Integration of Aortic Nerve Inputs in Hypertensive Rats

Zhang, Jing; Mifflin, Steve

doi:10.1161/01.hyp.35.1.430

Cited by 18 publications

(22 citation statements)

References 23 publications

(28 reference statements)

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“…A shift from predominantly GABA A -to GABA Bmediated inhibition may provide a more metabolically favorable mechanism to offset increased baroreceptor excitatory inputs to NTS neurons in HT rats (7). Our previous work (20) and the present study found no difference in the spontaneous discharge of AN-evoked NTS neurons between NT and HT rats; therefore, enhanced GABA B inhibition may normalize the discharge of NTS neurons receiving increased baroreceptor inputs in HT. It has been suggested that such adaptations enable the neurons to respond normally to changes in arterial pressure (10) and limit reductions in baroreflex performance in HT.…”

Section: Discussionsupporting

confidence: 50%

Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract

Mei

Zhang

Mifflin

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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. Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract. Am J Physiol Regul Integr Comp Physiol 285: R1276-R1286, 2003 10.1152/ajpregu. 00255.2003.-Previous studies have demonstrated that microinjection of baclofen, a GABA B receptor agonist, into the nucleus of the solitary tract (NTS) results in an enhanced pressor response in hypertensive (HT) rats compared with normotensive (NT) rats, suggesting a possible alteration in the responses of neurons in this area to activation of GABA B receptors. The following studies were designed to determine whether HT alters the sensitivity of neurons in the NTS to GABA receptor agonists. Sham-operated NT and unilateral nephrectomized, renal-wrap HT Sprague-Dawley rats were anesthetized, and the responses of NTS neurons receiving aortic nerve (AN) afferent inputs to iontophoretic application of GABA, the GABA A receptor agonist muscimol, and the GABA B agonist baclofen were examined. The AN input was classified as monosynaptic (MSN) if the cell responded to each of two stimuli separated by 5 ms with an action potential. If the cell did not respond, the input was considered polysynaptic (PSN). In MSNs, inhibition of AN-evoked discharge by GABA was not altered in 1 wk of HT but was reduced in 4 wk of HT, whereas in PSNs, sensitivity to GABA was reduced at 1 and 4 wk of HT. In HT rats, inhibition of AN-evoked discharge by baclofen was enhanced in MSNs, but not in PSNs, after 1 and 4 wk of HT, whereas inhibition by muscimol was reduced in MSNs and PSNs at 1 and 4 wk of HT. Changes in sensitivity to muscimol and baclofen within MSNs were the same whether the MSN received a slowly or a rapidly conducted AN afferent input. The results demonstrate that early in HT the sensitivity of NTS neurons to inhibitory amino acids is altered and that these changes are maintained for Ն4 wk. The alterations are dependent on the subtype of GABA receptor being activated and whether the neuron receives a mono-or polysynaptic baroreceptor afferent input. (12), and GABA B receptors are metabotropic, G protein-coupled receptors that mediate presynaptic and postsynaptic inhibition by reductions in calcium conductance or increases in potassium conductance, respectively (8). Activation of GABA A receptors on NTS neurons results in chloride-dependent membrane hyperpolarization and inhibition of baroreceptor-evoked discharge (10,19). Activation of GABA B receptors can evoke presynaptic and/or postsynaptic inhibition of NTS neurons (1, 19) and inhibit baroreceptor-evoked discharge in NTS neurons (19).The sensitivity of NTS neurons to the selective GABA A agonist muscimol was the same whether the neuron received a monosynaptic or a polysynaptic aortic nerve (AN) input (19). In contrast, NTS neurons receiving a monosynaptic AN input were much less sensitive to the inhibitory effects of the GABA B agonist baclofen than were NTS neurons receiving a polysynaptic AN input (19). An in vitro study reported that presynaptic inhibition of monosynaptic tractus inputs t...

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Section: Discussionsupporting

confidence: 50%

Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract

Mei

Zhang

Mifflin

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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“…1 However, we have previously demonstrated in this model of HT that NTS neurons receiving aortic baroreceptor afferent inputs exhibit normal discharge frequencies and responses to aortic nerve stimulation. 14 We have also demonstrated enhanced responses to activation of GABA B receptors in this model of HT, 15 and this may mitigate the consequences of reduced GABA A -mediated inhibition.…”

