NITRIC OXIDE AND HEREDITARY LOW RENIN HYPERTENSION

原发性高血压的低肾素血症的发病机制， 黑人的发病率不成比例地高，仍然未知，但 推测反映了相对动脉容积扩张（1，2）。 遗传 高盐饮食易患高血压 已经证明（1，2）。 Dahl/Rapp大鼠是一种有用的模型， 遗传性低肾素盐敏感性高血压 在高 盐（8%NaCl）饮食，Dahl/Rapp盐敏感（SS/Jr）大鼠一致， 迅速发展为高血压并死于继发于 小动脉硬化和肾小球硬化，除非提供 肠胃外或口服L-精氨酸。 L-精氨酸完全阻止了这一点 以浓度依赖性方式产生高血压反应， 高血压性肾硬化症。 这种非必需氨基酸是氮的代谢前体 一氧化氮（NO），内源性硝基血管舒张剂，是一个主要的调节剂， 体内血管平滑肌张力（3-6）。 这其中的关键假设 盐敏感性高血压及其导致的肾功能衰竭 在SS/Jr大鼠中发生，因为NO产生的遗传缺陷， 通过提供NO合酶的底物L-精氨酸来克服。 使用Dahl/Rapp大鼠，广泛的长期目标包括：1） 了解内源性硝基血管扩张剂NO及其作用 代谢前体，L-精氨酸，在盐敏感的发病机制， 高血压; 2）证实响应于 饮食中氯化钠摄入量和/或L-精氨酸的变化，并确定 NO和L-精氨酸在肾处理氯化钠中作用 大鼠;和3）进一步表征NO和L-精氨酸对 盐敏感性高血压终末器官（肾）损害的进展。 最终的目标是将这些结果应用于特定的人群 人低肾素原发性高血压（7）。 完成这些 为了实现这一目标，我们将进行以下实验。1.检查酶 血管平滑肌中诱导型NO合酶的动力学 来自SS/Jr、SR/Jr和Sprague-Dawley大鼠的细胞。B）相关，SS/Jr 高盐饮食加和不加L-精氨酸的大鼠， 平滑肌和系膜细胞增生与组织病理学 肾小球、肾小球、血浆和尿液中cGMP浓度的变化。 我们还将检查L-精氨酸、血管紧张素II、心房肌张力和收缩压的影响。 利钠肽和8-溴环鸟苷酸对血管内皮生长的影响 从SS/Jr和SR/Jr大鼠获得的平滑肌细胞。c）确定 饮食氯化钠和L-精氨酸是否诱导 NO合成酶在血管平滑肌和肾脏中的诱导型 体外和体内。d）确定L-精氨酸是否纠正了 在高血压前期SS/Jr大鼠中观察到的肾脏氯化钠排泄， 检测NO和cGMP对内髓钠吸收的作用 集合管细胞

The pathogenesis of low-renin essential hypertension, which has a disproportionately higher incidence in blacks, remains unknown, but is presumed to reflect relative arterial volume expansion (1,2). A genetic predisposition to develop high blood pressure while on a high salt diet has been demonstrated (1,2). The Dahl/Rapp rat is a useful model of genetically induced low-renin salt-sensitive hypertension. On a high salt (8% NaCl) diet, Dahl/Rapp salt-sensitive (SS/Jr) rats uniformly and rapidly develop hypertension and die from renal failure secondary to arteriolosclerosis and glomerulosclerosis, unless provided either parenteral or oral L-arginine. L-arginine completely prevents this hypertensive response in a concentration-dependent fashion and prevents hypertensive nephrosclerosis in these animals on the high salt diet. This nonessential amino acid serves as the metabolic precursor of nitric oxide (NO), the endogenous nitrovasodilator that is a major regulator of vascular smooth muscle tone (3-6) in vivo. The key hypothesis in this project is that salt-sensitive hypertension and resultant renal failure occur in SS/Jr rats because of a genetic defect in NO production that is overcome with provision of L-arginine, the substrate for NO synthase. Using the Dahl/Rapp rat, the broad, long-term objectives include: 1) understand the role of the endogenous nitrovasodilator, NO, and its metabolic precursor, L-arginine, in the pathogenesis of salt-sensitive hypertension; 2) demonstrate modulation of NO production in response to changes in dietary sodium chloride intake and/or L-arginine and determine the role of NO and L-arginine on renal handling of sodium chloride in rats; and 3) characterize further the role of NO and L-arginine on progression of end-organ (kidney) damage in salt-sensitive hypertension. The ultimate goal will be to apply these results to defined populations of human low-renin essential hypertension (7). To accomplish these goals, we will perform the following experiments. a ) Examine the enzyme kinetics of the inducible form of NO synthase in vascular smooth muscle cells from SS/Jr, SR/Jr and Sprague-Dawley rats. b) Correlate, in SS/Jr rats on a high salt diet with and without L-arginine, the time-course of smooth muscle and mesangial cell proliferation with histopathologic changes and cGMP concentrations in glomeruli, aortae, plasma and urine. We will also examine the effects of L-arginine, angiotensin II, atrial natriuretic peptide, and 8-bromo-cGMP on growth of cultured vascular smooth muscle cells obtained from SS/Jr and SR/Jr rats. c) Determine whether dietary sodium chloride and L-arginine induce the expression of the inducible form of NO synthase in vascular smooth muscle and kidney in vitro and in vivo. d) Determine whether L-arginine corrects the defect in renal sodium chloride excretion seen in prehypertensive SS/Jr rats and examine the role of NO and cGMP on sodium absorption by inner medullary collecting duct cells.