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The Journal of Neurophysiology Vol. 81 No. 4 April 1999, pp. 1802-1809
Copyright ©1999 by the American Physiological Society
Department of Anaesthesia and Department of Pharmacology & Therapeutics, Faculty of Medicine, The University of British Columbia Vancouver, British Columbia V6T 1Z3 Canada
Ries, Craig R. and
Ernest Puil.
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 the whole cell, patch-clamp method with current- and
voltage-clamp recording techniques, we found that IFL increased a
noninactivating membrane conductance in a concentration-dependent
reversible manner. In an eightfold concentration range that extended
into equivalent in vivo lethal concentrations, IFL did not produce a
maximal effect on the conductance; this is consistent with a
nonreceptor-mediated mechanism of action. TTX eliminated action
potential activity but did not alter IFL effects. The effects on the
membrane potential and current induced by IFL were voltage independent
but depended on the external [K+], reversing near the
equilibrium potential for K+. External Ba2+ or
internal Cs+ applications, which block K+
channels, suppressed the conductance increase caused by IFL. External
applications of the Ca2+ channel 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 the effects of IFL, implying little involvement of
Ca2+-dependent K+ currents. A contribution of
inwardly rectifying K+ channels to the increased
steady-state conductance seemed unlikely because IFL decreased inward
rectification. An involvement of ATP-mediated K+ channels
also was unlikely because application of the ATP-mediated K+ channel blocker glibenclamide (1-80 µM) did not
prevent IFL's actions. In contrast to spiking cells, IFL depolarized
presumed glial cells, consistent with an efflux of K+ from
thalamocortical neurons. The results imply that a leak K+
channel mediated the IFL-induced 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+ and Ca2+ spikes, as reported in the
preceding paper. Although anesthetics influence various neurological
systems, an enhanced K+ leak generalized in thalamocortical
neurons alone could account for anesthesia in vivo.
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