Abnormal Pressure Natriuresis in Hypertension

描述(由申请人提供)：首席研究员研究计划的一个长期目标是确定肾脏在盐敏感型高血压等病理生理条件下调节动脉压中的作用。到目前为止，在所有形式的高血压检查中都发现了一个共同的缺陷，包括遗传和实验模型以及人类原发性高血压，这是血压钠尿关系的高血压转变。本研究的一个主要目的是研究肾髓质内皮质素系统在调节血压、钠尿和血压中的作用。来自我们实验室的数据表明，慢性钠负荷使肾髓质内皮素的产生明显增加。此外，我们实验室的数据表明，长期阻断肾髓质内的ETB受体会导致高钠摄入大鼠明显的高血压。然而，参与调节高血压的确切机制尚不清楚。令人信服的证据表明，肾脏延髓内皮素和细胞色素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，这项提议的目的是验证一个中心假设，即慢性阻断肾脏延髓ETB受体通过损害压力钠尿而导致盐敏感型高血压。减压性钠尿的发生是由于ETB受体对钠排泄的直接影响和/或通过肾髓质20-HETE合成减少而间接发生的。此外，我们认为肾髓质内皮素的产生和/或ETB受体功能的异常参与了Dahl盐敏感大鼠的高血压。我们将使用广泛的分子、生化、药理学和生理学技术来检验我们的假设。要解决的具体目标是：1)检验随着饮食钠摄入量的增加，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说；2)检验肾髓质ETB受体阻断期间钠排泄减少和动脉血压升高是由于肾髓质20-HETE产量减少的假说；3)检验肾髓质内皮素产生和/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