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Ischemic and pharmacological postconditioning in experimental ischemia and reperfusion


Rasmus Haarup Lie


The experiments performed in conjuncture to this thesis were carried out at the Department ofAnaesthesiology and Intensive Care and the Institute of Experimental Clinical Medicine, AarhusUniversity Hospital, Skejby. Throughout the three studies this thesis addressed the issue ofadaptation and efficacy of ischemic and pharmacological postconditioning strategies using an invivoporcine model of acute myocardial ischemia and reperfusion.Study I investigated whether myocardial salvage could be achieved from ischemicpostconditioning applied as an algorithm consisting of 15 seconds of occlusion interspersed with15 seconds of reperfusion immediately upon reperfusion after a lethal ischemic period of 45minutes. The study showed a significantly reduced infarct size in the intervention groupcompared with the untreated control group. Supplemental experiments showed that our modelrequired a short-cycled reperfusion algorithm since neither 60 nor 30 seconds repetitiveocclusions yielded myocardial salvage.Study II investigated the putative infarct sparing effect of pharmacological postconditioning withcyclosporine A. An ischemic preconditioning group was included serving as a positive controlgroup. Myocardial metabolism was evaluated by measuring the interstitial lactate concentrationusing microdialysis. Cyclosporine A in a dose of 10 mg/kg administered 5 minutes prior toreperfusion by intravenous injection did not change the infarct size compared with controlanimals. Ischemic preconditioning substantially reduced the infarct size demonstrating theamenability of the model to activate endogenous cardioprotection. The changes in the interstitiallactate concentration supported the assumption of ischemia and reperfusion resulting from LADocclusion and release respectively.Study III In the porcine model a positive significant correlation between the end ischemicinterstitial glutamate concentration and the final infarct size was found. A mounted rat heartmodel was utilized to examine the effect of specific glutamate receptor blockage during ischemiaand reperfusion. Blockage of either the N-methyl-D-aspartate (NMDA) or the metabotrobicglutamate receptor mGlur5 results in profound myocardial salvage. While the exact mechanismsremain to be elucidated, the provisional results from Study III suggest the existence of amyocardial equivalent to neuronal damage from the injurious process of excessive glutamatereceptor activation.In conclusion, a working porcine model of ischemic postconditioning suitable for further studiesof the phenomenon was established. Pharmacological postconditioning with Cyclosporine A wastrialed in our large mammalian model without finding support of a favourable effect onmyocardial salvage as previously demonstrated by others in small animal models. Porcinemicrodialysis data and ischemia-reperfusion experiments in the mounted rat supported thehypothesis of endogenous glutamate receptor activation playing a role in myocardial ischemiareperfusion injury.