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.

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 > School of Cancer Sciences
• 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: https://theses.gla.ac.uk/id/eprint/4127