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David Mendelowitz - One of the best experts on this subject based on the ideXlab platform.
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dexmedetomidine decreases inhibitory but not excitatory neurotransmission to cardiac vagal neurons in the Nucleus Ambiguus
Brain Research, 2014Co-Authors: Douglas Sharp, Xin Wang, David MendelowitzAbstract:Dexmedetomidine, an α2 adrenergic agonist, is a useful sedative but can also cause significant bradycardia. This decrease in heart rate may be due to decreased central sympathetic output as well as increased parasympathetic output from brainstem cardiac vagal neurons. In this study, using whole cell voltage clamp methodology, the actions of dexmedetomidine on excitatory glutamatergic and inhibitory GABAergic and glycinergic neurotransmission to parasympathetic cardiac vagal neurons in the rat Nucleus Ambiguus was determined. The results indicate that dexmedetomidine decreases both GABAergic and glycinergic inhibitory input to cardiac vagal neurons, with no significant effect on excitatory input. These results provide a mechanism for dexmedetomidine induced bradycardia and has implications for the management of this potentially harmful side effect.
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β adrenergic receptor modulation of neurotransmission to cardiac vagal neurons in the Nucleus Ambiguus
Neuroscience, 2012Co-Authors: Ryan Bateman, Kerry E Philbin, Carie R Boychuk, David MendelowitzAbstract:Abstract β-adrenergic receptors are a class of G protein-coupled receptors that have essential roles in regulating heart rate, blood pressure, and other cardiorespiratory functions. Although the role of β adrenergic receptors in the peripheral nervous system is well characterized, very little is known about their role in the central nervous system despite being localized in many brain regions involved in autonomic activity and regulation. Since parasympathetic activity to the heart is dominated by cardiac vagal neurons (CVNs) originating in the Nucleus Ambiguus (NA), β adrenergic receptors localized in the NA represent a potential target for modulating cardiac vagal activity and heart rate. This study tests the hypothesis that activation of β adrenergic receptors alters the membrane properties and synaptic neurotransmission to CVNs. CVNs were identified in brainstem slices, and membrane properties and synaptic events were recorded using the whole-cell voltage-clamp technique. The nonselective β agonist isoproterenol significantly decreased inhibitory GABAergic and glycinergic as well as excitatory glutamatergic neurotransmission to CVNs. In addition, the β1-selective receptor agonist dobutamine, but not β2 or β3 receptor agonists, significantly decreased inhibitory GABAergic and glycinergic and excitatory glutamatergic neurotransmission to CVNs. These decreases in neurotransmission to CVNs persisted in the presence of tetrodotoxin (TTX). These results provide a mechanism by which activation of adrenergic receptors in the brainstem can alter parasympathetic activity to the heart. Likely physiological roles for this adrenergic receptor activation are coordination of parasympathetic-sympathetic activity and β receptor-mediated increases in heart rate upon arousal.
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α1 adrenergic receptors facilitate inhibitory neurotransmission to cardiac vagal neurons in the Nucleus Ambiguus
Neuroscience, 2011Co-Authors: Carie R Boychuk, Ryan Bateman, Kerry E Philbin, David MendelowitzAbstract:Abstract The cholinergic cardiac vagal neurons (CVNs), located in the Nucleus Ambiguus, are the origin of cardioinhibitory parasympathetic activity. Catecholaminergic neurons in nearby regions of the brainstem, including the C1 and C2 cell groups, are thought to play a key role in both arousing from sleep and maintaining wakefulness. Because norepinephrine (NE) could play an important role in influencing the activity of CVNs, particularly in response to sleeping/waking and arousal states, the present study investigated the contribution of α 1 -adrenergic receptor activation to augment inhibitory and/or blunt excitatory neurotransmission to CVNs. To test the effects of α 1 -adrenergic receptor activation, CVNs were labeled in rats by retrograde tracing and synaptic events were recorded by whole cell voltage clamp techniques in vitro . Prazosin, an inverse agonist of α 1 -adrenergic receptor, significantly decreased the frequency of both GABAergic and glycinergic neurotransmission to CVNs. Activation of α 1 -adrenergic receptors by the α 1 -adrenergic receptor agonists NE or phenylephrine (PE) both significantly increased GABAergic and glycinergic inhibitory event frequency. This effect was prevented by the sodium channel blocker tetrodotoxin (TTX). Activation of α 1 -adrenergic receptors did not alter glutamatergic neurotransmission to CVNs. This study indicates that α 1 -adrenergic receptor activation in the brainstem can facilitate inhibitory GABAergic and glycinergic neurotransmission so as to reduce CVN activity; this synaptic modulation may play a role in the tachycardia seen during NE-dependent behavioral arousal.
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clonidine an α2 receptor agonist diminishes gabaergic neurotransmission to cardiac vagal neurons in the Nucleus Ambiguus
Brain Research, 2010Co-Authors: Kerry E Philbin, Ryan Bateman, David MendelowitzAbstract:Abstract In hypertension, there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the Nucleus Ambiguus. Presympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these presympathetic neurons are catecholaminergic. In addition to their projection to the spinal cord, many of these presympathetic neurons have axon collaterals that arborize into neighboring cardiorespiratory locations and likely release norepinephrine onto nearby neurons. Activation of α2-adrenergic receptors in the central nervous system evokes a diverse range of physiological effects, including reducing blood pressure. This study tests whether clonidine, an α2-adrenergic receptor agonist, alters excitatory glutamatergic, and/or inhibitory GABAergic or glycinergic synaptic neurotransmission to cardiac vagal neurons in the Nucleus Ambiguus. Cardiac vagal neurons were identified in an in vitro brainstem slice preparation, and synaptic events were recording using whole cell voltage clamp methodologies. Clonidine significantly inhibited GABAergic neurotransmission but had no effect on glycinergic or glutamatergic pathways to cardiac vagal neurons. This diminished inhibitory GABAergic neurotransmission to cardiac vagal neurons would increase parasympathetic activity to the heart, decreasing heart rate and blood pressure. The results presented here provide a cellular substrate for the clinical use of clonidine as a treatment for hypertension as well as a role in alleviating posttraumatic stress disorder by evoking an increase in parasympathetic cardiac vagal activity, and a decrease in heart rate and blood pressure.
