Early and Late Effects of Ischemic Preconditioning on Microcirculation of Skeletal Muscle Flaps

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 δ1-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.

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Role of ATP-sensitive K+ channels in ischemic preconditioning of skeletal muscle against infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.1.h44 ◽

1997 ◽

Vol 273 (1) ◽

pp. H44-H51 ◽

Cited By ~ 9

Author(s):

C. Y. Pang ◽

P. Neligan ◽

H. Xu ◽

W. He ◽

A. Zhong ◽

...

Keyword(s):

Skeletal Muscle ◽

Ischemic Preconditioning ◽

Ischemia Reperfusion ◽

Energy Charge ◽

Katp Channels ◽

High Energy ◽

Intraarterial Infusion ◽

Muscle Flaps ◽

Charge Potential

We studied the role and mechanism of ATP-sensitive K+ (KATP) channels in ischemic preconditioning (IPC) of skeletal muscle against infarction in vivo. Surgically denervated, noncontractile latissimus dorsi muscle flaps in pentobarbitone-anesthetized pigs were assigned to nine groups: control; IPC (3 cycles of 10-min ischemia/reperfusion); preischemic lemakalim (LMK, 0.18 mg/muscle); postischemic LMK; sodium 5-hydroxydecanoate (5-HD, 27 mg/muscle) before IPC; glibenclamide (Glib 0.3 mg/kg iv) before IPC; 5-HD before preischemic LMK; 5-HD before ischemia; and Glib before ischemia. Except for Glib, all drugs were delivered to each muscle by 10-min local intraarterial infusion to avoid systemic effects. All muscle flaps underwent 4 h of global ischemia. Infarction was assessed at 48 h of reperfusion. In a separate study, muscle biopsies were taken before, during, and after ischemia for assay of high-energy phosphate and lactate contents and myeloperoxidase (MPO) activity. It was observed that muscle infarction in the IPC (24 +/- 2%) and preischemic LMK (21 +/- 2%) groups were smaller (P < 0.05) than that in the control (42 +/- 2%). The anti-infarction effect of IPC and LMK was blocked by 5-HD or Glib. IPC and preischemic LMK caused a higher (P < 0.05) muscle content of ATP and energy charge potential, a lower (P < 0.05) muscle content of lactate during ischemia, and a lower (P < 0.05) muscle MPO activity throughout 16 h of reperfusion compared with the control. These observations indicated for the first time that KATP channels are also involved in the anti-infarction effect of IPC in noncontractile skeletal muscle in vivo. Presently, the cause and importance of energy-sparing and neutrophil-inhibitory effects of IPC and LMK are not known.

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Effector mechanism of adenosine in acute ischemic preconditioning of skeletal muscle against infarction

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.3.r887 ◽

1997 ◽

Vol 273 (3) ◽

pp. R887-R895 ◽

Cited By ~ 11

Author(s):

C. Y. Pang ◽

P. Neligan ◽

A. Zhong ◽

W. He ◽

H. Xu ◽

...

Keyword(s):

