Effects of CI-930, a novel phosphodiesterase III inhibitor, on platelet aggregation and arachidonic acid metabolism.
In the platelet-rich plasma of rabbits, 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone (CI-930) inhibited platelet aggregation triggered by AA, U-46619, ADP, collagen and PAF, with the IC50 values of 0.91, 0.73, 2.12, 2.35 and 7.15 mumols/L, respectively. The inhibitory effect of CI-930 on AA-induced aggregation was potentiated by PGE1, an adenylate cyclase activator, and antagonized by SQ-22536, an adenylate cyclase inhibitor. The contents of cAMP in washed rabbit platelets were increased by CI-930 5-50 mumols/L. In the concentration range of 0.5-500 mumols/L, CI-930 reduced the synthesis of TXB2 by either washed rat or rabbit platelets or rat pleural neutrophils. At the same time, CI-930 induced a dose-dependent increase of PGE2, PGF2a, and PGD2 biosynthesis by rat platelets and had no significant influence on the formation of 6-keto-PGF1a by the neutrophils. It is showed that CI-930 is an anti-platelet agent with a wide-spectrum activity and its anti-aggregating action may be exerted by dual mechanisms, both increasing cAMP contents and selectively inhibiting TXA2 synthesis in platelets.
Chen
X S
XS
Department of Pharmacology and Medicinal Chemistry, Second Military Medical University, Shanghai, China.
Zeng
H W
HW
Jiang
Y Y
YY
Wan
W Q
WQ
Long
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000378:metabolism
D001095:Arachidonic Acids; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C042528:4,5-dihydro-6-(4-(imidazol-1-yl)phenyl)-5-methyl-3(2H)-pyridazinone; D015237:Dinoprost; D000242:Cyclic AMP; D015232:Dinoprostone