RENIN-ANGIOTENSIN SYSTEM AND ALDOSTERONE REGULATION

本项目的目的是分析生理和病理 肾素-血管紧张素系统的各个方面，重点是AII的作用 调节醛固酮分泌和循环稳态。 AII介导钠诱导的醛固酮分泌增加 限制，但肽的肾上腺作用取决于 肾小球细胞对AII的敏感性。 肾上腺对 AII在限钠期间增加，在限钠期间减少。 通过涉及多巴胺能系统的机制加载。 先前 大鼠研究表明肾上腺AII受体的重要性 调节肾上腺对AII敏感性的变化。 但在 在灵长类动物中，肾上腺对AII的敏感性取决于 18-羟化酶活性而不是AII受体调节。 最近 心钠素（ANF）是一种强心肽， 在体内和体外的醛固酮产生的抑制剂， 比ACTH刺激的类固醇生成更有效地抑制AII-。 目前正在进行研究，以确定胜利阵线在 调节肾上腺对AII的敏感性在几个生理 条件 AII的作用高度依赖于钙， 使用二氢吡啶钙通道激动剂Bay K 8644的大鼠 为电压依赖性钙离子参与提供了进一步的证据， 通道的作用机制的AII，但不是ACTH。 的 钙依赖性蛋白激酶参与 肾上腺肾小球的功能是由优先的位置， 钙-钙调蛋白和钙-磷脂依赖性蛋白激酶 肾上腺皮质的肾小球，并通过AII的能力， 降低细胞质钙-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， 描述AII的核心作用，包括AII的相互作用 与ANF和AII受体在灵长类动物脑中的定位。

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.