Neural Circulatory Control: Pregnancy & Ovarian Hormones

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DESCRIPTION (provided by applicant): Normal pregnancy is associated with a 40 percent increase in blood volume and cardiac output, slight tachycardia and a decrease in arterial blood pressure. Phasic baroreflex sympathoinhibition is enhanced, while baroreflex sympathoexcitation is attenuated in pregnant animals. Tonic baseline sympathetic outflow is well maintained or moderately increased in pregnancy. The primary metabolite of progesterone, 3a-hydroxydihydroprogesterone (3a-OH-DHP), which is elevated in pregnancy, is a potent positive modulator of central nervous system inhibitory GABAA receptors (Paul & Purdy, 1992). Exogenous administration of 3a-OHDHP to virgin animals mimics the effects of pregnancy: arterial baroreflex sympathoinhibition is enhanced and sympathoexcitation is attenuated, through a central nervous system mechanism. Previous studies focused mainly on phasic arterial baroreflex responses and enhanced arterial baroreflex sympathoinhibition. In the current proposal, experiments are designed to evaluate potential mechanisms for the attenuation of phasic sympathoexcitatory responses (likely not arterial baroreflex dependent), and the mechanisms for maintenance of baseline sympathetic tone in pregnancy. The general hypothesis to be tested is: Pregnancy alters the balance between tonic inhibitory and excitatory influences on efferent sympathetic outflow, such that tonic (baseline) sympathetic drive is well maintained, while phasic (reflex) increases in sympathetic nerve activy are attenuated. Planned experiments address enhanced tonic inhibitory mechanisms in the rostral ventrolateral medulla (RVLM) and enhanced tonic excitation originating from the paraventricular nucleus of the hypothalamus (PVN) in pregnant rats. Regional efferent sympathetic nerve activity will be recorded in experiments in which inhibitory afferent inputs, central nervous system inhibitory influences, and excitatory and inhibitory influences in the RVLM and PVN will be altered. Experiments will evaluate the source and potential mediators of observed responses. Understanding the mechanism for suppressed phasic sympathoexcitatory responses and maintenance of tonic sympathetic outflow in normal pregnant animals will have important implications for hypertensive disorders of pregnancy which are associated with exaggerated sympathoexcitatory responses.