The prorenin-renin-angiotensin-aldosterone system (RAAS) will be investigated in normal and hypertensive pregnancy. To evaluate the role of angiotensin II in the hemo-dynamic changes of pregnancy, the effect of converting enzyme inhibition (CEI) will be studied in women with scheduled abortions; blood pressure, renin, glomerular filtration rate (GFR), renal plasma flow (RPF), urine sodium excretion and uteroplacental flow velocity profiles will be measured. To relate hemodynamic changes to RAAS in pregnancy, longitudinal studies of normals, pregnancy-induced hypertensives and chronic hypertensives (30% develop superimposed preeclampsia) will be carried out; GFR and RPF or uterine blood flow (vaginal Doppler ultrasound) will be measured. To define first trimester changes, in vitro fertilization and ovarian failure patients, who have a broad spectrum of plasma prorenins will be studied. Since interrelated changes in renin and prostaglandins may participate in pathogenesis of hypertensive pregnancy, RAAS, prostaglandins and uteroplacental flow velocity profiles will be monitored during a placebo controlled trail of low dose aspirin in chronic hypertensives. In parallel invasive studies, microsphere measurements of the distribution of cardiac output to the reproductive and non- reproductive organs and bloods volume measurements will be made in unrestrained, awake pregnant cynomolgus monkeys. In them the effects of both acute and chronic blockade of the RAAS will CEI will also be monitored. During years 4 and 5 hypertensive monkeys will be bred and similarly studied. The function of placental prorenin will be investigated in vitro. The effects of the renin system on steroid biosynthesis and of steroids and gonadotropins on prorenin biosynthesis and secretion will be evaluated using tissue culture, cell superfusion and cotyledon perfusion techniques. Ligand binding studies will be performed to identify and characterize prorenin receptors. The transfer of prorenin between maternal and fetal circulations will be investigated. This application is from an internist/nephrologist, an obstetrician and a basic scientist who have on ongoing and interdependent relationship because of their common interest in hypertension of pregnancy. Together their studies should help to clarify the role of the prorenin-renin-angiotensin-aldosterone system in the maintenance of cardiovascular homeostasis in normal and hypertensive pregnancy.
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