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

作者：Redel Andreas; Lange Markus; Jazbutyte Virginija; Lotz Christopher; Smul Thorsten M; Roewer Norbert; Kehl Franz^*

来源：Anesthesia and Analgesia, 2008, 106(2): 384-391.

DOI：10.1213/ane.0b013e318160650f

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 mu g/g i.p.), its respective vehicle dimethylsulfoxide (10 mu L/g i.p.), the large-conductance K-Ca channel blocker iberiotoxin (0.05 mu g/g i.p.), or the protein kinase A (PKA) inhibitor H-89 (0.5 mu g/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.

• 出版日期2008-2