Inhibition by propofol (2,6 di‐isopropylphenol) of the N‐methyl‐D‐aspartate subtype of glutamate receptor in cultured hippocampal neurones

Orser, Beverley A.; Bertlik, Maria; Wang, Lu-Yang; MacDonald, John F.

doi:10.1111/j.1476-5381.1995.tb16660.x

Cited by 227 publications

(123 citation statements)

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“…It also has been reported that propofol inhibits N-methyl-Daspartate (NMDA) receptor in cultured hippocampal neurons. 24 Results of our present in vivo experiment show that propofol inhibited the Glu-induced vasomotor action not only in the RVLM but also in the DM. The latter structure has been shown repeatedly to contain neuronal cell bodies sharing vasomotor integration.…”

Section: Discussionmentioning

confidence: 50%

Propofol inhibits medullary pressor mechanisms in cats

et al. 1997

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Purpose: Propofol may cause hypotension and the mechanism is complex. The present study was designed to determine the direct actions of propofol in medulla of cats.Methods: Mean systemic arterial pressure (MSAP), heart rate (HR) and cardiac contractility (dp/dt) were compared before and after administration of propofol through the femoral vein (2, 3 or 4 mg.kg ~), vertebral artery (I mg.kg ') or the lateral cerebral ventricle (0.5 mg.kg ~) in eight anaesthetized cats. To study the direct effect of propofol in medulla, pressor areas of the dorsomedial medulla (DM) and rostral ventrolateral medulla (RVLM), or the depressor area of the caudal ventrolateral medulla (CVLM) were first identified with electrical stimuli and then confirmed by pressure microinjection of glutamate (Glu, 0.25M, 30 hi) via a multibarrel-micropipette in 28 cats. One hour later, propofol (0.001%, 50 hi) was microinjected at the same site. Electncal stimulation and Glu were applied again to compare changes of SAP, HR and dp/dt with that of the control.Results: Propofol dose-dependently decreased SAP, HR and cardiac contractility. The percent increase of MSAP induced by Glu were reduced by propofol in DN (59 +_ 3 % r 13 • 2 %, n = I I, P < 0.0 I) or in RVLM (56 _+ 4 % vs 18 • 2 %, n = 9, P < 0.01 ). In CVLN, propofol slightly but not significantly increased the depressor responses elicited by Glu (-27 • 2 % vs -33 _+ 3 %, n = 5, P > 0.05).Conclusion: Our results show that propofol principally inhibits the vasomotor mechanism in the dorsomedial and ventrolateral medulla to effect its hypotensive actions.Objectif : Le propofol produit de I'hypotension par un m&anisme complexe. Cette Etude avait pour object~f de delimiter sur le bulbe du chat I'activit6 directe du propofol.M&hodes : La pression artErielle systEmique moyenne (PASM), la frEquence cardiaque (FC) et la contractilitE cardiaque (dp/dt) ont ErE comparEes avant et apr& I'injection de propofol dans la veine fEmorale (2,3 et 4 mg.kg '), I'art&e vertEbrale (I mg-kg -~) et le ventricule cErEbral lateral (0,5 mg'kg -~ ) chez six chats anesthEsiEs. Pour &udier les effets bulbalres directs du propofol, les zones vasopressives dorsomEdiane (DM) et ventrolatErale rostrale (BVLR) bulbaires, ou la zone vasodEpressive ventrolatErale caudale (BVLC) bulbalre ont d'abord ErE identifiEes par stimulation Electrique et confirmEes par micro-injection sous pression de glutamate (Glu 0.25M, 30 ml) I'aide d'une micropipette ,~ plusieurs barillets chez 28 chats. Une heure plus tard, du propofol (0,001%, 50 hi) Etait injectE au m~me site. I'Electrostimulation et Glu Etaient appliques encore une lois pour comparer les changements de PAS, le FC et de dp/dt avec ceux du contrEle.REsultats : DEpendamment de la dose, le propofol diminue PAS, FC et alp~tit. En pourcentage, I'augmentation de PASM induite par Glu Etait rEduite par le propofol dans DM 159 • 3 % vs 13 • 2 %, n = I I, P < 0,01 ) ou dans BLVR (56 -+ 4 % vs 18 • 2%, n = 9, P < 0,01 ). Dans BLVM, le propofol a augmentE IEg&ement mais non significativement les...

