Premium
Redirection of arachidonic acid metabolism by ICI D1542: effects on thrombus formation in the coronary artery of the anaesthetized dog
Author(s) -
McAuliffe S.J.G.,
Moors J.A.,
Snow H.M.,
Wayne M.,
Jessup R.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13484.x
Subject(s) - arachidonic acid , thrombus , thromboxane a2 , chemistry , thromboxane , metabolism , prostaglandin h2 , thromboxane a synthase , prostaglandin , cyclooxygenase , pharmacology , platelet , aspirin , medicine , endocrinology , receptor , biochemistry , enzyme
1 The effects of simultaneous redirection of arachidonic acid metabolism, by inhibition of thromboxane A 2 (TXA 2 ) synthase and blockade of the platelet thromboxane A 2 receptor (TP‐receptor), was examined on the rate of thrombus formation in a stenosed coronary artery with damaged endothelium in an anaesthetized dog. 2 Redirection of arachidonic acid metabolism was achieved by intravenous doses of ICI D1542, a selective and potent inhibitor of TXA 2 synthase and the TP‐receptor. 3 Redirection of arachidonic acid metabolism was demonstrated in whole blood, stimulated ex vivo by collagen. The ED 50 for inhibition of TXB 2 production was 7.1 μg kg −1 , i.v.; there were corresponding increases in the production of the eicosanoids prostaglandin D 2 (PGD 2 ), PGE 2 and PGF 2α . 4 Thrombus formation was inhibited by D1542 (ED 50 0.55 μg kg −1 , i.v.), but could be restarted by an intravenous infusion of adrenaline (0.2–38 μg kg −1 min −1 , i.v.). In the presence of the maximum effective dose of D1542 (1 mg kg −1 , i.v.) a 190 fold increase in the infusion rate of adrenaline was required to restore thrombus formation. 5 In the presence of D1542, removal of endoperoxide metabolites by inhibition of cyclo‐oxygenase with aspirin (5 mg kg −1 , i.v.) caused thrombus formation to restart, indicating the ability of the endoperoxide metabolites to inhibit thrombus formation in vivo . 6 These results indicate that, in the stenosed and damaged coronary artery of the dog, redirection of arachidonic acid metabolism by D1542 is more effective at preventing thrombus formation than inhibition of cyclo‐oxygenase by aspirin.