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LH Lin, LL Chen, JA Zirrolli and RA Harris
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado.
Potentiation of the gamma-aminobutyric acid (GABAA) receptor-gated Cl- channel response has been suggested to be a primary action of some anesthetic agents. We asked whether the GABAA receptor is a target site common for general anesthetics that are chemically and structurally diverse. This hypothesis was tested in Xenopus oocytes expressing mouse cortical mRNA, and GABA-activated Cl- currents were measured using two- electrode voltage clamping. General anesthetics, including inhalational (halothane, diethylether, enflurane and isoflurane), i.v. (3 alpha- hydroxy-5 alpha-dihydroprogesterone, ketamine and propofol) and alcohol (pentanol) anesthetics, enhanced GABA-induced currents by 56 to 1089% at concentrations that were clinically relevant. The results suggest that potentiation of the GABAA receptor/channel response may be a common action for anesthetic agents. Moreover, anesthetic effects were dependent on GABA concentrations; the enhancement was marked with low GABA concentrations and was exponentially decreased as the GABA concentration increased. Also, anesthetic effects were dependent on anesthetic concentrations. The apparent EC50 of halothane was found to be similar to the anesthetic ED50. We also investigated the role of intracellular Ca++ in mediating anesthetic enhancement of the GABA current. We found that intracellular injection of the Ca++ chelator, EGTA, did not change the enhancement by anesthetics. In addition, these anesthetics alone did not produce significant currents, suggesting that the Ca(++)-dependent Cl- current was not activated by these anesthetics per se. Thus, we found that diverse anesthetics potentiate GABA-induced Cl- currents, but this action is not mediated by a release of intracellular Ca++.
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