Reactive Oxygen Species Precede Protein Kinase C-δ Activation Independent of Adenosine Triphosphate-sensitive Mitochondrial Channel Opening in Sevoflurane-induced Cardioprotection

R. Arthur Bouwman, René J P Musters, Brechje J. Van Beek-Harmsen, Jaap J. De Lange, Christa Boer

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59 Citations (Scopus)


Background: In the current study, the authors investigated the distinct role and relative order of protein kinase C (PKC)-δ adenosine triphosphate-sensitive mitochondrial K + (mito K + ATP) channels, and reactive oxygen species (ROS) in the signal transduction of sevoflurane-induced cardioprotection and specifically addressed their mechanistic link. Methods: Isolated rat trabeculae were preconditioned with 3.8% sevoflurane and subsequently subjected to an ischemic protocol by superfusion of trabeculae with hypoxic, glucose-free buffer (40 min) followed by 60 min of reperfusion. In addition, the acute affect of sevoflurane on PKC-δ and PKC-δ translocation and nitrotyrosine formation was established with use of immunofluorescent analysis. The inhibitors chelerythrine (6 μM), rottlerin (1 μM), 5-hydroxydecanoic acid sodium (100 μM), and n-(2-mercaptopropionyl)-glycine (300 μM) were used to study the particular role of PKC, PKC-δ, mito K + ATP, and ROS in sevoflurane-related intracellular signaling. Results: Preconditioning of trabeculae with sevoflurane preserved contractile function after ischemia. This contractile preservation was dependent on PKC-δ activation, mito K + ATP channel opening, and ROS production. In addition, on acute stimulation by sevoflurane, PKC-δ but not PKC-ε translocated to the sarcolemmal membrane. This translocation was inhibited by PKC inhibitors and ROS scavenging but not by inhibition of mito K + ATP channels. Furthermore, sevoflurane directly induced nitrosylation of sarcolemmal proteins, suggesting the formation of peroxynitrite. Conclusions: In sevoflurane-induced cardioprotection, ROS release but not mito K + ATP channel opening precedes PKC-δ activation. Sevoflurane induces sarcolemmal nitrotyrosine formation, which might be involved in the recruitment of PKC-δ to the cell membrane.

Original languageEnglish
Pages (from-to)506-514
Number of pages9
Issue number3
Publication statusPublished - 1 Mar 2004

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