In cardiomyocytes and neurons, mitochondria produce the majority of cellular adenosine triphosphate (ATP) and pathological reactive oxygen species (ROS) during I/R injury [
6,
7]. They also play a key role in VA-induced preconditioning. Numerous studies have demonstrated that sevoflurane and other VAs protect the myocardium and brain during I/R injury via the mitochondrial ATP-sensitive potassium (mK
ATP) channels, opening of mK
ATP channels results in potassium influx, slowing of calcium overload in the mitochondria, the production of reactive oxygen species and the activation of multiple downstream kinases and molecular cascades of cardiac protection, and this has been considered as a critical step in APC [
8,
9]. It is verified that isoflurane can directly activate the human cardiac mK
ATP channels in vitro. ATP-sensitive K
+ currents were significantly increased after isoflurane exposure, and this effect was completely abolished by mK
ATP channels blocker 5-hydroxydecanoate (5-HD) [
10]. Riess et al. provided the first evidence that sevoflurane is able to prevent mitochondrial matrix volume (MMV) contraction during ischemia, and this effect is mediated via mK
ATP channel opening [
11]. Among all the signaling kinases which are involved in cardiovascular functions, protein kinase C (PKC) and its subgroup PKCε are believed to be key signaling pathway associated with mK
ATP channel-mediated cardiac protection [
8,
12,
13]. Wang et al. demonstrated that sevoflurane preconditioning exhibits a delayed cardioprotection against I/R injury by increasing PKCε phosphorylation, and this effect is inhibited by mK
ATP channel blocker 5-HD [
14]. Similar effects were also reported by Kaneda et al. [
15] and Weber et al. [
16] confirming the key role of PKCε/mK
ATP signaling pathway in cardiac protective effect induced by APC.
Mitochondrial K
ATP channel proteins, which are partially purified from rat brain mitochondria, exhibit ligand-binding properties similar to those of heart mK
ATP channels, and the amount of mK
ATP channels in brain seems to be much higher than in the heart, suggesting the crucial role of mK
ATP channel in central nervous system [
17]. Numerous studies have proved that VA preconditioning provides neuroprotection via mK
ATP channel both in vivo and in vitro. Kehl et al. demonstrated that the preconditioning induced by sevoflurane was abolished by 5HD, a mK
ATP channel blocker, in rat hippocampal slices [
18]. Likewise, it was observed that the opening of mK
ATP channel mimicked delayed preconditioning induced by sevoflurane, whereas sevoflurane postconditioning was also blocked by 5-HD given at the end of ischemia [
19]. Interestingly, it was also reported for the first time by the same research team [
19] that neuroprotective effects mediated by sevoflurane were observed when sevoflurane was given at the onset of reperfusion, and this effect was lost when it is given 5 min after the onset of reperfusion, indicating the time, duration and other factors also associate and play potential relevance in APC. Moreover, it is found recently that the P38 phosphorylation was decreased after the administration of 5-HD, suggesting that mK
ATP channel opening and p38 phosphorylation are both involved sevoflurane-induced preconditioning and p38 MAPK activation may be a downstream of opening mK
ATP channels [
20]. Similar to cardioprotection, PKCε is also involved in APC-mediated neuroprotection. Ye et al. demonstrated that application of 5-HD 30 min before sevoflurane exposure could not only attenuate its beneficial effects in reducing neurological deficit scores and brain infarct volume, but also inhibit the translocation of PKC ε to the membrane fraction at 24 h after reperfusion [
21]. This result also indicates the role of PKC ε as the upstream target of mK
ATP channels and thus the similar cell signal pathway in APC-mediated protective effects in both cardiac and neural system.