The mechanisms responsible for normal maternal cardiovascular adaptation during pregnancy are unknown, but likely include the interaction of the cardiovascular system with various steroid and peptide hormones along with other vasoactive substances, e.g., prostanoids (PGs). Therefore, the long-term objective of this project is to determine those factors in the maternal and fetoplacental compartments normally involved with regulation of the magnitude and distribution of uteroplacental perfusion and general maternal and fetal cardiovascular adaptation. To achieve this goal, the chronically instrumented sheep and fetus will be studied using 3 methods of assessing local and systemic hemodynamic responses to vasoactive agents and normally occurring changes in pregnancy: flow probes, dye-dilution measurements of cardiac output (CO) and radionuclide-labeled microspheres. This combined approach permits simultaneous comparisons between local organ, in particular the gravid uterus, and systemic responses, e.g., CO. Timely blood samples will be obtained, permitting the evaluation of relationships between circulating hormones and physiologic events. From these same animals, samples of arteries will be obtained from the gravide uterus and various systemic vascular beds in order to evaluate and compare vessel metabolism and hormone production as well as reactivity; this is done using incubation and perfusion techniques. Using these methods it is proposed to define in detail the roles of the renin-angiotensin and sympathetic nervous systems in adaptation after estrogen (E)-induced systemic vasodilation, to determine the role of Ca++ fluxes in E-mediated vasodilation, to examine the role of E as a Ca++ channel inhibitor as an explanation for vascular refractoriness in pregnancy, to further define the role of E in cardiovascular adaptation in pregnancy using E receptor blockade, to determine the role of PGs in vascular refractoriness and examine cellular events resulting in angiotensin II-induced increases in PG production, to described the changes in AII vascular receptors that occur in pregnancy in uterine and systemic arteries, correlating this with PG production and vessel responses, and to examine smooth muscle function by studies of myosin light chain phosphorylation. By achieving these aims the cardiovascular physiology of normal pregnancy will be better understood, thereby potentially improving our approach to abnormal pregnancies.
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