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Brain Res. 1993 Jun 25;615(1):101-6.

Stereospecific actions of the inhalation anesthetic isoflurane at the GABAA receptor complex.

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Laboratory of Neuroscience, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.


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.

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