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1 The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada
2 The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
3 The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada
4 Research Institute, Bristol-Myers Squibb Pharmaceutical, Pennington, New Jersey, USA
5 The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: pang{at}sickkids.ca.
We previously demonstrated in the pig that instigation of 3 cycles of 10 minutes of occlusion and reperfusion in a hind limb by tourniquet application (~300 mmHg) elicited protection against ischemia/reperfusion injury (infarction) in multiple distant skeletal muscles subsequently subjected to 4h of ischemia and 48h of reperfusion, but the mechanism was not studied. The aim of this project was to test our hypothesis that mitochondrial KATP (mKATP) channels play a central role in the trigger and mediator mechanisms of hind limb remote IPC of skeletal muscle against infarction in the pig. We observed that hind limb remote IPC reduced the infarct size of latissimus dorsi (LD) muscle flaps (8 x 13 cm) in the pig from 45 ± 2% to 22 ± 3% (n=10; p<0.05). The non-selective KATP channel inhibitor glibenclamide (0.3 mg. kg-1) or the selective mKATP channel inhibitor 5-hydroxydecanoate (5-HD, 5 mg . kg-1), but not the selective sarcolemmal KATP (sKATP) channel inhibitor HMR 1098 (3 mg . kg-1) abolished the infarct-protective effect of hind limb remote IPC in LD muscle flaps (n=10, p<0.05) when these drugs were injected intravenously at 10 minutes before remote IPC. In addition, intravenous bolus injection of glibenclamide (1 mg . kg-1) or 5-HD (10 mg . kg-1) at the end of hind limb remote IPC also abolished the infarct protection in LD muscle flaps (n=10; p<0.05). Furthermore, intravenous injection of the specific mKATP channel opener BMS 191095 (2 mg . kg-1) at 10 minutes before 4h of ischemia protected LD muscle flap against infarction to a similar extent as hind limb remote IPC and this infarctprotective effect of BMS 191095 was abolished by intravenous bolus injection of 5-HD (5 mg . kg-1) at 10 minutes before or after intravenous injection of BMS 191095 (n=10;p<0.05). The infarct protective effect of BMS 191095 was associated with a higher muscle content of ATP at the end of 4h of ischemia and a decrease in muscle neutrophilic myeloperoxidase activity at the end of 1.5h of reperfusion compared with the timematched control (n=10, p<0.05). These observations led us to conclude that mKATP channels play a central role in the trigger and mediator mechanisms of hind limb remote IPC of skeletal muscle against infarction in the pig, and opening of mKATP channels in ischemic skeletal muscle is associated with an ATP-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion.
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