Arachidonic acid metabolites, ADP and thrombin modulate occlusive thrombus formation over extensive arterial injury in the rat.
Platelet-dependent occlusive thrombosis at sites of deep vessel wall injury elicited by electrical stimulation of rat carotid arteries was significantly reduced by thromboxane A2 (TXA2) synthetase inhibition and/or TXA2/prostaglandin endoperoxide receptor antagonism (ridogrel 1.25 mg/kg i.v.; dazoxiben 5 mg/kg i.v.; sulotroban 20 mg/kg i.v.), by inhibition of ADP-dependent platelet responses (ticlopidine 3 x 200 mg/kg orally) and by anticoagulation (heparin 250 U/kg i.v.; warfarin 1.25 mg/kg i.p.). This points to an involvement of arachidonic acid metabolites, ADP and thrombin as modulators of the thrombotic process. The antithrombotic effect of ridogrel (IC50 = 0.22 mg/kg i.v.) was abolished by cyclooxygenase inhibition (suprofen 5 mg/kg i.v.) but enhanced by cAMP phosphodiesterase inhibition (HL 725 6 micrograms/kg/min i.v.), demonstrating the importance of platelet inhibitory prostanoids such as PGD2, and prostacyclin formed after TXA2 synthetase inhibition. High doses of ridogrel (1.25 mg/kg i.v.) producing additional TXA2/prostaglandin endoperoxide receptor antagonism were more effective than lower doses (0.16 mg/kg i.v.) providing TXA2 synthetase inhibition alone. The antithrombotic effect of ridogrel, when combined with ticlopidine or heparin, exceeded that of the single compounds, pointing to interactions between arachidonic acid metabolites, ADP and thrombin in the formation of occlusive thrombosis at sites of arterial injury.
De Clerck
F
F
Department of Haematology, Janssen Research Foundation, Beerse, Belgium.
Van Gorp
L
L
Beetens
J
J
Verheyen
A
A
Janssen
P A
PA
D000244:Adenosine Diphosphate / Q000502:physiology*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001777:Blood Coagulation; D001792:Blood Platelets / Q000502:physiology*; D002341:Carotid Artery Thrombosis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D004558:Electric Stimulation; D006493:Heparin / Q000494:pharmacology; D008297:Male; D010421:Pentanoic Acids / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane; D013917:Thrombin / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013988:Ticlopidine / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology
D000925:Anticoagulants; D001095:Arachidonic Acids; D010421:Pentanoic Acids; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D014859:Warfarin; D000244:Adenosine Diphosphate; D006493:Heparin; D013917:Thrombin; D013930:Thromboxane-A Synthase; D013988:Ticlopidine; C060219:ridogrel