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

Dahl盐敏感大鼠(SS)肾素-血管紧张素调节缺陷 导致慢性低血浆肾素活性(PRA)的系统(RAS) 循环Ang“水平，即使他们血压正常并喂食正常的盐(NS) 饮食(0.4%NaCI)。喂食生理盐水的血压正常的SS大鼠也表现出反应受损 对血管扩张剂的刺激，这与血管内皮功能障碍惊人地相似 已被证明是包括死亡在内的不良心血管事件的预测因子 人类。该项目将检验长期暴露在低水平血浆中的假设 血管紧张素转换酶活性调节缺陷导致携带 SS肾素等位基因导致血管松弛受损。最近，小说的范围缩小了 已开发出携带SS肾素等位基因(受损)的同源大鼠品系 RAS调节)或棕色挪威(BN)肾素等位基因(RAS的正常调节)。 该项目的具体目标是：1)利用SS大鼠和新的缩小同源基因 显示肾素-血管紧张素系统差异调节的大鼠品系 假设慢性暴露于低水平的循环血管紧张素“有助于 维持正常血压SS大鼠阻力动脉的血管松弛受损 在NS饮食上；2)利用循环Ang“水平的扰动和 血管紧张素转换酶(ACE)抑制等药理学方法 和慢性AT1受体阻断直接评估生理水平的作用 血管紧张素转换酶在维持阻力动脉正常血管松弛机制中的作用。 这些目标将通过测量血管直径和评估 SS大鼠血管对不同内皮依赖性血管扩张剂刺激的反应 缩小的同源大鼠品系要么保留SS肾素等位基因，要么携带正常的 功能正常的BN肾素等位基因，应恢复RAS和RAS的正常调节 挽救阻力动脉中正常的血管松弛机制。这些研究将 不仅加深了我们对血管紧张素转换酶在调节中的新角色的认识 血管在正常生理条件下的反应性，但也会提供有价值的 对阻力血管反应性受损机制的认识 对SS大鼠血管扩张剂刺激的影响及血管升高的可能机制 人类盐敏感型高血压的抵抗和心血管死亡率增加。

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.