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mapping and identification of gabaergic neurons in transgenic mice projecting to cardiac vagal neurons in the Nucleus Ambiguus using photo uncaging
Journal of Neurophysiology, 2009Co-Authors: J G Frank, Christopher Gorini, Heather Jameson, David MendelowitzAbstract:The neural control of heart rate is determined primarily by the activity of preganglionic parasympathetic cardiac vagal neurons (CVNs) originating in the Nucleus Ambiguus (NA) in the brain stem. GA...
Mustapha Irnaten - One of the best experts on this subject based on the ideXlab platform.
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synaptic and neurotransmitter activation of cardiac vagal neurons in the Nucleus Ambiguus
Annals of the New York Academy of Sciences, 2006Co-Authors: Jijiang Wang, Mustapha Irnaten, Priya Venkatesan, Cory Evans, Robert A Neff, Arthur D Loewy, Thomas C Mettenleiter, David MendelowitzAbstract:Abstract: Cardiac vagal neurons play a critical role in the control of heart rate and cardiac function. These neurons, which are primarily located in the Nucleus Ambiguus (NA) and the dorsal motor Nucleus of the vagus (DMNX), dominate the neural control of heart rate under normal conditions. Cardiac vagal activity is diminished and unresponsive in many disease states, while restoration of parasympathetic activity to the heart lessens ischemia and arrhythmias and decreases the risk of sudden death. Recent work has demonstrated that cardiac vagal neurons are intrinsically silent and therefore rely on synaptic input to control their firing. To date, three major synaptic inputs to cardiac vagal neurons have been identified. Stimulation of the Nucleus tractus solitarius evokes a glutamatergic pathway that activates both NMDA and non-NMDA glutamatergic postsynaptic currents in cardiac vagal neurons. Acetylcholine excites cardiac vagal neurons via three mechanisms, activating a direct ligand-gated postsynaptic nicotinic receptor, enhancing postsynaptic non-NMDA currents, and presynaptically by facilitating transmitter release. This enhancement by nicotine is dependent upon activation of pre- and postsynaptic P-type voltage-gated calcium channels. Additionally, there is a GABAergic innervation of cardiac vagal neurons. The transsynaptic pseudorabies virus that expresses GFP (PRV-GFP) has been used to identify, for subsequent electrophysiologic study, neurons that project to cardiac vagal neurons. Bartha PRV-GFP-labeled neurons retain their normal electrophysiological properties, and the labeled baroreflex pathways that control heart rate are unaltered by the virus.
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μ opioid receptors are located postsynaptically and endomorphin 1 inhibits voltage gated calcium currents in premotor cardiac parasympathetic neurons in the rat Nucleus Ambiguus
Neuroscience, 2003Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Sue A Aicher, Sunit Baxi, David MendelowitzAbstract:Activation of opioid receptors in the CNS evokes a dramatic decrease in heart rate which is mediated by increases in inhibitory parasympathetic activity to the heart. Injection of opiates into the Nucleus Ambiguus, where premotor cardiac parasympathetic Nucleus Ambiguus neurons are located elicits an increase in parasympathetic cardiac activity and bradycardia. However, the mechanisms responsible for altering the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons is unknown. This study examined at the electron microscopic level whether premotor cardiac parasympathetic Nucleus Ambiguus neurons possess postsynaptic opioid receptors and whether mu-opioid receptor agonists alter voltage-gated calcium currents in these neurons. Premotor cardiac parasympathetic Nucleus Ambiguus neurons were identified in the rat using retrograde fluorescent tracers. One series of experiments utilized dual-labeling immunocytochemical methods combined with electron microscopic analysis to determine if premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. In a second series of experiments whole cell patch clamp methodologies were used to determine whether activation of postsynaptic opioid receptors altered voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons in brainstem slices. The perikarya and 78% of the dendrites of premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. Voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons were comprised nearly entirely of omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents. Activation of mu-opioid receptors inhibited these voltage-gated calcium currents and this inhibition was blocked by pretreatment with pertusis toxin. The mu-opioid receptor agonist endomorphin-1, but not the mu-opioid receptor agonist endomorphin-2, inhibited the calcium currents. In summary, mu-opioid receptors are located postsynaptically on premotor cardiac parasympathetic Nucleus Ambiguus neurons. The mu-opioid receptor agonist endomorphin1 inhibited the omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents in premotor cardiac vagal Nucleus Ambiguus neurons. This inhibition is mediated via a G-protein mediated pathway which was blocked by pretreatment with pertusis toxin. It is possible that the inhibition of calcium currents may act to indirectly facilitate the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons by disinhibition, such as by a reduction in inhibitory calcium activated potassium currents.
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μ opioid receptors are located postsynaptically and endomorphin 1 inhibits voltage gated calcium currents in premotor cardiac parasympathetic neurons in the rat Nucleus Ambiguus
Neuroscience, 2003Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Sue A Aicher, Sunit Baxi, David MendelowitzAbstract:Abstract Activation of opioid receptors in the CNS evokes a dramatic decrease in heart rate which is mediated by increases in inhibitory parasympathetic activity to the heart. Injection of opiates into the Nucleus Ambiguus, where premotor cardiac parasympathetic Nucleus Ambiguus neurons are located elicits an increase in parasympathetic cardiac activity and bradycardia. However, the mechanisms responsible for altering the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons is unknown. This study examined at the electron microscopic level whether premotor cardiac parasympathetic Nucleus Ambiguus neurons possess postsynaptic opioid receptors and whether μ-opioid receptor agonists alter voltage-gated calcium currents in these neurons. Premotor cardiac parasympathetic Nucleus Ambiguus neurons were identified in the rat using retrograde fluorescent tracers. One series of experiments utilized dual-labeling immunocytochemical methods combined with electron microscopic analysis to determine if premotor cardiac parasympathetic Nucleus Ambiguus neurons contain μ-opioid receptors. In a second series of experiments whole cell patch clamp methodologies were used to determine whether activation of postsynaptic opioid receptors altered voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons in brainstem slices. The perikarya and 78% of the dendrites of premotor cardiac parasympathetic Nucleus Ambiguus neurons contain μ-opioid receptors. Voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons were comprised nearly entirely of ω-agatoxin-sensitive P/Q-type voltage-gated calcium currents. Activation of μ-opioid receptors inhibited these voltage-gated calcium currents and this inhibition was blocked by pretreatment with pertusis toxin. The μ-opioid receptor agonist endomorphin-1, but not the μ-opioid receptor agonist endomorphin-2, inhibited the calcium currents. In summary, μ-opioid receptors are located postsynaptically on premotor cardiac parasympathetic Nucleus Ambiguus neurons. The μ-opioid receptor agonist endomorphin1 inhibited the ω-agatoxin-sensitive P/Q-type voltage-gated calcium currents in premotor cardiac vagal Nucleus Ambiguus neurons. This inhibition is mediated via a G-protein mediated pathway which was blocked by pretreatment with pertusis toxin. It is possible that the inhibition of calcium currents may act to indirectly facilitate the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons by disinhibition, such as by a reduction in inhibitory calcium activated potassium currents.
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ketamine inhibits sodium currents in identified cardiac parasympathetic neurons in Nucleus Ambiguus
Anesthesiology, 2002Co-Authors: Mustapha Irnaten, Jijiang Wang, Kyoung S K Chang, Michael C Andresen, David MendelowitzAbstract:Background: Ketamine increases both blood pressure and heart rate, effects commonly thought of as sympathoexcitatory. The authors investigated the possibility that ketamine increases heart rate by inhibiting the central cardiac parasympathetic mechanisms. Methods: We used a novel in vitro approach to study the effect of ketamine on the identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the Nucleus Ambiguus were retrogradely prelabeled with the fluorescent tracer by placing rhodamine into the pericardial sac. Dye-labeled neurons were visually identified for patch clamp recording, and ketamine effects on isolated potassium (K + ) and sodium (Na + ) currents were studied. Results: Cardiac Nucleus Ambiguus neurons (n = 14) were inherently silent, but depolarization evoked sustained action potential trains with little delay or adaptation. Ketamine (10 μM) reduced this response but had no effect on the voltage threshold for action potentials (n = 14; P > 0.05). The current-voltage relations for the transient K + current and the delayed rectified K + current (n = 5) were unaltered by ketamine (10 μM-1 mM). Ketamine depressed the total Na + current dose-dependently (10 μM-1 mM). In addition, ketamine shifted the Na + current inactivation curves to more negative potentials, thus suggesting the enhancement of the Na + channel inactivation (P < 0.05; n = 7). In the presence of Cd 2+ , ketamine (10 μM) continued to inhibit voltage-gated Na + currents, which recovered completely within 10 min. Conclusions: Ketamine inhibits Na + but not K + channel function in brainstem parasympathetic cardiac neurons, and such actions may mediate the decrease in parasympathetic cardiac activity and increase in heart rate that occurs with ketamine.
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ketamine inhibits presynaptic and postsynaptic nicotinic excitation of identified cardiac parasympathetic neurons in Nucleus Ambiguus
Anesthesiology, 2002Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Kyoung S K Chang, Michael C Andresen, David MendelowitzAbstract:BACKGROUND Ketamine increases both blood pressure and heart rate, effects commonly thought of as sympathoexcitatory. The authors investigated possible central nervous system actions of ketamine to inhibit cardiac parasympathetic neurons in the brainstem by inhibiting multiple nicotinic excitatory mechanisms. METHODS The authors used a novel in vitro approach to study the effect of ketamine on identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the Nucleus Ambiguus were retrogradely prelabeled with the fluorescent tracer by placing rhodamine into the pericardial sac. Dye-labeled neurons were visually identified for patch clamp recording. The effects of ketamine were tested on nicotine-evoked ligand-gated currents and spontaneous glutamatergic miniature synaptic currents (mini) in cardiac parasympathetic preganglionic neurons. RESULTS Ketamine (10 microm) inhibited (1) the nicotine (1 microm)-evoked presynaptic facilitation of glutamate release (mini frequency, 18 +/- 7% of control; n = 9), and (2) the direct postsynaptic ligand-gated current (27 +/- 8% of control; n = 9), but ketamine did not alter the amplitude of postsynaptic miniature non-N-methyl-D-aspartate currents. alpha Bungarotoxin, an antagonist of alpha 7 containing nicotinic presynaptic receptors, blocked ketamine actions on mini frequency (n = 10) but not mini amplitude. CONCLUSIONS Ketamine inhibits the presynaptic nicotinic receptors responsible for facilitating neurotransmitter release, as well as the direct ligand-gated inward current, but does not alter the nicotinic augmentation of non-N-methyl-D-aspartate currents in brainstem parasympathetic cardiac neurons. Such actions may mediate the decrease in parasympathetic cardiac activity and increase in heart rate that occurs with ketamine.
