Molecular Pharmacology, Vol 13, 400-406, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Selective Inhibition of Separated Forms of Human Platelet Cyclic Nucleotide Phosphodiesterase by Platelet Aggregation Inhibitors

¹ Department of Biochemistry, Institute for Developmental Research, Aichi Prefecture Colony, 713-8 Kamiyacho, Kasugai, Aichi 480-03, Japan
² Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606, Japan

Human platelets contain three distinct cyclic nucleotide phosphodiesterases which catalyze the hydrolysis of both cyclic 3',5'-AMP and cyclic 3',5'-GMP. These are a relatively specific cyclic GMP phosphodiesterase (F I), a cyclic nucleotide phosphodiesterase (F II), and a relatively specific cyclic AMP phosphodiesterase (F III). This study was conducted to evaluate the possibility of selective inhibition of these three forms of the phosphodiesterase by various platelet aggregation inhibitors: papaverine, theophylline, caffeine, EG 626, adenosine, 2-chloroadenosine, and dipyridamole. Selective inhibition was found when the inhibitory potencies of the compounds were compared by means of Dixon plots. All agents tested except dipyridamole showed relatively selective inhibition for F III, and the order of potency of these drugs as inhibitor of the F III enzyme was papaverine, EG 626, dipyridamole, theophylline, 2-chloroadenosine, caffeine, and adenosine. EG 626 was 30 times more potent as an inhibitor of F III than of F I. On the other hand, dipyridamole was 20 times more potent as an inhibitor of F I than of F III. The K_i values of these agents for F I and F III were identical whether cyclic AMP or cyclic GMP was used as substrate. However, these compounds revealed approximately 2 times more affinity for F II using cyclic GMP than with cyclic AMP as substrate. The K_i values of these compounds for inhibition of cyclic AMP hydrolysis by F II decreased by half in the presence of 2 µM cyclic GMP and were found to correspond to the K_i values obtained using cyclic GMP as substrate. Hydrolysis of cyclic AMP by F II was stimulated by 0.1-10 µM cyclic GMP. The decreased K_i values in the presence of a low concentration of cyclic GMP may be due to the effect of cyclic GMP on the active site of F II.

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