Sympathoexcitation from the rostral ventrolateral medulla is mediated by spinal NMDA receptors

doi:10.1016/0361-9230(93)90217-Y

Brain Research Bulletin

Volume 31, Issues 3–4, 1993, Pages 273-278

https://doi.org/10.1016/0361-9230(93)90217-Y Get rights and content

Abstract

These studies examined the role of spinal N-methyl-D-aspartic acid (NMDA) receptors in mediating Sympathoexcitation evoked by stimulation of neurons in the rostral ventrolateral medulla (RVLM). In urethane-anesthetized rats, blood pressure, heart rate, and splanchnic sympathetic nerve activity (SNA) were recorded. The NMDA receptor antagonist D-2-amino-7-phosphonoheptanoic acid (D-AP7) was administered to the spinal cord via intrathecal (IT) catheter. Blockade of spinal NMDA receptors reduced arterial blood pressure, heart rate, and SNA. Spinal administration of D-AP7 markedly attenuated the pressor and sympathoexcitatory responses evoked by L-glutamate stimulation of the RVLM. The small increases in heart rate evoked by stimulation of the RVLM were not affected by IT administration of D-AP7. These results indicate that NMDA receptors in the spinal cord mediate the pressor and sympathoexcitatory responses evoked by activation of a bulbospinal pathway originating from the RVLM. Moreover, these data suggest that excitatory amino acid neurotransmitters and NMDA receptors in the spinal cord play an important role in the maintenance and regulation of SNA and cardiovascular function.

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Cited by (33)