Cory Evans - One of the best experts on this subject based on the ideXlab platform.
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synaptic and neurotransmitter activation of cardiac vagal neurons in the Nucleus Ambiguus
Annals of the New York Academy of Sciences, 2006Co-Authors: Jijiang Wang, Mustapha Irnaten, Priya Venkatesan, Cory Evans, Robert A Neff, Arthur D Loewy, Thomas C Mettenleiter, David MendelowitzAbstract:Abstract: Cardiac vagal neurons play a critical role in the control of heart rate and cardiac function. These neurons, which are primarily located in the Nucleus Ambiguus (NA) and the dorsal motor Nucleus of the vagus (DMNX), dominate the neural control of heart rate under normal conditions. Cardiac vagal activity is diminished and unresponsive in many disease states, while restoration of parasympathetic activity to the heart lessens ischemia and arrhythmias and decreases the risk of sudden death. Recent work has demonstrated that cardiac vagal neurons are intrinsically silent and therefore rely on synaptic input to control their firing. To date, three major synaptic inputs to cardiac vagal neurons have been identified. Stimulation of the Nucleus tractus solitarius evokes a glutamatergic pathway that activates both NMDA and non-NMDA glutamatergic postsynaptic currents in cardiac vagal neurons. Acetylcholine excites cardiac vagal neurons via three mechanisms, activating a direct ligand-gated postsynaptic nicotinic receptor, enhancing postsynaptic non-NMDA currents, and presynaptically by facilitating transmitter release. This enhancement by nicotine is dependent upon activation of pre- and postsynaptic P-type voltage-gated calcium channels. Additionally, there is a GABAergic innervation of cardiac vagal neurons. The transsynaptic pseudorabies virus that expresses GFP (PRV-GFP) has been used to identify, for subsequent electrophysiologic study, neurons that project to cardiac vagal neurons. Bartha PRV-GFP-labeled neurons retain their normal electrophysiological properties, and the labeled baroreflex pathways that control heart rate are unaltered by the virus.
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fentanyl inhibits gabaergic neurotransmission to cardiac vagal neurons in the Nucleus Ambiguus
Brain Research, 2004Co-Authors: Kathleen J Griffioen, Priya Venkatesan, Cory Evans, Xin Wang, Zhenggui Huang, Evguenia Bouairi, Allison Gold, David MendelowitzAbstract:Fentanyl citrate is a synthetic opiate analgesic often used clinically for neonatal anesthesia. Although fentanyl significantly depresses heart rate, the mechanism of inducing bradycardia remains unclear. One possible site of action is the cardioinhibitory parasympathetic vagal neurons in the Nucleus Ambiguus (NA), from which originates control of heart rate and cardiac function. Inhibitory synaptic activity to cardiac vagal neurons is a major determinant of their activity. Therefore, the effect of fentanyl on GABAergic neurotransmission to parasympathetic cardiac vagal neurons was studied using whole-cell patch clamp electrophysiology. Application of fentanyl induced a reduction in both the frequency and amplitude of GABAergic IPSCs in cardiac vagal neurons. This inhibition was mediated at both pre- and postsynaptic sites as evidenced by a dual decrease in the frequency and amplitude of spontaneous miniature IPSCs. Application of the selective micro-antagonist CTOP abolished the fentanyl-mediated inhibition of GABAergic IPSCs. These results demonstrate that fentanyl acts on micro-opioid receptors on cardiac vagal neurons and neurons preceding them to reduce GABAergic neurotransmission and increase parasympathetic activity. The inhibition of GABAergic effects may be one mechanism by which fentanyl induces bradycardia.
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action of κ and δ opioid agonists on premotor cardiac vagal neurons in the Nucleus Ambiguus
Neuroscience, 2004Co-Authors: Xin Wang, Cory Evans, Olga Dergacheva, Zhenggui Huang, Evguenia Bouairi, Kathleen J Griffioen, Allison Gold, David MendelowitzAbstract:Both enkephalin and dynorphin containing fibers are in close proximity to neurons in the Nucleus Ambiguus, including cardiac vagal neurons. Microinjection of Delta and kappa agonists into the Nucleus Ambiguus have been shown to evoke decreases in heart rate. Yet little is known about the mechanisms by which Delta and kappa opioid receptors alter the activity of cardiac vagal neurons. This study tests whether kappa and Delta opioid agonists can alter the activity of cardiac vagal neurons by modulating likely opioid targets including voltage gated calcium currents, and both glycinergic and GABA) neurotransmission to cardiac vagal neurons. Cardiac vagal neurons were identified in vitro by a fluorescent tracer and studied using patch clamp techniques. Neither the kappa agonist spiradoline or the Delta agonist [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) modulated the voltage gated calcium currents in cardiac vagal neurons. DPDPE also did not alter either glycinergic or GABAergic synaptic neurotransmission. Spiradoline did not change GABAergic synaptic inputs, but did significantly inhibit glycinergic synaptic inputs to cardiac vagal neurons. At a concentration of 1 microM, spiradoline inhibited the amplitude of glycinergic events, and at a concentration of 5 microM, spiradoline inhibited both glycinergic amplitude and frequency. Spiradoline also inhibited both the amplitude and frequency of glycinergic miniature inhibitory post-synaptic currents, indicating kappa agonists likely act at both presynaptic and postsynaptic sites to inhibit glycinergic neurotransmission to cardiac vagal neurons.
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glycinergic inputs to cardiac vagal neurons in the Nucleus Ambiguus are inhibited by nociceptin and μ selective opioids
Journal of Neurophysiology, 2003Co-Authors: Priya Venkatesan, Cory Evans, Sunit Baxi, Robert A Neff, Xin Wang, David MendelowitzAbstract:Most parasympathetic regulation of heart rate originates from preganglionic cardiac vagal neurons within the Nucleus Ambiguus. Little is known regarding the modulation of glycinergic transmission t...
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μ opioid receptors are located postsynaptically and endomorphin 1 inhibits voltage gated calcium currents in premotor cardiac parasympathetic neurons in the rat Nucleus Ambiguus
Neuroscience, 2003Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Sue A Aicher, Sunit Baxi, David MendelowitzAbstract:Activation of opioid receptors in the CNS evokes a dramatic decrease in heart rate which is mediated by increases in inhibitory parasympathetic activity to the heart. Injection of opiates into the Nucleus Ambiguus, where premotor cardiac parasympathetic Nucleus Ambiguus neurons are located elicits an increase in parasympathetic cardiac activity and bradycardia. However, the mechanisms responsible for altering the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons is unknown. This study examined at the electron microscopic level whether premotor cardiac parasympathetic Nucleus Ambiguus neurons possess postsynaptic opioid receptors and whether mu-opioid receptor agonists alter voltage-gated calcium currents in these neurons. Premotor cardiac parasympathetic Nucleus Ambiguus neurons were identified in the rat using retrograde fluorescent tracers. One series of experiments utilized dual-labeling immunocytochemical methods combined with electron microscopic analysis to determine if premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. In a second series of experiments whole cell patch clamp methodologies were used to determine whether activation of postsynaptic opioid receptors altered voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons in brainstem slices. The perikarya and 78% of the dendrites of premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. Voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons were comprised nearly entirely of omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents. Activation of mu-opioid receptors inhibited these voltage-gated calcium currents and this inhibition was blocked by pretreatment with pertusis toxin. The mu-opioid receptor agonist endomorphin-1, but not the mu-opioid receptor agonist endomorphin-2, inhibited the calcium currents. In summary, mu-opioid receptors are located postsynaptically on premotor cardiac parasympathetic Nucleus Ambiguus neurons. The mu-opioid receptor agonist endomorphin1 inhibited the omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents in premotor cardiac vagal Nucleus Ambiguus neurons. This inhibition is mediated via a G-protein mediated pathway which was blocked by pretreatment with pertusis toxin. It is possible that the inhibition of calcium currents may act to indirectly facilitate the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons by disinhibition, such as by a reduction in inhibitory calcium activated potassium currents.
Priya Venkatesan - One of the best experts on this subject based on the ideXlab platform.
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synaptic and neurotransmitter activation of cardiac vagal neurons in the Nucleus Ambiguus
Annals of the New York Academy of Sciences, 2006Co-Authors: Jijiang Wang, Mustapha Irnaten, Priya Venkatesan, Cory Evans, Robert A Neff, Arthur D Loewy, Thomas C Mettenleiter, David MendelowitzAbstract:Abstract: Cardiac vagal neurons play a critical role in the control of heart rate and cardiac function. These neurons, which are primarily located in the Nucleus Ambiguus (NA) and the dorsal motor Nucleus of the vagus (DMNX), dominate the neural control of heart rate under normal conditions. Cardiac vagal activity is diminished and unresponsive in many disease states, while restoration of parasympathetic activity to the heart lessens ischemia and arrhythmias and decreases the risk of sudden death. Recent work has demonstrated that cardiac vagal neurons are intrinsically silent and therefore rely on synaptic input to control their firing. To date, three major synaptic inputs to cardiac vagal neurons have been identified. Stimulation of the Nucleus tractus solitarius evokes a glutamatergic pathway that activates both NMDA and non-NMDA glutamatergic postsynaptic currents in cardiac vagal neurons. Acetylcholine excites cardiac vagal neurons via three mechanisms, activating a direct ligand-gated postsynaptic nicotinic receptor, enhancing postsynaptic non-NMDA currents, and presynaptically by facilitating transmitter release. This enhancement by nicotine is dependent upon activation of pre- and postsynaptic P-type voltage-gated calcium channels. Additionally, there is a GABAergic innervation of cardiac vagal neurons. The transsynaptic pseudorabies virus that expresses GFP (PRV-GFP) has been used to identify, for subsequent electrophysiologic study, neurons that project to cardiac vagal neurons. Bartha PRV-GFP-labeled neurons retain their normal electrophysiological properties, and the labeled baroreflex pathways that control heart rate are unaltered by the virus.
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fentanyl inhibits gabaergic neurotransmission to cardiac vagal neurons in the Nucleus Ambiguus
Brain Research, 2004Co-Authors: Kathleen J Griffioen, Priya Venkatesan, Cory Evans, Xin Wang, Zhenggui Huang, Evguenia Bouairi, Allison Gold, David MendelowitzAbstract:Fentanyl citrate is a synthetic opiate analgesic often used clinically for neonatal anesthesia. Although fentanyl significantly depresses heart rate, the mechanism of inducing bradycardia remains unclear. One possible site of action is the cardioinhibitory parasympathetic vagal neurons in the Nucleus Ambiguus (NA), from which originates control of heart rate and cardiac function. Inhibitory synaptic activity to cardiac vagal neurons is a major determinant of their activity. Therefore, the effect of fentanyl on GABAergic neurotransmission to parasympathetic cardiac vagal neurons was studied using whole-cell patch clamp electrophysiology. Application of fentanyl induced a reduction in both the frequency and amplitude of GABAergic IPSCs in cardiac vagal neurons. This inhibition was mediated at both pre- and postsynaptic sites as evidenced by a dual decrease in the frequency and amplitude of spontaneous miniature IPSCs. Application of the selective micro-antagonist CTOP abolished the fentanyl-mediated inhibition of GABAergic IPSCs. These results demonstrate that fentanyl acts on micro-opioid receptors on cardiac vagal neurons and neurons preceding them to reduce GABAergic neurotransmission and increase parasympathetic activity. The inhibition of GABAergic effects may be one mechanism by which fentanyl induces bradycardia.
