The anti-aggregation effects of ondansetron on platelets involve IP3 signaling and MAP kinase pathway, but not 5-HT3-dependent pathway

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• 作者：Fu-Chao Liu ; Jiin-Tarng Liou ; Hsiang-Ruei Liao ; Chih-Chieh Mao ; Polung Yang ; Yuan-Ji Day
• 关键词：SIR2 ; silent information regulator 2 ; TXB2 ; thromboxane B2 ; AA ; arachidonic acid ; 5-HT3 ; 5-hydroxytryptamine 3 ; histone deacetylase ; IP ; inositol phosphate ; IP3 ; inositol 1 ; 4 ; 5-triphosphate ; MAPK ; mitogen-activated protein kinases ; ERK ; extra cellular reg
• 刊名：Thrombosis Research
• 出版年：2012
• 出版时间：September, 2012
• 年：2012
• 卷：130
• 期：3
• 页码：e84-e94
• 全文大小：1143 K

文摘

Ondansetron is a 5-HT3 receptor antagonist with potent antiemetic, analgesic, and antiphlogistic effects. Literature concerning 5-HT3 antagonists on platelets is limited. In this report we examined the pharmacological effects of ondansetron on human washed platelets. Platelet aggregation induced by thrombin (0.1 U/mL), collagen (2 ¦Ìg/mL), arachidonic acid (0.5 mM), ADP (10 ¦ÌM), or U46619 (2 ¦ÌM) was observed. The effects of ondansetron on platelet aggregation and ATP release were investigated at different concentrations. Cytosolic Ca²⁺ influx concentration, TXB2, IP3, and the levels of cAMP and cGMP were monitored, and flow cytometric analysis and immunoblotting were performed to investigate downstream signaling components. Our results showed that ondansetron, in a concentration-dependent manner, inhibited agonist-induced platelet aggregation. At 75 ¦ÌM, ondansetron significantly attenuated intracellular Ca²⁺ mobilization, thromboxane B2 formation, and ATP release by human washed platelets activated by thrombin, collagen, or U46619, whereas it only partially attenuated arachidonic acid-driven platelet activation. Administration of ondansetron resulted in attenuated IP3 production in the washed platelets stimulated by thrombin, as determined by reduced IP1 levels, as well as diminished p38 and ERK2 phosphorylation in response to thrombin. No effect of ondansetron on the levels of either cAMP or cGMP in washed platelets was observed. Furthermore, ondansetron-mediated inhibition of platelet aggregation was not impacted by SR 57227A, the 5-HT3 agonist. Thus, rather than involving the 5-HT3-dependent pathway, the negative effect of ondansetron on platelet aggregation is instead manifested through the attenuation of agonist-induced IP3 production and MAPK (p38 and ERK2) phosphorylation that results in suppressed intracellular Ca²⁺ mobilization, TXB2 formation, and ATP release.