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Cardioprotection against ischemia-reperfusion injury and

Nicolaj Brejnholt Støttrup

Summary

The isolated perfused global no flow model and radioisotope labelled isotopes enables assessment of de novo glycogen synthesis, glucose uptake, glycolysis and glucose oxidation. •

Exogenously administrated glutamate and glutamine induce increased post ischemic de novo glycogen synthesis rate and improve hemodynamic recovery. •

Transient inhibition of the malateaspartate shuttle by aminoocyacetate (AOA) loading before ischemia induces post-ischemic infarct reduction, improved hemodynamic recovery and modulated glucose metabolism comparable to that of IPC. •

Inhibition of the malate-aspartate shuttle in isolated mitochondria reduces complex I respiration and ROS production. •

Aminooxyacetate inhibits interstitial TCA metabolite concentration during ischemia and early reperfusion and modulates purine metabolism. •

The use of computer-assisted image analysis in assessing infarct size in isolated globally infarcted hearts enables Rapid, accurate and reproducible results. •

Modulation of the malate-aspartate shuttle activity during ischemia and reperfusion may constitute a new target for cardioprotection against ischemiareperfusion injury. The concept of mediating cardioprotection by modulation of the malate-aspartate shuttle as already attracted international attention.149

Future studies will show if this finding will open new ways of generating preconditioninglike cardiac protection by means of pharmacological intervention. 

FUTURE PERSPECTIVES 

The methods established and used during this dissertation have subsequently proven useful in a number of other projects. The tracer methods have been applied to several metabolic studies on remote precondition including both neonatal and adult isolated rabbit hearts. The analytical method published by Birkler et al. for measuring metabolite concentrations in microdialysis samples3 has been applied to various experimental animal models in four different species and the results will hopefully provide interesting new insights into the intermediary metabolism in the context of cardioprotection. With the development of our computer-assisted image analysis algorithm we hope to improve infarct analysis and provide future studies with documented threshold values for reproducibility. 

Further studies: The addition of free fatty acids to our model may yield additional knowledge about the prerequisites for inducing cardioprotection in models that come closer to biological conditions. The addition of new more selective inhibiters may further substantiate the importance of this membrane spanning NADH shuttle. The addition of declofenac, a clinically used NSAID and a potential reversible inhibitor of the MA-shuttle would be an interesting addendum to an isolated heart study looking at pharmacological postconditioning. Future studies on isolated neonatal rabbit hearts could provide valuable information on the importance of the physiological high activity of the MA-shuttle in regards to cardioprotection. Preliminary studies by Schmidt  et al. points to a markedly altered glucose handling and altered ischemic tolerance during conditioning to cardioprotection, when compared to adult animals. This is further strengthening the importance and possibilities of this model.