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Paul M Pilowsky - One of the best experts on this subject based on the ideXlab platform.
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orexin a in rat Rostral Ventrolateral Medulla is pressor sympatho excitatory increases barosensitivity and attenuates the somato sympathetic reflex
British Journal of Pharmacology, 2012Co-Authors: Ahmed A Rahman, I Z Shahid, Paul M PilowskyAbstract:BACKGROUND AND PURPOSE The Rostral Ventrolateral Medulla (RVLM) maintains sympathetic nerve activity (SNA), and integrates adaptive reflexes. Orexin A-immunoreactive neurones in the lateral hypothalamus project to the RVLM. Microinjection of orexin A into RVLM increases blood pressure and heart rate. However, the expression of orexin receptors, and effects of orexin A in the RVLM on splanchnic SNA (sSNA), respiration and adaptive reflexes are unknown. EXPERIMENTAL APPROACH The effect of orexin A on baseline cardio-respiratory variables as well as the somato-sympathetic, baroreceptor and chemoreceptor reflexes in RVLM were investigated in urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats (n= 50). orexin A and its receptors were detected with fluorescence immunohistochemistry. KEY RESULTS Tyrosine hydroxylase-immunoreactive neurones in the RVLM were frequently co-localized with orexin 1 (OX1) and orexin 2 (OX2) receptors and closely apposed to orexin A-immunoreactive terminals. Orexin A injected into the RVLM was pressor and sympatho-excitatory. Peak effects were observed at 50 pmol with increased mean arterial pressure (42 mmHg) and SNA (45%). Responses to orexin A (50 pmol) were attenuated by the OX1 receptor antagonist, SB334867, and reproduced by the OX2 receptor agonist, [Ala11, D-Leu15]orexin B. Orexin A attenuated the somato-sympathetic reflex but increased baroreflex sensitivity. Orexin A increased or reduced sympatho-excitation following hypoxia or hypercapnia respectively. CONCLUSIONS AND IMPLICATIONS Although central cardio-respiratory control mechanisms at rest do not rely on orexin, responses to adaptive stimuli are dramatically affected by the functional state of orexin receptors.
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orexin a in rat Rostral Ventrolateral Medulla is pressor sympatho excitatory increases barosensitivity and attenuates the somato sympathetic reflex
British Journal of Pharmacology, 2012Co-Authors: Ahmed A Rahman, I Z Shahid, Paul M PilowskyAbstract:BACKGROUND AND PURPOSE The Rostral Ventrolateral Medulla (RVLM) maintains sympathetic nerve activity (SNA), and integrates adaptive reflexes. Orexin A-immunoreactive neurones in the lateral hypothalamus project to the RVLM. Microinjection of orexin A into RVLM increases blood pressure and heart rate. However, the expression of orexin receptors, and effects of orexin A in the RVLM on splanchnic SNA (sSNA), respiration and adaptive reflexes are unknown. EXPERIMENTAL APPROACH The effect of orexin A on baseline cardio-respiratory variables as well as the somato-sympathetic, baroreceptor and chemoreceptor reflexes in RVLM were investigated in urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats (n= 50). orexin A and its receptors were detected with fluorescence immunohistochemistry. KEY RESULTS Tyrosine hydroxylase-immunoreactive neurones in the RVLM were frequently co-localized with orexin 1 (OX1) and orexin 2 (OX2) receptors and closely apposed to orexin A-immunoreactive terminals. Orexin A injected into the RVLM was pressor and sympatho-excitatory. Peak effects were observed at 50 pmol with increased mean arterial pressure (42 mmHg) and SNA (45%). Responses to orexin A (50 pmol) were attenuated by the OX1 receptor antagonist, SB334867, and reproduced by the OX2 receptor agonist, [Ala11, D-Leu15]orexin B. Orexin A attenuated the somato-sympathetic reflex but increased baroreflex sensitivity. Orexin A increased or reduced sympatho-excitation following hypoxia or hypercapnia respectively. CONCLUSIONS AND IMPLICATIONS Although central cardio-respiratory control mechanisms at rest do not rely on orexin, responses to adaptive stimuli are dramatically affected by the functional state of orexin receptors.
