RENIN-ANGIOTENSIN SYSTEM AND ALDOSTERONE REGULATION

本课题的目的是分析生理学和病理学。 肾素-血管紧张素系统的几个方面，重点是AII的作用 在调节醛固酮分泌和循环动态平衡方面。 ALII介导钠离子刺激时醛固酮分泌的增加 限制，但该肽对肾上腺的作用依赖于 肾小球细胞对AII的敏感性。肾上腺对 AII在限钠时升高，在钠时降低 通过涉及多巴胺能系统的机制加载。上一首 在大鼠身上的研究表明肾上腺AII受体的重要性 调节肾上腺对AII敏感性的变化。然而，在 灵长类肾上腺对AII的敏感性取决于 18-羟基酶活性而不是AII受体的调节。最近的 心房利钠因子(ANF)是一种具有心脏特征的多肽 体内和体外的醛固酮生成的抑制物，显著 在抑制AII-刺激的类固醇合成方面比ACTH更有效。 目前正在进行研究，以确定ANF在 肾上腺对AII敏感性的几种生理调节机制 条件。AII的作用是高度依赖钙的，研究表明 二氢吡啶钙通道激动剂Bay K 8644对大鼠的作用 为电压依赖性钙的参与提供进一步的证据 通道参与AII的作用机制，但不参与ACTH的作用机制。这个 钙依赖蛋白激酶参与血管紧张素转换酶的调控 肾上腺小球功能提示肾上腺皮质的优势部位 钙-钙调蛋白与钙磷脂依赖性蛋白激酶 肾上腺皮质的球状带，以及所有人 降低细胞内钙-钙调蛋白依赖性蛋白激酶活性 分离的肾上腺小球细胞。研究正在进行中，以进一步 描述AII的中心作用，包括AII的相互作用 ANF和AII受体在灵长类动物大脑中的定位。

The purpose of this project is to analyze physiological and pathological aspects of the renin-angiotensin system, with emphasis in the role of AII in the regulation of aldosterone secretion and circulatory homeostasis. AII mediates the increases in aldosterone secretion during sodium restriction, but the adrenal effects of the peptide are dependent on the sensitivity of the glomerulosa cell to AII. The adrenal sensitivity to AII is increased during sodium restriction and decreased during sodium loading through mechanisms involving the dopaminergic system. Previous studies in the rat have indicated the importance of adrenal AII receptor regulation in the changes in adrenal sensitivity to AII. However, in the primate the adrenal sensitivity to AII depends on regulatory changes in 18-hydroxylase activity rather than AII receptor regulation. The recently characterized cardiac peptide, atrial natriuretic factor (ANF) is a potent inhibitor of aldosterone production in vivo and in vitro, being markedly more effective in inhibiting AII- than ACTH-stimulated steroidogenesis. Studies are in progress to determine the possible role of ANF in the regulation of adrenal sensitivity to AII in several physiological conditions. The action of AII is highly calcium-dependent, and studies in the rat using the dihydropyridine calcium channel agonist Bay K 8644 provide further evidence for the involvement of voltage-dependent calcium channels in the mechanism of action of AII, but not of that of ACTH. The participation of calcium-dependent protein kinases in the control of adrenal glomerulosa function was suggested by the preferential location of calcium-calmodulin and calcium-phospholipid dependent protein kinases in the zona glomerulosa of the adrenal cortex, and by the ability of AII to decrease cytosolic calcium-calmodulin dependent protein kinase activity in isolated adrenal glomerulosa cells. Studies are in progress to further characterize the central actions of AII, including the interaction of AII with ANF and localization of AII receptors in the primate brain.