Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon

Background: The mechanisms by which the inhalational general anesthetics is oflurane and xenon exert their effects are unknown. Moreover, there have be en surprisingly few quantitative studies of the effects of these agents on central synapses, with virtually no information available regarding the act ions of xenon. Methods: The actions of isoflurane and xenon on gamma-aminobutyric acid-med iated (GABAergic) and glutamatergic synapses were investigated using voltag e-clamp techniques on autaptic cultures of rat hippocampal neurons, a prepa ration that avoids the confounding effects of complex neuronal networks. Results: Isoflurane exerts its greatest effects on GABAergic synapses, caus ing a marked increase in total charge transfer (by approximately 70% at min imum alveolar concentration) through the inhibitory postsynaptic current. T his effect is entirely mediated by an increase in the slow component of the inhibitory postsynaptic current, At glutamatergic synapses, isoflurane has smaller effects, but it nonetheless significantly reduces the total charge transfer (by approximately 30% at minimum alveolar concentration) through the excitatory postsynaptic current, with the N-methyl-D-aspartate (NMDA) a nd alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor-mediated components being roughly equally sensitive. Xenon has no measurable effect on GABAergic inhibitory postsynaptic currents or on curre nts evoked by exogenous application of GABA, but it substantially inhibits total charge transfer (by approximately 60% at minimum alveolar concentrati on) through the excitatory postsynaptic current. Xenon selectively inhibits the NMDA receptor-mediated component of the current but has little effect on the AMPA/kainate receptor-mediated component. Conclusions: For both isoflurane and xenon, the most important targets appe ar to be postsynaptic, The authors' results show that isoflurane and xenon have very different effects on GABAergic and glutamatergic synaptic transmi ssion, and this may account for their differing pharmacologic profiles.