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

• Published in: Journal of thrombosis and haemostasis 2010-02, Vol.8 (2), p.331-340
• Main Authors: PRZYKLENK, K., FRELINGER, A. L., LINDEN, M. D., WHITTAKER, P., LI, Y., BARNARD, M. R., ADAMS, J., MORGAN, M., AL‐SHAMMA, H., MICHELSON, A. D.
• Format: Article
• Language: English
• Subjects: angina; Animals; Benzamides - blood; Benzamides - pharmacology; Benzamides - toxicity; Blood Platelets - drug effects; Blood Platelets - metabolism; Coronary Circulation - drug effects; Coronary Thrombosis - blood; Coronary Thrombosis - drug therapy; Coronary Thrombosis - pathology; Coronary Thrombosis - physiopathology; Disease Models, Animal; Dogs; Drug Inverse Agonism; Fibrinolytic Agents - blood; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - toxicity; Hemodynamics - drug effects; Hemorrhage - chemically induced; Morpholines - blood; Morpholines - pharmacology; Morpholines - toxicity; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - blood; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - toxicity; platelets; Pyrazoles - blood; Pyrazoles - pharmacology; Pyrazoles - toxicity; Receptor, Serotonin, 5-HT2A - blood; Recurrence; serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists - blood; Serotonin Antagonists - pharmacology; Serotonin Antagonists - toxicity; thrombosis; Time Factors; Vascular Patency - drug effects
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2009.03693.x

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