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CARDIOVASCULAR ANESTHESIOLOGY

Activation of Mitochondrial Large-Conductance Calcium-Activated K⁺ Channels via Protein Kinase A Mediates Desflurane-Induced Preconditioning

From the Department of Anesthesiology, University of Würzburg, Bayerische Julius-Maximilians-Universität, Würzburg, Germany.

Address correspondence and reprint requests to Franz Kehl, MD, PhD, DEAA, Universität Würzburg, Klinik und Poliklinik für Anästhesiologie, Zentrum Operative Medizin, Oberdürrbacher Str. 6, 97080 Würzburg, Germany. Address e-mail to franz.kehl{at}mail.uni-wuerzburg.de.

Abstract

BACKGROUND: ATP-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).

METHODS: Pentobarbital-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 µg/g i.p.), its respective vehicle dimethylsulfoxide (10 µL/g i.p.), the large-conductance K_Ca channel blocker iberiotoxin (0.05 µg/g i.p.), or the protein kinase A (PKA) inhibitor H-89 (0.5 µg/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.

RESULTS: Desflurane 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.

CONCLUSION: These 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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