RT Journal Article
SR Electronic
T1 Selective Inhibition of Separated Forms of Human Platelet Cyclic Nucleotide Phosphodiesterase by Platelet Aggregation Inhibitors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 400
OP 406
VO 13
IS 3
A1 TOMIKO ASANO
A1 YASUO OCHIAI
A1 HIROYOSHI HIDAKA
YR 1977
UL http://molpharm.aspetjournals.org/content/13/3/400.abstract
AB 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 Ki 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 Ki 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 Ki 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 Ki 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.