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glycinergic inputs to cardiac vagal neurons in the Nucleus Ambiguus are inhibited by nociceptin and μ selective opioids
Journal of Neurophysiology, 2003Co-Authors: Priya Venkatesan, Cory Evans, Sunit Baxi, Robert A Neff, Xin Wang, David MendelowitzAbstract:Most parasympathetic regulation of heart rate originates from preganglionic cardiac vagal neurons within the Nucleus Ambiguus. Little is known regarding the modulation of glycinergic transmission t...
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μ opioid receptors are located postsynaptically and endomorphin 1 inhibits voltage gated calcium currents in premotor cardiac parasympathetic neurons in the rat Nucleus Ambiguus
Neuroscience, 2003Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Sue A Aicher, Sunit Baxi, David MendelowitzAbstract:Activation of opioid receptors in the CNS evokes a dramatic decrease in heart rate which is mediated by increases in inhibitory parasympathetic activity to the heart. Injection of opiates into the Nucleus Ambiguus, where premotor cardiac parasympathetic Nucleus Ambiguus neurons are located elicits an increase in parasympathetic cardiac activity and bradycardia. However, the mechanisms responsible for altering the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons is unknown. This study examined at the electron microscopic level whether premotor cardiac parasympathetic Nucleus Ambiguus neurons possess postsynaptic opioid receptors and whether mu-opioid receptor agonists alter voltage-gated calcium currents in these neurons. Premotor cardiac parasympathetic Nucleus Ambiguus neurons were identified in the rat using retrograde fluorescent tracers. One series of experiments utilized dual-labeling immunocytochemical methods combined with electron microscopic analysis to determine if premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. In a second series of experiments whole cell patch clamp methodologies were used to determine whether activation of postsynaptic opioid receptors altered voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons in brainstem slices. The perikarya and 78% of the dendrites of premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. Voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons were comprised nearly entirely of omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents. Activation of mu-opioid receptors inhibited these voltage-gated calcium currents and this inhibition was blocked by pretreatment with pertusis toxin. The mu-opioid receptor agonist endomorphin-1, but not the mu-opioid receptor agonist endomorphin-2, inhibited the calcium currents. In summary, mu-opioid receptors are located postsynaptically on premotor cardiac parasympathetic Nucleus Ambiguus neurons. The mu-opioid receptor agonist endomorphin1 inhibited the omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents in premotor cardiac vagal Nucleus Ambiguus neurons. This inhibition is mediated via a G-protein mediated pathway which was blocked by pretreatment with pertusis toxin. It is possible that the inhibition of calcium currents may act to indirectly facilitate the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons by disinhibition, such as by a reduction in inhibitory calcium activated potassium currents.
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μ opioid receptors are located postsynaptically and endomorphin 1 inhibits voltage gated calcium currents in premotor cardiac parasympathetic neurons in the rat Nucleus Ambiguus
Neuroscience, 2003Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Sue A Aicher, Sunit Baxi, David MendelowitzAbstract:Abstract Activation of opioid receptors in the CNS evokes a dramatic decrease in heart rate which is mediated by increases in inhibitory parasympathetic activity to the heart. Injection of opiates into the Nucleus Ambiguus, where premotor cardiac parasympathetic Nucleus Ambiguus neurons are located elicits an increase in parasympathetic cardiac activity and bradycardia. However, the mechanisms responsible for altering the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons is unknown. This study examined at the electron microscopic level whether premotor cardiac parasympathetic Nucleus Ambiguus neurons possess postsynaptic opioid receptors and whether μ-opioid receptor agonists alter voltage-gated calcium currents in these neurons. Premotor cardiac parasympathetic Nucleus Ambiguus neurons were identified in the rat using retrograde fluorescent tracers. One series of experiments utilized dual-labeling immunocytochemical methods combined with electron microscopic analysis to determine if premotor cardiac parasympathetic Nucleus Ambiguus neurons contain μ-opioid receptors. In a second series of experiments whole cell patch clamp methodologies were used to determine whether activation of postsynaptic opioid receptors altered voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons in brainstem slices. The perikarya and 78% of the dendrites of premotor cardiac parasympathetic Nucleus Ambiguus neurons contain μ-opioid receptors. Voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons were comprised nearly entirely of ω-agatoxin-sensitive P/Q-type voltage-gated calcium currents. Activation of μ-opioid receptors inhibited these voltage-gated calcium currents and this inhibition was blocked by pretreatment with pertusis toxin. The μ-opioid receptor agonist endomorphin-1, but not the μ-opioid receptor agonist endomorphin-2, inhibited the calcium currents. In summary, μ-opioid receptors are located postsynaptically on premotor cardiac parasympathetic Nucleus Ambiguus neurons. The μ-opioid receptor agonist endomorphin1 inhibited the ω-agatoxin-sensitive P/Q-type voltage-gated calcium currents in premotor cardiac vagal Nucleus Ambiguus neurons. This inhibition is mediated via a G-protein mediated pathway which was blocked by pretreatment with pertusis toxin. It is possible that the inhibition of calcium currents may act to indirectly facilitate the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons by disinhibition, such as by a reduction in inhibitory calcium activated potassium currents.