Renal sympathetic activation triggered by the rostral ventrolateral medulla is dependent of spinal cord AT1 receptors in Goldblatt hypertensive rats
2021, Peptides
Citation Excerpt :
Descending glutamatergic pathways from the rostral ventrolateral medulla (RVLM) are well-known to have a key role in the control of SPGN activity. Bazil and Gordon reported that intrathecal (i.t.) injection of D-2-amino-7-phosphonoheptanoic acid, a selective N-methyl-D-aspartate (NMDA) receptor antagonist, attenuated the pressor and sympathetic vasomotor responses triggered by RVLM activation [16,17]. In contrast, spinal cord NMDA receptors play a minor role in cardiovascular responses mediated by the stimulation of the paraventricular nucleus of the hypothalamus (PVN) [18].
Spinal cord neurons contribute to elevated sympathetic vasomotor activity in renovascular hypertension (2K1C), particularly, increased actions of angiotensin II. However, the origin of these spinal angiotensinergic inputs remains unclear. The present study aimed to investigate the role of spinal angiotensin II type 1 receptor (AT1) receptors in the sympathoexcitatory responses evoked by the activation of the rostral ventrolateral medulla (RVLM) in control and 2K1C Goldblatt rats. Hypertension was induced by clipping of the left renal artery. After 6 weeks, a catheter (PE-10) filled with losartan was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of glutamate microinjection into the RVLM on blood pressure (BP), heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated in the presence or absence of spinal AT1 blockade. Tachycardic, pressor, and renal sympathoexcitatory effects caused by RVLM activation were significantly blunted by losartan in 2K1C rats, but not in control rats. However, no differences were found in the gene expression of angiotensin-converting enzyme, angiotensinogen, and renin in the spinal cord segments between the groups. In conclusion, acute sympathoexcitation induced by RVLM activation is dependent on the spinal AT1 receptor in Goldblatt, but not in control, rats. The involvement of other central cardiovascular nuclei in spinal angiotensinergic actions, as well as the source of angiotensin II, remains to be determined in the Goldblatt model.
Angiotensin 1-7 in the rostro-ventrolateral medulla increases blood pressure and splanchnic sympathetic nerve activity in anesthetized rats
2018, Respiratory Physiology and Neurobiology
Citation Excerpt :
The C1 adrenergic cell group is thought to be the primary source of innervation of the IML from the RVLM, but this is an area of contention (Lipski et al., 1995; Ruggiero et al., 1994; Schreihofer and Guyenet, 1997). There are catecholamines released at the spine (Head and Howe, 1987; Sevigny et al., 2008); however the principle excitatory neurotransmitter secreted by all RVLM vasomotor cells at the IML is glutamate (Bazil and Gordon, 1993; Llewellyn-Smith et al., 1998; Verberne et al., 1990). Since the 1970s, there has been increasing interest in the role of angiotensin peptides in the central nervous system (CNS) and central regulation of blood pressure and sympathetic nerve activity.
Angiotensin 1-7 (ANG-(1-7)), a derivative of angiotensin I or II, is involved in the propagation of sympathetic output to the heart and vasculature, and the receptor for ANG-(1-7), the Mas receptor, is expressed on astrocytes in the rostral ventrolateral medulla (RVLM). We recorded blood pressure (BP) and splanchnic sympathetic nerve activity (SSNA) before and after focal injection of ANG-(1-7) into the RVLM of rats. Unilateral injection of ANG-(1-7) into the RVLM, acting through the Mas receptor, increased SSNA and BP, and glutamate receptor antagonists, CNQX and D-AP5, partially reduced the ANG-(1-7) effect. ATP is often co-released with glutamate, and blocking ATP with PPADS also reduced the pressor response to microinjection of ANG-(1-7) within the RVLM. The effects of ANG-(1-7) were blocked by the MAS receptor antagonist, A-779 (which had no consistent effect on blood pressure or sympathetic nerve activity when injected on its own). We conclude that astrocytes in the RVLM participate in central, angiotensin-dependent regulation of blood pressure and sympathetic nerve activity, and the Mas receptor, when activated by ANG-(1-7), elicits the release of the gliotransmitters, glutamate and ATP. These gliotransmitters then cause an increase in sympathetic nerve activity and blood pressure by interacting with AMPA/kainate and P2X receptors in the RVLM.
Anesthetic synergy between two n-alkanes
2017, Veterinary Anaesthesia and Analgesia
Citation Excerpt :
The potent inhaled anesthetics all cause dose-dependent depression of cardiovascular and respiratory system function (Steffey et al. 2015). NMDA receptors within the hypothalamus, medulla and thoracic spinal cord mediate sympathetic baroreceptor reflexes, and NMDA receptor antagonists selectively administered at these locations result in attenuation of inotropic, chronotropic and pressor responses (Gordon 1987; Jung et al. 1991; Soltis & DiMicco 1991; Hong & Henry 1992; Bazil & Gordon 1993). In addition, NMDA receptors stimulate phrenic inspiratory drive and peripheral chemoreceptor hypoxic ventilation, thus NMDA receptors in pontine-medullary neurons help regulate breathing pattern whereas their inhibition results in apneusis (Jung et al. 1991; Connelly et al. 1992; Fung et al. 1994; Chitravanshi & Sapru 1996; Ohtake et al. 1998).
N-butane and n-pentane can both produce general anesthesia. Both compounds potentiate γ-aminobutyric acid type A (GABA_A) receptor function, but only butane inhibits N-methyl-d-aspartate (NMDA) receptors. It was hypothesized that butane and pentane would exhibit anesthetic synergy due to their different actions on ligand-gated ion channels.
Prospective experimental study.
A total of four Xenopus laevis frogs and 43 Sprague–Dawley rats.
Alkane concentrations for all studies were determined via gas chromatography. Using a Xenopus oocyte expression model, standard two-electrode voltage clamp techniques were used to measure NMDA and GABA_A receptor responses in vitro as a function of butane and pentane concentrations relevant to anesthesia. The minimum alveolar concentrations (MAC) of butane and pentane were measured separately in rats, and then pentane MAC was measured during coadministration of 0.25, 0.50 or 0.75 times MAC of butane. An isobole with 95% confidence intervals was constructed using regression analysis. A sum of butane and pentane that was statistically less than the lower-end confidence bound isobole indicated a synergistic interaction.
