RENIN, RENAL FUNCTION, AND ENDOTHELIUM

我们建议研究内皮细胞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 具体目标1，我们假设各种内皮衍生因子 （EDFs），响应于不同的激素刺激，抑制或 刺激肾素的释放，以及最终的调节活性， 内皮细胞代表这些作用之间的平衡。 我们建议 确定是否抑制内皮源性舒张因子 （EDRF）、内皮源性收缩因子（EDCF）和/或PGI 2 当激动剂如缓激肽（BK）或花生四烯酸（AA） 酸（AA）（刺激EDF和肾素释放）或乙酰胆碱 (Ach)（仅刺激EDF）。 我们将在体外使用3个 制备（肾皮质切片、分离的肾小球和级联反应） 由内皮与肾切片串联组成的生物测定系统）。 这些制剂将用BK、AA和/或Ach进行攻毒， 单独或与EDF的抑制剂组合，并且肾素释放将被抑制。 测定 在具体目标2中，我们假设EDRF有助于控制 变化期间的肾素分泌、肾血流量（RBF）和肾功能 在灌注压上。 我们还假设旁分泌激素， 由于胰高血糖素、血管紧张素II（AII）和激肽与EDRF相互作用， 调节肾素分泌和肾功能。 我们将在体内测定 EDRF是否发挥不同的作用（在范围内或低于范围 a）肾素分泌，B）肾血流动力学和 c）水和电解质排泄。 我们会阻止EDRF，PG合成， 在肾灌注压变化过程中激肽和/或AII的变化，并评估 血浆肾素活性（PRA）、RBF、肾小球滤过率（GFR），以及 水和电解质排泄。 在具体目标3中，我们假设， 在高血压中，EDRF与 肾功能由于内皮功能障碍和肾功能增加 灌注压 我们将研究自发性肾功能 高血压大鼠（SHR），Dahl盐敏感大鼠使用抑制剂， EDRF和EDCF在自动调节范围内和以下，我们还将 逆转2K，1C Goldblatt可能内皮成分的研究 高血压 这些研究将进一步加深我们对 内皮细胞作为一种调节因子在控制肾素释放 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.