期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 8, 期 2, 页码 331-340出版社
WILEY
DOI: 10.1111/j.1538-7836.2009.03693.x
关键词
angina; platelets; serotonin; thrombosis
资金
- Arena Pharmaceuticals, Inc.
- NIH [R01 HL072684]
Background: Release of serotonin and activation of serotonin 5HT(2A) receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT(2A) receptor subtype. Objective: To assess whether targeted inhibition of the serotonin 5HT(2A) receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina. Methods: In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT(2A) receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury + stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin. Results: APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow-time area (index of coronary patency; normalized to baseline coronary flow) averaged 58-59% (P < 0.01) following administration of APD791 vs. 21-28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation. Conclusion: 5HT(2A) receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.
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