Efficacy and mechanism of nicorandil in perioperative protection of skeletal muscle from ischaemia and reperfusion injury in a porcine model

Cahoon, Neil John (2012) Efficacy and mechanism of nicorandil in perioperative protection of skeletal muscle from ischaemia and reperfusion injury in a porcine model. MD thesis, University of Glasgow.

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Abstract

Background: Prolonged ischaemia time during autogenous free muscle transfer, can lead to ischaemia reperfusion (I/R) injury and local necrosis of the muscle. It has been demonstrated that the phenomenon of ischaemic preconditioning (IPC) confers biphasic infarct protection in a porcine skeletal muscle flap model. Further to this, the hybrid nitrovasodilator and KATP channel opener Nicorandil, is known to induce 24h uninterrupted infarct protection in myocardial models. We therefore hypothesised that Nicorandil could pharmacologically confer late-phase infarct protection of skeletal muscle from I/R injury. Methods: Yorkshire pigs (mean 17.9kg) with bilateral 8x13cm Latissimus Dorsi (LD) muscle flaps, received i.v. Nicorandil (3mg/kg) before being subjected to 4h ischaemia followed by 48h reperfusion. Results: Nicorandil induced late-phase preconditioning appeared at 24h after Nicorandil injection and lasted for 72h before waning. LD infarction rates were reduced to 22+/-2, 25+/-2 and 28+/-2% at 24h, 48h and 72h respectively, compared to the ischaemic control of 40+/-2%. Further to this, Nicorandil preconditioning was associated with a reduction in mitochondrial free calcium content, preservation of muscle ATP content and attenuation of neutrophilic myeloperoxidase activity during the first hour of reperfusion. Injection with the specific sarcolemmal KATP (sKATP) inhibitor HMR-1098 or non-specific KATP inhibitor Glibenclamide before Nicorandil injection completely blocked the infarct-protective effects. Injection of the specific mitochondrial KATP (mKATP) inhibitor 5-HD or Glibenclamide before the onset of reperfusion also abolished Nicorandil preconditioning. Conclusion: These findings support the hypothesis that a single dose of Nicorandil induces 48h of uninterrupted late-phase infarct protection in skeletal muscle. Further to this, sKATP and mKATP channels play a central role in the trigger and mediator mechanisms, respectively. Nicorandil is a potential new therapy to augment the ischaemic tolerance of skeletal muscle for patients undergoing autogenous free muscle transfer or composite tissue allotransplantation.

Item Type: Thesis (MD)
Qualification Level: Postdoctoral
Subjects: R Medicine > RD Surgery
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Funder's Name: UNSPECIFIED
Supervisor's Name: Horgan, Prof. Paul
Date of Award: 2012
Depositing User: Mr Neil J. Cahoon
Unique ID: glathesis:2012-4127
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 03 May 2013 12:35
Last Modified: 07 May 2013 13:08
URI: http://theses.gla.ac.uk/id/eprint/4127

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