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monosynaptic excitatory connection from the Rostral Ventrolateral Medulla to sympathetic preganglionic neurons revealed by simultaneous recordings
Hypertension Research, 2008Co-Authors: Naoki Oshima, Paul M Pilowsky, Hiroo Kumagai, Hiroshi Onimaru, Akira Kawai, Kamon Iigaya, Takao Saruta, Chie Takimoto, Koichi Hayashi, Hiroshi ItohAbstract:To directly investigate whether a monosynaptic connection exists between neurons in the Rostral Ventrolateral Medulla (RVLM) and sympathetic preganglionic neurons (SPNs), we used simultaneous extracellular recordings of RVLM neurons and whole-cell patch-clamp recordings of SPNs at the Th2 level and analyzed them by spike-triggered averaging. We averaged 200 sweeps of membrane potentials in SPN triggered by the spikes in the RVLM neuron. No clear postsynaptic potentials were detected in the averaged wave of SPNs before angiotensin II (Ang II) superfusion, whereas during superfusion with Ang II (6 μmol/L) on the Medulla oblongata side alone excitatory postsynaptic potentials (EPSPs) were clearly found in the SPN of 3 out of 10 pairs at 40±1 ms after the averaged triggering spike in the RVLM neuron. We consider them to be monosynaptic EPSPs, because 1) the averaged EPSPs exhibited a sharp rise time, 2) the onset latency of the averaged EPSPs in the SPNs after the trigger spike in the RVLM was the same as the latency of the antidromic action potentials in the RVLM neurons in response to electrical stimulation of the SPNs, and 3) the amplitude of the averaged EPSPs was over 2 mV. In summary, combining simultaneous recording and spike-triggered averaging allowed us to demonstrate a monosynaptic excitatory connection between a single RVLM neuron and a single SPN in the thoracic spinal cord. Such connections provide the basis for the maintenance of sympathetic tone and the integrative reflex that relays through the RVLM. The results explain the mechanism by which Ang II in the RVLM area increases peripheral sympathetic activity and blood pressure.
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nk1 receptor activation in rat Rostral Ventrolateral Medulla selectively attenuates somato sympathetic reflex while antagonism attenuates sympathetic chemoreflex
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: John M Makeham, Paul M Pilowsky, Ann K GoodchildAbstract:The effects of activation and blockade of the neurokinin 1 (NK1) receptor in the Rostral Ventrolateral Medulla (RVLM) on arterial blood pressure (ABP), splanchnic sympathetic nerve activity (sSNA),...
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cannabinoid receptor activation in the Rostral Ventrolateral Medulla oblongata evokes cardiorespiratory effects in anaesthetised rats
British Journal of Pharmacology, 2003Co-Authors: Paul M Pilowsky, Ann K Goodchild, James R Padley, Qun LiAbstract:The nature of the cardiorespiratory effects mediated by cannabinoids in the hindbrain is poorly understood. In the present study we investigated whether cannabinoid receptor activation in the Rostral Ventrolateral Medulla oblongata (RVLM) affects cardiovascular and/or respiratory function. Initially, we looked for evidence of CB1 receptor gene expression in Rostral and caudal sections of the rat Ventrolateral Medulla (VLM) using reverse transcription–polymerase chain reaction. Second, the potent cannabinoid receptor agonists WIN55,212-2 (0.05, 0.5 or 5 pmol per 50 nl) and HU-210 (0.5 pmol per 50 nl) or the CB1 receptor antagonist/inverse agonist AM281 (1 pmol per 100 nl) were microinjected into the RVLM of urethane-anaesthetised, immobilised and mechanically ventilated male Sprague–Dawley rats (n=22). Changes in splanchnic nerve activity (sSNA), phrenic nerve activity (PNA), mean arterial pressure (MAP) and heart rate (HR) in response to cannabinoid administration were recorded. The CB1 receptor gene was expressed throughout the VLM. Unilateral microinjection of WIN55,212-2 into the RVLM evoked short-latency, dose-dependent increases in sSNA (0.5 pmol; 175±8%, n=5) and MAP (0.5 pmol; 26±3%, n=8) and abolished PNA (0.5 pmol; duration of apnoea: 5.4±0.4 s, n=8), with little change in HR (P<0.005). HU-210, structurally related to Δ9-tetrahydrocannabinol (THC), evoked similar effects when microinjected into the RVLM (n=4). Surprisingly, prior microinjection of AM281 produced agonist-like effects, as well as significantly attenuated the response to subsequent injection of WIN55,212-2 (0.5 pmol, n=4). The present study reveals CB1 receptor gene expression in the rat VLM and demonstrates sympathoexcitation, hypertension and respiratory inhibition in response to RVLM-administered cannabinoids. These findings suggest a novel link between CB1 receptors in this region of the hindbrain and the central cardiorespiratory effects of cannabinoids. The extent to which these central effects contribute to the cardiovascular and respiratory outcomes of cannabis use remains to be investigated. British Journal of Pharmacology (2003) 140, 384–394. doi:10.1038/sj.bjp.0705422
Takao Kubo - One of the best experts on this subject based on the ideXlab platform.
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evidence for involvement of the lateral parabrachial nucleus in mediation of cholinergic inputs to neurons in the Rostral Ventrolateral Medulla of the rat
Brain Research, 1998Co-Authors: Takao Kubo, Yukihiko Hagiwara, Daisuke Sekiya, Ryuji FukumoriAbstract:We examined whether sites in the lateral parabrachial nucleus (PBN) where L-glutamate produced increases in arterial pressure were involved in mediation of cholinergic inputs to neurons in the Rostral Ventrolateral Medulla (RVLM). Male Wistar rats were anesthetized, paralyzed and artificially ventilated. Unilateral microinjection of L-glutamate into the lateral PBN produced a pressor response. Microinjection of the muscarinic receptor antagonist scopolamine into the unilateral RVLM inhibited the pressor response to L-glutamate injected ipsilaterally into the lateral PBN, whereas microinjection of the cholinesterase inhibitor physostigmine into the RVLM enhanced it. PBN microinjection of L-glutamate also enhanced the firing rate of RVLM sympathoexcitatory neurons and the enhancement of the firing rate was inhibited by scopolamine iontophoretically applied on neurons. PBN injection of L-glutamate produced a tetrodotoxin (TTX)-sensitive release of ACh in the RVLM. Unilateral microinjection of TTX into the lateral PBN inhibited the pressor response induced by RVLM microinjection of physostigmine. These results provide evidence that neurons in the pressor sites of the lateral PBN are involved in mediation of cholinergic inputs responsible for pressor responses in the RVLM.
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Excitatory amino acid receptors in the Rostral Ventrolateral Medulla mediate hypertension induced by carotid body chemoreceptor stimulation
Naunyn-Schmiedeberg's Archives of Pharmacology, 1994Co-Authors: Motoaki Amano, Tetsuya Asari, Takao KuboAbstract:The Rostral Ventrolateral Medulla (RVLM) is involved in the mediation of cardiovascular responses to peripheral chemoreceptor stimulation. To investigate whether excitatory amino acid inputs in the RVLM are related to the responses to chemoreceptor stimulation, we microinjected kynurenate, an amino acid antagonist, unilaterally into the RVLM and examined its effects on the pressor response to stimulation of carotid body chemoreceptors. Male Wistar rats were anesthetized with urethane, paralyzed and artificially ventilated. The carotid chemoreceptors were stimulated with isotonic solutions of inorganic phosphate solution. Stimulation of carotid body chemoreceptors produced increases in blood pressure. Kynurenate injected ipsilaterally but not contralaterally into the RVLM markedly inhibited the pressor response to chemoreceptor stimulation. In rats with spinal transection, stimulation of carotid body chemoreceptors also produced increases in blood pressure. The pressor response in rats with spinal transection was inhibited by intravenous injection of a vasopressin antagonist or by kynurenate injected ipsilaterally into the RVLM. Kynurenate injected into the RVLM inhibited the pressor response to NMDA, AMPA and kainate but not to acetylcholine in intact rats. These findings indicate that excitatory amino acid receptors are involved in mediating the pressor response to carotid body chemoreceptor stimulation in the rat RVLM. It appears that the chemoreceptor stimulation produces an increase in vasopressin release and the enhancement of vasopressin release is also mediated by an increase in excitatory amino acid inputs in the RVLM.
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N-methyl-D-aspartate receptors but not non-N-methyl-D-aspartate receptors mediate hypertension induced by carotid body chemoreceptor stimulation in the Rostral Ventrolateral Medulla of the rat.
