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


CONCLUSIONS
5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.
Przyklenk
K
K
Center for Platelet Function Studies, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA. kprzykle@med.wayne.edu
Frelinger
A L
AL
Linden
M D
MD
Whittaker
P
P
Li
Y
Y
Barnard
M R
MR
Adams
J
J
Morgan
M
M
Al-Shamma
H
H
Michelson
A D
AD
D000818:Animals; D001549:Benzamides / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D054314:Drug Inverse Agonism; D005343:Fibrinolytic Agents / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D006439:Hemodynamics / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced; D009025:Morpholines / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D011720:Pyrazoles / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D044402:Receptor, Serotonin, 5-HT2A / Q000097:blood; D012008:Recurrence; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D014654:Vascular Patency / Q000187:drug effects*
C544126:APD791; D001549:Benzamides; D005343:Fibrinolytic Agents; D009025:Morpholines; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists