Mapping the contribution of β3-containing GABAA receptors to volatile and intravenous general anesthetic actions

Anja Zeller,Uwe Rudolph,Rachel Jurd,Margarete Arras

doi:10.1186/1471-2210-7-2

Abstract

BackgroundAgents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by β3-containing GABAA receptors. This was determined by using the β3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABAA receptors. In this communication, we analyzed the contribution of β3-containing GABAA receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of β3(N265M) mice.ResultsIsoflurane decreased core body temperature and heart rate to a smaller degree in β3(N265M) mice than in wild type mice, indicating a minor but significant role of β3-containing GABAA receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of β3-containing GABAA receptors. The anterograde amnesic action of propofol was indistinguishable in β3(N265M) and wild type mice, suggesting that it is independent of β3-containing GABAA receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in β3(N265M) mice than in wild type mice, pointing to a limited involvement of β3-containing GABAA receptors in these actions. The lack of etomidate- and propofol-induced immobilization in β3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds.ConclusionOur results provide evidence for a defined role of β3-containing GABAA receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed.

Highlights

Agents belonging to diverse chemical classes are used clinically as general anesthetics
We investigated whether the heart rate depressant action of isoflurane is dependent on β3-containing GABAA receptors
The decrease of the heart rate after isoflurane is significantly smaller in β3(N265M) mice compared to wild type mice under these experimental conditions (p < 0.001), the difference is rather small and the heart rate depressant action of isoflurane is largely mediated by targets other than β3-containing GABAA receptors

Summary

Introduction

Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are still only poorly defined Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by β3-containing GABAA receptors This was determined by using the β3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABAA receptors. In line with these findings, β2(N265S) mice are still sensitive to the immobilizing and hypnotic actions of etomidate, but lack the sedative response to low doses of etomidate [11]

Methods

Results

Discussion

Conclusion