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RO3244794, an IP receptor antagonist, shortens the time to occlusion in a canine model of coronary artery thrombosis
Author(s) -
Lauver D. Adam,
Lucchesi Benedict R.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.640
Subject(s) - thromboxane a2 , prostacyclin , thrombus , pharmacology , receptor antagonist , bleeding time , medicine , tissue plasminogen activator , chemistry , vasodilation , receptor , antagonist , platelet , platelet aggregation
Prostacyclin (PGI 2 ), a member of the eicosanoid family of lipid mediators, is a major product of arachidonic acid metabolism formed in the vascular endothelium and other tissues. PGI 2 is a potent vasodilator and antiplatelet agent whose action is in direct opposition of thromboxane A 2 (TXA 2 ). PGI 2 mediates its effects primarily through a membrane‐associated G protein‐coupled receptor termed the IP receptor. Activation of this receptor is important not only in regulation of the cardiovascular system, but also in response to mechanical injury or inflammation. To investigate the physiological role of PGI 2 , specific IP receptor antagonists have been developed. One such antagonist, RO3244794, demonstrates high antagonist affinity with a p K i of 8.5 ± 0.11. In this study, we tested the ability of the molecule to alter thrombus formation in a canine model of coronary artery thrombosis and thrombolysis. Pretreatment with RO3244794 (3 mg/kg i.v.) significantly reduced the time to vessel occlusion compared to control (31.3 ± 6.7 vs. 63.0 ± 6.9 min, respectively, p < 0.05). Additionally, time to tissue plasminogen activator (tPA)‐mediated thrombolysis was prolonged in RO3244794‐treated animals. Ex vivo platelet aggregation and tongue bleeding time were unaltered in both treatment groups. The data provide evidence for the important regulatory role of PGI 2 in the formation of arterial thrombi in vivo .