• Anesthesia and analgesia · Feb 2008

    Comparative Study

    Activation of mitochondrial large-conductance calcium-activated K+ channels via protein kinase A mediates desflurane-induced preconditioning.

    • Andreas Redel, Markus Lange, Virginija Jazbutyte, Christopher Lotz, Thorsten M Smul, Norbert Roewer, and Franz Kehl.
    • Department of Anesthesiology, University of Würzburg, Bayerische Julius-Maximilians-Universität, Würzburg, Germany.
    • Anesth. Analg. 2008 Feb 1;106(2):384-91, table of contents.

    BackgroundATP-regulated K+ channels are involved in anesthetic-induced preconditioning (APC). The role of other K+ channels in APC is unclear. We tested the hypothesis that APC is mediated by large-conductance calcium-activated K+ channels (K(Ca)).MethodsPentobarbital-anesthetized male C57BL/6 mice were subjected to 45 min of coronary artery occlusion and 3 h reperfusion. Thirty minutes before coronary artery occlusion, 1.0 MAC desflurane was administered for 15 min alone or in combination with the large-conductance K(Ca) channel activator NS1619 (1 microg/g i.p.), its respective vehicle dimethylsulfoxide (10 microL/g i.p.), the large-conductance K(Ca) channel blocker iberiotoxin (0.05 microg/g i.p.), or the protein kinase A (PKA) inhibitor H-89 (0.5 microg/g intraventricular). Infarct size was determined with triphenyltetrazolium chloride and area at risk with Evans blue. Mitochondrial and sarcolemmal localization of large-conductance K(Ca) channels in cardiac myocytes was investigated with immunocytochemical staining of isolated cardiac myocytes.ResultsDesflurane significantly reduced infarct size compared with control animals (7.4% +/- 0.8% vs 51.3% +/- 6.1%; P < 0.05). Activation of large-conductance K(Ca) channels by NS1619 (7.5% +/- 1.8%; P < 0.05) mimicked and blockade of large-conductance K(Ca) channels by iberiotoxin (49.1% +/- 7.5%) abrogated desflurane-induced preconditioning. PKA blockade by H-89 abolished desflurane-induced (45.1% +/- 4.0%) but not NS1619-induced (9.0% +/- 2.4%, P < 0.05) preconditioning. Immunocytochemical staining revealed that large-conductance K(Ca) channels were localized in the mitochondria but not in the sarcolemma of cardiac myocytes.ConclusionThese data suggest that desflurane-induced APC is mediated in part by activation of mitochondrial large-conductance K(Ca) channels, and that activation of these channels by desflurane is mediated by PKA.

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