The cardioprotective effect of sevoflurane depends on protein kinase C activation, opening of mitochondrial K(+)(ATP) channels, and the production of reactive oxygen species.

Abstract

Several studies suggest that the cardioprotective effect of sevoflurane depends on protein kinase C (PKC) activation, mitochondrial K(+)(ATP) channel (mitoK(+)(ATP)) opening, and reactive oxygen species (ROS). However, evidence for their involvement was obtained in separate experimental models. Here, we studied the relative roles of PKC, mitoK(+)(ATP), and ROS in sevoflurane-induced cardioprotection in one model. Rat trabeculae were subjected to simulated ischemia by applying metabolic inhibition (MI) through buffer containing NaCN, followed by 60-min reperfusion. Recovery of active force (F(a)) was assessed as percentage of pre-MI force. In time controls, F(a) amounted 60% +/- 5% at the end of the experiment. The recovery of F(a) after MI was reduced to 28% +/- 5% (P = 0.045 versus time control), whereas sevoflurane reversed the detrimental effect of MI (F(a) recovery, 67% +/- 8%; P = 0.01 versus MI). The PKC inhibitor chelerythrine, the mitoK(+)(ATP) inhibitor 5-hydroxy decanoic, and the ROS scavenger N-(2-mercaptopropionyl)-glycine all completely abolished the protective effect of sevoflurane (recovery of F(a), 31% +/- 8%, 33% +/- 8%, and 24% +/- 9% for chelerythrine, 5-hydroxy decanoic, and N-(2-mercaptopropionyl)-glycine, respectively). In conclusion, PKC activation, mitoK(+)(ATP) channel opening, and ROS production are all essential for sevoflurane-induced cardioprotection. These signaling events are arranged in series within a common signaling pathway, rather than in parallel cascades. Our findings implicate that the perioperative use of sevoflurane preserves cardiac function by preventing ischemia-reperfusion injury. Protein kinase C, mitochondrial K(+)(ATP) channels and reactive oxygen species act within one downstream signaling pathway in mediating the cardioprotective effect of sevoflurane.