Sympathoexcitation and pressor responses induced by acetate, an ethanol metabolite in the hypothalamic paraventricular nucleus involves activation of NMDA receptors in rats
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Alcohol abuse plays a crucial role in the prevalence of cardiovascular and neuronal degenerated diseases. However, the central mechanism that mediates these effects are not fully understood. It has been well know that autonomic hypothalamic paraventricular nucleus (PVN) play an important role in regulating sympathetic outflow and arterial blood pressure (ABP). Moreover, it has been demonstrated that the increased glutamatergic activity among PVN neurons contributed to the sympathoexcitation and development of hypertension. Furthermore, we have reported that ethanol and acetate increase sympathetic outflow and arterial pressure, which may involve the activation of NMDA receptors in autonomic central nucleus of amygdala. Combing with the fact that autonomic PVN neurons are abundantly expressed NMDA receptors, we hypothesize that acetate, the metabolic products from alcohol, activates the PVN neurons through the increase in glutamatergic activity and contributes to the sympathoexcitation and development of chronic diseases, such as hypertension. In anesthetized rats, the effect of acetate microinjected in the PVN on the renal sympathetic nerve activity (RSNA) and arterial blood pressure (ABP) was determined. The PVN acetate microinjection increased sympathoexcitatiory and pressor response in a dose dependent dose-dependent (1.5mm, 0.5mm, 2.0mm, 7.5mm) manner, and 2mm of acetate showed a minimum dose evoked a maximal response. To determine the role of acetate-stimulated glutamatergic receptor activation in driving sympathoexcitatory and pressor responses, either 2mm acetate or pre-treatment of Kynurenic acid (KYN, 7.2mm) ionotropic excitatory amino acid receptor blocker, or D-2-amino-5-phosphopentanoate (AP5, 3.0mm), a N-methyl-D-aspartate (NMDA) receptor antagonist, followed by 2mm acetate were microinjected into the PVN of male Sprague Dawley rats (300-500g, n= 6-9/ group). RSNA and ABP responses were compared among vehicle (saline) and 2mm acetate, pre-treatment of KYN and 2mm acetate, or pre-treatment AP5 and 2mm acetate protocols. 2mm acetate significantly increased RSNA (60-70% baseline, p < 0.001) and mean arterial pressure (MAP, 10-12mmHg, p < 0.05). Non-selective glutamatergic receptor antagonist, KYN significantly blocked the sympathoexcitatory (RSNA, p < 0.05) and pressor response (MAP, p < 0.05) evoked by 2mm acetate in the PVN. Furthermore, selective NMDA receptor antagonist, AP5 significantly attenuates the sympathoexcitatory response induced by PVN 2mm acetate (RSNA, P < 0.05 and MAP, p < 0.01). These data indicate acetate can increase glutamatergic activity and excitability of pre-sympathetic PVN neurons via activation of local NMDA receptors. The metabolism of ethanol to acetate following by alcohol consumption may contribute, in part, to the development of neurogenic hypertension and/or other cardiovascular diseases associated with increased sympathetic outflow. R15HL145655, R15HL150703 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.Keywords:
Rostral ventrolateral medulla
Kynurenic acid
Abstract —The major aim of the present study was to evaluate the role of the rostral ventrolateral medulla (RVLM) in the maintenance of hypertension in rats subjected to long-term treatment with N G -nitro- l -arginine methyl ester (L-NAME) (70 mg/kg orally for 1 week). We inhibited or stimulated RVLM neurons with the use of drugs such as glycine, l -glutamate, or kynurenic acid in urethane-anesthetized rats (1.2 to 1.4 g/kg IV). Bilateral microinjection of glycine (50 nmol, 100 nL) into the RVLM of hypertensive rats produced a decrease in mean arterial blood pressure (MAP) from 158±4 to 71±4 mm Hg ( P <0.05), which was similar to the decrease produced by intravenous administration of hexamethonium. In normotensive rats, glycine microinjection reduced MAP from 106±4 to 60±3 mm Hg ( P <0.05). Glutamate microinjection into the RVLM produced a significant increase in MAP in both hypertensive rats (from 157±3 to 201±6 mm Hg) and normotensive rats (from 105±5 to 148±9 mm Hg). No change in MAP was observed in response to kynurenic acid microinjection into the RVLM in either group. These results suggest that hypertension in response to long-term L-NAME treatment is dependent on an increase in central sympathetic drive, mediated by RVLM neurons. However, glutamatergic synapses within RVLM are probably not involved in this response.
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The goal of the present study was to test the hypothesis that the balance of tonic excitation and inhibition of vasomotor neurons in the rostral ventrolateral medulla (RVLM) driven by excitatory amino acid (EAA)–mediated inputs to the RVLM is shifted toward excitation in Dahl salt-sensitive (DS) rats compared with Dahl salt-resistant (DR) rats. Glutamate and the EAA antagonist kynurenic acid were microinjected into the RVLM of chloralose-anesthetized DS and DR rats maintained on diets containing either 0.3% NaCl or 8.0% NaCl. DS rats had a higher arterial pressure than DR rats, and this difference was greatly exaggerated by high dietary salt intake. Bilateral injection of kynurenic acid (2.7 nmol) into the RVLM decreased mean arterial pressure by 16±2 mm Hg in DS rats fed a diet containing 0.3% NaCl, and this effect was significantly larger in DS rats fed the high-salt diet (40±2 mm Hg). In contrast, injections of kynurenic acid into the RVLM did not significantly decrease arterial pressure in DR rats fed either diet. In DR rats, the pressor response elicited by the injection of glutamate into the RVLM was potentiated in rats fed the high-salt diet. The glutamate-evoked pressor response was greater in DS rats compared with DR rats, and the response in DS rats was not influenced by the salt content of the diet. These data suggest that tonically active EAA inputs to the RVLM may contribute to salt-sensitive hypertension in the Dahl model.
