Ionic mechanism of isoflurane's actions on thalamocortical neurons

We studied the actions of isoflurane (IFL) applied in aqueous solutions on ventrobasal neurons from thalamic brain slices of juvenile rats. By using t he whole cell, patch-clamp method with current-and voltage-clamp recording techniques, we found that IFL increased a noninactivating membrane conducta nce in a concentration-dependent reversible manner. In an eightfold concent ration range that extended into equivalent in vivo lethal concentrations, I FL did not produce a maximal effect on the conductance; this is consistent with a nonreceptor-mediated mechanism of action. TTX eliminated action pote ntial activity but did not alter IFL effects. The effects on the membrane p otential and current induced by IFL were voltage independent but depended o n thr external [K+], reversing near the equilibrium potential for K+. Exter nal Ba2+ or internal Cs+ applications, which block K+ channels, suppressed the conductance increase caused by IFL. External applications of the Ca2+ c hannel blockers Co2+ or Cd2+ or internal application of the Ca2+ chelator 1 ,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid did not prevent t he effects of IFL, implying little involvement of Ca2+-dependent K+ current s. A contribution of inwardly rectifying KI channels to the increased stead y-state conductance seemed unlikely because IFL decreased inward rectificat ion An involvement of ATP-mediated K+ channels also was unlikely because ap plication of the ATP-mediated K+ channel blocker glibenclamide (1-80 mu M) did not prevent IFL's actions. in contrast to spiking cells. IFL depolarize d presumed glial cells, consistent with an efflux of K+ from thalamocortica l neurons. The results imply that a leak K+ channel mediated the IFL-induce d increase in postsynaptic membrane conductance in thalamic relay neurons. Thus a single nonreceptor-mediated mechanism of IFL action was responsible for the hyperpolarization and conductance shunt of voltage-dependent Na+ an d Ca2+ spikes, as reported in the pre ceding paper. Although anesthetics in fluence various neurological systems, an enhanced K+ leak generalized in th alamocortical neurons alone could account for anesthesia in vivo.