Acute arterial thrombosis in rabbits: reduced platelet accumulation after treatment with dazoxiben hydrochloride (UK 37,248-01).

Abstract

1 Acute thrombosis was induced in the carotid arteries of anaesthetized rabbits by local electrical stimulation (1 mA for 2 min) of the vessel wall. Histological findings confirmed the platelet-rich composition of the thrombus. Platelet accumulation at the stimulus site was quantitated with 111Indium-labelling of autologous platelets. 2 In rabbits injected intravenously with either the thromboxane synthetase inhibitor dazoxiben 2 mg/kg or aspirin 10 mg/kg, accumulation of labelled platelets was considerably reduced. Animals which received vehicle injection only, showed no such reduced thrombus formation. 3 In separate experiments in anaesthetized rabbits, the levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha in clotting blood were measured in blood samples taken from animals which had received the above drug treatments. Aspirin markedly reduced the production of both arachidonate metabolites. In contrast, dazoxiben almost totally inhibited TXB2 production but caused a 3.5-fold increase in the levels of 6-keto PGF1 alpha. 4 These findings demonstrate an antithrombotic effect and confirm the mechanistic selectivity of a thromboxane synthetase inhibitor.