Inhibition by purine compounds of cyclic GMP-stimulated cyclic AMP phosphodiesterase activity from a particulate fraction of rat striatum

Cyclic AMP phosphodiesterase activity in a particulate fraction of rat striatum is stimulated two fold by cyclic GMP. An investigation of the effects of various purine compounds on basal and cyclic GMP-stimulated cyclic AMP phosphodiesterase activity as measured at a low substrate concentration (3 uM) was carried out. Adenosine inhibits cyclic GMP-stimulated cyclic AMP phosphodiesterase activity with an IC 50 of 400 uM while inhibiting basal cyclic AMP phosphodiesterase activity with an IC 50 of 2.4 mM. Adenosine blocks cyclic GMP stimulation of cyclic AMP hydrolysis with an IC 50 of 80 uM. Inosine and hypoxanthine have a similar profile of action but are less effective with IC 50's of 200 and 400 uM respectively on cyclic GMP stimulation of phosphodiesterase activity and only 20–40% inhibition of basal enzyme activity up to 2.4 mM. Adenine, guanosine and guanine block cyclic GMP stimulation of cyclic AMP phosphodiesterase activity with IC 50's of 100–200 uM. Classical phosphodiesterase inhibitors of the alkylxanthine type are also selective for the stimulated enzyme with IC 50's of 200 and 25 uM for theophylline and IBMX on cyclic GMP-stimulated cyclic AMP hydrolysis and IC 50's of 500 and 50 uM respectively on basal phosphodiesterase activity. Theophylline and IBMX are potent inhibitors of cyclic GMP stimulation of cyclic AMP phosphodiesterase activity with IC 50's of 50 and 5 uM. These findings suggest a role for physiologically available purine compounds and alkylxanthines in the regulation of cyclic nucleotide metabolism through interaction with cyclic GMP stimulation of cyclic AMP phosphodiesterase activity.