EFFECTS OF PREGNANCY AND PROGESTERONE METABOLITES ON REGULATION OF SYMPATHETIC OUTFLOW

1. Pregnancy is characterized by a 40% increase in blood volume and ca rdiac output, a decrease in arterial blood pressure and thus a substan tial decrease in total peripheral resistance. The aims of the experime nts described in this manuscript were: (i) to determine if pregnancy r esulted in alterations in baroreflex control of sympathetic outflow; a nd (ii) to evaluate possible mechanisms for pregnancy-induced changes in control of sympathetic outflow. 2. Arterial baroreflex control of e fferent renal sympathetic nerve activity was examined in female pregna nt and nonpregnant normotensive Sprague-Dawley and Wistar-Kyoto rats. In both rat strains, pregnancy was associated with a decrease in basel ine arterial pressure, a shift in the baroreflex function curve to a l ower operating pressure range and an attenuated ability to reflexly in crease sympathetic outflow above baseline levels during a hypotensive challenge. Pregnant Sprague-Dawley rats retained their ability to resp ond to a hypertensive challenge, whereas pregnant Wistar-Kyoto rats ex hibited 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 medu lla (RVLM) of the brainstem. Since 3 alpha-OH dihydroprogesterone (3 a lpha-OH-DHP), a major metabolite of progesterone, is elevated in pregn ancy and has been reported to potentiate central nervous system GABA(A ) inhibitory responses, experiments were performed to determine if eff ects of this metabolite of progesterone could contribute to the pregna ncy associated changes in control of sympathetic outflow. Acute intrav enous 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 adm inistration of 3 alpha-OH-DHP to virgin female rats mimics the effects of pregnancy on baroreflex control of sympathetic outflow. These resu lts are consistent with potentiation of GABAergic sympatho-inhibition by circulating levels of the major metabolite of progesterone during p regnancy.