Maternal renal and cardiovascular vasodilation, attenuation of systemic vascular reactivity as well as vascular volume expansion are constant features of normal gestation. We first propose to explore potential mechanisms for renal vasodilation and for attenuation of systemic vascular reactivity. Specifically, a role for endothelium-derived relaxing factor (EDRF) and for altered vascular phosphoinositide metabolism will be examined. Second, we intend to characterize the state of volume homeostasis in early gestation, i.e., does a decline in total peripheral resistance precede expansion of vascular volume, thus, producing a state of vascular underfilling? Third, we will test whether renal sympathetic nerve activity -- a potent antinatriuretic factor -- contributes to renal sodium retention, and consequently, to expansion of vascular volume during pregnancy. Because we have found that the conscious, chronically instrumented gravid rat undergoes many renal, cardiovascular and endocrine changes which resemble those of gravid women, this species will be used to address the following Specific Aims: 1. To assess in freshly isolated aortic vasculature from gravid and virgin rats (a) basal and hormone- stimulated production of individual [3H] inositol phosphates including [3H]1,4,5 inositol triphosphate and (b) basal and hormone-stimulated turnover of phosphoinositides and production of diacylglycerol. 2.(a) To serially assess in conscious rats before, during and after pregnancy, the renal vasodilatory response to methacholine and histamine - hormones whose vasodilatory action is most likely mediated by stimulation of EDRF release. (b) To serially assess in conscious rats before, during and after pregnancy, the renal hemodynamic response to NG-monomethyl-L-arginine -- an inhibitor of endothelium-derived relaxing factor production. 3. To serially assess cardiac output and total peripheral resistance in the same unrestrained, chronically instrumented conscious rats before, during and after pregnancy. 4. To measure plasma and total blood volume in conscious pregnant rats (and in age-matched virgin control animals) during that gestational period when the first detectable reductions in total peripheral resistance are observed. 5. To serially quantitate sodium balance during pregnancy in rats subjected to chronic bilateral renal denervation or sham denervation. It is expected that these studies will provide new and important insights into the mechanisms of maternal renal and cardiovascular vasodilation, attenuation of systemic vascular reactivity as well as vascular volume expansion during pregnancy. Improved understanding of these adaptations in normal pregnancy may facilitate efforts to unravel the pathogenesis of preeclampsia --a hypertensive disease peculiar to gestation.
Showing the most recent 10 out of 18 publications
