Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis

UMMS Affiliation

Department of Emergency Medicine; Department of Anesthesiology; Department of Pediatrics

Publication Date


Document Type



Animals; Benzamides; Blood Platelets; Coronary Circulation; Coronary Thrombosis; Disease Models, Animal; Dogs; Drug Inverse Agonism; Fibrinolytic Agents; Hemodynamics; Hemorrhage; Morpholines; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrazoles; Receptor, Serotonin, 5-HT2A; Recurrence; *Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Time Factors; Vascular Patency


Hematology | Oncology | Pediatrics


BACKGROUND: Release of serotonin and activation of serotonin 5HT2A 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 5HT2A receptor subtype.

OBJECTIVE: To assess whether targeted inhibition of the serotonin 5HT2A 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 5HT2A 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% (Pandlt;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: 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.

DOI of Published Version



J Thromb Haemost. 2010 Feb;8(2):331-40. Epub 2009 Nov 17. Link to article on publisher's website

Journal/Book/Conference Title

Journal of thrombosis and haemostasis : JTH

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Link to article in PubMed

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