Neuroscience Letters, 1993Co-Authors: Takao Kubo, Motoaki Amano, Tetsuya AsariAbstract:Abstract In urethane-anesthetized rats, excitatory amino acid antagonists were microinjected into the Rostral Ventrolateral Medulla (RVLM) and their effects on the pressor response and tachycardia evoked by carotid chemoreceptor stimulation were examined. Microinjections of the N- methyl- d -aspartate (NMDA) receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 into the RVLM inhibited these chemoreceptor reflex responses whereas these responses were not affected by injection of the non-NMDA receptor antagonist CNQX. AP5 and MK-801 but not CNQX abolished the pressor response evoked by NMDA whereas CNQX but not AP5 and MK-801 abolished that evoked by AMPA or kainate. These results provide evidence that NMDA receptors in the RVLM of the rat are involved in the carotid chemoreceptor reflex.
Andrew M Allen - One of the best experts on this subject based on the ideXlab platform.
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angiotensin type 1a receptor expression in c1 neurons of the Rostral Ventrolateral Medulla contributes to the development of angiotensin dependent hypertension
Experimental Physiology, 2014Co-Authors: Nikola Jancovski, Jaspreet K Bassi, Andrew M Allen, David A Carter, Angela A Connelly, Elyse Stevens, Clement MenuetAbstract:New Findings What is the central question of this study? This study addresses the mechanism by which deletion of angiotensinII type1A receptors from catecholaminergic neurons reduces angiotensin-dependent hypertension, as well as the identity of the cells involved.What is the main finding and its importance? Deletion of angiotensinII type1A receptors from catecholaminergic neurons results in reduced sympathetic nerve activation and fluid and electrolyte retention during angiotensin infusion. The C1 neurons of the Rostral Ventrolateral Medulla are involved in the later phase of the hypertension. We demonstrate that at least two different populations of catecholaminergic neurons are involved in the sympathetic nerve activation required for the full development of angiotensin-dependent hypertension.Chronic low-dose systemic infusion of angiotensinII induces hypertension via activation of the angiotensinII type1A receptor (AT(1A)R). Previously, we have demonstrated that expression of the AT(1A)R on catecholaminergic neurons is necessary for the full development of angiotensin-dependent hypertension. In the present study, we examined the mechanism by which selective deletion of the AT(1A)R from these cells affects the development of hypertension. We also tested the hypothesis that AT(1A)Rs expressed by catecholaminergic C1 neurons in the Rostral Ventrolateral Medulla play an important role in angiotensin-induced hypertension. A Cre-lox approach was used to delete the AT(1A)R from all catecholaminergic cells or from C1 neurons selectively. Subcutaneous administration of angiotensinII induced hypertension in all mice, with delayed onset and reduced maximal response in the global AT(1A)R catecholaminergic knockout mice. The AT(1A)R catecholaminergic knockout mice had decreased renal fluid and electrolyte retention and urinary noradrenaline excretion. The blood pressure response was reduced only during the second week of angiotensinII infusion in the mice with selective C1 AT(1A)R deletion, demonstrating that AT(1A)R expression by C1 neurons plays a moderate role in angiotensin-induced hypertension. The difference in the time course of development of hypertension between the mice with global AT(1A)R knockout from catecholaminergic cells and the mice with C1 AT(1A)R deletion suggests that other catecholaminergic neurons are important.
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control of sympathetic vasomotor tone by catecholaminergic c1 neurones of the Rostral Ventrolateral Medulla oblongata
Cardiovascular Research, 2011Co-Authors: Nephtali Marina, Andrew M Allen, Julian F R Paton, Ana P Abdala, Alla Korsak, Annabel E Simms, Alexander V GourineAbstract:Aims Increased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re-evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the Rostral Ventrolateral Medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses. Methods and results In anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ , C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor. In anaesthetized rats with denervated peripheral chemoreceptors, acute inhibition of 50% of the C1 neuronal population resulted in ∼50% reduction in renal sympathetic nerve activity and a profound fall in arterial blood pressure (by ∼25 mmHg). However, under these conditions systemic hypercapnia still evoked vigorous sympathetic activation and the slopes of the CO2-evoked sympathoexcitatory and cardiovascular responses were not affected by inhibition of C1 neurones. Inhibition of C1 neurones in situ resulted in a reversible fall in perfusion pressure and the amplitude of respiratory-related bursts of thoracic sympathetic nerve activity. Conclusion These data confirm a fundamental physiological role of Medullary catecholaminergic C1 neurones in maintaining resting sympathetic vasomotor tone and arterial blood pressure. However, C1 neurones do not appear to mediate sympathoexcitation evoked by central actions of CO2.
