ABNORMAL PRESSURE NATRIURESIS IN HYPERTENSION

有相当多的证据支持这样的理论，即某种形式的 肾功能障碍在慢性肾功能衰竭的发生和维持中起着重要作用 高血压。在多种形式的遗传性高血压中，一种常见的缺陷 已被确认为与压力钠尿的关系。这一缺陷 在高血压动物中的部分原因是无法传递肾脏 肾间质的灌流压力。这项提案的目标是 是为了研究调节这种肾内病变的可能机制 反常现象。 在最近的研究中，内皮素(ET)和一氧化氮(NO)被发现 对肾脏排泄功能有显著影响 高血压患者体内这些因子的合成可能会发生改变。主 这项提议的目的是检验假设，即 将肾灌注压传递到肾间质是 由于NO、ET等肾脏自体激素的异常。品种繁多 包括微循环技术、全肾技术和全动物技术 将被用来研究ET和NO在促进 不同高血压模型的异常压力性钠尿。这个 将解决的问题包括：1)无法传输 Dahl-S大鼠肾间质的肾灌注压 减少NO的合成？2)L精氨酸是通过什么机制 能否恢复达尔-S大鼠的正常血压排钠关系？会吗？ L-精氨酸通过以下途径促进RPP向肾间质的转运 影响髓质血流动力学？3)慢性肾间质 将一氧化氮合酶抑制剂注入Dahl R大鼠体内，使其盐分下降。 敏感？4)ET在异常压力中起什么作用 各种形式的高血压患者的钠尿症？输注ET是否 受体拮抗剂改善RPP向肾脏的传递 间质？ET在血管内皮细胞癌的发展中起什么作用 高血压：长期输注ET受体拮抗剂是否会导致 各种形式的动脉血压的长期降低 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?