Role of ANG II in Maintaining Vascular Relaxation in Dahl S Rats

ANG II 在维持 Dahl S 大鼠血管舒张中的作用

• 批准号: 7725484
• 负责人: JULIAN H LOMBARD
• 金额: $ 38万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725484
• 关键词: ANG gene; African American; Alleles; Angiotensin II; Animals; Arteries; Blood Vessels; Caliber; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Research; Dahl Hypertensive Rats; Defect; Diet; Dose; Employee Strikes; Endothelium-Dependent Relaxing Factors; Enzyme Inhibition; Event; Exhibits; Exposure to; Functional disorder; Genetic Models; Human; Hypertension; Inbred Dahl Rats; Individual; Knowledge; Laboratories; Lead; Light; Measures; Mediating; Norway; Oxidases; Oxidative Stress; Peptidyl-Dipeptidase A; Physiological; Plasma; Population; Rat Strains; Rattus; Rattus norvegicus; Regulation; Relaxation; Renin; Renin-Angiotensin System; Reporting; Resistance; Rodent; Rodent Model; Role; Sodium Chloride; Sprague-Dawley Rats; Stimulus; System; Testing; Ursidae Family; Vascular resistance; Vasodilator Agents; congenic; feeding; functional restoration; mortality; normotensive; novel; oxidant stress; receptor; response; salt intake; salt sensitive

Dahl salt-sensitive rats (SS) exhibit defects in the regulation of their renin-angiotensin system (RAS) that result in chronically low plasma renin activity (PRA) and low circulating ANG " levels, even when they are normotensive and fed a normal salt (NS) diet (0.4% NaCI). Normotensive SS rats fed NS diet also exhibit an impaired response to vasodilator stimuli, which is strikingly similar to the endothelial dysfunction that has been show to be a predictor of adverse cardiovascular events, including death, in humans. This project will test the hypothesis that exposure to chronically low plasma ANG " levels occurring as a result of defective regulation of the RAS in rats carrying the SS renin allele leads to impaired vascular relaxation. Recently, novel narrowed congenic rat strains have been developed that carry either the SS renin allele (impaired RAS regulation) or the Brown Norway (BN) renin allele (normal regulation of the RAS). The specific aims of the project are to: 1) utilize SS rats and novel narrowed congenic rat strains showing differential regulation of the renin-angiotensin system to test the hypothesis that chronic exposure to low levels of circulating ANG " contributes to impaired vascular relaxation in resistance arteries of normotensive SS rats maintained on NS diet; and 2), employ perturbations of circulating ANG " levels and pharmacological approaches such as angiotensin converting enzyme (ACE) inhibition and chronic AT1 receptor blockade to directly evaluate the role of physiological levels ANG " in maintaining normal vascular relaxation mechanisms in resistance arteries. These objectives will be accomplished by measuring vessel diameters and evaluating vessel responses to different endothelium-dependent vasodilator stimuli in SS rats and narrowed congenic rat strains either retaining the SS renin allele or carrying the normally functioning BN renin allele, which should restore normal regulation of the RAS and rescue normal vascular relaxation mechanisms in resistance arteries. These studies will not only enhance our understanding of the newly emerging role of ANG " in regulating vascular reactivity under normal physiological conditions, but will also provide valuable knowledge concerning the mechanisms of the impaired reactivity of resistance vessels to vasodilator stimuli in SS rats, and the potential mechanisms of elevated vascular resistance and increased cardiovascular mortality in human salt-sensitive hypertension.

Dahl盐敏感大鼠（SS）的肾素-血管紧张素调节存在缺陷， 导致慢性低血浆肾素活性（PRA）和低 循环ANG“水平，即使当他们血压正常并进食正常盐（NS）时 饮食（0.4%NaCl）。喂食NS饮食的血压正常的SS大鼠也表现出受损的反应 血管扩张刺激，这是惊人的相似，内皮功能障碍， 已被证明是不良心血管事件的预测因子，包括死亡， 人类这个项目将测试的假设，暴露于长期低血浆 ANG“水平的出现是由于RAS的调节缺陷，在大鼠携带 SS肾素等位基因导致血管舒张受损。最近，小说缩小了 已经开发出携带SS肾素等位基因（受损的 RAS调节）或Brown Norway（BN）肾素等位基因（RAS的正常调节）。 本项目的具体目标是：1）利用SS大鼠和新的狭窄同源基因 大鼠品系显示差异调节的肾素-血管紧张素系统，以测试 假设慢性暴露于低水平的循环ANG“有助于 正常血压SS大鼠阻力动脉血管舒张功能受损 NS饮食;和2）采用循环ANG水平的扰动， 药理学方法如血管紧张素转化酶（ACE）抑制 和慢性AT 1受体阻滞剂，以直接评估生理水平的作用 ANG“在维持阻力动脉正常血管舒张机制中的作用。 这些目标将通过测量血管直径和评价 SS大鼠血管对不同内皮依赖性血管舒张刺激的反应， 狭窄的同类大鼠品系保留SS肾素等位基因或携带正常的 功能性BN肾素等位基因，这应该恢复RAS的正常调节， 挽救阻力动脉中的正常血管舒张机制。这些研究将 这不仅加深了我们对ANG“在监管方面的新出现的作用的理解， 正常生理条件下的血管反应性，但也将提供有价值的 关于阻力血管反应性受损机制的知识 对SS大鼠血管扩张刺激的反应，以及血管扩张刺激升高的可能机制。 盐敏感性高血压患者的心血管疾病死亡率增加。