Redirection of arachidonic acid metabolism by ICI D1542: effects on thrombus formation in the coronary artery of the anaesthetized dog.
1. The effects of simultaneous redirection of arachidonic acid metabolism, by inhibition of thromboxane A2 (TXA2) synthase and blockade of the platelet thromboxane A2 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 TXA2 synthase and the TP-receptor. 3. Redirection of arachidonic acid metabolism was demonstrated in whole blood, stimulated ex vivo by collagen. The ED50 for inhibition of TXB2 production was 7.1 micrograms kg-1, i.v.; there were corresponding increases in the production of the eicosanoids prostaglandin D2 (PGD2), PGE2 and PGF2 alpha. 4. Thrombus formation was inhibited by D1542 (ED50 0.55 micrograms kg-1, i.v.), but could be restarted by an intravenous infusion of adrenaline (0.2-38 micrograms 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.
McAuliffe
S J
SJ
ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire.
Moors
J A
JA
Snow
H M
HM
Wayne
M
M
Jessup
R
R
D000758:Anesthesia; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000378:metabolism* / Q000503:physiopathology; D004146:Dioxanes / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D004146:Dioxanes; D011725:Pyridines; D017482:Receptors, Thromboxane; C081036:ICI D1542; D016718:Arachidonic Acid; D013930:Thromboxane-A Synthase; D001241:Aspirin; D004837:Epinephrine