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Thromboxane A2 synthase inhibition and thromboxane A2 receptor blockade by 2-[(4-cyanophenyl)amino]-3-chloro-1,4-naphthalenedione (NQ-Y15) in rat platelets

Title
Thromboxane A2 synthase inhibition and thromboxane A2 receptor blockade by 2-[(4-cyanophenyl)amino]-3-chloro-1,4-naphthalenedione (NQ-Y15) in rat platelets
Authors
Chang T.-S.Kim H.-M.Lee K.-S.Khil L.-Y.Mar W.-C.Ryu C.-K.Moon C.-K.
Ewha Authors
유충규
SCOPUS Author ID
유충규scopus
Issue Date
1997
Journal Title
Biochemical Pharmacology
ISSN
0006-2952JCR Link
Citation
vol. 54, no. 2, pp. 259 - 268
Indexed
SCI; SCIE; SCOPUS scopus
Abstract
The effects of 2-[(4-acetylphenyl)amino]-3-chloro-1,4-napthalenedione (NQ-Y15), a synthetic 1,4-naphthoquinone derivative, on platelet activity and its mechanism of action were investigated. NQ-Y15 caused a concentration-dependent inhibition of the aggregation induced by thrombin, collagen, arachidonic acid (AA), and A23187. The IC50 values of NQ-Y15 on thrombin (0.1 U/mL)-, collagen (10 μg/mL)-, AA (50 μM)-, and A23187 (2 μM)-induced aggregation were 36.2 ± 1.5, 6.7 ± 0.7, 35.4 ± 1.7, and 93.1 ± 1.4 μM, respectively. NQ-Y15 also inhibited thrombin-, collagen-, AA-, and A23187-stimulated serotonin secretion in a concentration dependent manner. However, a high concentration (100 μM) of NQ-Y15 showed no significant inhibitory effect on ADP-induced primary aggregation, which is independent of thromboxane A2 (TXA2) production in rat platelets. In fura-2-loaded platelets, the elevation of intracellular free calcium concentration stimulated by AA, thrombin, and 4-bromo-A23187 was inhibited by NQ-Y15 in a concentration-dependent manner. The formation of TXA2 caused by AA, thrombin, and collagen was inhibited significantly by NQ-Y15. NQ-Y15 inhibited TXA2 synthase in intact rat platelets, since this agent reduced the conversion of prostaglandin (PG) H2 to TXA2. Similarly, NQ-Y15 selectively inhibited the TXA2 synthase activity in human platelet microsomes, whereas it had no effect on activity of phospholipase A2, cyclooxygenase, and PGI2 synthase in vitro. NQ-Y15 inhibited platelet aggregation induced by the endoperoxide analogue U46619 in human platelets, indicating TXA2 receptor antagonism, possibly of a competitive nature. These results suggest that the antiplatelet effect of NQ-Y15 is due to a combination of TXA2 synthase inhibition with TXA2 receptor blockade, and that it may be useful as an antithrombotic agent.
DOI
10.1016/S0006-2952(97)00179-2
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약학대학 > 약학과 > Journal papers
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