Effects of Temperature and Volatile Anesthetics on GABAAReceptors

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Abstract
Background: Potentiation of the activity of the gamma-aminobutyric acid type A (GABA(A)) receptor channel by volatile anesthetic agents is usually studied in vitro at room temperature. Systematic variation of temperature can be used to assess the relevance of this receptor to general anesthesia and to characterize the modulation of its behavior by volatile agents at normal body temperature. Methods: Potentiation of the GABA(A) receptor by halothane, sevoflurane, isoflurane, and methoxyflurane was studied at six temperatures in the range 10-37 degrees C using the whole-cell patch-clamp technique and mouse fibroblast cells stably transfected with defined GABA(A) receptor subunits. Results: Control GABA concentration-response plots showed small and physically reasonable changes in the GABA concentration required for a half-maximal effect, the Hill coefficient, and maximal response over the range 10-30 degrees C. Potentiations of GABA (1 microM) responses by aqueous minimum alveolar concentrations of the volatile anesthetic agents decreased with increasing temperature from 10-37 degrees C in an agent-specific manner (methoxyflurane > isoflurane > sevoflurane > halothane) but tended to equalize at normal body temperature (37 degrees C). These findings are in line with published results on the temperature dependence of anesthetic potencies in animals. Conclusions: These results are consistent with direct binding of volatile anesthetic agents to the GABA(A) receptor channel playing an important role in general anesthesia. The finding that the degree of anesthetic potentiation was agent-specific at low temperatures but not at 37 degrees C emphasizes the importance of doing in vitro experiments at normal body temperature.