RENAL HUMORAL FACTORS IN RENAL FUNCTION AND HYPERTENSION

这项建议的研究所依据的假设是， 钠平衡的调节涉及许多利尿钠机制， 然而，最重要的组成部分是合成的变化， 前列腺素（PG）、一氧化氮（NO）和血管紧张素II（Ang II）， 可以直接耦合到血流的肾内分布。的 钠平衡的调节可以在两个水平上发生。第一，海拔 钠摄入量和伴随的血容量增加引起 尿钠排泄增加主要通过NO介导的 机制在这些条件下，NO合成的抑制损害了 钠尿，而PG合成的抑制没有影响。 容量扩张期间钠排泄受损导致钠 保持和血压升高。发展中 高血压导致压力诱导的尿钠排泄（第二水平 钠调节），甚至能够克服 NO合成抑制。压力诱导的尿钠排泄是PG- 依赖性，因为PG合成抑制显着钝化 反应本提案旨在阐明PG、Ang II和/或NO作用于肾皮质和髓质循环， 将血流动力学变化与钠排泄的改变相结合。这是 通过以下方式实现：a）特异性阻断Ang II、PG或 压力性尿钠排泄或扩容恢复期NO 通过给予外源性Ang II、PG或NO供体的作用， 和B）使用选择性肾皮质或髓质血管扩张剂， 探讨皮质和髓质血管舒张对 钠排泄此外，具体的方式， 停用PG和/或NO会减弱钠排泄并促进盐- 敏感性高血压将使用三维 计算机断层扫描（电影CT），可以精确确定 在这些情况下发生的血流动力学和肾小管事件。Cine CT还将用于评价血流动力学与肾小管的耦合， Goldblatt高血压致慢性肾脏高灌注和低灌注 并探讨Ang Ⅱ、PG和NO在这一过程中的调节作用 偶合器.最后，提出了新的研究，使用电影CT评估 通过Henle袢和远端小管的通过时间。我们认为 这些研究将大大推进我们对 高血压的基本机制。大多数拟议的研究是 基于我们的观察，心血管系统的解耦变化 容量或动脉压和钠排泄产生盐敏感 高血压因此，阐明这一病理生理学， 这种现象具有重要的临床和治疗意义。

The hypothesis underlying the studies of this proposal is that the regulation of sodium balance involves a number of natriuretic mechanisms, however, the most essential components are changes in the synthesis of prostaglandins (PG), nitric oxide (NO), and angiotensin II (Ang II) which may be directly coupled to the intrarenal distribution of blood flow. The regulation of sodium balance may occur on two levels. First, elevations in sodium intake and-the accompanying increases in blood volume induce increases in urinary sodium excretion predominately through a NO-mediated mechanism. Under these conditions, inhibition of NO synthesis impairs the natriuresis, whereas, inhibition of PG synthesis has no effect The impairment of sodium excretion during volume expansion leads to sodium retention and an elevation of the blood pressure. The developing hypertension results in a pressure-induced natriuresis (the second level of sodium regulation), which is even capable of overcoming the effects of NO synthesis inhibition. The pressure-induced natriuresis is PG- dependent because PG synthesis inhibition significantly blunts the response. This proposal intends to elucidate the manner in which PG, Ang II, and/or NO act upon the renal cortical and medullary circulations to couple hemodynarnic changes to alterations in sodium excretion. This is achieved by: a) specifically blocking the production of Ang II, PG, or NO during pressure-induced natriuresis or volume expansion and restoring their effects by administration of exogenous Ang II, PG, or NO donors, and b) using selective renal cortical or medullary vasodilators to explore the significance of cortical and medullary vasodilatation on sodium excretion. Furthermore, the specific manner in which the withdrawal of PG and/or NO blunts sodium excretion and fosters salt- sensitive hypertension will he explored using three dimensional computerized tomography (cine CT) which allows the precise determination of the hemodynamic and tubular events occurring in these situations. Cine CT will also be used to evaluate hemodynamic-to-tubular coupling during chronic renal hyper-and hypo-perfusion induced by Goldblatt hypertension and to evaluate the regulatory roles of Ang II, PG, and NO on this coupling. Finally, novel studies are proposed to use cine CT to assess transit times through the loop of Henle and distal tubules. We believe that these studies will considerably advance our knowledge about fundamental mechanisms of hypertension. Most of the proposed studies are based on our observations that uncoupling changes in cardiovascular volume or arterial pressure and sodium excretion produces salt sensitive hypertension. Consequently, elucidation of the pathophysiology of this phenomenon has important clinical and therapeutical implications.