Targeted Inhibition of the Serotonin 5HT2A Receptor Improves Coronary Patency in an in Vivo Model of Recurrent Thrombosis

J Thromb Haemost. 2010 Feb;8(2):331-40. doi: 10.1111/j.1538-7836.2009.03693.x. Epub 2009 Nov 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Pyrazoles / blood
  • Pyrazoles / pharmacology*
  • Pyrazoles / toxicity
  • Receptor, Serotonin, 5-HT2A / blood
  • Recurrence
  • Serotonin 5-HT2 Receptor Antagonists*
  • Serotonin Antagonists / blood
  • Serotonin Antagonists / pharmacology*
  • Serotonin Antagonists / toxicity
  • Time Factors
  • Vascular Patency / drug effects*

Substances

  • APD791
  • Benzamides
  • Fibrinolytic Agents
  • Morpholines
  • Platelet Aggregation Inhibitors
  • Pyrazoles
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists