Stereospecific actions of the inhalation anesthetic isoflurane at the GABAA receptor complex.
The inhalation anesthetic isoflurane stereoselectively modulates ligand binding to the GABAA receptor complex. The (+)-isomer of isoflurane was more potent and efficacious than the (-)-isomer in enhancing [3H]flunitrazepam binding to benzodiazepine receptors. For example, concentration effect curves for Cl- enhancement of [3H]flunitrazepam binding were significantly different (P < 0.001) in the presence of (+)- and (-)-isoflurane (0.44 and 0.88 mM). At the higher anesthetic concentration, they potency of Cl- to increase [3H]flunitrazepam binding was increased 3.2- and 1.45-fold by (+)- and (-)-isoflurane, respectively (P < 0.05). Likewise, concentration-effect curves for (+) isoflurane-enhanced [3H]flunitrazepam binding were significantly different (P < 0.05-P < 0.001) from the (-)-isomer in the presence of 0-200 mM Cl-. Stereoselectivity was not observed with respect to the potencies of these enantiomers as inhibitors of [35S]t-butylbicyclophosphorothionate (TBPS) binding to sites within the Cl- ionophore. In this measure, the isomers had similar potencies (P > 0.05), although at higher concentrations (> 0.1 mM) (+)-isoflurane produced significantly more inhibition than (-)-isoflurane. While the absolute potency differences between isomers were modest (< or = 2-fold) and measure dependent, these effects were manifested at clinically relevant concentrations of isoflurane and are consistent with in vivo studies demonstrating (+)-isoflurane is a more effective anesthetic than the (-)-isomer. This is the first demonstration of an inhalation anesthetic producing a stereoselective perturbation of the GABAA receptor complex.
Laboratory of Neuroscience, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
E J
EJ
Moody
B D
BD
Harris
P
P
Skolnick
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects*; D013237:Stereoisomerism; D013462:Sulfur Radioisotopes
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D007530:Isoflurane