Papaverine, a Potent Inhibitor of Respiration in C-6 Astrocytoma Cells

Papaverine was used as an inhibitor of cyclic nucleotide phosphodiesterase in C-6 astrocytoma cells. That the diesterase was inhibited is suggested by the result that papaverine together with norepinephrine elevated the adenosine cyclic 3',5'-monophosphate (cAMP) level more than did norepinephrine alone. Papaverine alone induced 3 times as much glycogen breakdown as did norepinephrine in 10 min, but did not cause cAMP elevation after this 10-min period. The adenine nucleotide content of these cells was analyzed with the purpose of accounting for the rapid glycogenolysis. Papaverine lowered creatine phosphate and ATP to 3% and 38%, respectively, of control values, whereas ADP and 5'-AMP were increased complementary to the ATP decline at the end of 10 min. Decreased creatine phosphate was apparent by 0.5 min after papaverine addition, whereas changes in adenine nucleotides occurred later. Conversion of phosphorylase b to phosphorylase a also occurred. Papaverine inhibited respiration in C-6 cells 50% at 5 µM and 90% at 0.5 mM, which accounted for the effect of papaverine on the phosphoryl energy carriers. These results demonstrate that the site of action of papaverine in C-6 astrocytoma cells is not limited to cyclic nucleotide phosphodiesterase. The data suggest that papaverine be used only with great caution as an inhibitor of this enzyme in cellular experimental systems.