RENAL CONTROL OF BODY FLUID VOLUMES AND CIRCULATORY DYNAMICS

肾脏在细胞外的长期调节中起着核心作用。 体液量和动脉压。有几条证据也支持 肾脏在高血压中起着重要作用。一个常见的缺陷是 迄今为止在所有形式的高血压检查中都发现了一种 高血压与血压、钠尿关系的转变。在 之前的计划项目期，我们实验室的研究确定 血管内皮细胞衍生因子改变血管内皮生长因子的生理机制 肾脏排泄钠和水的能力导致高血压。 在目前的提案中，一个主要目标是审查 内皮素、一氧化氮、血栓素等体液因子 以特定形式调节肾压性钠尿的降低 高血压伴内皮细胞功能障碍--妊娠所致 高血压(PIH)。尽管是产妇死亡的主要原因， 孕产妇和围产儿发病率的主要贡献者，其机制 PIH的发病机制目前尚不清楚。启动事件 在妊高征中被认为是子宫胎盘灌注量减少， 导致广泛的母体血管内皮细胞功能障碍 有待定义的机制。需要检验的中心假说 在这项建议中，子宫胎盘灌注量减少是由于 肾压钠尿受损引起的高血压。衰减压力 钠尿是胎盘因子引起血管内皮细胞的结果(S) 细胞功能障碍导致血管收缩物质的形成增强 (内皮素和血栓素)和减少血管扩张剂的形成 (一氧化氮和前列环素)。这些内皮素的异常，反过来， 减少肾血浆流量和肾小球滤过率或增加肾小管 重吸收，从而降低肾钠排泄功能。为了测试 这一假说是对动脉压、肾压、 荷尔蒙和血管内皮细胞的调节将在有意识的， 慢性仪器化大鼠子宫灌流压降低模型 (RUPP)。该模型中的初步数据表明，高血压 子宫胎盘单位的灌流压力降低所产生的 与蛋白尿相关的肾脏血浆流量显著减少 和GFR，这是血压钠尿关系中的高血压变化， 和内皮功能障碍。本提案中概述的实验包括 旨在量化内皮素、一氧化氮、血栓烷的作用 和其他体液因素在调节肾血流动力学降低中的作用 以及排泄功能和RUPP期间动脉压的升高 诱发性高血压。该项目将利用专业知识和资源 从PPG的核心和其他几个项目中帮助实现 提出了具体目标。这些研究的结果应该会提供新的和 有关相关生理机制的重要信息 降低肾脏血流动力学和排泄功能 妊高征期动脉压升高。

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.