RENAL CONTROL OF BODY FLUID VOLUMES AND CIRCULATORY DYNAMICS

肾脏在长期调节细胞外 液体容量和动脉压。一些证据也支持 肾脏在高血压中的重要作用。一个常见的缺陷， 在迄今为止检查的所有形式的高血压中发现的是一种 高血压移位与血压性尿钠排泄的关系。在 上一个计划项目期间，我们实验室的研究确定 内皮衍生因子改变血管内皮细胞的生理机制 肾脏排泄钠和水的能力，导致高血压。 在本提案中，一个主要目标是审查 内皮素、一氧化氮、血栓素等体液因子 以特定形式介导肾压尿钠排泄减少 与内皮功能障碍相关的高血压 高血压（PIH）。尽管这是产妇死亡的主要原因， 产妇和围产期发病率的一个主要因素， 妊高征的发病机制尚不清楚。始发事件 在妊高征中，假定子宫胎盘灌注减少， 导致母体血管内皮的广泛功能障碍， 这些机制尚待确定。待检验的中心假设 在该建议中，子宫胎盘灌注减少导致 通过损害肾压尿钠排泄而导致高血压。衰减压力 尿钠排泄是由于胎盘因子引起内皮细胞 导致血管收缩剂形成增强的细胞功能障碍 （内皮素和血栓素）和血管扩张剂形成减少 （一氧化氮和前列环素）。反过来，这些内皮素异常， 降低肾血浆流量和肾小球滤过率或增强肾小管 重吸收，从而降低肾钠排泄功能。测试 这一假设是对动脉压，肾压， 激素和内皮调节将在有意识的， 子宫灌注压降低的慢性内固定大鼠模型 （RUPP）。该模型的初步数据表明， 子宫胎盘中央单位的灌注压降低所产生的 与蛋白尿相关，肾血浆流量显著减少 和GFR，压力尿钠排泄关系中的高血压变化， 和内皮功能障碍。该提案中概述的实验是 旨在定量内皮素、一氧化氮、血栓素 和其他体液因子介导肾血流动力学降低 以及RUPP期间的排泄功能和动脉压升高- 诱发性高血压该项目将利用专门知识和资源 从核心和PPG的其他几个项目，以帮助实现 提出具体目标。这些研究的结果将提供新的和 重要的信息，关于生理机制负责 肾血流动力学和排泄功能降低， 妊高征期间动脉压升高。

The kidneys play a central role in long-term regulation of extracellular fluid volume and arterial pressure. Several lines of evidence also support an important role for the kidneys in hypertension. A common defect that has been found in all forms of hypertension examined to date is a hypertensive shift in the pressure natriuresis relationship. In the previous Program Project period, studies from our laboratory determined the physiological mechanisms whereby endothelial derived factors alter the kidney's capability to excrete sodium and water and lead to hypertension. In the current proposal, a major objective is to examine the role of endothelin, nitric oxide, thromboxane and other humoral factors in mediating the reduction in renal-pressure natriuresis in a specific form of hypertension associated with endothelial dysfunction--pregnancy-induced hypertension (PIH). Despite being the leading cause of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of PIH are unclear. The initiating event in PIH has been postulated to be reduced uteroplacental perfusion which leads to widespread dysfunction of the maternal vascular endothelium by mechanisms that remain to be defined. The central hypothesis to be tested in this proposal is that reduced uteroplacental perfusion cause hypertension by impairing renal-pressure natriuresis. Attenuated pressure natriuresis occurs as a result of placental factor(s) causing endothelial cell dysfunction leading to enhanced formation of vasoconstrictors (endothelin and thromboxane) and decreased formation of vasodilators (nitric oxide and prostacyclin). These endothelin abnormalities, in turn, reduce renal plasma flow and glomerular filtration rate or enhance tubular reabsorption, thereby decreasing renal sodium excretory function. To test this hypothesis, an integrated analysis of arterial pressure, renal, hormonal, and endothelial regulation will be conducted in a conscious, chronically-instrumented rat model of reduced uterine perfusion pressure (RUPP). Preliminary data in this model indicate that the hypertension produced by decreased perfusion pressure to the uteroplacentral unit is associated with proteinuria, significant reductions in renal plasma flow and GFR, a hypertensive shift in the pressure natriuresis relationship, and endothelial dysfunction. Experiments outlined in this proposal are designed to quantitate the role of endothelin, nitric oxide, thromboxane and other humor factors in mediating the reduction in renal hemodynamic and excretory function and elevation in arterial pressure during RUPP- induced hypertension. This project will utilize expertise and resources from the cores and several other projects of the PPG to help achieve the proposed specific aims. Results from these studies should provide new and important information regarding the physiological mechanisms responsible for the reduction in renal hemodynamic and excretory function and elevation in arterial pressure during PIH.