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c1 neurons in the rat Rostral Ventrolateral Medulla differentially express vesicular monoamine transporter 2 in soma and axonal compartments
European Journal of Neuroscience, 2008Co-Authors: Charles P Sevigny, Jaspreet K Bassi, Kwangsoo Kim, Anja G Teschemacher, David A Williams, C R Anderson, Andrew M AllenAbstract:Vesicular monoamine transporter 2 (VMAT2) packages biogenic amines into large dense core and synaptic vesicles for either somatodendritic or synaptic release from neurons of the CNS. Whilst the distribution of VMAT2 has been well characterized in many catecholaminergic cell groups, its localization amongst C1 adrenergic neurons in the Medulla has not been examined in detail. Within the Rostral Ventrolateral Medulla (RVLM), C1 neurons are a group of barosensitive, adrenergic neurons. Rostral C1 cells project to the thoracic spinal cord and are considered sympathetic premotor neurons. The majority of caudal C1 cells project Rostrally to regions such as the hypothalamus. The present study sought to quantitate the somatodendritic expression of VMAT2 in C1 neurons, and to assess the subcellular distribution of the transporter. Immunoreactivity for VMAT2 occurred in 31% of C1 soma, with a high proportion of these in the caudal part of the RVLM. Retrograde tracing studies revealed that only two of 43 bulbospinal C1 neurons contained faint VMAT2-immunoreactivity, whilst 88 +/- 5% of Rostrally projecting neurons were VMAT2-positive. A lentivirus, designed to express green fluorescent protein exclusively in noradrenergic and adrenergic neurons, was injected into the RVLM to label C1 neurons. Eighty-three percent of C1 efferents that occurred in close proximity to sympathetic preganglionic neurons within the T(3) intermediolateral cell column contained VMAT2-immunoreactivity. These data demonstrate differential distribution of VMAT2 within different subpopulations of C1 neurons and suggest that this might reflect differences in somatodendritic vs. synaptic release of catecholamines.
Andrei V Derbenev - One of the best experts on this subject based on the ideXlab platform.
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synaptic and extrasynaptic transmission of kidney related neurons in the Rostral Ventrolateral Medulla
Journal of Neurophysiology, 2013Co-Authors: Hong Gao, Andrei V DerbenevAbstract:The Rostral Ventrolateral Medulla (RVLM) is a critical component of the sympathetic nervous system regulating homeostatic functions including arterial blood pressure. Using the transsynaptic retrog...
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abstract 438 rapid inhibition of pre sympathetic kidney related neurons in the Rostral Ventrolateral Medulla by leptin
Hypertension, 2013Co-Authors: Hong Gao, Maria J Barnes, D Safwan S Majid, Andrei V DerbenevAbstract:The adipocyte-derived hormone leptin regulates satiety and plays a vital role in energy homeostasis. Several lines of evidence suggest that obesity is associated with increased prevalence of hypertension and accountable at least in part for the elevation of sympathetic nerve activity. Neurons in the Rostral Ventrolateral Medulla (RVLM) are critical components of both the sympathetic nervous system and cardiovascular regulation. By using whole-cell patch-clamp recordings in brainstem slices we tested the hypothesis that leptin suppresses activity in pre-sympathetic kidney-related RVLM neurons. Application of leptin caused a rapid membrane hyperpolarization in 43% of recorded kidney-related RVLM neurons. Out of 14 neurons, leptin (500nM) hyperpolarized 6 neurons (from -53.3±3.5 mV to -57.0± 3.2 mV; P
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abstract 412 electrophysiological properties of kidney related neurons in the Rostral Ventrolateral Medulla
