EFFECTS OF PREGNANCY AND PROGESTERONE METABOLITES ON REGULATION OF SYMPATHETIC OUTFLOW

1. Pregnancy is characterized by a 40% increase in blood volume and cardiac output, a decrease in arterial blood pressure and thus a substantial decrease in total peripheral resistance. The aims of the experiments described in this manuscript were: (i) to determine if pregnancy resulted in alterations in baroreflex control of sympathetic outflow; and (ii) to evaluate possible mechanisms for pregnancy-induced changes in control of sympathetic outflow. 2. Arterial baroreflex control of efferent renal sympathetic nerve activity was examined in female pregnant and nonpregnant normotensive Sprague-Dawley and Wistar-Kyoto rats. In both rat strains, pregnancy was associated with a decrease in baseline arterial pressure, a shift in the baroreflex function curve to a lower operating pressure range and an attenuated ability to reflexly increase sympathetic outflow above baseline levels during a hypotensive challenge. Pregnant Sprague-Dawley rats retained their ability to respond to a hypertensive challenge, whereas pregnant Wistar-Kyoto rats exhibited a decreased sensitivity to hypertensive as well as hypotensive challenges. 3. The inhibitory amino acid transmitter, GABA, mediates baroreflex sympatho-inhibition within the rostral ventral lateral medulla (RVLM) of the brainstem. Since 3 alpha-OH dihydroprogesterone (3 alpha-OH-DHP), a major metabolite of progesterone, is elevated in pregnancy and has been reported to potentiate central nervous system GABA(A) inhibitory responses, experiments were performed to determine if effects of this metabolite of progesterone could contribute to the pregnancy associated changes in control of sympathetic outflow. Acute intravenous administration of 3 alpha-OH-DHP to virgin female Sprague-Dawley rats resulted in progressive changes in the baroreflex function curve that mimicked the effects of pregnancy. 4. Preliminary experiments in which the GABA(A) agonist, isoguvacine, and 3 alpha-OH-DHP were micro-injected into the RVLM of virgin female rats suggest that the 3 alpha-OH metabolite of progesterone potentiates sympatho-inhibitory effects of GABAA receptor activation in the RVLM. 5. In conclusion, acute administration of 3 alpha-OH-DHP to virgin female rats mimics the effects of pregnancy on baroreflex control of sympathetic outflow. These results are consistent with potentiation of GABAergic sympatho-inhibition by circulating levels of the major metabolite of progesterone during pregnancy.