OVARIAN HORMONE METABOLITES & NEURAL CIRCULATORY CONTROL

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DESCRIPTION: (Adapted from the application) Normal pregnancy is associated with a 40% increase in blood volume and cardiac output, slight tachycardia, and a decrease in arterial blood pressure. Enhanced baroreflex sympathoinhibition and attenuated sympathoexcitation have been reported in pregnant animals, although the mechanisms have not been well defined. The primary metabolite of progesterone, 3-alpha-hydroxy-dihydroprogesterone (3-alpha-OH-DHP), which is elevated in pregnancy, is a potent positive modulator of central nervous system (CNS) inhibitory GABA-A receptors. Exogenous administration of 3-alpha-OH-DHP to virgin animals mimics the effects of pregnancy: sympathoinhibition is enhanced and sympathoexcitation is attenuated, most likely through a CNS mechanism. Importantly, blocking the formation of endogenous 3-alpha-OH-DHP in pregnant reverses the attenuated sympathoinhibition. Previous studies focused mainly on enhanced arterial baroreflex sympathoinhibition. In the current proposal, experiments are designed to evaluate mechanisms for the attenuation of sympathoexcitatory responses (likely not arterial baroreflex mediated). The general hypothesis is to be tested that attenuated sympathoexcitation during pregnancy is associated with GABAergic mechanisms in central nervous system sites involved in regulation of cardiovascular function. Three possibilities will be evaluated: Increased inhibitory influences from peripheral receptors other than arterial baroreceptors, increased inhibitory influences from the CNS, and decreased excitatory effects in the rostral ventrolateral medulla (RVLM, brainstem site of cardiovascular sympathetic premotor neurons). Experiments in virgin and pregnant rats will evaluate the CNS expression of Fos protein in identified neuronal populations involved in central cardiovascular control following manipulations which normally increase or decrease efferent sympathetic nerve activity. Efferent sympathetic nerve activity will be recorded in other experiments in which inhibitory afferent inputs, CNS inhibitory influences, and excitatory inputs to the RVLM will be altered. Understanding the mechanism for suppressed sympathoexcitatory responses in normal pregnant animals will have important implications for hypertensive disorders or pregnancy which are associated with exaggerated sympathoexcitatory responses.