MECHANISMS OF SALT SENSITIVE HYPERTENSION

高血压仍然是老年人心血管疾病的主要危险因素。 美国。尽管很大比例的动脉压 高血压患者对高钠饮食敏感，其机制 盐敏感型高血压的发病机制尚不清楚。 高血压在人类和动物模型中的最新研究 表明一氧化氮(NO)的产生不足可能起到了一定作用 盐敏感型高血压。主要的假设是有缺陷的 一氧化氮合酶(NOS)的各种异构体的数量，特别是那些 在肾脏中，肾髓质在盐分的发展中起着重要作用。 敏感性高血压。达尔盐敏感(S)大鼠将被用作 盐敏感型高血压模型来验证这一假说，因为它已经 可能与对盐敏感的人类的共同特征包括 NO生成减少，肾素-血管紧张素系统受到抑制。 特定目标1将确定钝化是否会增加肾脏中的NO 达尔S大鼠高钠摄入量减量所致 以内皮型一氧化氮合酶、脑型一氧化氮合酶或诱导型一氧化氮合酶为主 肾实质带。信使RNA、蛋白质含量和活性 将在肾皮质和髓质组织中测量一氧化氮合酶亚型 在5~6周龄的Dahl，S和R和Lewis大鼠中，低钠或高钠饮食 入口处。特定的目标2和3将决定iNOS、bNOS和 肾素-血管紧张素系统在达尔·S盐敏感中的作用 高血压通过检测动脉血压的长期反应， 肾血流动力学、肾小管钠重吸收、尿硝酸盐/亚硝酸盐 排泄和血浆肾素活性与钠摄入量变化的关系 选择性全身或髓内诱导型一氧化氮合酶的存在或缺失 抑制或抑制bNOS。同时，髓内注射L-精氨酸 使用或不使用选择性髓内iNOS或bNOS抑制将 确定iNOS或bNOS在髓质中产生NO是否重要 在预防短跑S高血压方面。这些研究将提供新的 关于可能导致压力受损的肾内机制的信息 钠尿和盐敏感型高血压。

Hypertension continues to be a major cardiovascular risk factor in the United States. Although the arterial pressure of a large percentage of hypertensives is sensitive to a high sodium diet, the mechanisms underlying the pathogenesis of salt-sensitive hypertension are unknown. Recent studies in humans in human and animal models of hypertension indicate that a deficient production of nitric oxide (NO) may contribute to salt-sensitive hypertension. The primary hypothesis is that deficient amounts of the various isoforms of NO synthase (NOS), particularly those in renal the renal medulla, play a major role in the development of salt- sensitive hypertension. The Dahl salt-sensitive (S) rat will be used as a model of salt-sensitive hypertension to test this hypothesis, since it has may characteristics in common with salt-sensitive humans including decreased NO production and a suppressed renin-angiotensin system. Specific Aim 1 will determine if the blunted increased in NO in the kidney of the Dahl S rat during high sodium intake results from attenuated levels of endothelial NOS, brain NOS (bNOS) or inducible NOS (iNOS) in the main renal parenchymal zones. Messenger RNA, protein amounts and activities of the NOS isoforms will be measured in renal cortical and medullary tissues in 5 to 6 week old Dahl S and R and Lewis rats on a low or high sodium intake. Specific Aims 2 and 3 will determine the roles of iNOS, bNOS and the renin-angiotensin system in causing salt-sensitivity in Dahl S hypertension by examining the long-term responses of arterial pressure, renal hemodynamics, tubular sodium reabsorption, urinary nitrate/nitrite excretion and plasma renin activity to changes in sodium intake in the presence or absence of selective systematic or intramedullary iNOS inhibition or bNOS inhibition. Also, intramedullary L-arginine infusion with or without selective intramedullary iNOS or bNOS inhibition will determine whether medullary production of NO by iNOS or bNOS are important in preventing Dash S hypertension. These studies will provide new information about intrarenal mechanisms that can lead to impaired pressure natriuresis and salt-sensitive hypertension.