PATHOGENESIS OF HYPERTENSION

高血压的发病机制

基本信息

批准号：
2027231
负责人：
ALEXANDER C BROWNIE
金额：
$ 27.51万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
1974
资助国家：
美国
起止时间：
1974-09-01 至 1998-08-31
项目状态：
已结题

项目摘要

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对照改变有关的肾上腺皮质功能障碍关键类固醇生成酶的分泌增加肾上腺的高血压类固醇。主要重点最初将是雄激素诱导的发病机理高血压我们以前的研究表明那里是雄激素对细胞色素P-450-11β的选择性影响肾上腺皮质内部区域的活性。这个机制将通过测量类固醇生成酶基因研究来自对照和雄激素治疗的大鼠的表达。具体的抗体将用于定量细胞色素P-450-11β作为以及P-450SCC，肾上腺素毒素，P-450-21和NADPH-CYTOCHROME P-450还原酶使用免疫溶解技术。 cDNA的针对P-450-11 Beta，P-450SCC和P-450-21将用于定量mRNA编码这些酶。鉴于雄激素对分泌的潜在影响 proOpiomelanocortin（POMC）衍生的肽，这些研究将在原发性培养物中扩展到肾上腺皮质细胞。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上的雄激素。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为了了解更多的肾上腺中的酶这些酶的水平的变化与增加有关矿物皮质激素的生物合成。自发性高血压大鼠（SHR）也将在高型前后进行研究，高血压状态以确定潜在的异常肾上腺和垂体激素生物合成。我们的工作 POMC衍生的肽将强调Pro-Gamma-MSH所示我们在刺激醛固酮和糖皮质激素分泌。我们将研究作用机理 Pro-Gamma-Msh的正常大鼠肾上腺Zona glomerulosa 组织以及人醛固型细胞。这些研究有增强我们对改变的理解的潜力控制醛固酮分泌中的醛固酮产量腺瘤以及正常肾小球中的作用激素和cAMP响应的醛固型细胞类固醇生成激活剂多肽（SAP），最近分离出来，以我们为特征。