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


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.


CONCLUSIONS
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.
Redel
Andreas
A
Department of Anesthesiology, University of Würzburg, Bayerische Julius-Maximilians-Universität, Würzburg, Germany.
Lange
Markus
M
Jazbutyte
Virginija
V
Lotz
Christopher
C
Smul
Thorsten M
TM
Roewer
Norbert
N
Kehl
Franz
F
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000077335:Desflurane; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D000077335:Desflurane; D007530:Isoflurane; D017868:Cyclic AMP-Dependent Protein Kinases