ABNORMAL PRESSURE NATRIURESIS IN HYPERTENSION

有相当多的证据支持这一理论， 肾功能不全在发展和维持中起作用， 高血压在几种遗传性高血压中，一种常见的缺陷是 已确定与压力性尿钠排泄的关系。缺陷 在高血压动物中，部分原因是不能通过肾脏 灌注压进入肾动脉。这项提案的目的是 是研究可能的机制，介导这种肾内 异常 近年来的研究表明，内皮素（ET）和一氧化氮（NO） 对肾排泄功能有显著影响， 这些因子的合成在高血压中可能改变。主要 该提案的目的是检验假设，即 将肾灌注压传输到肾动脉中， 由于肾自体血中的异常，如NO和ET。各种 包括微循环、整个肾脏和整个动物 将被用来研究ET和NO在促进 不同高血压模型中的异常压力尿钠排泄。的 将解决的问题是：1）是否无法传输 Dahl S大鼠肾动脉灌注压 NO合成减少的原因吗2)L-精氨酸通过什么机制 恢复Dahl S大鼠的正常血压尿钠排泄关系？并 L-精氨酸促进RPP向肾组织的传递 影响延髓血流动力学吗 3)慢性肾间质性 向Dahl R大鼠中输注NO合酶抑制剂使其盐- 敏感？ 4)ET在异常压力中起什么作用 各种形式的高血压中的尿钠排泄？ET输注是否 受体拮抗剂改善RPP向肾脏的传递 氚？ 5)ET在疾病进展中扮演什么角色？ 高血压：长期输注内皮素受体拮抗剂是否会导致 长期降低动脉压的各种形式， 高血压？

There is considerable evidence to support the theory that some form of renal dysfunction plays a role in the development and maintenance of hypertension. In several forms of genetic hypertension, a common defect has been identified in the pressure natriuresis relationship. The defect in hypertensive animals is partly due to an inability to transmit renal perfusion pressure into the renal interstitium. The goal of this proposal is to examine possible mechanism that mediate this intrarenal abnormality. In recent studies, endothelin (ET) and nitric oxide (NO) have been shown to have significant effects on renal excretory function and that synthesis of these factors may be altered in hypertension. The main objective of this proposal is to test the hypothesis that the inability to transmit the renal perfusion pressure into the renal interstitium is due to abnormalities in the renal autocoids such as NO and ET. A variety of techniques including microcirculatory, whole kidney, and whole animal will be used to examine the roles of ET and NO in contributing to the abnormal pressure natriuresis in different models of hypertension. The questions that will be addressed are: 1) Is the inability to transmit renal perfusion pressure into the renal interstitium in Dahl S rats due to a decrease in NO synthesis? 2) By what mechanism does L-arginine restore the normal pressure natriuresis relationship in Dahl S rats? Does L-arginine improve transmission of RPP into the renal interstitium by affecting medullary hemodynamics? 3) Does chronic renal interstitial infusion of a NO synthase inhibitor into Dahl R rats render them salt- sensitive? 4) What role does ET play in the abnormal pressure natriuresis in various forms of hypertension? Does infusion of an ET receptor antagonist improve the transmission of RPP into the renal interstitium? 5) What role does ET lay in the progression of hypertension: Does chronic infusion of an ET receptor antagonist lead to long-term reductions in arterial pressure in various forms of hypertension?