Sevoflurane-induced cardioprotection depends on PKC-α activation via production of reactive oxygen species

Abstract

Background. We previously demonstrated the involvement of the Ca 2+-independent protein kinase C-δ (PKC-δ) 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 Ca 2+-dependent PKC-α isoform in sevoflurane-induced cardioprotective signalling in relation to reactive oxygen species (ROS), adenosine triphosphate-sensitive mitochondrial K+ (mitoK +ATP) channels, and PKC-δ. 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-α, ROS, mitoK+ATP channels, and PKC-δ 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-α translocated towards mitochondria, as shown by immunofluorescent co-localization analysis. GO and MPG, but not 5HD or ROT, abolished this translocation.ConclusionsSevoflurane improves post-ischaemic contractile recovery via activation of PKC-α. ROS production, but not opening of mitoK+ATP channels, precedes PKC-α translocation towards mitochondria. This study shows the involvement of Ca2+-dependent PKC-α in addition to the well-established role of Ca2+-independent PKC isoforms in sevoflurane-induced cardioprotection. © The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved.