Cyclic AMP and cyclic GMP phosphodiesterase inhibition by an antiplatelet agent, 6-[(3-methylene-2-oxo-5-phenyl-5-tetrahydrofuranyl)methoxy)quinol inone (CCT-62).
The antiplatelet activity of (6-[(3-methylene-2-oxo-5-phenyl-5-tetrahydrofuranyl)methoxy]quinol inone) (CCT-62) was determined in vitro in rabbit platelets. CCT-62 inhibited rabbit platelet aggregation and ATP release caused by thrombin (0.1 U/ml), platelet-activating factor (2 ng/ml), collagen (10 microg/ml), arachidonic acid (100 microM), and 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha (1 microM) in a concentration-dependent manner. The IC50 values for platelet aggregation were 18.4 +/- 4.5, 10.1 +/- 1.6, 3.0 +/- 0.9, 1.5 +/- 0.3 and 1.0 +/- 0.3 microM, respectively. In addition, CCT-62 disaggregated the clumped platelets caused by these aggregation inducers. It also inhibited phosphoinositide breakdown and intracellular calcium elevation induced by the above platelet aggregation inducers. CCT-62 increased intracellular cyclic AMP and cyclic GMP levels in a concentration- and time-dependent manner. Furthermore, it potentiated cyclic AMP formation caused by prostaglandin E1 but not that caused by 3-isobutyl-1-methylxanthine. CCT-62 did not affect adenylate or guanylate cyclase but inhibited cyclic AMP- and cyclic GMP-phosphodiesterase activities. The antiplatelet effect of CCT-62 was reversed by a protein kinase A inhibitor, N-[2-(P-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89). This data clearly indicated that CCT-62 is an inhibitor of phosphodiesterases and that its antiplatelet effect is mainly mediated by elevation of cyclic AMP levels.
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
C H
CH
Liao
C C
CC
Tzeng
C M
CM
Teng
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D011817:Rabbits
D005663:Furans; D007295:Inositol Phosphates; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D015363:Quinolones; C114148:CCT 62; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium