Abstract
As the major substrate of energy-consuming reactions, ATP plays a key role in cell metabolism. Hypoxia and ischemia impair the mitochondrial process of oxidative phosphorylation, resulting in a net catabolism of ATP. A primary goal of metabolic support should thus be the preservation of cellular ATP levels. One possible strategy is the enhancement of natural homeostatic mechanisms designed to decrease energy demand and to increase energy supply. At least 3 of these mechanisms involve purines themselves. The drop in cell ATP and the accompanying rise in ADP result in the allosteric activation of phosphofructokinase, a key enzyme in the glycolytic pathway, which under hypoxia, provides an alternative to oxidative phosphorylation as a source of ATP. This reciprocal change also induces the opening of a particular set of K + channels, resulting in hyperpolarization and decreased activity of excitable cells. AMP, which accumulates inside hypoxic cells, activates a specific AMP-dependent protein kinase which inhibits key enzymes in the biosynthesis of fatty acids and cholesterol. Finally, ATP catabolism leads to the accumulation of adenosine in the interstitial fluid. Activation of A1 adenosine receptors reduces the O2 demand of neurons and cardiomyocytes, whereas O2 supply is increased via the activation of vascular A2 adenosine receptors. Several pharmacological tools are becoming available to enhance these physiological mechanisms of protection: K+ channels openers, adenosine analogues, blockers of adenosine uptake, inhibitors of adenosine deaminase and allosteric enhancers of adenosine receptors. A number of animal studies indicate that these agents may indeed exert a cardio- and neuroprotective action.
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Boeynaems, J.M. (1993). Metabolic Support: Modulation of Purine Metabolism. In: Wilmore, D.W., Carpentier, Y.A. (eds) Metabolic Support of the Critically Ill Patient. Update in Intensive Care and Emergency Medicine, vol 17. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-85011-0_18
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DOI: https://doi.org/10.1007/978-3-642-85011-0_18
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