Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: efficacy and mechanism

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2005-12, Vol.289 (6), p.R1609-R1617
• Main Authors: Moses, Michael A, Addison, Patrick D, Neligan, Peter C, Ashrafpour, Homa, Huang, Ning, McAllister, Sandra E, Lipa, Joan E, Forrest, Christopher R, Pang, Cho Y
• Format: Article
• Language: English
• Subjects: Animals; Infarction - physiopathology; Infarction - prevention & control; Ischemic Preconditioning - methods; Male; Muscle, Skeletal - blood supply; Muscle, Skeletal - physiopathology; Swine; Time Factors; Treatment Outcome
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00395.2005

1 Research Institute, The Hospital for Sick Children; and Departments of 2 Surgery and 3 Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X8 Submitted 6 June 2005 ; accepted in final form 23 August 2005 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 µg/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 rep