Antiplatelet effect of NQ12: a possible mechanism through the arachidonic acid cascade.
NQ12, an antithrombotic agent, has been reported to display a potent antiplatelet activity. This study was undertaken to reveal the effect of NQ12 on rabbit platelet aggregation and signal transduction involved in the arachidonic acid (AA) cascade. NQ12 concentration-dependently suppressed collagen-, AA-, and U46619-induced rabbit platelet aggregation, with IC(50) values of 0.71 +/- 0.2, 0.82 +/- 0.3, and 0.45 +/- 0.1 microM, respectively. In addition, the concentration-response curve of U46619 was shifted to the right after NQ12 treatment, indicating an antagonism on thromboxane (TX) A(2) receptors. The collagen-stimulated AA liberation was inhibited by NQ12 in the same pattern as its inhibition of platelet aggregation. Further study revealed that NQ12 potently suppressed AA-mediated TXA(2) formation, but had no effect on the PGD(2) production, indicating an inhibitory effect on TXA(2) synthase, which was supported by a TXA(2) synthase activity assay indicating that NQ12 concentration-dependently inhibited TXA(2) formation converted from PGH(2). On the other hand, the AA-stimulated 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) formation was also suppressed by NQ12. Taken together, these results suggest that NQ12 has a potential to inhibit TXA(2) synthase activity and TXA(2) receptors, and it can modulate AA liberation as well as 12-HETE formation in platelets. This may be a convincing mechanism for the antithrombotic action of NQ12.
Jin
Yong-Ri
YR
Research Institute of Veterinary Medicine, CBITRC, Chungbuk National University, Cheongju, Korea.
Han
Xiang-Hua
XH
Lee
Jung-Jin
JJ
Lim
Yong
Y
Kim
Tack-Joong
TJ
Yoo
Hwan-Soo
HS
Hong
Jin-Tae
JT
Lee
Chong-Kil
CK
Yun
Yeo-Pyo
YP
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000096:biosynthesis; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000096:biosynthesis; D044262:Prostaglandin H2 / Q000378:metabolism; D011817:Rabbits; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013928:Thromboxane A2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000187:drug effects / Q000378:metabolism
C403720:2-chloro-3-((4-ethyl-phenyl)-amino)-1,4-naphthalendione; D005343:Fibrinolytic Agents; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016718:Arachidonic Acid; D044262:Prostaglandin H2; D013928:Thromboxane A2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D013930:Thromboxane-A Synthase; D015230:Prostaglandin D2