CARDIOVASCULAR/RENAL MECHANISMS OF HYPERTENSION

肾脏在细胞外液容量和动脉压的长期调节中起着核心作用。一些证据也支持肾脏在高血压发病机制中的重要作用。到目前为止，在所有形式的高血压检查中发现的一个共同缺陷是血压钠尿关系的高血压转变。在目前的提案中，一个主要目标是研究内皮素和一氧化氮在调节一种与内皮功能障碍相关的特殊形式的高血压--妊娠高血压综合征(PIH)--肾压钠尿减少中的作用。尽管妊高征是孕产妇死亡的主要原因，也是孕产妇和围产儿发病率的主要贡献者，但其发病机制尚不清楚。我们目前的工作假设是，子宫胎盘灌注减少通过损害肾压钠尿而导致高血压。降压性钠尿的发生是由于胎盘因子(S)导致内皮细胞功能障碍，导致血管收缩因子(内皮素和血栓素)的形成增加，血管扩张剂(一氧化氮和前列环素)的形成减少。这些内皮细胞的异常反过来降低了肾脏的血浆流量和肾小球滤过率或增强了肾小管的重吸收，从而降低了肾脏的钠排泄功能。为了验证这一假设，将在清醒的、长期使用仪器的子宫灌流压降低(RUPP)的大鼠模型中进行动脉压、肾脏、激素和内皮调节的综合分析。该模型的初步数据表明，子宫胎盘单位的灌流压力降低所产生的高血压与蛋白尿、肾血浆流量和肾小球滤过率显著减少、血压钠尿关系的高血压改变以及内皮功能障碍有关。

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 the pathogenesis of 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 current proposal, a major objective is to examine the role of endothelin and nitric oxide 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. Our current working hypothesis is that reduced uteroplacental perfusion causes 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 endothelial 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 uteroplacental unit is associated with proteinuria, significant reductions in renal plasma flow and GFR, a hypertensive shift in the pressure natriuresis relationship, and endothelial dysfunction.