Hypertension, 2012Co-Authors: Hong Gao, Amanda Krantz, Andrei V DerbenevAbstract:Presympathetic neurons in the Rostral Ventrolateral Medulla (RVLM) play an important integrative role in the neuronal network mediating cardiovascular regulation. In this study, we employed a retrograde, transsynaptic pseudorabies viral label (PRV-152), a PRV construct which expresses enhanced green fluorescent protein (EGFP), to identify kidney-related neurons in the RVLM. Whole-cell, patch-clamp recordings were made from 86 kidney-related neurons in the RVLM in transverse brainstem slices from 4-7-week-old rats. Under control conditions, we identified two populations of PRV-labeled RVLM neurons based on their electrophysiological properties. The resting membrane potential of large kidney-related neurons was -48 ± 2 mV and the input resistance was 205 ± 28 MΩ. The resting membrane potential of small kidney-related neurons was -51 ± 2 mV and the input resistance was 430 ± 36 MΩ. Spontaneous firing was observed in 2 out of 15 large cells with frequency of firing 0.008 and 0.05 Hz and 7 out of 16 small cells with average of firing 0.4 ± 0.2 Hz. Both spontaneous and miniature inhibitory and excitatory postsynaptic currents (i.e., sEPSCs, sIPSCs and mEPSCs, mIPSCs) were observed in small and large neurons. Tonic inhibitory and excitatory currents were identified in large kidney-related neurons of the RVLM. Application of the type A γ-aminobutyric acid (GABA A ) receptor-linked Cl - channel blocker, bicuculline methiodide (30 μM), blocked sIPSCs and revealed a robust tonic inhibitory current with an average amplitude of 145.3 ± 30 pA. The cocktail of potent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA)/kainate ionotropic glutamate receptor antagonist, AP-5 (50 μM) and CNQX (10 μM), blocked sEPSCs and revealed a two-component tonic excitatory current mediated by NMDA and AMPA/kainate ionotropic glutamate receptors with overall amplitude of 65.2 ± 11.3 pA. These data demonstrate the synaptic complexity involved in the regulation of kidney-related RVLM neurons.
Sean D Stocker - One of the best experts on this subject based on the ideXlab platform.
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cerebrospinal fluid hypernatremia elevates sympathetic nerve activity and blood pressure via the Rostral Ventrolateral Medulla
Hypertension, 2015Co-Authors: Sean D Stocker, Susan M Lang, Sarah S Simmonds, Megan M Wenner, William B FarquharAbstract:Elevated NaCl concentrations of the cerebrospinal fluid increase sympathetic nerve activity (SNA) in salt-sensitive hypertension. Neurons of the Rostral Ventrolateral Medulla (RVLM) play a pivotal role in the regulation of SNA and receive mono- or polysynaptic inputs from several hypothalamic structures responsive to hypernatremia. Therefore, the present study investigated the contribution of RVLM neurons to the SNA and pressor response to cerebrospinal fluid hypernatremia. Lateral ventricle infusion of 0.15 mol/L, 0.6 mol/L, and 1.0 mol/L NaCl (5 µL/10 minutes) produced concentration-dependent increases in lumbar SNA, adrenal SNA, and arterial blood pressure, despite no change in splanchnic SNA and a decrease in renal SNA. Ganglionic blockade with chlorisondamine or acute lesion of the lamina terminalis blocked or significantly attenuated these responses, respectively. RVLM microinjection of the gamma-aminobutyric acid (GABAA) agonist muscimol abolished the sympathoexcitatory response to intracerebroventricular infusion of 1 mol/L NaCl. Furthermore, blockade of ionotropic glutamate, but not angiotensin II type 1, receptors significantly attenuated the increase in lumbar SNA, adrenal SNA, and arterial blood pressure. Finally, single-unit recordings of spinally projecting RVLM neurons revealed 3 distinct populations based on discharge responses to intracerebroventricular infusion of 1 mol/L NaCl: type I excited (46%; 11/24), type II inhibited (37%; 9/24), and type III no change (17%; 4/24). All neurons with slow conduction velocities were type I cells. Collectively, these findings suggest that acute increases in cerebrospinal fluid NaCl concentrations selectively activate a discrete population of RVLM neurons through glutamate receptor activation to increase SNA and arterial blood pressure.
