8-phenyltheophylline as an inhibitor of cyclic AMP hydrolysis by cyclic nucleotide phosphodiesterase.

1. The inhibition, by theophylline and 8-phenyltheophylline, of cAMP hydrolysis by cyclic nucleotide phosphodiesterase from rat fat cells, abdominal aorta, gastrocnemius muscle, erythrocytes and cerebrum was examined. 2. Theophylline was an approximately equieffective inhibitor of cAMP hydrolysis in all tissue extracts. In contrast, 8-phenyltheophylline was a markedly more effective inhibitor of cAMP breakdown in erythrocytes and skeletal muscle than in smooth muscle, brain and fat cells. The 8-phenyl substituted compound was a more potent inhibitor in erythrocytes and skeletal muscle than theophylline. 3. 8-phenyltheophylline has been postulated to be a very selective adenosine receptor antagonist, the present study indicates, that in some tissues 8-phenyltheophylline is not so selective as an adenosine receptor antagonist as has previously been suggested. 4. Analysis of cyclic AMP breakdown by cyclic nucleotide phosphodiesterase in fat cells and erythrocytes demonstrated the presence of high and low affinity forms. 5. Theophylline was slightly more effective as an inhibitor of the high than of the low affinity forms in both tissues. 8-phenyltheophylline was weakly effective as an inhibitor of all isoenzymes from fat cells and selectively inhibited the high affinity phosphodiesterase from erythrocytes. 6. The results suggest that 8-phenyltheophylline is a selective inhibitor of a cyclic nucleotide phosphodiesterase with a high affinity for cAMP, which has relatively greater activity in erythrocytes, and presumably in skeletal muscle, than in other tissues such as fat cells.