The hypertensive disorders of pregnancy are a major contributor to perinatal morbidity and mortality and as such they represent an important public health problem. The main objectives of the proposed studies are to develop a model of uteroplacental ischemia-induced hypertension in the pregnant dog and then to study the specific renal and hormonal mechanisms involved in the development and maintenance of hypertension in this model.
The specific aims of these studies are 1) to develop a model of controllable, reversible uteroplacental ischemia-induced hypertension in the chronically instrumented pregnant dog by precisely servo-controlling uterine perfusion pressure at a reduced level for one to two weeks while continuously monitoring systemic arterial pressure, 2) to characterize this model of hypertension in pregnancy and evaluate it as a suitable model of pregnancy- induced hypertension (PIH) in women by looking at the variables that are often abnormal in PIH. Specifically, we plan to determine whether proteinuria, reduced blood volume, increased extracellular fluid volume, reduced renal plasma flow (RPF) and glomerular filtration rate (GFR), glomerular lesions, and coagulation defects are present in our model, 3) to test the hypothesis that a vasoconstrictor substance is released into the maternal circulation by the uterus/placenta during reductions in uterine perfusion pressure, and if so, to attempt to identify this substance and to determine the time course of its release, 4) to determine the renal mechanisms involved in the development and maintenance of hypertension, including changes in RPF, GFR, and tubular sodium handling, 5) to test the hypothesis that the renin- angiotensin system is involved in the development and maintenance of hypertension by fixing the activity of this system before reducing uterine perfusion pressure, 6) to test the hypothesis that the prostaglandin system is involved in the development and maintenance of hypertension by blocking prostaglandin synthesis before reducing uterine perfusion pressure, 7) to test the concept that the degree of hypertension developed is proportional to the level of sodium intake, and 8) to determine the degree to which uterine blood flow is capable of autoregulation during reductions in perfusion pressure, both acutely and chronically, and if autoregulation does occur, to test the hypotheses that the renin-angiotensin and prostaglandin systems are involved in mediating this response.
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