HYPOXIA-INDUCED INHIBITION OF ADENOSINE KINASE POTENTIATES CARDIAC ADENOSINE RELEASE

To elucidate the physiological role of the AMP-adenosine metabolic cyc le and to investigate the relation between AMP and adenosine formation ? the O-2 supply of isolated guinea pig hearts was varied (95% to 10% O-2). The net adenosine formation rate (AMP-->adenosine) and coronary venous effluent adenosine release rate were measured; free cytosolic A MP was determined by P-31-nuclear magnetic resonance. Switching from 9 5% to 40% O-2 increased free AMP and adenosine formation 4-fold, where as free cytosolic adenosine and venous adenosine release rose 15- to 2 0-fold. In the AMP range from 200 to 3000 nmol/L, there was a linear c orrelation between free AMP and adenosine formation (R-2=.71); however , adenosine release increased several-fold more than formation. At 95% O-2, only 6% of the adenosine formed was released; however, this frac tion increased to 22% at 40% O-2, demonstrating reduced adenosine salv age. Selective blockade of adenosine deaminase and adenosine kinase in dicated that flux through adenosine kinase decreased from 85% to 35% o f adenosine formation in hypoxia. Mathematical model analysis indicate d that this apparent decrease in enzyme activity was not due to satura tion but to the inhibition of adenosine kinase activity to 6% of the b asal levels. The data show (1) that adenosine: formation is proportion al to the AMP substrate concentration and (2) that hypoxia decreases a denosine kinase activity, thereby shunting myocardial adenosine from t he salvage pathway to venous release, In conclusion, because of the no rmal high turnover of the AMP-adenosine metabolic cycle, hypoxia-induc ed inhibition of adenosine kinase causes the amplification of small ch anges in free AMP into a major rise in adenosine, This mechanism plays an important role in the high sensitivity of the cardiac adenosine sy stem to impaired oxygenation.