INHIBITION OF [H-3] ISRADIPINE BINDING TO L-TYPE CALCIUM CHANNELS BY THE OPTICAL ISOMERS OF ISOFLURANE - LACK OF STEREOSPECIFICITY

Background: The dose-dependent myocardial depression of volatile gener al anesthetics such as isoflurane has been linked to blockade of L-typ e Ca2+ channels. The effects of (+)- and (-)-isoflurane on the inhibit ion of [H-3]isradipine binding to L-type Ca2+ channels in membranes pr epared from mouse heart were examined. In addition, because there is a stereospecific effect of these isomers on sleep time in mice, the pot ential contribution of L-type Ca2+ channels to isoflurane-induced slee p was assessed by determining whether a similar stereoselectivity woul d be manifested at these sites in cerebral cortical membranes. Methods : The effects of isoflurane stereoisomers on the binding of an L-type Ca2+ channel ligand ([H-3]isradipine) were studied in cardiac and brai n cortical membranes. Their potencies and effects on the K-d and B-max of [H-3]isradipine were measured. Results: Pharmacologically relevant concentrations of (+)- and (-)-isoflurane inhibited [H-3]isradipine b inding. The IC50 values for (+)-isoflurane were 0.48 +/- 0.02% and 0.4 0 +/- 0.01% in heart and brain membranes, respectively. The values for (-)-isoflurane were not significantly different from the respective v alues for the (+)-isomer. Saturation analysis demonstrated (+)- and (- )-isoflurane inhibited [H-3]isradipine binding by significantly reduci ng B-max and increasing K-d, but there were no significant differences between these isomers in either tissue. Conclusions: The stereoisomer s of isoflurane are equipotent as inhibitors of [H-3]isradipine bindin g to L-type Ca2+ channels. This lack of stereoselectivity between (+)- and (-)-isoflurane indicates that the [H-3]isradipine site on L-type Ca2+ channels in brain does not contribute to the differences in isofl urane-induced sleep time reported for these stereoisomers. Taken with a lack of stereoselectivity at L-type Ca2+ channels in heart, an optic ally resolved isomer of isoflurane may have clinical advantages compar ed to the current racemic mixture.