Effects of Intravenous Anesthetic Agents on Glutamate Release: A Role for GABAA Receptor-Mediated Inhibition.
Buggy, Donal J. M.D., M.Sc., D.M.E., M.R.C.P.I., F.F.A.R.C.S.I. *; Nicol, Beverley Ph.D. +; Rowbotham, David J. M.D., M.R.C.P., F.F.A.R.C.S.I., F.R.C.A. ++; Lambert, David G. Ph.D. [S]
92(4):1067-1073, April 2000.
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Background: Many anesthetic agents are known to enhance the [alpha]1[beta]2[gamma]2S[gamma]-aminobutyric acid type A (GABAA) chloride current; however, they also depress excitatory neurotransmission. The authors evaluated two hypotheses: intravenous anesthetic agents inhibit glutamate release and any observed inhibition may be secondary to GABAA receptor activation.
Methods: Cerebrocortical slices were prepared from Wistar rats. After perfusion in oxygenated Krebs buffer for 60 min at 37[degrees]C, samples for glutamate assay were obtained at 2-min intervals. After 6 min, a 2-min pulse of 46 mM K was applied to the slices (S1); this was repeated after 30 min (S2). Bicuculline (1-100 [mu]M) was applied when the S1 response returned to basal level, and 10 min later, thiopental (1-300 [mu]M), propofol (10 [mu]M), or ketamine (30 [mu]M) were also applied until the end of S2. Perfusate glutamate concentrations were measured fluorometrically, and the area under the glutamate release curves was expressed as a ratio (S2/S1).
Results: Potassium (46 mM) evoked a monophasic release of glutamate during S1 and S2, with a mean control S2/S1 ratio of 1.07 /- 0.33 (mean /- SD, n = 96). Ketamine and thiopental produced a concentration-dependent inhibition of K -evoked glutamate release with half-maximum inhibition of release values of 18.2 and 10.9 [mu]M, respectively. Release was also inhibited by propofol. Bicuculline produced a concentration dependent reversal of thiopental inhibition of glutamate release with a half-maximum reversal of the agonist effect of 10.3 [mu]M. Bicuculline also reversed the effects of propofol but not those of ketamine.
Conclusions: The authors' data indicate that thiopental, propofol, and ketamine inhibit K -evoked glutamate release from rat cerebrocortical slices. The inhibition produced by thiopental and propofol is mediated by activation of GABAA receptors, revealing a subtle interplay between GABA-releasing (GABAergic) and glutamatergic transmission in anesthetic action.A antagonist; mechanisms of anesthesia; neurotransmitter release; rat cerebrocortical slices.)
(C) 2000 American Society of Anesthesiologists, Inc.