ENZYME REGULATION IN MYOCARDIAL ADENOSINE PRODUCTION DURING ISCHEMIA & HYPOXIA

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To elucidate the physiological role of the AMP-adenosine metabolic cycle and to investigate the relation between AMP and adenosine formation, oxygen supply of isolated guinea pig hearts was varied (95-10% O2). Net adenosine formation rate (AMP - adenosine) and coronary venous effluent adenosine release rate were measured; free cytosolic AMP was determined by 31P NMR. Switching from 95 to 40% O2 increased free AMP and adenosine formation 4-fold while free cytosolic adenosine and venous adenosine release rose 15-20 fold. In the AMP range from 200 to 3000 nmol/L there was a linear correlation between free AMP and adenosine formation; however, adenosine release increased several-fold more than formation. While at 95% O2 only 6% of adenosine formed were released, this fraction increased to 22% already at 40% O2 demonstrating reduced adenosine salvage. Selective blockade of adenosine deaminase and kinase indicated that flux through adenosine kinase decreased from 85 to 35% of adenosine formation in hypoxia. Mathematical model analysis indicated that this apparent decrease in enzyme activity was not due to saturation but to the inhibition of adenosine kinase activity to 6% of basal levels. The data show a) that adenosine formation is proportional to the AMP substrate concentration and b) that hypoxia decreases adenosine kinase activity; thereby shunting myocardial adenosine from the salvage pathway to venous release. In conclusion, because of the normal high turnover of the AMP-adenosine metabolic cycle, hypoxia-induced inhibition of adenosine kinase causes the amplification of small changes in free AMP into a major rise in adenosine. This mechanism plays an important role in the high sensitivity of the cardiac adenosine system to impaired oxygenation.