CARDIOVASCULAR/RENAL MECHANISMS OF HYPERTENSION

肾脏在细胞外液量和动脉压的长期调节中发挥核心作用。 一些证据也支持肾脏在高血压发病机制中的重要作用。 迄今为止，在所有形式的高血压检查中发现的一个常见缺陷是血压尿钠排泄关系的高血压转变。 在目前的建议中，一个主要目标是研究内皮素和一氧化氮在介导与内皮功能障碍相关的高血压-妊娠高血压（PIH）的特定形式的肾压尿钠排泄减少中的作用。 尽管妊高征是孕产妇死亡的主要原因，也是孕产妇和围产期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尿钠排泄引起高血压。 由于胎盘因素导致内皮细胞功能障碍，导致血管收缩剂（内皮素和血栓素）形成增强和血管扩张剂（一氧化氮和前列环素）形成减少，从而发生压力性尿钠排泄减弱。 反过来，这些内皮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。 为了检验这一假设，将在子宫灌注压降低（RUPP）的清醒、慢性仪器化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，子宫胎盘单位灌注压降低所产生的高血压与蛋白尿、肾血浆流量和GFR显著降低、压力尿钠排泄关系的高血压转变和内皮功能障碍相关。

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.