INHIBITION OF HUMAN-LUNG CYCLIC-GMP AND CYCLIC-AMP PHOSPHODIESTERASES BY CERTAIN NULEOSIDES, NUCLEOTIDES, AND PHARMACOLOGICAL PHOSPHODIESTERASE INHIBITORS

The effects of various known inhibitors on the cyclic GMP phosphodiesterase and cyclic AMP phosphodiesterase enzymatic activities found in human lung tissue were investigated. Of the five compounds studied, 1-methyl-3-isobutylxanthine was the most specific for cyclic GMP hydrolysis, while 1-ethyl-4-(isopropylidine-hydrazino-1H-pyrazolo-(3,4-b)-pyr acid, ethyl ester hydrochloride (SQ 20009) was the most potent for inhibiting cyclic AMP hydrolysis. Common non-cyclic nucleotides were tested for their inhibitory abilities only. ATP, GMP and IMP revealed significant inhibition of both phosphodiesterase activities. Certain nucleosides and cyclic nucleotides were also tested at 1 μM substrate concentrations for their ability to inhibit hydrolysis. Cyclic IMP inhibited cyclic GMP activity, but it had no effect on the cyclic AMP phosphodiesterase. The 2′-deoxy nucleosides (2'-deoxy guanosine and 2′-deoxy inosine) inhibited both enzymes; 2′-deoxy GMP inhibited mainly the cyclic GMP acitivity, while 2′-deoxy adenosine inhibited only the cyclic AMP activity. The observation that 2′-deoxy guanosine was a non-competitive inhibitor of cyclic GMP hydrolysis suggested that a site on the enzyme, distinct from the active site, might be involved in the regulation of the human lung phosphodiesterase. © 1979.