Jijiang Wang - One of the best experts on this subject based on the ideXlab platform.
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synaptic and neurotransmitter activation of cardiac vagal neurons in the Nucleus Ambiguus
Annals of the New York Academy of Sciences, 2006Co-Authors: Jijiang Wang, Mustapha Irnaten, Priya Venkatesan, Cory Evans, Robert A Neff, Arthur D Loewy, Thomas C Mettenleiter, David MendelowitzAbstract:Abstract: Cardiac vagal neurons play a critical role in the control of heart rate and cardiac function. These neurons, which are primarily located in the Nucleus Ambiguus (NA) and the dorsal motor Nucleus of the vagus (DMNX), dominate the neural control of heart rate under normal conditions. Cardiac vagal activity is diminished and unresponsive in many disease states, while restoration of parasympathetic activity to the heart lessens ischemia and arrhythmias and decreases the risk of sudden death. Recent work has demonstrated that cardiac vagal neurons are intrinsically silent and therefore rely on synaptic input to control their firing. To date, three major synaptic inputs to cardiac vagal neurons have been identified. Stimulation of the Nucleus tractus solitarius evokes a glutamatergic pathway that activates both NMDA and non-NMDA glutamatergic postsynaptic currents in cardiac vagal neurons. Acetylcholine excites cardiac vagal neurons via three mechanisms, activating a direct ligand-gated postsynaptic nicotinic receptor, enhancing postsynaptic non-NMDA currents, and presynaptically by facilitating transmitter release. This enhancement by nicotine is dependent upon activation of pre- and postsynaptic P-type voltage-gated calcium channels. Additionally, there is a GABAergic innervation of cardiac vagal neurons. The transsynaptic pseudorabies virus that expresses GFP (PRV-GFP) has been used to identify, for subsequent electrophysiologic study, neurons that project to cardiac vagal neurons. Bartha PRV-GFP-labeled neurons retain their normal electrophysiological properties, and the labeled baroreflex pathways that control heart rate are unaltered by the virus.
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μ opioid receptors are located postsynaptically and endomorphin 1 inhibits voltage gated calcium currents in premotor cardiac parasympathetic neurons in the rat Nucleus Ambiguus
Neuroscience, 2003Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Sue A Aicher, Sunit Baxi, David MendelowitzAbstract:Activation of opioid receptors in the CNS evokes a dramatic decrease in heart rate which is mediated by increases in inhibitory parasympathetic activity to the heart. Injection of opiates into the Nucleus Ambiguus, where premotor cardiac parasympathetic Nucleus Ambiguus neurons are located elicits an increase in parasympathetic cardiac activity and bradycardia. However, the mechanisms responsible for altering the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons is unknown. This study examined at the electron microscopic level whether premotor cardiac parasympathetic Nucleus Ambiguus neurons possess postsynaptic opioid receptors and whether mu-opioid receptor agonists alter voltage-gated calcium currents in these neurons. Premotor cardiac parasympathetic Nucleus Ambiguus neurons were identified in the rat using retrograde fluorescent tracers. One series of experiments utilized dual-labeling immunocytochemical methods combined with electron microscopic analysis to determine if premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. In a second series of experiments whole cell patch clamp methodologies were used to determine whether activation of postsynaptic opioid receptors altered voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons in brainstem slices. The perikarya and 78% of the dendrites of premotor cardiac parasympathetic Nucleus Ambiguus neurons contain mu-opioid receptors. Voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons were comprised nearly entirely of omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents. Activation of mu-opioid receptors inhibited these voltage-gated calcium currents and this inhibition was blocked by pretreatment with pertusis toxin. The mu-opioid receptor agonist endomorphin-1, but not the mu-opioid receptor agonist endomorphin-2, inhibited the calcium currents. In summary, mu-opioid receptors are located postsynaptically on premotor cardiac parasympathetic Nucleus Ambiguus neurons. The mu-opioid receptor agonist endomorphin1 inhibited the omega-agatoxin-sensitive P/Q-type voltage-gated calcium currents in premotor cardiac vagal Nucleus Ambiguus neurons. This inhibition is mediated via a G-protein mediated pathway which was blocked by pretreatment with pertusis toxin. It is possible that the inhibition of calcium currents may act to indirectly facilitate the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons by disinhibition, such as by a reduction in inhibitory calcium activated potassium currents.
