RENIN, RENAL FUNCTION AND THE ENDOTHELIUM

我们建议研究内皮在血管内皮细胞中的调节作用 控制肾素释放、肾血流量和肾功能。在……里面 具体目标1，我们假设各种内皮衍生因子 (EDF)对不同的激素刺激作出反应，抑制或 刺激肾素的释放，而肾素的最终调节活动 内皮细胞代表了这些影响之间的平衡。我们建议 确定是否抑制内皮源性松弛因子 血管内皮生长因子(EDRF)、内皮衍生收缩因子(S)和/或PGI2 当激动剂如缓激肽(BK)或花生四烯酸时改变肾素的释放 酸(AA)(刺激EDF和肾素释放)或乙酰胆碱 (ACH)(仅刺激EDF)被使用。我们将在体外使用3 准备(肾皮质切片、离体肾小球和级联 由内皮与肾脏切片串联组成的生物测定系统)。 这些制剂将受到BK、AA和/或Ach的挑战， 单独或与EDF的抑制剂联合使用，肾素释放将 下定决心。在具体目标2中，我们假设EDRF有助于控制 肾素分泌、肾血流量(RBF)和肾功能变化 在灌流压力上。我们还假设旁分泌激素 作为前列腺素，血管紧张素II(AII)和激动素与EDRF相互作用 调节肾素分泌和肾功能。我们将在活体内确定 EDRF是否发挥不同的效果(在该范围内或以下 RBF自身调节)对a)肾素分泌、b)肾血流动力学和 C)水和电解质排泄。我们将阻止EDRF，PG合成， 肾血流灌注压变化过程中激肽和/或AII的变化及评估 血浆肾素活性(PRA)、RBF、肾小球滤过率(GFR)和 水和电解质的排泄。在具体目标3中，我们假设 在高血压患者中，EDRF和ERF的关系发生了变化 内皮功能障碍和肾功能增加所致的肾功能 灌流压。我们将研究自发性肾功能。 高血压大鼠(SHR)、Dahl盐敏感大鼠使用 EDRF和EDCF在自动调节范围内和以下，我们还将 逆转2K，LC Goldblatt的一种可能的内皮成分研究 高血压。这些研究将进一步加深我们对这一角色的理解 血管内皮细胞作为控制肾素释放的调节因子 和肾功能。

We propose to examine the regulatory role of the endothelium in the control of renin release, renal blood flow and renal function. In specific aim 1, we hypothesize that various endothelium-derived factors (EDFs), in response to different hormonal stimuli, either inhibit or stimulate renin release, and that the final regulatory activity of the endothelium represents a balance between these effects. We propose to determine whether inhibition of endothelium-derived relaxing factor (EDRF), endothelium-derived contracting factor(s) (EDCF) and/or PGI2 alters renin release when agonists such as bradykinin (BK) or arachidonic acid (AA) (which stimulate both EDFs and renin release) or acetylcholine (Ach) (which stimulates only EDFs) are used. We will use 3 in vitro preparations (renal cortical slices, isolated glomeruli and a cascade bioassay system composed of endothelium in series with kidney slices). These preparations will be challenged with BK, AA and/or Ach, either alone or combined with inhibitors of EDFs, and renin release will be determined. In specific aim 2 we hypothesize that EDRF helps control renin secretion, renal blood flow (RBF) and renal function during changes in perfusion pressure. We also hypothesize that paracrine hormones such as prostaglandins, angiotensin II (AII) and kinins interact with EDRF to regulate renin secretion and renal function. We will determine in vivo whether EDRF exerts different effects (either within or below the range of RBF autoregulation) upon a) renin secretion, b) renal hemodynamics and c) water and electrolyte excretion. We will block EDRF, PG synthesis, kinins and/or AII during changes in renal perfusion pressure and assess plasma renin activity (PRA), RBF, glomerular filtration rate (GFR), and water and electrolyte excretion. In specific aim 3 we hypothesize that in hypertension there are changes in the relationship between EDRF and renal function due to endothelial dysfunction and increased renal perfusion pressure. We will study renal function in spontaneously hypertensive rats (SHR), Dahl salt sensitive rats using inhibitors of EDRF and EDCF within and below the range of autoregulation, we will also study a possible endothelial component of reversing 2K,lC Goldblatt hypertension. These studies will further our understanding of the role of the endothelium as a regulatory factor in the control of renin release and renal function.