Abstract:
BACKGROUND:The dose-dependent myocardial depression of volatile general anesthetics such as isoflurane has been linked to blockade of L-type Ca2+ channels. The effects of (+)- and (-)-isoflurane on the inhibition of [3H]isradipine binding to L-type Ca2+ channels in membranes prepared from mouse heart were examined. In addition, because there is a stereo-specific effect of these isomers on sleep time in mice, the potential contribution of L-type Ca2+ channels to isoflurane-induced sleep was assessed by determining whether a similar stereoselectivity would 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 ([3H]isradipine) were studied in cardiac and brain cortical membranes. Their potencies and effects on the Kd and Bmax of [3H]isradipine were measured. RESULTS:Pharmacologically relevant concentrations of (+)- and (-)-isoflurane inhibited [3H]isradipine binding. The IC50 values for (+)-isoflurane were 0.48 +/- 0.02% and 0.40 +/- 0.01% in heart and brain membranes, respectively. The values for (-)-isoflurane were not significantly different from the respective values for the (+)-isomer. Saturation analysis demonstrated (+)- and (-)-isoflurane inhibited [3H]isradipine binding by significantly reducing Bmax and increasing Kd, but there were no significant differences between these isomers in either tissue. CONCLUSIONS:The stereoisomers of isoflurane are equipotent as inhibitors of [3H]isradipine binding to L-type Ca2+ channels. This lack of stereoselectivity between (+)- and (-)-isoflurane indicates that the [3H]isradipine site on L-type Ca2+ channels in brain does not contribute to the differences in isoflurane-induced sleep time reported for these stereoisomers. Taken with a lack of stereoselectivity at L-type Ca2+ channels in heart, an optically resolved isomer of isoflurane may have clinical advantages compared to the current racemic mixture.
journal_name
Anesthesiologyjournal_title
Anesthesiologyauthors
Moody EJ,Harris B,Hoehner P,Skolnick Pdoi
10.1097/00000542-199407000-00018subject
Has Abstractpub_date
1994-07-01 00:00:00pages
124-8issue
1eissn
0003-3022issn
1528-1175journal_volume
81pub_type
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