Normal pregnancy is associated with a decrease in arterial blood pressure, a shift in the arterial baroreflex function curve towards a lower operating pressure range, and an attenuated ability to increase sympathetic outflow above baseline levels. The mechanisms for these changes are not known, but effects of ovarian hormones may contribute, since circulating levels of both estrogen and progesterone are elevated in pregnancy. The classical mechanism of action for steroid hormones requires binding to a nuclear receptor, followed by protein synthesis, the products of which mediate the steroid hormone's action (genomic effect). However, recently it has been convincingly demonstrated that steroid hormone metabolites such as the primary progesterone metabolite, 3alpha-hydroxy-dihydroprogesterone (3alpha-OH-DHP), have immediate and stereospecific membrane effects not requiring protein synthesis (nongenomic effect). In fact, 3alpha-OH-DHP, which is elevated in pregnancy, is the most potent endogenous positive modulator of central nervous system GABA(A) receptors. Recent experiments in our laboratory have provided exciting preliminary data suggesting that immediate actions of 3alpha-OH-DHP mimic the effects of pregnancy on baroreflex control of sympathetic outflow. The general hypothesis to be tested is that the effects of steroid hormones on control of sympathetic outflow are mediated in part by nongenomic actions of the progesterone metabolite, 3alpha-OH-DHP, on GABAergic mechanisms in cardiovascularly relevant sites in the brainstem. Experiments are designed to evaluate a possible interaction between genomic and nongenomic effects of ovarian hormones and progesterone metabolites; to determine if acute administration of progesterone has effects similar to its metabolite and possible mechanisms; to evaluate if the effects of 3alpha-OH-DHP and/or progesterone are mediated through a modulation of GABA(A) receptors in the brainstem; to determine if 3alpha-OH-DHP modulation of GABA(A) ligand binding to cardiovascularly relevant areas in the brainstem correlates with physiological responses; and lastly to determine if heterogeneity of the GABA(A) receptor in regard to subunit composition correlates with regional variations in central nervous system responsiveness to 3alpha- OH-DHP.
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