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glutamatergic receptor activation in the Rostral Ventrolateral Medulla mediates the sympathoexcitatory response to hyperinsulinemia
Hypertension, 2010Co-Authors: Megan E Bardgett, John J Mccarthy, Sean D StockerAbstract:Hyperinsulinemia increases sympathetic nerve activity (SNA) and has been linked to cardiovascular morbidity in obesity. The Rostral Ventrolateral Medulla (RVLM) plays a key role in the regulation of SNA and arterial blood pressure (ABP). Many sympathoexcitatory responses are mediated by glutamatergic receptor activation within the RVLM, and both the central renin–angiotensin and melanocortin systems are implicated in the sympathoexcitatory response to hyperinsulinemia. Therefore, we hypothesized that one or more of these neurotransmitters in the RVLM mediate the sympathoexcitatory response to insulin. Hyperinsulinemic–euglycemic clamps were performed in α-chloralose anesthetized, male Sprague–Dawley rats by infusion of insulin (3.75 mU/kg per minute, IV) and 50% dextrose solution for 120 minutes. Physiological increases in plasma insulin elevated lumbar SNA, with no change in renal SNA, ABP, or blood glucose. Microinjection of the ionotropic glutamate receptor antagonist kynurenic acid into the RVLM significantly reduced lumbar SNA and ABP. Selective blockade of NMDA but not non-NMDA glutamate receptors resulted in similar reductions of lumbar SNA. In marked contrast, microinjection of the angiotensin II type 1 receptor antagonist losartan or the melanocortin 3/4 antagonist SHU9119 had no effect on lumbar SNA or ABP. Western blot analysis showed that insulin receptor expression is significantly lower in the RVLM than the hypothalamus, and direct microinjection of insulin into the RVLM did not significantly increase lumbar SNA. These findings suggest that hyperinsulinemia increases lumbar SNA by activation of a glutamatergic NMDA-dependent projection to the RVLM.
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ventral lamina terminalis mediates enhanced cardiovascular responses of Rostral Ventrolateral Medulla neurons during increased dietary salt
Hypertension, 2009Co-Authors: Julye M Adams, Megan E Bardgett, Sean D StockerAbstract:Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses evoked from the Rostral Ventrolateral Medulla (RVLM). The purpose of the present study was to determine whether n...
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water deprivation activates a glutamatergic projection from the hypothalamic paraventricular nucleus to the Rostral Ventrolateral Medulla
The Journal of Comparative Neurology, 2006Co-Authors: Sean D Stocker, Johnny R Simmons, Ruth L Stornetta, Patrice G GuyenetAbstract:Elevated sympathetic outflow contributes to the maintenance of blood pressure in water-deprived rats. The neural circuitry underlying this response may involve activation of a pathway from the hypothalamic paraventricular nucleus (PVH) to the Rostral Ventrolateral Medulla (RVLM). We sought to determine whether the PVH-RVLM projection activated by water deprivation is glutamatergic and/or contains vasopressin- or oxytocin-neurophysins. Vesicular glutamate transporter 2 (VGLUT2) mRNA was detected by in situ hybridization in the majority of PVH neurons retrogradely labeled from the ipsilateral RVLM with cholera toxin subunit B (CTB; 85% on average, with regional differences). Very few RVLM-projecting PVH neurons were immunoreactive for oxytocin- or vasopressin-associated neurophysin. Injection of biotinylated dextran amine (BDA) into the PVH produced clusters of BDA-positive nerve terminals within the ipsilateral RVLM that were immunoreactive (ir) for the VGLUT2 protein. Some of these terminals made close appositions with tyrosine-hydroxylase-ir dendrites (presumptive C1 cells). In water-deprived rats (n=4), numerous VGLUT2 mRNA-positive PVH neurons retrogradely labeled from the ipsilateral RVLM with CTB were c-Fos-ir (16-40%, depending on PVH region). In marked contrast, few glutamatergic, RVLM-projecting PVH neurons were c-Fos-ir in control rats (n=3; 0-3%, depending on PVH region). Most (94% +/- 4%) RVLM-projecting PVH neurons activated by water deprivation contained VGLUT2 mRNA. In summary, most PVH neurons that innervate the RVLM are glutamatergic, and this population includes the neurons that are activated by water deprivation. One mechanism by which water deprivation may increase the sympathetic outflow is activation of a glutamatergic pathway from the PVH to the RVLM.
