Mechanisms of antiplatelet activity of PC-09, a newly synthesized pyridazinone derivative.
In this study, we examined whether PC-09, a new pyridazinone derivative, has antiplatelet activity in vitro and further investigated the possible mechanisms involved. Pretreatment with PC-09 resulted in an inhibition on rabbit platelet aggregation and ATP release induced by arachidonic acid, collagen or thrombin, with the IC(50) values of 5.4 to 76.8 muM. The thromboxane B(2) formation caused by collagen or thrombin was markedly inhibited by PC-09, but there was no alteration in that caused by arachidonic acid. The rise of platelet intracellular calcium level stimulated by aggregation agonists and collagen-induced platelet membrane surface glycoprotein IIb/IIIa expression was also reduced by PC-09. In addition, PC-09 itself significantly increased the cyclic AMP level through inhibiting cyclic AMP phosphodiesterase activity. These findings demonstrate that PC-09 is an inhibitor of platelet aggregation, which may be associated with mechanisms including inhibition of thromboxane A(2) formation, intracellular calcium mobilization and platelet surface GPIIb/IIIa expression accompanied by increasing cyclic AMP level.
Cherng
Shiou-Chi
SC
Department of Nuclear Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.
Huang
Wen-Hsin
WH
Shiau
Chia-Yang
CY
Lee
An-Rong
AR
Chou
Tz-Chong
TC
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000096:biosynthesis; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000378:metabolism
D007093:Imidazoles; D009281:Naphthalenes; C510587:PC-09 compound; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011724:Pyridazines; D016718:Arachidonic Acid; D013928:Thromboxane A2; C029899:imidazole; D000255:Adenosine Triphosphate; D003094:Collagen; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D013917:Thrombin; D013930:Thromboxane-A Synthase; D000527:Alprostadil; D006152:Cyclic GMP; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D007213:Indomethacin