BJA Advance Access originally published online on September 27, 2007
British Journal of Anaesthesia 2007 99(5):639-645; doi:10.1093/bja/aem202
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Sevoflurane-induced cardioprotection depends on PKC-
activation via production of reactive oxygen species
1 VU University Medical Center (VUMC), Department of Anaesthesiology, Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
2 VU University Medical Center (VUMC), Laboratory for Physiology, Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU), Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
* Corresponding author. E-mail: a.bouwman{at}vumc.nl
Background: We previously demonstrated the involvement of the Ca2+-independent protein kinase C-
(PKC-) isoform in sevoflurane-induced cardioprotection against ischaemia and reperfusion (I/R) injury. Since sevoflurane is known to modulate myocardial Ca2+-handling directly, in this study we investigated the role of the Ca2+-dependent PKC-
isoform in sevoflurane-induced cardioprotective signalling in relation to reactive oxygen species (ROS), adenosine triphosphate-sensitive mitochondrial K+ (mitoK+ATP) channels, and PKC-.
Methods: Preconditioned (15 min 3.8 vol% sevoflurane) isolated rat right ventricular trabeculae were subjected to I/R, consisting of 40 min superfusion with hypoxic, glucose-free buffer, followed by normoxic glucose-containing buffer for 60 min. After reperfusion, contractile recovery was expressed as percentage of force development before I/R. The role of PKC-, ROS, mitoK+ATP channels, and PKC- was established using the following pharmacological inhibitors: Go6976 (GO; 50 nM), n-(2-mercaptopropionyl)-glycine (MPG; 300 µM), 5-hydroxydecanoic acid sodium (5HD; 100 µM), and rottlerin (ROT; 1 µM).
Results: Preconditioning of trabeculae with sevoflurane improved contractile recovery after I/R [65 (3)% (I/R + SEVO) vs 47 (3)% (I/R); n = 8; P < 0.05]. This cardioprotective effect was attenuated in trabeculae treated with GO [42 (4)% (I/R + SEVO + GO); P > 0.05 vs (I/R)]. In sevoflurane-treated trabeculae, PKC- translocated towards mitochondria, as shown by immunofluorescent co-localization analysis. GO and MPG, but not 5HD or ROT, abolished this translocation.
Conclusions: Sevoflurane improves post-ischaemic contractile recovery via activation of PKC-. ROS production, but not opening of mitoK+ATP channels, precedes PKC- translocation towards mitochondria. This study shows the involvement of Ca2+-dependent PKC- in addition to the well-established role of Ca2+-independent PKC isoforms in sevoflurane-induced cardioprotection.
Keywords: anaesthetics volatile, sevoflurane; enzymes, protein kinase C; enzymes, signal transduction; heart, cardioprotection; heart, ischaemia; signal transduction
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