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Moxonidine
Rostral ventrolateral medulla
Imidazoline receptor
Sympathetic nervous system
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Background: Previous studies suggest that the increased reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, contributes to sympathoexcitation. It has been well established that cardiovascular diseases often impair baroreflex. Hypothesis: The aim of the present study was to determine whether the inhibition of ROS in the RVLM by the overexpression of Mn superoxide dismutase (MnSOD) improves baroreflex function and to determine the process of change between baroreflex sensitivity (BRS) and blood pressure (BP) or heart rate (HR) in stroke-prone spontaneously hypertensive rats (SHRSP). Methods and Results: We inhibited ROS production in the RVLM by transfecting adenovirus vectors encoding either MnSOD (AdMnSOD) or β-galactosidase (Adβgal) into the RVLM. Baroreflex sensitivity (spontaneous sequence method) was significantly lower in untreated-SHRSP than in Wistar-Kyoto rats (WKY) (1.66±0.02 vs. 2.15±0.06 ms/mmHg, p Conclusion: These results indicate that ROS in the RVLM impairs BRS via activation of sympathetic nervous system. Second, our findings suggest that the improved BRS is due to the inhibition of the activity of the sympathetic nervous system, but not activation of the parasympathetic nervous system.
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The hypothesis that changes in neurotransmission within the rostral ventrolateral medulla (RVLM) are important to maintain the high blood pressure (BP) was tested in Goldblatt one kidney-one clip hypertension model (1K-1C). Male Wistar rats were anesthetized (urethane 1.2 g/kg, i.v.), and the effects of bilateral microinjections into the RVLM of the following drugs were measured in 1K-1C or control groups: glutamate (0.1 mol/L, 100 nL) and its antagonist kynurenic acid (0.02 mol/L, 100 nL), the angiotensin AT 1 receptor antagonist candesartan (0.01 mol/L, 100 nL), and the nonselective 5-HT receptor antagonist methiothepin (0.06 mol/L, 100 nL). Experiments in 1K-1C rats were performed 6 weeks after surgery. In anesthetized rats glutamate response was larger in hypertensive than in normotensive rats (H:Δ 67 ± 6.5 Δ 43 ± 3.54
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Experiments were done to test the hypothesis that inhibition of neurons in the rostral ventrolateral medulla (RVLM) elicited by stimulation of the nucleus tractus solitarii (NTS) is relayed through the caudal ventrolateral medulla (CVLM). We recorded activity from 56 spontaneously firing units in the right RVLM of urethan-anesthetized and artificially ventilated rats. Eleven of these units were classified as cardiovascular neurons, because they were silenced by baroreceptor activation (1-3 micrograms phenylephrine iv) and showed rhythmicity of their spontaneous activity in synchrony with the cardiac cycle. Single pulses (0.1 ms, 30-75 microA) delivered 1/s to depressor sites in the ipsilateral NTS inhibited the activity of all these cardiovascular neurons. Microinjection of the glutamate antagonist kynurenic acid (0.15 M, 50 nl) into the ipsilateral CVLM blocked the inhibitory response of RVLM units to the administration of phenylephrine and increased the firing frequency of cardiovascular neurons in the RVLM by 43%. Moreover, kynurenic acid administration attenuated the inhibitory response of cardiovascular neurons in the RVLM to NTS stimulation. Finally, stimulation of the NTS that elicited depressor responses under control conditions produced a pressor response after kynurenic acid administration. The remaining 45 RVLM neurons were barosensitive but lacked cardiac cycle-related rhythmicity. These results provide direct evidence for the existence of a tonic inhibitory pathway from NTS to RVLM that is relayed through the CVLM probably by a glutamatergic projection from NTS to CVLM.
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Abstract The aim of the present study was to examine the participation of the rostral ventrolateral medulla (RVLM) in the maintenance of hypertension in rats submitted to the renovascular Goldblatt (two-kidney, one clip) procedure. We inhibited or stimulated this area with the use of drugs such as glycine, l -glutamate, or kynurenic acid. (1) Bilateral microinjection of glycine (100 nmol, 200 nL, n=13) into the RVLM of hypertensive rats produced a decrease in mean arterial blood pressure (MAP) from 177.2±29.3 to 102.3±20.9 mm Hg ( P <.05), which was similar to the decrease produced by intravenous administration of hexamethonium. The inhibition of RVLM with glycine in normotensive rats produced a decrease in MAP from 106±17.1 to 59.7±7.3 mm Hg ( P <.05, n=9). (2) An impressive increase in MAP from 153.3±16.3 to 228±34.9 mm Hg ( P <.05) occurred in hypertensive rats after microinjection of l -glutamate (50 nmol, 200 nL, n=6) into the RVLM. The same procedure caused a significant but less intense increase in MAP from 105±13.8 to 148.3±24.9 mm Hg in normotensive rats ( P <.05, n=6). (3) A decrease in MAP from 151.6±25.3 to 96.8±22.5 mm Hg occurred in hypertensive rats after microinjection of the broad-spectrum glutamate antagonist kynurenic acid (4 nmol, 200 nL, n=6) into the RVLM, whereas the same procedure did not change MAP in normotensive animals (n=6). Heart rate was not significantly affected in any group. Together these results show that the activity of RVLM neurons is important in the maintenance of arterial blood pressure in Goldblatt hypertensive rats and probably indicate a change in the sensitivity and/or number of glutamatergic receptors in this area after the development of hypertension.
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