Vasculopathic Effects of Aldosterone in Dahl Rats

描述（由申请方提供）：Dahl盐敏感性（SS）大鼠模型发生高血压，与激活肾素-血管紧张素-醛固酮系统相关，导致血管紧张素II增加，进而导致醛固酮水平增加。醛固酮被认为主要在肾上腺中合成，也在血管系统中合成，部分由血管紧张素II控制，并参与血管肥大的发展。然而，关于醛固酮对血管系统的血管病变作用的机制知之甚少。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。具体目标是：（1）确定醛固酮在Dahl盐敏感性和盐耐受性大鼠中的血管病变作用;（2）确定前列腺素类是否通过以下方式促进醛固酮诱导的血管损伤：（a）确定环加氧酶（考克斯）抑制剂是否预防或减少由醛固酮诱导的血管损伤和（B）评估大鼠中由醛固酮诱导的内皮功能障碍是否是由于血管收缩剂前列腺素类，异前列烷和前列环素（PGI 2）通过血栓烷（TXA 2）受体起作用。为了实现第一个目标，在其饮用水中存在醛固酮、依普利酮（100 mg/kg/天）、夹竹桃麻素（1.5 mM/天）或AMT的情况下，将大鼠喂食低盐或高盐（HS）饮食4周。将通过遥测监测BP和HR。将采集组织和血液样本，用于分析醛固酮、PGI 2、TXA 2、异前列腺素、NO水平。考克斯和前列腺素酶（即，还将使用微阵列分析和组织病理学对选定组织（心脏、肾脏）和脉管系统（主动脉）进行评估。为了实现第二个目标，将测试考克斯、PGI 2合成和TXA 2受体活性的抑制剂。将对异前列烷的血浆/尿液水平、尿蛋白以及NAD（P）H氧化酶亚基的基因和蛋白表达进行分析。了解与醛固酮的血管病变作用相关的病理生理机制将显著有助于开发治疗多种疾病的治疗干预措施，包括中风、充血性心力衰竭、高血压和醛固酮增多症。

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.