Halothane's effects on GABA-gated chloride flux in mice selectively bred for sensitivity or resistance to diazepam.
The DS (diazepam-sensitive) and DR (diazepam-resistant) lines of mice, selected on the basis of their ataxic response to diazepam, also diverge in the physiologic response of their brain gamma-aminobutyric acidA (GABAA) receptors to benzodiazepines, as indicated by augmentation of GABA-mediated chloride flux. Cross-sensitivity and -resistance to other sedatives known to interact with the GABAA-receptor have also been demonstrated in DS and DR mice. Based on the finding that these mice also show cross-sensitivity and -resistance to obtundation by halothane, we predicted that their GABAA-receptors would also exhibit a differential response to halothane as assayed by an in vitro 36Cl- influx assay using purified brain microvesicles. Consistent with this prediction, therapeutic concentrations of halothane enhanced 1 mumol/l GABA-gated flux with significantly greater potency in DS than in DR mice (halothane EC50 336 +/- 64 mumol/l (S.E.M.) vs. 605 +/- 110 mumol/l, respectively, P = 0.03), but there was no difference in maximal flux enhancement between the two lines (DS 4.7 +/- 0.4 nmol.mg-1 x 3 s-1, vs. DR 4.7 +/- 0.5 nmol.mg-1 x 3 s-1). Halothane (500 mumol/l) also shifted the entire GABA concentration-flux relationship significantly to the left, decreasing the EC50 for GABA in both the DS and DR lines. Importantly, the shift in the GABA concentration-flux response in the presence of halothane was more pronounced in the DS mice (GABA EC50 1.8 +/- 0.4 mumol/l vs. 14.7 +/- 0.9 mumol/l without halothane) than in the DR mice (GABA EC50 4.7 +/- 0.6 mumol/l vs. 14.7 +/- 0.9 mumol/l without halothane).(ABSTRACT TRUNCATED AT 250 WORDS)
Quinlan
J J
JJ
Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh, PA 15261.
Gallaher
E J
EJ
Firestone
L L
LL
D000818:Animals; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D004351:Drug Resistance; D006221:Halothane / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*
D018118:Chloride Channels; D002712:Chlorides; D007473:Ion Channels; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D003975:Diazepam; D006221:Halothane