Both butane and pentane dose-dependently potentiated GABA_A receptor currents over the study concentration range. Butane dose-dependently inhibited NMDA receptor currents, but pentane did not modulate NMDA receptors. Butane and pentane MAC in rats was 39.4 ± 0.7 and 13.7 ± 0.4 %, respectively. A small but significant (p < 0.03) synergistic anesthetic effect with pentane was observed during administration of either 0.50 or 0.75 × MAC butane.
Butane and pentane show synergistic anesthetic effects in vivo consistent with their different in vitro receptor effects.
Findings support the relevance of NMDA receptors in mediating anesthetic actions for some, but not all, inhaled agents.
N-Methyl-D-aspartate receptor blockade by dizocilpine prevents stress-induced sudden death in cardiomyopathic hamsters
2002, Brain Research
We previously demonstrated that repeated cold-immobilization stress exposure had lethal effects in cardiomyopathic Syrian hamsters. To clarify the mechanisms of the sudden death, we investigated the effects of N-methyl-d-aspartate (NMDA) receptor blockade by dizocilpine on the sudden death of cardiomyopathic hamsters. Repeated exposure (5 days) to cold-immobilization stress induced a lethal effect in the cardiomyopathic hamsters in agreement with our previous results. Dizocilpine (0.1–10 mg/kg, i.p.), administered just prior to the stress, for 5 consecutive days markedly prevented the lethal effects of the stress. It was further demonstrated that treatment drug significantly reduced the observed increase in organ weights. These results suggest that NMDA receptors have an important role in stress-induced sudden death in cardiomyopathic hamsters and provide the first evidence for the potential therapeutic value of NMDA antagonists against cardiac sudden death.
N-methyl-D-aspartate-type glutamate receptors are found in post-synaptic targets of adrenergic terminals in the thoracic spinal cord
2000, Brain Research
Citation Excerpt :
Glutamate is contained both within catecholaminergic neurons in the RVL and in terminals in the spinal cord arising from the RVL [24, 26, 28]. Activation of the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor has been proposed to partially mediate the excitatory effects on SPNs caused by stimulation of the RVL [4, 7, 44]. However, these physiological studies have not determined the precise cellular mechanisms for the NMDA effects on the excitatory responses to RVL stimulation.
Adrenergic (C1) neurons in the rostral ventrolateral medulla (RVL) are sympathoexcitatory and project directly to sympathetic preganglionic neurons (SPNs) in the thoracic spinal cord. C1 neurons also contain glutamate which may mediate the excitatory effects of RVL stimulation on SPNs through the N-methyl-d-aspartate (NMDA)-type receptor. Dual-labeling immunocytochemistry, combined with electron microscopy, was used to determine if NMDA receptors are located post-synaptic to adrenergic terminals in the spinal cord. Adrenergic terminals were labeled using an antibody directed against phenylethanolamine-N-methyl transferase (PNMT) and the NMDA receptor was identified using an antibody directed against the R1 subunit of the receptor (NMDAR1). NMDAR1 was found primarily in large and small dendrites and a few perikarya. The presence of NMDAR1 in the dendritic targets of PNMT-containing terminals was quantified in spinal cords sectioned either horizontally or coronally. PNMT-labeled terminals formed asymmetric synapses on dendrites containing immunogold labeling for NMDAR1, but NMDAR1 was more often detected in the targets of PNMT terminals when spinal cords were sectioned horizontally (59%) rather than coronally (28%). This difference in prevalence of NMDAR1 in targets of PNMT terminals is likely due to the preferential orientation of SPN dendrites in the horizontal plane, since longer dendritic shafts were visible in horizontal sections. When NMDAR1 was present in the dendritic targets of many adrenergic terminals, it was usually located at sites distal to the adrenergic input. We conclude that NMDA receptor ligands are likely to modulate the activity of dendritic targets of adrenergic terminals in the spinal cord, but are not closely associated with adrenergic synaptic input.
Modulation of hypoxic ventilatory response by systemic platelet-activating factor receptor antagonist in the rat
1998, Respiration Physiology
Platelet activating factor (PAF) has recently emerged as an important modulator of neuronal excitability by enhancing synaptic glutamate release. Since PAF receptors (PAFR) are ubiquitously distributed in the brain, we hypothesized that PAF may play a role in respiratory control. To examine this issue, hypoxic (10% O₂ for 15 min, n=14) and hypercapnic (5% CO₂ for 30 min, n=6) challenges were performed in chronically-instrumented, unrestrained adult rats following administration of the pre-synaptic PAFR antagonist BN52021 (i.p. 20 mg/kg in 0.5 ml) or vehicle (Veh). In normoxia, BN52021 elicited Vt decreases and corresponding f increases such that minute ventilation ( $V ̇$ e) was unaffected. During hypercapnia, peak $V ̇$ e increased similarly after both treatments (103±18% in BN52021 vs. 94±19% in Veh, p-NS). In contrast, significant reductions in the peak hypoxic Ve response occurred after BN52021 (42±10% vs. 104±18% in Veh, P<0.002). BN52021 increased normoxic arterial blood pressure and decreased heart rate. However, hypoxia-induced chronotropic responses were attenuated and depressor responses were enhanced by BN52021. We further examined protein kinase C (PKC) translocation patterns during acute hypoxia after systemic BN52021 administration. Activation of PKC β and δ was blocked by BN52021, PKC γ was attenuated, with no effects on PKC α, ϵ, θ, ι, μ, and ζ. We conclude that systemic administration of a PAFR antagonist attenuates cardioventilatory recruitment to hypoxia and selectively attenuates activation of PKC in the rat brainstem. We speculate that enhanced regional PAF production and release during hypoxic conditions may contribute important excitatory inputs and signal transduction pathways within neuronal structures underlying cardiovascular and respiratory control.

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¹: Present address: American Cyanamid, Investigative Toxicology, North Middletown Road, Pearl River, NY 10965.

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ArticleSympathoexcitation from the rostral ventrolateral medulla is mediated by spinal NMDA receptors

Abstract

Neuropharmacology

Brain Res. Rev.

J. Neurosci. Methods

Brain Res.

Brain Res.

Neuroscience

Neurosci. Lett.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

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Sympathoexcitation from the rostral ventrolateral medulla is mediated by spinal NMDA receptors