Skeletal Muscle ◽

Ischemic Preconditioning ◽

Energy Charge ◽

Muscle Flap ◽

Katp Channels ◽

Channel Blockers ◽

Muscle Flaps ◽

Latissimus Dorsi Muscle Flap ◽

Effector Mechanism ◽

A1 Receptor

We used adenosine A1 receptor agonist N6-1(phenyl-2R-isopropyl)-adenosine (PIA), A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and ATP-sensitive K+ (KATP) channel blockers sodium 5-hydroxydecanoate (5-HD) and glibenclamide (Glib), as probes to investigate the role and mechanism of adenosine in ischemic preconditioning (IPC) of noncontractile skeletal muscle against infarction, using the pig latissimus dorsi muscle flap model. Except for Glib, all drugs were delivered to each muscle flap by 10-min local intra-arterial infusion to avoid systemic effects. Muscle flaps that were subjected to 4 h of global ischemia and 48 h of reperfusion sustained 40 +/- 2% infarction. IPC with three cycles of 10 min ischemia and reperfusion, preischemic adenosine, or PIA treatment reduced (P < 0.05) muscle infarction to 24 +/- 2, 18 +/- 2, and 24 +/- 2%, respectively. The anti-infarction effect of IPC and adenosine was blocked by DPCPX, 5-HD, and Glib (P < 0.05). Preischemic adenosine treatment also maintained higher muscle contents of phosphocreatine, ATP, and energy charge potential and lower muscle contents of dephosphorylated metabolites and lactate during ischemia and a lower muscle myeloperoxidase (MPO) activity during reperfusion compared with the control (P < 0.05). Preischemic adenosine treatment did not increase muscle content of adenosine during ischemia or reperfusion. Furthermore, adenosine given at the onset of reperfusion was not effective in attenuating muscle MPO activity or infarction. Taken together, these observations indicate that adenosine, through A1 receptors, initiates the mechanism of IPC with postreceptor involvement of KATP channels in skeletal muscle. However, adenosine is unlikely to play a key role in the effector mechanism. Presently, the cause and role of energy sparing and neutrophil inhibitory effects associated with the anti-infarction effect of preischemic adenosine treatment are unknown.

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Mitochondrial KATPchannels in hindlimb remote ischemic preconditioning of skeletal muscle against infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00845.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. H559-H567 ◽

Cited By ~ 59

Author(s):

Michael A. Moses ◽

Patrick D. Addison ◽

Peter C. Neligan ◽

Homa Ashrafpour ◽

Ning Huang ◽

...

Keyword(s):

Skeletal Muscle ◽

Protective Effect ◽

Intravenous Injection ◽

Ischemic Preconditioning ◽

Bolus Injection ◽

Remote Ischemic Preconditioning ◽

Myeloperoxidase Activity ◽

Intravenous Bolus ◽

Muscle Flaps ◽

Intravenous Bolus Injection

We previously demonstrated in the pig that instigation of three cycles of 10 min of occlusion and reperfusion in a hindlimb by tourniquet application (∼300 mmHg) elicited protection against ischemia-reperfusion injury (infarction) in multiple distant skeletal muscles subsequently subjected to 4 h of ischemia and 48 h of reperfusion, but the mechanism was not studied. The aim of this project was to test our hypothesis that mitochondrial ATP-sensitive potassium (KATP) (mKATP) channels play a central role in the trigger and mediator mechanisms of hindlimb remote ischemic preconditioning (IPC) of skeletal muscle against infarction in the pig. We observed in the pig that hindlimb remote IPC reduced the infarct size of latissimus dorsi (LD) muscle flaps (8 × 13 cm) from 45 ± 2% to 22 ± 3% ( n = 10; P < 0.05). The nonselective KATPchannel inhibitor glibenclamide (0.3 mg/kg) or the selective mKATPchannel inhibitor 5-hydroxydecanoate (5-HD, 5 mg/kg), but not the selective sarcolemmal KATP(sKATP) channel inhibitor HMR-1098 (3 mg/kg), abolished the infarct-protective effect of hindlimb remote IPC in LD muscle flaps ( n = 10, P < 0.05) when these drugs were injected intravenously at 10 min before remote IPC. In addition, intravenous bolus injection of glibenclamide (1 mg/kg) or 5-HD (10 mg/kg) at the end of hindlimb remote IPC also abolished the infarct protection in LD muscle flaps ( n = 10; P < 0.05). Furthermore, intravenous injection of the specific mKATPchannel opener BMS-191095 (2 mg/kg) at 10 min before 4 h of ischemia protected the LD muscle flap against infarction to a similar extent as hindlimb remote IPC, and this infarct-protective effect of BMS-191095 was abolished by intravenous bolus injection of 5-HD (5 mg/kg) at 10 min 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 4 h of ischemia and a decrease in muscle neutrophilic myeloperoxidase activity at the end of 1.5 h of reperfusion compared with the time-matched control ( n = 10, P < 0.05). These observations led us to conclude that mKATPchannels play a central role in the trigger and mediator mechanisms of hindlimb remote IPC of skeletal muscle against infarction in the pig, and the opening of mKATPchannels 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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