Section: Perspectivesmentioning

confidence: 54%

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

2004

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Abstract-The inhibitory amino acid GABA is a potent modulator of the spontaneous discharge and the responses to afferent inputs of neurons in the nucleus of the solitary tract (NTS). To determine if responses to activation of GABA A receptors are altered in hypertension, GABA A receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from 33 normotensive (NT, 109Ϯ4 mm Hg, nϭ7) and 24 hypertensive (HT, 167Ϯ5 mm Hg, nϭ24) rats. GABA A receptor-evoked currents reversed at the calculated equilibrium potential for chloride and were blocked by bicuculline (nϭ6). Membrane capacitance was the same in neurons from NT (7.5Ϯ0.6 pF, nϭ62) and HT (6.8Ϯ0.6 pF, nϭ51) rats. The EC 50 for peak GABA-evoked currents cells was significantly greater in neurons from HT (21.0Ϯ2.6 mol/L, nϭ16) compared with NT rats (13.0Ϯ1.8 mol/L, nϭ14, Pϭ0.01). The EC 50 of neurons exhibiting DiA labeling of presumptive aortic nerve terminals was no different than that observed in the nonlabeled cells (19.0Ϯ4.9 mol/L, nϭ4). The time constant for desensitization of GABA A -evoked currents was the same in neurons from HT (4.5Ϯ0.3 seconds, nϭ17) and NT rats (3.8Ϯ0.3 seconds, nϭ17, PϾ0.05). Repetitive pulse application of GABA revealed a more rapid decline in the evoked current in neurons from HT compared with NT rats. The amplitude of the 5th pulse of GABA (5-second duration, 2-second interval) was 21Ϯ2% the amplitude of the 1st pulse in NT rats (nϭ10) and 14Ϯ2% in HT rats (nϭ11, PϽ0.05). These alterations in GABA A -receptor evoked currents could render the neurons less sensitive to GABA A receptor inhibition and influence afferent integration by NTS neurons in HT. [2][3][4] Within the NTS, activation of GABA A receptors inhibits virtually all neurons tested and results in an increase in arterial pressure, heart rate, and sympathetic outflow, effects consistent with inhibitory modulation of arterial baroreceptor reflexes. 1 The function of GABA A receptors has been shown to be modulated by a variety of factors. Receptor number, subunit composition, and phosphorylation state are but a few of the ways that GABA receptor function can be altered after chronic exposure to alcohol, barbiturates, benzodiazepines, and GABA itself. [2][3][4] Alterations in the responses of NTS neurons to GABA A receptor activation could result in alterations in the integration of afferent inputs, reflex function, and resting cardiovascular parameters. The goal of the current study was to determine if the responses of isolated NTS neurons to activation of GABA A receptors are altered in hypertension. Methods GeneralSuccessful experiments were performed on adult (1 to 3 months), male Sprague-Dawley rats (375 to 500 g, Charles River Laboratories or Harlan Sprague-Dawley Inc). Rats were housed 2 per cage in a fully accredited (Association for Assessment and Accreditation of Laboratory Animal Care and the United States Department of Agriculture) laboratory animal room with free access to food and water. All rats were given at least 1 week to acclimat...

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“…Specifically, aortic depressor nerve activity is elevated under baseline conditions in OZR compared with LZR, and direct electrical stimulation of these afferent nerve fibers evokes attenuated inhibitions of SNA and MAP in OZR (16). In a renal wrap hypertensive rat model, increased basal MAP is accompanied by altered processing of baroreceptor inputs at the NTS (47). Augmented inputs from excitatory baroreceptor afferent nerves are met with enhanced presynaptic GABAergic inhibition of glutamate release from baroreceptor afferent terminals combined with a postsynaptic GABA B receptor-mediated reduction in the excitability of NTS neurons receiving baroreceptor inputs (46,48).…”

Section: Discussionmentioning

confidence: 97%

Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

Huber

Schreihofer

2011

American Journal of Physiology-Heart and Circulatory Physiology

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rats (OZR) have elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) compared with lean Zucker rats (LZR). We examined whether altered tonic glutamatergic, angiotensinergic, or GABAergic inputs to the rostral ventrolateral medulla (RVLM) contribute to elevated SNA and MAP in OZR. Male rats (14 -18 wk) were anesthetized with urethane (1.5 g/kg iv), ventilated, and paralyzed to record splanchnic SNA, heart rate (HR), and MAP. Inhibition of the RVLM by microinjections of muscimol eliminated SNA and evoked greater decreases in MAP in OZR vs. LZR (P Ͻ 0.05). Antagonism of angiotensin AT 1 receptors in RVLM with losartan yielded modest decreases in SNA and MAP in OZR but not LZR (P Ͻ 0.05). However, antagonism of ionotropic glutamate receptors in RVLM with kynurenate produced comparable decreases in SNA, HR, and MAP in OZR and LZR. Antagonism of GABA A receptors in RVLM with gabazine evoked smaller rises in SNA, HR, and MAP in OZR vs. LZR (P Ͻ 0.05), whereas responses to microinjections of GABA into RVLM were comparable. Inhibition of the caudal ventrolateral medulla, a major source of GABA to the RVLM, evoked attenuated rises in SNA and HR in OZR (P Ͻ0.05). Likewise, inhibition of nucleus tractus solitarius, the major excitatory input to caudal ventrolateral medulla, produced smaller rises in SNA and HR in OZR. These results suggest the elevated SNA and MAP in OZR is derived from the RVLM and that enhanced angiotensinergic activation and reduced GABAergic inhibition of the RVLM may contribute to the elevated SNA and MAP in the OZR.hypertension; sympathetic nerve activity; muscimol; kynurenate; gabazine; losartan ACCUMULATION OF EXCESS BODY fat is an independent risk factor for elevated mean arterial pressure (MAP; Refs. 8, 13, 26). Over activation of sympathetic nerves that regulate MAP is a hallmark of obesity-induced hypertension (8, 11). Obese hypertensive human subjects have increased muscle sympathetic nerve activity (SNA) characterized by a recruitment of previously silent sympathetic fibers (24). Some obese hypertensives present with elevated plasma levels of catecholamines (26), whereas others report increases in norepinephrine spillover only to selective targets such as the kidney (30). Nevertheless, acute elimination of SNA evokes larger decreases in MAP in obese subjects compared with gender and age-matched lean subjects (36), suggesting an enhanced sympathetic contribution to the maintenance of MAP with obesity-related hypertension.Rat models of obesity mimic the enhanced sympathetic vasomotor tone observed in obese humans. In adult obese Zucker rats (OZR), renal and splanchnic SNA and MAP are elevated (16, 27) compared with age-matched lean Zucker rats (LZR). Furthermore, autonomic ganglionic blockade evokes a larger decrease in basal MAP in OZR than in LZR (31). Similarly, elimination of sympathetic vasomotor tone by inhibition of rostral ventrolateral medulla (RVLM), the primary source of drive for SNA, evokes a greater decrease in MAP in Sprague-Dawley rats made obese by a high-f...

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Integration of Aortic Nerve Inputs in Hypertensive Rats

Cited by 18 publications

References 23 publications

Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract

Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

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