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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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© The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Sevoflurane-induced cardioprotection depends on PKC-{alpha} activation via production of reactive oxygen species

R. A. Bouwman1,*, R. J. P. Musters2, B. J. van Beek-Harmsen2, J. J. de Lange1, R. R. Lamberts1, S. A. Loer1 and C. Boer1

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-{delta} (PKC-{delta}) 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-{alpha} isoform in sevoflurane-induced cardioprotective signalling in relation to reactive oxygen species (ROS), adenosine triphosphate-sensitive mitochondrial K+ (mitoK+ATP) channels, and PKC-{delta}.

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-{alpha}, ROS, mitoK+ATP channels, and PKC-{delta} 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-{alpha} 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-{alpha}. ROS production, but not opening of mitoK+ATP channels, precedes PKC-{alpha} translocation towards mitochondria. This study shows the involvement of Ca2+-dependent PKC-{alpha} 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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