MECHANISMS OF SALT SENSITIVE HYPERTENSION

高血压仍然是世界上主要的心血管危险因素 美国的尽管很大一部分人的动脉压 高血压患者对高钠饮食敏感， 盐敏感性高血压的发病机制尚不清楚。 高血压的人类和动物模型的最新研究 表明一氧化氮（NO）产生不足可能有助于 盐敏感性高血压主要假设是， NO合酶（NOS）的各种亚型的量，特别是那些 在肾脏中，肾髓质在盐的发育中起主要作用- 敏感性高血压Dahl盐敏感（S）大鼠将用作 盐敏感性高血压模型来检验这一假设，因为它 与盐敏感的人类共同的特征包括 减少NO的产生和抑制肾素-血管紧张素系统。 特异性目的1将确定肾脏中NO的钝化增加是否 Dahl S大鼠在高钠摄入过程中， 内皮型NOS、脑型NOS（bNOS）或诱导型NOS（iNOS）主要 肾实质区信使RNA、蛋白质量和活性 将在肾皮质和髓质组织中测量NOS同工型 在5 - 6周龄Dahl S和R以及刘易斯大鼠中， 摄入具体目标2和3将确定iNOS、bNOS和 肾素-血管紧张素系统在Dahl S细胞盐敏感性中作用 高血压通过检查动脉压的长期反应， 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对钠摄入量变化的影响 存在或不存在选择性系统或髓内iNOS 抑制或bNOS抑制。同时，髓内L-精氨酸灌注 有或没有选择性髓内iNOS或bNOS抑制将 确定iNOS或bNOS在髓质产生NO是否重要 预防Dash S型高血压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 尿钠排泄和盐敏感性高血压。

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.