We have previously demonstrated that remote ischemic preconditioning (IPC) by instigation of three cycles of 10-min occlusion/reperfusion in a hindlimb of the pig elicits an early phase of
infarct protection in local and distant skeletal muscles subjected to 4 h of
ischemia immediately after remote IPC. The aim of this project was to test our hypothesis that hindlimb remote IPC also induces a late phase of
infarct protection in skeletal muscle and that K(
ATP) channels play a pivotal role in the trigger and mediator mechanisms. We observed that pig bilateral latissimus dorsi (LD) muscle flaps sustained 46 +/- 2%
infarction when subjected to 4 h of
ischemia/48 h of reperfusion. The late phase of
infarct protection appeared at 24 h and lasted up to 72 h after hindlimb remote IPC. The LD muscle
infarction was reduced to 28 +/- 3, 26 +/- 1, 23 +/- 2, 24 +/- 2 and 24 +/- 4% at 24, 28, 36, 48 and 72 h after remote IPC, respectively (P < 0.05; n = 8). In subsequent studies, hindlimb remote IPC or
intravenous injection of the sarcolemmal K(
ATP) (sK(
ATP)) channel opener
P-1075 (2 microg/kg) at 24 h before 4 h of sustained
ischemia (i.e., late preconditioning) reduced muscle
infarction from 43 +/- 4% (ischemic control) to 24 +/- 2 and 19 +/- 3%, respectively (P < 0.05, n = 8).
Intravenous injection of the sK(
ATP) channel inhibitor
HMR 1098 (6 mg/kg) or the nonspecific K(
ATP) channel inhibitor
glibenclamide (Glib; 1 mg/kg)
at 10 min before remote IPC completely blocked the
infarct- protective effect of remote IPC in LD muscle flaps subjected to 4 h of sustained
ischemia at 24 h after remote IPC. Intravenous bolus injection of the mitochondrial K(
ATP) (mK(
ATP)) channel inhibitor
5-hydroxydecanoate (5-HD; 5 mg/kg) immediately before remote IPC and 30-min
intravenous infusion of 5-HD (5 mg/kg) during remote IPC did not affect the
infarct-protective effect of remote IPC in LD muscle flaps. However, intravenous Glib or 5-HD, but not
HMR 1098, given 24 h after remote IPC completely blocked the late
infarct-protective effect of remote IPC in LD muscle flaps. None of these
drug treatments affected the
infarct size of control LD muscle flaps. The late phase of
infarct protection was associated with a higher (P < 0.05) muscle content of
ATP at the end of 4 h of
ischemia and 1.5 h of reperfusion and a lower (P < 0.05) neutrophilic activity at the end of 1.5 h of reperfusion compared with the time-matched control. In conclusion, these findings support our hypothesis that hindlimb remote IPC induces an uninterrupted long (48 h) late phase of
infarct protection, and sK(
ATP) and mK(
ATP) channels play a central role in the trigger and mediator mechanism, respectively.