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.
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