CNS Effects of Ovarian Hormones and Metabolites on Neural Control of Circulation

Pregnant women often experience orthostatic hypotension, and pregnancy is associated with increased susceptibility to hemorrhagic hypotension. Experiments evaluating arterial baroreflex control of efferent sympathetic nerve activity in virgin and term-pregnant rats revealed that arterial baroreflex sympathoexcitation is attenuated, while sympathoinhibitory responses are well-maintained or potentiated. Following a hypotensive challenge, pregnant animals exhibit attenuated Fos expression in the rostral ventrolateral medulla (RVLM), suggesting that unloading of arterial baroreceptors results in less excitation of presympathetic neurons in the brain stem. Other experiments, in which afferent baroreceptor discharge was recorded, suggest that this was not due to differences in afferent baoreceptor function. GABAergic mechanisms are responsible for tonic inhibition of sympathoexcitatory neurons in the RVLM and the major metabolite of progesterone, 3 alpha-OH-dihydro-progesterone (3 alpha-OH-DHP), which is elevated in pregnancy, is the most potent endogenous positive modulator of CNS GABAA receptor function. Additional experiments revealed that acutely administered 3 alpha-OH-DHP, either intravenously or directly into the RVLM, mimicked the effects of pregnancy on baroreflex control of efferent sympathetic nerve activity and potentiated pressure sensitivity of spinally projecting RVLM neurons. Preliminary experiments using semiquantitative RT-PCR, evaluated the relative expression of three subunits (alpha 1-3) of the GABAA receptor, and suggest that chronic exposure to elevated levels of ovarian hormones can result to changes in GABAA receptor subunit composition. It is likely that changes in control of sympathetic outflow in pregnancy are related to complex interactions between genomic and nongenomic actions of ovarian hormones and metabolites.