NITRIC OXIDE AND HEREDITARY LOW RENIN HYPERTENSION

低肾素高血压的发病机制 黑人的发病率高得不成比例，这一点仍然未知，但事实是 假定反映相对动脉容量扩张(1，2)。一种基因 高盐饮食时易患高血压 已证明(1，2)。Dahl/Rapp大鼠是一种有用的 遗传性低肾素盐敏感型高血压。兴高采烈 盐(8%氯化钠)饲料，Dahl/Rapp盐敏感(SS/JR)大鼠均匀和 迅速发展为高血压并死于继发性肾功能衰竭 小动脉硬化和肾小球硬化，除非提供 注射用或口服L-精氨酸。L-精氨酸完全阻止了这一点 浓度依赖的高血压反应和预防 在这些高盐饮食的动物中，高血压肾病。 这种非必需氨基酸是硝酸的代谢前体。 一氧化氮(NO)，内源性硝基血管扩张剂，是血管紧张素转换酶的主要调节因子 活体血管平滑肌张力(3-6)。其中的关键假设是 项目是盐敏感型高血压和由此导致的肾功能衰竭 在SS/JR大鼠中发生，是因为NO产生的遗传缺陷 克服与提供L-精氨酸，底物为一氧化氮合酶。 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及其受体的作用 代谢前体L-精氨酸在盐敏感发病机制中的作用 高血压；2)表现出对NO产生的调节 膳食氯化钠摄入量和/或L精氨酸摄入量的变化及测定 一氧化氮和L精氨酸在大鼠肾脏处理氯化钠中的作用 3)进一步研究了NO和L精氨酸在大鼠血管内皮细胞中的作用 盐敏感型高血压终末器官(肾)损害的研究进展。 最终目标将是将这些结果应用于确定的人群 人类低肾素高血压病(7)。要实现这些目标 为了实现这些目标，我们将进行以下实验。A)检查酶 血管平滑肌诱导型一氧化氮合酶的动力学研究 SS/JR、SR/JR和Spraogue-Dawley大鼠的细胞。B)相互关联，用SS/Jr 高盐饮食加和不加L-精氨酸大鼠的时程 血管平滑肌和系膜细胞增殖与组织病理学 肾小球、主动脉、血浆和尿液中cGMP含量的变化。 我们还将检查L-精氨酸、血管紧张素II、心房肌的作用 利钠肽和8-溴-cGMP对培养血管生长的影响 取自SS/JR和SR/JR大鼠的平滑肌细胞。C)确定 膳食氯化钠和L-精氨酸是否诱导血管内皮生长因子的表达 一氧化氮合酶在大鼠血管平滑肌和肾脏中的诱导形式 体外和体内。D)确定L-精氨酸是否纠正了 高血压前期SS/JR大鼠肾脏氯化钠排泄 检测NO和cGMP在内髓钠吸收中的作用 收集导管细胞。

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.