Pronounced vasodilation of the maternal circulation typified normal gestation and is critical to successful outcome of pregnancy. Our objective is to identify the mechanisms responsible for this adaptation in normal pregnancy. Another goal is to understand the pathogenesis of pathogenesis of preeclampsia, which is a leading cause of fetal and maternal, morbidity and mortality. An essential step toward understanding the pathological changes that produce preeclampsia is to understand the mechanisms that lead to circulatory changes in normal pregnancy. Alterations of vascular wall function during pregnancy contribute to systemic and renal vasodilation. Vasodilatory factors such as prostaglandins and endogenous nitric oxide (NO) may play a role. Although we previously showed that prostaglandins are most likely not involved, recent evidence suggest that NO may contribute, and we propose to test this hypothesis. We have found that chronically instrumented gravid rats undergo circulatory changes that are remarkably similar to those of gravid women. We further showed that endogenous biosynthesis of NO and cGMP, the second messenger of NO, are increased in pregnant rats. Therefore, a role of NO will be tested in this animal preparation as well as in gravid women. Evidence for increased functional and biochemical activity of No will also be sought in resistance vessel in vitro. (1)Hypothesis. Production of NO increases during normal human pregnancy.
Specific Aim. To assess plasma level and urinary excretion of nitrate (a stable metabolite of NO) as well as blood level of NO hemoglobin in gravid women. Nitrate and NO- hemoglobin are measured by enzymatic/spectrophotometric analysis and electron paramagnetic resonance spectroscopy, respectively. (2) Hypothesis. Production of NO decrease in preeclampsia.
Specific Aim. To determine plasma level and urinary excretion of nitrate as well as blood level of NO-hemoglobin in women with preeclampsia. (3) Hypothesis. NO mediates systemic and renal vasodilation in rat pregnancy.
Specific Aim. To test whether nitroarginine methyl ester (NAME) and N-monomethyl arginine (NMA)--inhibitors of NO synthase--will inhibit systemic an renal vasodilation in conscious, pregnant rats. (4) Hypothesis. NO mediates reduced myogenic tone of the mesenteric and renal resistance vasculature during gestation.
Specific Aim. To examine the effect of endothelial removal, NAME and other NO and guanylate cyclase inhibitors on myogenic tone of mesenteric and renal arterioles in vitro. (5) hypothesis. NO biosynthesis increase in resistance vessels during pregnancy.
Specific Aim. To assess NO synthase activity in isolated mesenteric arterioles. If a role for NO is implicated in pregnancy, then future experiments will explore the stimulus for altered NO production, as well as biochemical and molecular changes of NO synthase(s) which account for altered NO activity.
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