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Section: Discussionmentioning

confidence: 50%

Propofol inhibits medullary pressor mechanisms in cats

et al. 1997

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“…Potentiation of glycine receptors by propofol has also been demonstrated in mouse spinal neurones (Hales & Lambert, 1991). Propofol inhibits whole cell currents activated by N-methyl-D-aspartate (NMDA) without affecting kainate-evoked currents in cultured mouse hippocampal neurones (Orser et al, 1995). Propofol also inhibits T-type and L-type voltage-dependent Ca2" channels in chick dorsal root ganglion neurones (Olcese et al, 1994), as well as KCl-evoked, and presumably Ca2" channelmediated, [3H]-noradrenaline release from human neuroblastoma cells .…”

Section: Discussionmentioning

confidence: 99%

Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Lingamaneni

Hemmings

1996

British J Pharmacology

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“…This study is primarily focused on gaining a better understanding of the relative role (if any) of GABA tonic in producing depression of intrinsic neuronal excitability in neurons in intact acute brain slices, where the neuronal properties should be similar to in vivo. In the case of propofol, a widely used anesthetic, there are many sites of action that may affect intrinsic excitability, including effects on phasic (Trapani et al 2000) and tonic (Bai et al 2001) inhibition mediated by GABA A receptors (GABA A -Rs); sodium channels (Ratnakumari and Hemmings 1997;Rehberg and Duch 1999); potassium channels (Magnelli et al 1992); cation channels (I h ) (Higuchi et al 2003); calcium channels (Guertin and Hounsgaard 1999;Inoue et al 1999); glutamate channels (Orser et al 1995); and glutamate release (Ratnakumari and Hemmings 1997). Assuming that propofol suppresses intrinsic excitability, two critical questions emerge: is GABA tonic enhancement by anesthetics of sufficient magnitude to affect intrinsic excitability and given the existence of other proposed sites of propofol action that would affect intrinsic excitability, are effects on GABA tonic relatively dominant, relatively unimportant, or one contributor among many?…”

Section: Introductionmentioning

confidence: 99%

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Bieda

MacIver

2004

Journal of Neurophysiology

117

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Bieda, Mark C. and M. Bruce MacIver. Major role for tonic GABA A conductances in anesthetic suppression of intrinsic neuronal excitability. J Neurophysiol 92: 1658 -1667, 2004. First published May 12, 2004 10.1152/jn.00223.2004. Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABA A inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABA A but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABA A -mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABA A -mediated inhibition using the GABA A receptor antagonist SR95531 (gabazine). Gabazine (20 M) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABA A inhibition. Glutamatergic synaptic responses were not altered by propofol (Յ30 M). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABA A conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABA A conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

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Inhibition by propofol (2,6 di‐isopropylphenol) of the N‐methyl‐D‐aspartate subtype of glutamate receptor in cultured hippocampal neurones

Abstract: 1 The effects of propofol (2,6 di-isopropylphenol) on

Cited by 227 publications

References 39 publications

Propofol inhibits medullary pressor mechanisms in cats

Propofol inhibits medullary pressor mechanisms in cats

Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

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Inhibition by propofol (2,6 di‐isopropylphenol) of the N‐methyl‐D‐aspartate subtype of glutamate receptor in cultured hippocampal neurones

Abstract: 1 The effects of propofol (2,6 di-isopropylphenol) on

Cited by 227 publications

References 39 publications

Propofol inhibits medullary pressor mechanisms in cats

Propofol inhibits medullary pressor mechanisms in cats

Inhibition by propofol of [3H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

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Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability