Document Detail

Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis.
MedLine Citation:
PMID:  19922435     Owner:  NLM     Status:  MEDLINE    
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% (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: 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.
K Przyklenk; A L Frelinger; M D Linden; P Whittaker; Y Li; M R Barnard; J Adams; M Morgan; H Al-Shamma; A D Michelson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-11-17
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  8     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-19     Completed Date:  2010-05-20     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  331-40     Citation Subset:  IM    
Center for Platelet Function Studies, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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MeSH Terms
Benzamides / blood,  pharmacology*,  toxicity
Blood Platelets / drug effects*,  metabolism
Coronary Circulation / drug effects
Coronary Thrombosis / blood,  drug therapy*,  pathology,  physiopathology
Disease Models, Animal
Drug Inverse Agonism
Fibrinolytic Agents / blood,  pharmacology*,  toxicity
Hemodynamics / drug effects
Hemorrhage / chemically induced
Morpholines / blood,  pharmacology*,  toxicity
Platelet Aggregation / drug effects
Platelet Aggregation Inhibitors / blood,  pharmacology*,  toxicity
Pyrazoles / blood,  pharmacology*,  toxicity
Receptor, Serotonin, 5-HT2A / blood
Serotonin 5-HT2 Receptor Antagonists*
Serotonin Antagonists / blood,  pharmacology*,  toxicity
Time Factors
Vascular Patency / drug effects*
Grant Support
Reg. No./Substance:
0/APD791; 0/Benzamides; 0/Fibrinolytic Agents; 0/Morpholines; 0/Platelet Aggregation Inhibitors; 0/Pyrazoles; 0/Receptor, Serotonin, 5-HT2A; 0/Serotonin 5-HT2 Receptor Antagonists; 0/Serotonin Antagonists

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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