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。 除了调节 生长抑素和多巴胺能机制作为可能的调节剂的作用 在肾上腺对AII的敏感性中，心房钠尿因子（ANF）是一种 有效的醛固酮分泌抑制剂。 除了施加一个 对AII刺激的醛固酮分泌的优先抑制作用 体内实验表明，心钠素能拮抗 AII输注和限钠后的血浆醛固酮，而 ACTH依赖性醛固酮刺激不受影响。 的这些行动 ANF支持肽在肾上腺皮质激素调节中的作用。 对一切的反应。 对AII作用机制的研究表明， 一种新的钙/钙调蛋白蛋白激酶，磷酸化100 kDa的 肾上腺肾小球区的胞浆蛋白。 这种酶 与肌球蛋白轻链激酶不同，其活性被证明是 由AII监管。 先前的研究表明AII的存在 大鼠脑中的受体延伸到灵长类动物。 在猴脑中， AII受体主要分布于室管膜周围器官和其他边缘系统 结构，所有这些都与水的摄入量，血压 和自主神经功能。 在大鼠脑垂体中，AII刺激 催乳素分泌后，结合到特定的受体位于 催乳素 与肾上腺和血管AII受体相反， 垂体受体不受钠饮食和血浆中钠含量变化的影响， 但受雌激素调节。 垂体细胞孵育 雌二醇增加催乳素对AII的反应，但引起时间延长， AII受体的剂量依赖性降低，表明主要 雌激素的调节作用在受体后位点发挥。

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. In addition to the modulatory action of somatostatin and dopaminergic mechanisms as possible regulators of the adrenal sensitivity to AII, atrial natriuretic factor (ANF) is a potent inhibitor of aldosterone secretion. As well as exerting a preferential inhibitory effect on AII-stimnulated aldosterone secretion in vitro, experiments in vivo showed that ANF antagonized the increases in plasma aldosterone following AII infusion and sodium restriction, while ACTH-dependent aldosterone stimulation was unaffected. These actions of ANF are in support of a role for the peptide in the regulation of adrenal responsiveness to AII. Studies on the mechanism of action of AII revealed a novel calcium/calmodulin protein kinase that phosphorylates a 100 kDa cytosolic protein in the adrenal glomerulosa zone. This enzyme is different from myosin light chain kinase and its activity was shown to be regulated by AII. Previous studies demonstrating the presence of AII receptors in the rat brain were extended to the primate. In monkey brain, AII receptors were found in the circumventicular organs and other limbic structures, all related to the regulation of water intake, blood pressure and autonomic function. In the rat pituitary gland, AII stimulates prolactin secretion after binding to specific receptors located in the lactotrophs. In contrast to the adrenal and vascular AII receptors, pituitary receptors were unaffected by changes in sodium diet and plasma AII levels, but were regulated by estrogens. Incubation of pituitary cells with estradiol increased prolactin responses to AII but caused a time and dose dependent decrease in AII receptors, indicating that the major regulatory effects of estrogens are exerted at post-receptor sites.