PROSTAGLANDINS, ANGIOTENSIN, NUCLEOTIDES IN PREGNANCY

长期目标是阐明调节 母体肾脏和心血管对妊娠的适应。 这种知识 将加强我们对正常妊娠的理解， 有助于揭示先兆子痫的发病机制。 研究 本文提出的建议应该产生新的和重要的信息，主要是因为 我们实验方法的双重性 第一，利用 我们开发的人类妊娠动物模型， 仪器，清醒的怀孕大鼠，不仅提供可靠的 观察产妇对怀孕的适应，但也使 使用药物抑制剂的潜在机制研究 荷尔蒙系统 第二，私家侦探最近获得的技术。将 促进激素生物合成和受体改变的研究， 和细胞生物学，这可能介导母体适应， 怀孕 具体目的是：（1）检验妊娠期 大鼠受到“应激”，例如，钠耗竭（容量收缩）， 招募血管扩张性前列腺素（PG）的程度比 钠耗尽的处女动物，以抵消血管收缩剂 刺激。 也就是说，假设在饮食钠限制的情况下： (a)PG合成的抑制将产生更急剧的下降 孕鼠肾血流动力学较未孕鼠明显降低，（B）孕鼠肾血流动力学较未孕鼠明显降低，（B）孕鼠肾血流动力学较未孕鼠明显降低，（C）孕鼠肾血流动力学较未孕鼠明显降低，（D）孕鼠肾血流动力学较未孕鼠明显降低，（B）孕鼠肾血流动力学较未孕鼠明显降低，（C）孕鼠肾血流动力学较未孕鼠明显降低，（D）孕鼠肾血流动力学较未孕鼠明显降低，（C）孕鼠肾血流动力学较未孕鼠明显降低，（D）孕鼠肾血流动力学较未孕鼠肾血流动力学明显降低，（C）孕鼠肾血流动力学较未孕鼠明显降低，（D）孕鼠肾血流动力学较未孕鼠明显降低，（C）孕鼠肾血流动力学较未孕鼠明显降低，（D）孕鼠肾血流动力学较未孕鼠肾血流动力学较未孕鼠明显降低。 观察到肾脏和全身对外源性血管收缩剂的升压反应 在怀孕期间将开发PG依赖性，和（c）在体外生物合成 的PG将在肾小球和主动脉节段中更大， 比处女的动物怀孕。 (2)为了验证一个假设， 观察到的PGE 2和PGF 2 α尿排泄增加的来源 在妊娠期间是肾髓质/乳头。 (3)以确定是否或 2，3-dinor 6-keto-PGF 1 α的尿排泄量未反映全身性 前列环素的合成，在大鼠妊娠期间增强。 (4)测试 分离肾小球血管紧张素II受体密度 大鼠妊娠期肠系膜动脉减少。 (5)测试 性类固醇减弱肾收缩能力假说 培养的系膜细胞。 (6)为了确定环腺苷酸和 环GMP，涉及介导许多 血管舒张激素，是不同的刺激药理学， 以及在新鲜分离的肾和血管中的受体偶联手段 妊娠和未孕大鼠的组织。 总而言之，本提案涉及 血管紧张素II和环 核苷酸在母体肾脏和心血管适应怀孕。

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.