Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways

BACKGROUND: Volatile anesthetics induce pharmacological preconditioning in cardiac tissue. The purpose of this study was to test whether volatile anesthetics mediate this effect by activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) or sarcolemmal K(ATP) (sarcK(ATP)) channel in rat ventricular myocytes and to evaluate the signaling pathways involved. METHODS: A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to determine the effects of 5-hydroxydecanoate, a selective mitoK(ATP) channel blocker, HMR-1098, a selective sarcK(ATP) channel blocker, diazoxide, a preconditioning mimicking agent, and various modulators of putative signaling pathways on cardioprotection elicited by sevoflurane and isoflurane. Microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct index of mitoK(ATP) channel activity. RESULTS: Volatile anesthetics significantly enhanced diazoxide-mediated activation of mitoK(ATP) channels as assessed by autofluorescence of myocytes. Conversely, volatile anesthetics alone did not alter mitoK(ATP) channel activity, implying a priming effect of volatile anesthetics on mitoK(ATP) channels. Administration of the protein kinase C inhibitor chelerythrine completely blocked this effect. Also, pretreatment with volatile anesthetics potentiated diazoxide-mediated protection against ischemia, as indicated by a reduction in trypan blue-positive myocytes. Importantly, cardioprotection afforded by volatile anesthetics was unaffected by the sarcK(ATP) channel blocker HMR-1098 but sensitive to modulations of nitric oxide and adenosine-G(i) signaling pathways. CONCLUSIONS: Using autofluorescence in live cell imaging microscopy and a simulated model of ischemia, the authors present evidence that volatile anesthetics mediate their protection in cardiomyocytes by selectively priming mitoK(ATP) channels through multiple triggering protein kinase C-coupled signaling pathways. These observations provide important new insight into the mechanisms of anesthetic-induced preconditioning.