Abnormal Pressure Natriuresis in Hypertension

描述（由申请人提供）：主要研究者研究计划的长期目标是确定肾脏在盐敏感性高血压等病理生理条件下调节动脉压的作用。迄今为止，在所有形式的高血压中发现的一个常见缺陷，包括遗传和实验模型以及人类原发性高血压，是压力尿钠排泄关系中的高血压转变。目前的建议的一个主要目标是检查肾髓质内皮素系统在调节压力尿钠排泄和血压的作用。来自我们实验室的数据表明，慢性钠负荷特别是在肾髓质中增强内皮素的产生。此外，来自我们实验室的数据表明，慢性阻断肾髓质内的ETB受体导致高钠摄入大鼠的显著高血压。然而，介导高血压的确切机制尚不清楚。令人信服的证据表明肾髓质内皮素和细胞色素P450酶/20-羟基二十碳四烯酸（20-HETE）系统之间存在潜在的相互作用。因此，本研究的目的是检验肾髓质ETB受体的慢性阻断通过损害压力性尿钠排泄引起盐敏感性高血压的中心假设。由于ETB受体对钠排泄的直接影响和/或肾髓质20-HETE合成减少间接导致压力性尿钠排泄减弱。此外，我们建议，肾髓质内皮素生产和/或ETB受体功能的异常介导的高血压在达尔盐敏感大鼠。广泛的分子，生物化学，药理学和生理学技术将被用来测试我们的假设。具体的目的是：1）验证随着饮食中钠摄入量的增加，肾髓质内皮素系统在调节钠排泄和血压方面发挥更大作用的假设; 2）验证在肾髓质ETB受体阻断期间钠排泄减少和动脉压升高是由于肾髓质20-HETE产生减少的假设; 3）验证Dahl盐敏感大鼠肾髓质内皮素生成和/或ETB受体功能异常介导高血压的假设

DESCRIPTION (provided by applicant): A long-term goal of the principal investigator's research program is to determine the role of the kidneys in the regulation of arterial pressure during pathophysiological conditions such as salt-sensitive hypertension. A common defect that has been found in all forms of hypertension examined to date, including genetic and experimental models and human essential hypertension, is a hypertensive shift in the pressure natriuresis relationship. A major objective of the current proposal is to examine the role of the renal medullary endothelin system in modulating pressure natriuresis and blood pressure. Data from our laboratory indicates that the production of endothelin is enhanced specifically in the renal medulla by chronic sodium loading. Moreover, data from our laboratory indicate that chronic blockade of ETB receptors within the renal medulla results in significant hypertension in rats on a high sodium intake. The exact mechanisms involved in mediating the hypertension, however, are unknown. Compelling evidence indicates a potential interaction between the renal medullary endothelin and cytochrome P450 enzyme /20-Hydroxyeicosatetraenoic acid (20-HETE) systems. Thus, the goal of this proposal is to test the central hypothesis that chronic blockade of renal medullary ETB receptors causes salt-sensitive hypertension by impairing pressure natriuresis. Attenuated pressure natriuresis occurs as a result of a direct influence of ETB receptors on sodium excretion and/or indirectly by decreased synthesis of renal medullary 20-HETE. Furthermore, we propose that abnormalities in renal medullary endothelin production and/or ETB receptor function mediate the hypertension in Dahl salt-sensitive rats. A wide range of molecular, biochemical, pharmacological, and physiological techniques will be used to test our hypothesis. Specific aims to be addressed are: 1) To test the hypothesis that the renal medullary endothelin system plays a greater role in regulating sodium excretion and blood pressure as dietary sodium intake is increased; 2) To test the hypothesis that the reduction in sodium excretion and elevation in arterial pressure during renal medullary ETB receptor blockade is due to a decrease in renal medullary production of 20-HETE; 3) To test the hypothesis that abnormalities in renal medullary endothelin production and/or ETB receptor function mediate the hypertension in Dahl salt-sensitive rats