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Title: Remote, non-invasive ischaemic preconditioning of skeletal muscle flaps against ischaemic necrosis : efficacy and mechanism
Author: Addison, Patrick
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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The efficacy and mechanism of a novel, non-invasive, remote ischaemic preconditioning (IPC) technique for the protection of skeletal muscle against necrosis resulting from prolonged ischaemia, were studied in a porcine model. It was observed that three brief cycle of non-invasive hindlimb ischaemia, induced by application of a tourniquet, reduced the infarct size in Latissimus Dorsi (LD) muscle flaps by 62% and Rectus Abdominis (RA) and Gracilis (Gc) muscle flaps by 50% and 60% respectively (n=6, p<0.01) compared with sham manipulated controls, when these flaps were subsequently subjected to 4 hours continuous ischaemia and 48 hours of reperfusion. The onset and duration of this ischaemic protection were studied in LD flaps also subjected to 4 hours ischaemia and 48 hours reperfusion beginning 1, 8, 24, 48 or 72 hours after the remote IPC stimulus. Protection against prolonged ischaemia develops rapidly following the preconditioning stimulus, but is short lived. By 8 hours, the protective effect was lost. A second period of protection then develops approximately 24 hours after preconditioning and is maintained beyond 72 hours. The ischaemic protection afforded by remote IPC was abolished by the non-selective opioid receptor antagonist Naloxone (3mg/Kg) and the Nitric Oxide (NO) synthase inhibitor L-NNA (1mg/Kg). the mitochondrial KATP­ channel blocking agent 5-Hydroxydecanoate 95HD, 5mg/Kg) abolished protection whereas infusion of the mitochondrial K­ATP channel opener Diazoxide (10mg/Kg) mimicked the protection afforded by remote IPC in the absence of preconditioning. Taken together these results suggest that the activation of opioid receptors, but not adenosine receptors, is sufficient to induce the protective pathways of remote IPC in this model. The pathway appears to involve the synthesis of NO and the opening of mitochondrial KATP channels. Finally it was shown that remote, non-invasive IPC is associated with slower rates of muscle Adenosine triphosphate (ATP) hydrolysis and Lactate accumulation during subsequent prolonged ischaemia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available