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ANESTHETIC PHARMACOLOGY

The Cardioprotective Effect of Sevoflurane Depends on Protein Kinase C Activation, Opening of Mitochondrial K⁺_ATP Channels, and the Production of Reactive Oxygen Species

Wouter de Ruijter, MD^*, René J.P. Musters, PhD, Christa Boer, PhD^*,*, Ger J. M. Stienen, PhD, Warner S. Simonides, PhD, and Jaap J. de Lange, MD PhD^*

*Department of Anesthesiology and Laboratory for Physiology, Vrije Universiteit University Medical Center, Institute for Cardiovascular Research Vrije Universiteit, Amsterdam, the Netherlands

Address correspondence and reprint requests to Christa Boer, PhD, Department of Physiology, Vrije Universiteit University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands. Address e-mail to boer{at}physiol.med.vu.nl

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.

IMPLICATIONS: Protein kinase C, mitochondrial K⁺_ATP channels and reactive oxygen species act within one downstream signaling pathway in mediating the cardioprotective effect of sevoflurane.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999