Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction.
The aim of this study was to investigate the efficacy and mechanism of action of a noninvasive remote ischemic preconditioning (IPC) technique for the protection of multiple distant skeletal muscles against ischemic necrosis (infarction). It was observed in the pig that three cycles of 10-min occlusion and reperfusion in a hindlimb by tourniquet application reduced the infarction of latissimus dorsi (LD), gracilis (GC), and rectus abdominis (RA) muscle flaps by 55%, 60%, and 55%, respectively, compared with their corresponding control (n = 6, P < 0.01) when they were subsequently subjected to 4 h of ischemia and 48 h of reperfusion. This infarct-protective effect of remote IPC in LD muscle flaps was abolished by an intravenous bolus injection of the nonselective opioid receptor antagonist naloxone (3 mg/kg) 10 min before remote IPC and a continuous intravenous infusion (3 mg/kg) during remote IPC and by an intravenous bolus injection of the selective delta 1-opioid receptor antagonist 7-benzylidenealtrexone maleate (3 mg/kg). However, this infarct-protective effect of remote IPC was not affected by an intravenous bolus injection of the ganglionic blocker hexamethonium chloride (20 mg/kg) or the nonspecific adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (10 mg/kg) or by a local intra-arterial injection of the adenosine1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (3 mg/muscle flap) given 10 min before remote IPC. It was also observed that this remote IPC of skeletal muscle against infarction was associated with a slower rate of muscle ATP depletion during the 4 h of sustained ischemia and a reduced muscle neutrophilic myeloperoxidase activity after 1.5 h of reperfusion. These observations led us to speculate that noninvasive remote IPC by brief cycles of occlusion and reperfusion in a pig hindlimb is effective in global protection of skeletal muscle against infarction. This infarct-protective effect is most likely triggered by the activation of opioid receptors in the skeletal muscle, and remote IPC is associated with an energy-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion.
Addison
Patrick D
PD
Research Institute, The Hospital for Sick Children, and Department of Surgery, University of Toronto, Ontario, Canada M5G 1X8.
Neligan
Peter C
PC
Ashrafpour
Homa
H
Khan
Asim
A
Zhong
Anguo
A
Moses
Michael
M
Forrest
Christopher R
CR
Pang
Cho Y
CY
D000005:Abdomen; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005730:Ganglionic Blockers / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D006614:Hindlimb; D007238:Infarction / Q000517:prevention & control*; D019194:Ischemic Preconditioning / Q000379:methods*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000201:enzymology; D009292:Narcotic Antagonists; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism; D013524:Surgical Flaps / Q000098:blood supply; D013552:Swine; D013848:Thigh; D013909:Thorax
D005730:Ganglionic Blockers; D009292:Narcotic Antagonists; D019344:Lactic Acid; D018738:Hexamethonium; D000255:Adenosine Triphosphate; D009195:Peroxidase