Vasculopathic Effects of Aldosterone in Dahl Rats

描述（由申请人提供）：Dahl盐敏感（SS）大鼠模型发生高血压，与肾素-血管紧张素-醛固酮系统的激活相关，导致血管紧张素II的增加，从而导致醛固酮水平的增加。醛固酮被认为主要在肾上腺合成，但也在血管中合成，部分受血管紧张素II控制，参与血管肥大的发生。然而，关于醛固酮对血管病变作用的相关机制知之甚少。我们假设醛固酮的血管病变作用是醛固酮对心脏或肾脏组织的直接作用，高盐使组织对醛固酮诱导的血管损伤敏感。具体目的是：(1)确定醛固酮对达尔盐敏感和耐盐大鼠的血管病变作用；(2)确定类前列腺素是否与醛固酮诱导的血管损伤有关，具体方法为：(a)确定环氧化酶（COX）抑制剂是否能预防或减轻醛固酮诱导的血管损伤；(b)评估醛固酮诱导的大鼠内皮功能障碍是否与血管收缩剂类前列腺素、异前列腺素和前列环素（PGI2）通过血栓素（TXA2）受体作用有关。为了实现第一个目标，将给大鼠喂食低盐或高盐（HS）饮食，并在其饮用水中添加醛固酮、依普利酮（100mg/kg/天）、罗布麻素（1.5 mM/天）或AMT，持续4周。血压和心率将通过遥测监测。收集组织和血液样本，分析醛固酮、PGI2、TXA2、异前列腺素、NO水平。使用微阵列分析和组织病理学对选定组织（心脏、肾脏）和血管系统（主动脉）进行COX和前列腺素合成酶（即PGH2/PGG2、PGI2）的组织水平进行评估。为了解决第二个目标，将测试COX， PGI2合成和TXA2受体活性的抑制剂。分析血浆/尿液中异前列腺素水平、尿蛋白水平以及NAD(P)H氧化酶亚基的基因和蛋白表达。了解与醛固酮血管病变作用相关的病理生理机制，将极大地有助于开发治疗多种疾病的干预措施，包括中风、充血性心力衰竭、高血压和高醛固酮增多症。

DESCRIPTION (provided by applicant): The Dahl salt-sensitive (SS) rat model develops hypertension that is associated with activation of the renin-angiotensin-aldosterone system resulting in increases of angiotensin II which leads to increases in aldosterone levels. Aldosterone, thought to be mainly synthesized in the adrenal gland, is also synthesized in the vasculature, in part, controlled by angiotensin II and participates in the development of vascular hypertrophy. However, little is known about the mechanism(s) associated with the vasculopathic effects of aldosterone on the vasculature. We hypothesize that the vasculopathic effect of aldosterone is a direct effect of aldosterone on cardiac or renal tissue and that high salt sensitizes tissue to aldosterone-induced vascular injury. The specific aims are: (1) to determine the vasculopathic effect of aldosterone in Dahl salt-sensitive and salt-resistant rats; (2) to determine whether the prostanoids contribute to the vascular injury induced by aldosterone by specifically: (a) determining whether cyclooxygenase (COX) inhibitors prevent or reduce vascular damage induced by aldosterone and (b) assessing whether endothelial dysfunction induced by aldosterone in rats is due to vasoconstrictor prostanoids, isoprostanes and prostacyclin (PGI2) acting via thromboxane (TXA2) receptors. To address the first aim, rats will be fed either a low or high salt (HS) diet in the presence of aldosterone, eplerenone (100mg/kg/day), apocynin (1.5 mM/day), or AMT in their drinking water for 4 weeks. BP and HR will be monitored by telemetry. Tissue and blood samples will be collected for analysis of aldosterone, PGI2, TXA2, isoprostanes, NO levels. Tissue levels of COX, and prostaglandin synthases (i.e., PGH2/PGG2, PGI2) using microarray analysis and histopathology on selected tissues (heart, kidney) and vasculature (aorta) will also be assessed. To address the second aim, inhibitors of COX, PGI2 synthesis, and TXA2 receptor activity will be tested. Analysis of plasma/urinary levels of isoprostane, urinary protein, and gene and protein expression of the subunits of NAD(P)H oxidase will be conducted. Understanding of pathophysiological mechanisms associated with vasculopathic effects of aldosterone will significantly aid in the development of therapeutic interventions in the treatment of several diseases conditions including stroke, congestive heart failure, hypertension and hyperaldosteronism.