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 IC₅₀ of 400 uM while inhibiting basal cyclic AMP phosphodiesterase activity with an IC₅₀ of 2.4 mM. Adenosine blocks cyclic GMP stimulation of cyclic AMP hydrolysis with an IC₅₀ of 80 uM. Inosine and hypoxanthine have a similar profile of action but are less effective with IC₅₀'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 IC₅₀'s of 100–200 uM. Classical phosphodiesterase inhibitors of the alkylxanthine type are also selective for the stimulated enzyme with IC₅₀'s of 200 and 25 uM for theophylline and IBMX on cyclic GMP-stimulated cyclic AMP hydrolysis and IC₅₀'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 IC₅₀'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.