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


CONCLUSIONS
Protein kinase C, mitochondrial K(+)(ATP) channels and reactive oxygen species act within one downstream signaling pathway in mediating the cardioprotective effect of sevoflurane.
*Department of Anesthesiology and †Laboratory for Physiology, Vrije Universiteit University Medical Center, Institute for Cardiovascular Research Vrije Universiteit, Amsterdam, the Netherlands.
Wouter
W
de Ruijter
René J P
RJP
Musters
Christa
C
Boer
Ger J M
GJM
Stienen
Warner S
WS
Simonides
Jaap J
JJ
de Lange
D018528:ATP-Binding Cassette Transporters; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006331:Heart Diseases / Q000201:enzymology / Q000517:prevention & control*; D054086:KATP Channels; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000150:complications / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects
D018528:ATP-Binding Cassette Transporters; D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D054086:KATP Channels; D008738:Methyl Ethers; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; C092520:uK-ATP-1 potassium channel; D000077149:Sevoflurane; D011493:Protein Kinase C