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Background The inhaled anesthetic sevoflurane has been demonstrated to protect against myocardial ischemia/reperfusion (MI/R) injury, via mechanisms involving AMP-activated protein kinase (AMPK) and caveolin-3 (Cav-3). However, the relative contributions of AMPK and Cav-3 to sevoflurane preconditioning-mediated cardioprotection, and their precise underlying mechanisms of action, remain incompletely understood. Methods and Results Sevoflurane preconditioning (SF-PreCon, consisting of 3 cycles of 15 minute-exposures to 2% sevoflurane prior to 30 minutes of MI) decreased MI/R injury in WT mice (caspase-3 activity −29.1%, infarct size −20.2%, and LVEDP −33.8%). In cardiac-specific AMPKα2 dominant negative overexpression (AMPK-DN) mice, the cardioprotective effect of SF-PreCon was largely retained (caspase-3 activity −26.7%, infarct size −16.7%, and LVEDP −25.9%, P<0.01). In contrast, SF-PreCon failed to significantly protect Cav3-knockout (Cav3-KO) mice against MI/R injury (P>0.05). SF-PreCon significantly decreased MI/R-induced superoxide generation in WT (−43.6%) and AMPK-DN mice (−35.5%, P<0.01), but not in Cav3-KO mice. SF-PreCon did not affect NADPH oxidase expression, but significantly inhibited COX-2 expression in WT (−38.7%) and AMPK-DN mice (−35.8%), but not in Cav-3KO mice. Conclusions We demonstrate for the first time sevoflurane preconditioning mediates cardioprotection against MI/R injury via Cav-3 dependent-COX-2 inhibition and anti-oxidative effects.

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