Involvement of cyclic GMP in the mode of action of a new antithrombotic agent PCA-4230; inhibition of the platelet cyclic GMP dependent phosphodiesterase.
The effect of PCA-4230, a new dihydropyridine derivative with a potent antithrombotic activity, on cyclic nucleotide phosphodiesterase in platelets was studied. PCA-4230 inhibited (54%) cyclic GMP hydrolytic activity of a platelet cytosolic fraction, whereas it did not affect that of cyclic AMP. Results suggested that PCA-4230 inhibited a cyclic GMP-dependent phosphodiesterase, known as cGB PDE or type V, on a purified enzyme from rabbit platelets by a non-competitive-uncompetitive type inhibition. In addition, PCA-4230 potentiated the increase in both cyclic GMP and cyclic AMP levels evoked by sodium nitroprusside. Furthermore, PCA-4230 and forskolin caused a synergistic effect in cyclic AMP, and also potentiated the phosphorylation of 50 kDa and 22 kDa proteins, reported as substrates of cyclic GMP- and cyclic AMP-dependent protein kinases that are related to the inhibition of platelet functions. Finally, PCA-4230 also potentiated the forskolin- and sodium nitroprusside-inhibited serotonin release evoked by thrombin, probably related to the increased cyclic nucleotide level.
Catalán
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Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Spain.
Martínez
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Aragonés
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MD
Lombardía
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007700:Kinetics; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D004095:Dihydropyridines; D005343:Fibrinolytic Agents; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; C073664:PCA 4230; D009599:Nitroprusside; D005576:Colforsin; D012701:Serotonin; D000242:Cyclic AMP; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D013917:Thrombin; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine