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.
ing baroreceptor unloading, sympathoexcitation is attenuated in nearterm pregnant compared with nonpregnant rats. Alterations in balance among different excitatory and inhibitory inputs within central autonomic pathways likely contribute to changes in regulation of sympathetic outflow in pregnancy. Both baroreflex-dependent and baroreflex-independent GABAergic inputs inhibit sympathoexcitatory neurons within rostral ventrolateral medulla (RVLM). The present experiments tested the hypothesis that influence of baroreflex-independent GABAergic inhibition of RVLM is greater in pregnant compared with nonpregnant rats. Afferent baroreceptor inputs were eliminated by bilateral sinoaortic denervation in inactin-anesthetized rats. In pregnant compared with nonpregnant rats, baseline mean arterial pressure (MAP) was lower (pregnant ϭ 75 Ϯ 6 mmHg, nonpregnant ϭ 115 Ϯ 7 mmHg) and heart rate was higher (pregnant ϭ 381 Ϯ 10 beats/min, nonpregnant ϭ 308 Ϯ 10 beats/min). Pressor and sympathoexcitatory [renal sympathetic nerve activity, (RSNA)] responses due to bilateral GABA A receptor blockade (bicuculline, 4 mM, 100 nl) of the RVLM were greater in pregnant rats (⌬MAP: pregnant ϭ 101 Ϯ 4 mmHg, nonpregnant ϭ 80 Ϯ 6 mmHg; ⌬RSNA: pregnant ϭ 182 Ϯ 23% control, nonpregnant ϭ 133 Ϯ 10% control). Unexpected transient sympathoexcitatory effects of angiotensin AT 1 receptor blockade in the RVLM were greater in pregnant rats. Although excitatory responses to bicuculline were attenuated by prior RVLM AT 1 receptor blockade in both groups, pressor responses to disinhibition of the RVLM remained augmented in pregnant rats. Increased influence of baroreflex-independent GABAergic inhibition in RVLM could contribute to suppressed sympathoexcitation during withdrawal of arterial baroreceptor input in pregnant animals. sympathetic nerve activity; brain stem; cardiovascular regulation; angiotensin II PREGNANCY IS CHARACTERIZED by increased blood volume and cardiac output, mild tachycardia, and decreased arterial blood pressure due to a significant decrease in total peripheral resistance (21, 47). Pregnant women and animals are more susceptible to orthostatic (3) and hemorrhagic hypotension (6,8). Although decreased vascular sensitivity to endogenous vasoconstrictors likely contributes to decreased compensatory responses (21), there is evidence that alterations in central nervous system (CNS) autonomic control mechanisms play a major role in regulation of sympathetic outflow and blood pressure during pregnancy.Attenuated arterial baroreflex control of heart rate (HR) has been reported in pregnant animals (5, 50) and women (28,49) and is partly due to suppression of the sympathetic component of the reflex. Direct assessment of arterial baroreflex control of renal sympathetic nerve activity (RSNA) in near-term pregnant rats (14, 43, 51) and rabbits (7, 54, 55) revealed that maximum baroreflex gain is decreased, largely due to an attenuated ability to increase RSNA above baseline levels in response to a hypotensive challenge. However, arterial baror...
Depressor responses to peripheral or central infusion of Angiotensin II type 1 (AT1) receptor antagonists (AT1X) are greater in pregnant (P) compared to nonpregnant (NP) animals. AT1 and ionotropic excitatory amino acid (EAA) receptors contribute to pressor responses to GABAA receptor blockade with bicuculline (Bic) in the paraventricular nucleus (PVN) of male rats. Therefore, we hypothesized that GABAergic inhibition is decreased and AT1 receptors play a greater excitatory role in the PVN of P versus NP rats. Unilateral microinjection of Bic was performed before (Bic1), after AT1X (Bic2), and after AT1X + EAA blockade (kynurenate, Kyn) (Bic3) in the PVN. Increases in mean arterial pressure (MAP: NP= 20 ± 2; P= 12 ± 2 mmHg), heart rate (HR: NP= 57 ± 6; P= 19 ± 6 beats/min) and renal sympathetic nerve activity (RSNA: NP= 70 ± 9; P= 33 ± 7 %) due to Bic (Bic1) were attenuated in P rats. Responses to AT1X and Kyn alone were insignificant in both groups. In NP rats, AT1X attenuated (+12 ± 4 mmHg), and AT1X + Kyn further decreased the pressor response to Bic in the PVN (+6 ± 2 mmHg). In P rats AT1X reduced the pressor response to Bic (+5 ± 1 mm Hg), and Kyn had no additional effect (+3 ± 1 mmHg). Effects of PVN Bic to alter the autospectra of RSNA were suppressed by prior AT1X and Kyn in both groups. Thus, tonic GABAergic inhibition is decreased and the contribution of AT1 receptors in the PVN may be greater in P rats.
Interactions between GABA and angiotensin AT1 receptors modulate activity of RVLM sympathoexcitatory neurons, with effects of endogenous A II in the RVLM dependent on physiological state. Pregnancy is associated with decreased mean arterial pressure (MAP) and attenuated baroreflex (BX) sympathoexcitation. To investigate if increased tonic BX‐independent inhibition of the RVLM occurs in pregnancy, and a potential role for RVLM AT1 receptors, experiments were performed in inactin anesthetized sinoaortic denervated female virgin (V) and pregnant (P) Sprague Dawley rats. Responses to bilateral RVLM GABAA receptor blockade (Bic= Bicuculline, 400 pmol, 100 nl) were determined before and after bilateral RVLM AT1 receptor blockade (AT1X= L‐158,809, 1 nmol, 100 nl). Pressor responses to RVLM Bic were greater in P rats. MAP and renal sympathetic nerve activity (RSNA) initially increased following AT1X (3 min) and returned to baseline values at 20 min. In the presence of AT1X, responses to Bic were decreased. * P> V; † AT1X< Control (C). Thus, tonic GABAergic inhibition of the RVLM is greater in P versus V rats and partially dependent on AT1 receptor activation, since AT1 X attenuated responses to RVLM Bic in both groups. (NIH R01‐HL‐36245, CMH)
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