Abnormal Pressure Natriuresis in Hypertension

描述（由申请人提供）：主要研究者的研究项目的长期目标是确定在病理生理条件下，如盐敏感性高血压，肾脏在动脉压调节中的作用。迄今为止，在所有形式的高血压（包括遗传和实验模型以及人类原发性高血压）中发现的一个共同缺陷是压力钠尿关系中的高血压转变。当前建议的一个主要目的是检查肾髓质内皮素系统在调节压力、尿钠和血压中的作用。我们实验室的数据表明，内皮素的产生在肾髓质中被慢性钠负荷特异性地增强。此外，我们实验室的数据表明，在高钠摄入的大鼠中，肾髓质内ETB受体的慢性阻断会导致显著的高血压。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，本研究的目的是验证慢性阻断肾髓质ETB受体通过损害压力钠尿导致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合成的减少间接导致了低压钠尿的发生。此外，我们认为肾髓质内皮素生成和/或ETB受体功能异常介导了Dahl盐敏感大鼠的高血压。广泛的分子、生化、药理学和生理学技术将被用来检验我们的假设。具体目的是：1)验证随着膳食钠摄入量的增加，肾髓内皮素系统在钠排泄和血压调节中发挥更大作用的假设；2)验证肾髓ETB受体阻断期间钠排泄减少和动脉压升高是由于肾髓20-HETE生成减少的假设；3)验证肾髓质内皮素生成和/或ETB受体功能异常介导Dahl盐敏感大鼠高血压的假说

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