PATHOGENESIS OF HYPERTENSION

高血压的发病机制

• 批准号: 3485239
• 负责人: ALEXANDER C BROWNIE
• 金额: $ 20.79万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1974
• 资助国家: 美国
• 起止时间: 1974-09-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3485239
• 关键词: adenoma; adrenal ferredoxin; adrenal glands; adrenocorticotropic hormone; aldosterone; androgens; complementary DNA; cyclic AMP; electron microscopy; fluorimetry; gene expression; glucocorticoids; hormone regulation /control mechanism; human tissue; melanocyte stimulating hormone; messenger RNA; pituitary adrenal axis; proopiomelanocortin; protein biosynthesis; radioimmunoassay; spontaneous hypertensive rat; steroid 11beta monooxygenase; steroid biosynthesis

The proposed studies are designed to evaluate the hypothesis that adrenocortical dysfunction related to altered synthesis or control of key steroidogenic enzymes can lead to increased secretion of hypertensinogenic steroids from the adrenal. The major focus initially will be on the pathogenesis of androgen-induced hypertension where our previous studies have revealed that there are selective effects of androgens on cytochrome P-450-11 beta activity of the adrenocortical inner zones. The mechanism of this will be studied by measuring steroidogenic enzyme gene expression from control and androgen-treated rats. Specific antibodies will be used to quantitate cytochrome P-450-11 beta as well as P-450scc, adrenodoxin, P-450-21 and NADPH-cytochrome P-450 reductase using immunoisolation techniques. cDNA's against P-450-11 beta, P-450scc and P-450-21 will be used to quantitate mRNA's encoding for these enzymes. In view of potential effects of androgen on the secretion of proopiomelanocortin (POMC)-derived peptides, these studies will be extended to adrenocortical cells in primary culture. Also, we will measure the effect of androgens on circulating and pituitary levels of POMC-derived peptides as well as direct effects of androgens on pituitary cell cultures. In related studies we examine the gene expression of key adrenal steroidogenic enzymes in regenerating adrenals in order to understand more fully how altered levels of these enzymes is related to increased biosynthesis of mineralocorticoids. Spontaneously hypertensive rats (SHR) will also be studied in the prehypertensive and hypertensive state in order to identify potential abnormalities in adrenal and pituitary hormone biosynthesis. Our work with POMC-derived peptides will emphasize pro-gamma-MSH's shown by us to synergize with ACTH in stimulating aldosterone and glucocorticoid secretion. We will study the mechanism of action of pro-gamma-MSH's in normal rat adrenal zona glomerulosa tissue and also in human aldosteronoma cells. These studies have the potential for enhancing our understanding of the altered control of aldosterone production in aldosterone-secreting adenomas as well as the role in normal glomerulosa and aldosteronoma cells of a hormone- and cAMP-responsive steroidogenesis activator polypeptide (SAP), recently isolated and characterized by us.

拟议的研究旨在评估以下假设： 与合成或控制改变有关的肾上腺皮质功能障碍 关键的类固醇生成酶可以导致分泌增加 来自肾上腺的致高血压类固醇。 主要焦点 首先将探讨雄激素诱发的发病机制 我们之前的研究表明，高血压 是雄激素对细胞色素 P-450-11 beta 的选择性作用 肾上腺皮质内部区域的活动。 这个的机制 将通过测量类固醇生成酶基因来研究 对照和雄激素处理的大鼠的表达。 具体的 抗体将用于定量细胞色素 P-450-11 beta 以及 P-450scc、肾上腺素、P-450-21 和 NADPH-细胞色素 使用免疫分离技术的 P-450 还原酶。 cDNA的 针对 P-450-11 beta，P-450scc 和 P-450-21 将用于 定量这些酶的 mRNA 编码。 鉴于 雄激素对分泌的潜在影响 阿黑皮素原 (POMC) 衍生的肽，这些研究将 扩展到原代培养物中的肾上腺皮质细胞。 另外，我们 将测量雄激素对循环和垂体的影响 POMC 衍生肽的水平以及直接影响 垂体细胞培养物中的雄激素。 在相关研究中我们 检查关键肾上腺类固醇生成的基因表达 肾上腺再生酶，以便了解更多 充分了解这些酶的水平改变与增加 盐皮质激素的生物合成。 自发性高血压 大鼠（SHR）也将在高血压前期和 高血压状态，以识别潜在的异常 肾上腺和垂体激素的生物合成。 我们的工作与 POMC 衍生肽将强调 pro-gamma-MSH 我们与 ACTH 协同刺激醛固酮， 糖皮质激素的分泌。 我们将研究作用机制 正常大鼠肾上腺球状带中前-gamma-MSH的变化 组织以及人醛固酮瘤细胞中。 这些研究有 增强我们对改变的理解的潜力 醛固酮分泌中醛固酮产生的控制 腺瘤以及在正常肾小球和中的作用 激素和 cAMP 响应的醛固酮瘤细胞 类固醇生成激活剂多肽（SAP），最近分离和 以我们为特色。