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μ opioid receptors are located postsynaptically and endomorphin 1 inhibits voltage gated calcium currents in premotor cardiac parasympathetic neurons in the rat Nucleus Ambiguus
Neuroscience, 2003Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Sue A Aicher, Sunit Baxi, David MendelowitzAbstract:Abstract Activation of opioid receptors in the CNS evokes a dramatic decrease in heart rate which is mediated by increases in inhibitory parasympathetic activity to the heart. Injection of opiates into the Nucleus Ambiguus, where premotor cardiac parasympathetic Nucleus Ambiguus neurons are located elicits an increase in parasympathetic cardiac activity and bradycardia. However, the mechanisms responsible for altering the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons is unknown. This study examined at the electron microscopic level whether premotor cardiac parasympathetic Nucleus Ambiguus neurons possess postsynaptic opioid receptors and whether μ-opioid receptor agonists alter voltage-gated calcium currents in these neurons. Premotor cardiac parasympathetic Nucleus Ambiguus neurons were identified in the rat using retrograde fluorescent tracers. One series of experiments utilized dual-labeling immunocytochemical methods combined with electron microscopic analysis to determine if premotor cardiac parasympathetic Nucleus Ambiguus neurons contain μ-opioid receptors. In a second series of experiments whole cell patch clamp methodologies were used to determine whether activation of postsynaptic opioid receptors altered voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons in brainstem slices. The perikarya and 78% of the dendrites of premotor cardiac parasympathetic Nucleus Ambiguus neurons contain μ-opioid receptors. Voltage-gated calcium currents in premotor cardiac parasympathetic Nucleus Ambiguus neurons were comprised nearly entirely of ω-agatoxin-sensitive P/Q-type voltage-gated calcium currents. Activation of μ-opioid receptors inhibited these voltage-gated calcium currents and this inhibition was blocked by pretreatment with pertusis toxin. The μ-opioid receptor agonist endomorphin-1, but not the μ-opioid receptor agonist endomorphin-2, inhibited the calcium currents. In summary, μ-opioid receptors are located postsynaptically on premotor cardiac parasympathetic Nucleus Ambiguus neurons. The μ-opioid receptor agonist endomorphin1 inhibited the ω-agatoxin-sensitive P/Q-type voltage-gated calcium currents in premotor cardiac vagal Nucleus Ambiguus neurons. This inhibition is mediated via a G-protein mediated pathway which was blocked by pretreatment with pertusis toxin. It is possible that the inhibition of calcium currents may act to indirectly facilitate the activity of premotor cardiac parasympathetic Nucleus Ambiguus neurons by disinhibition, such as by a reduction in inhibitory calcium activated potassium currents.
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ketamine inhibits sodium currents in identified cardiac parasympathetic neurons in Nucleus Ambiguus
Anesthesiology, 2002Co-Authors: Mustapha Irnaten, Jijiang Wang, Kyoung S K Chang, Michael C Andresen, David MendelowitzAbstract:Background: Ketamine increases both blood pressure and heart rate, effects commonly thought of as sympathoexcitatory. The authors investigated the possibility that ketamine increases heart rate by inhibiting the central cardiac parasympathetic mechanisms. Methods: We used a novel in vitro approach to study the effect of ketamine on the identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the Nucleus Ambiguus were retrogradely prelabeled with the fluorescent tracer by placing rhodamine into the pericardial sac. Dye-labeled neurons were visually identified for patch clamp recording, and ketamine effects on isolated potassium (K + ) and sodium (Na + ) currents were studied. Results: Cardiac Nucleus Ambiguus neurons (n = 14) were inherently silent, but depolarization evoked sustained action potential trains with little delay or adaptation. Ketamine (10 μM) reduced this response but had no effect on the voltage threshold for action potentials (n = 14; P > 0.05). The current-voltage relations for the transient K + current and the delayed rectified K + current (n = 5) were unaltered by ketamine (10 μM-1 mM). Ketamine depressed the total Na + current dose-dependently (10 μM-1 mM). In addition, ketamine shifted the Na + current inactivation curves to more negative potentials, thus suggesting the enhancement of the Na + channel inactivation (P < 0.05; n = 7). In the presence of Cd 2+ , ketamine (10 μM) continued to inhibit voltage-gated Na + currents, which recovered completely within 10 min. Conclusions: Ketamine inhibits Na + but not K + channel function in brainstem parasympathetic cardiac neurons, and such actions may mediate the decrease in parasympathetic cardiac activity and increase in heart rate that occurs with ketamine.
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ketamine inhibits presynaptic and postsynaptic nicotinic excitation of identified cardiac parasympathetic neurons in Nucleus Ambiguus
Anesthesiology, 2002Co-Authors: Mustapha Irnaten, Jijiang Wang, Priya Venkatesan, Cory Evans, Kyoung S K Chang, Michael C Andresen, David MendelowitzAbstract:BACKGROUND Ketamine increases both blood pressure and heart rate, effects commonly thought of as sympathoexcitatory. The authors investigated possible central nervous system actions of ketamine to inhibit cardiac parasympathetic neurons in the brainstem by inhibiting multiple nicotinic excitatory mechanisms. METHODS The authors used a novel in vitro approach to study the effect of ketamine on identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the Nucleus Ambiguus were retrogradely prelabeled with the fluorescent tracer by placing rhodamine into the pericardial sac. Dye-labeled neurons were visually identified for patch clamp recording. The effects of ketamine were tested on nicotine-evoked ligand-gated currents and spontaneous glutamatergic miniature synaptic currents (mini) in cardiac parasympathetic preganglionic neurons. RESULTS Ketamine (10 microm) inhibited (1) the nicotine (1 microm)-evoked presynaptic facilitation of glutamate release (mini frequency, 18 +/- 7% of control; n = 9), and (2) the direct postsynaptic ligand-gated current (27 +/- 8% of control; n = 9), but ketamine did not alter the amplitude of postsynaptic miniature non-N-methyl-D-aspartate currents. alpha Bungarotoxin, an antagonist of alpha 7 containing nicotinic presynaptic receptors, blocked ketamine actions on mini frequency (n = 10) but not mini amplitude. CONCLUSIONS Ketamine inhibits the presynaptic nicotinic receptors responsible for facilitating neurotransmitter release, as well as the direct ligand-gated inward current, but does not alter the nicotinic augmentation of non-N-methyl-D-aspartate currents in brainstem parasympathetic cardiac neurons. Such actions may mediate the decrease in parasympathetic cardiac activity and increase in heart rate that occurs with ketamine.
