The caudal ventrolateral medulla (CVLM) provides tonic inhibitory and also excitatory inputs to the rostral ventrolateral medulla (RVLM). These experiments evaluated the role of RVLM γ-amino butyric acid (GABA) receptor subtypes and glycine receptors in mediating CVLM sympathoinhibition. In Inactin anesthetized female rats, the CVLM and RVLM were functionally defined by pressor and depressor responses to microinjected GABA (500 pmol, 50 nl). Although reduced, pressor and sympathoexcitatory responses due to inhibition of the CVLM with GABA persisted following ipsilateral RVLM GABA A receptor blockade (bicuculline, BIC, 400 pmol, 100 nl; n=12) in rats with contralateral nucleus tractus solitarius (NTS) lesion. In the presence of either ipsilateral (+contralateral NTS lesion; n= 8) or bilateral (n=6) GABA A and GABA B receptor blockade of the RVLM (400 pmol BIC + 400 pmol CGP35348, 100 nl), inhibition of the CVLM still increased MAP and renal sympathetic nerve activity (RSNA). Thus neither GABA B receptors nor a contralateral CVLM to RVLM GABAergic pathway explains residual responses CVLM blockade. The addition of strychnine (300 pmol, 100 nl) to the RVLM eliminated responses to CVLM inhibition, suggesting that a GABA A and GABA B independent sympathoinhibitory influence from CVLM to RVLM is mediated by glycine receptors. Decreases in MAP and RSNA due to activation of the CVLM with glutamate (500 pmol, 50 nl) were reversed to increases in the presence of RVLM GABA A receptor blockade (n=7). Thus, a sympathoexcitatory pathway from the CVLM can be activated in the presence of RVLM GABA receptor blockade, but sympathoinhibitory influences from the CVLM predominate.
The baroreflex function curve is shifted to lower operating pressures, efferent sympathoexcitatory responses are attenuated, and sympathoinhibitory responses are potentiated in pregnant compared with virgin rats. It has been proposed that during pregnancy, elevated levels of 3 alpha-hydroxy-dihydroprogesterone (3 alpha-OH-DHP), a major metabolite of progesterone, may contribute to this difference, because acute intravenous administration of 3 alpha-OH-DHP to virgin female rats mimics the effects of pregnancy on the baroreflex. To determine whether changes in the afferent limb might contribute to these baroreflex responses, the effects of pregnancy and 3 alpha-OH-DHP on aortic depressor nerve activity were assessed in the current study. Baroreceptor discharge curves were obtained in Inactin-anesthetized rats by recording aortic nerve activity during ramp increases and decreases in mean arterial pressure (MAP) [intravenous phenylephrine and nitroprusside infusion] before [(control, C) 15 min (E1), and 30 min (E2) after 3 alpha-OH-DHP (220 microg/kg bolus + 22 microg x kg(-1) x min(-1) infusion iv)]. Baseline blood pressure was significantly lower in pregnant (109 +/- 4.4 mmHg) compared with virgin (122 +/- 2.8 mmHg) rats. The only significant difference in the baroreceptor discharge curves was a decrease in curve midpoint in pregnant rats (virgin = 140 +/- 2.7 vs. pregnant = 124 +/- 3.6 mmHg). 3 alpha-OH-DHP had no effect on afferent baroreceptor discharge curves in either virgin or pregnant groups. These results suggest that pressure-dependent baroreceptor resetting may contribute to a shift in the baroreflex curve to lower operating pressures, but cannot completely explain differences in baroreflex function between virgin and pregnant animals.
The major metabolite of progesterone, 3α-OH-dihydroprogesterone (3α-OH-DHP), is the most potent endogenous positive modulator of central nervous system GABAA receptors. Acute intravenous administration of 3α-OH-DHP to virgin female rats potentiates arterial baroreflex sympathoinhibitory responses. The current experiments tested the possibility that circulating 3α-OH-DHP potentiates central GABAergic influences in the rostral ventrolateral medulla (RVLM). The unit activity of spontaneously active, spinally projecting, and arterial pressure-sensitive neurons was recorded in the RVLM of urethan-anesthetized rats. Arterial pressure sensitivity of RVLM neurons was tested before (control) and 10 min after bolus injection (44 μl iv) of 3α-OH-DHP (1.12 μg/kg, n = 19) or vehicle (40% β-cyclodextrin, n = 8). Both threshold pressure and saturation pressure for inhibition of RVLM neurons were decreased after acute administration of a physiological dose of 3α-OH-DHP (1.12 μg/kg iv), which produces plasma concentrations similar to those seen during pregnancy (20–30 ng/ml), suggesting potentiated responsiveness to endogenously released GABA. Following suppression by 3α-OH-DHP, high doses of the inactive stereoisomer 3β-OH-DHP (112–224 μg/kg iv; n = 8) restored unit activity, presumably by displacing 3α-OH-DHP from the neurosteroid binding site on GABAA receptors.
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