成被增强。(4)测试 肾小球血管紧张素II受体密度的假说 大鼠妊娠期间肠系膜动脉减少。(5)测试 性激素(S)减弱肾脏收缩能力的假说 系膜细胞在培养中。(6)确定环状AMP和 环状GMP，一种与许多 血管扩张激素，有不同的药理作用。 在新鲜分离的肾脏和血管中作为受体偶联手段 妊娠大鼠和处女大鼠的组织。总而言之，这项提案涉及 前列腺素、血管紧张素II和环磷酰胺的潜在作用 核苷酸在母体肾脏和心血管对妊娠的适应中。

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.