Thrombin inhibition compared with other antithrombotic drugs in rats

An aspirin-sensitive model of arterial thrombosis suitable for rapid evaluation of antithrombotic drugs was developed and characterized in anesthetized rats. Carotid artery thrombi were formed in response to electrical stimulation and were occlusive in 84% of vehicle-treated rats. Light and electron microscopy revealed these thrombi to be platelet-rich and fibrin-rich masses adherent to the injured vessel wall. Intravenous administration of aspirin (10 mg/kg), heparin (300 U/kg), a thromboxane (Tx) A2-receptor antagonist (SQ 29,548, 0.2 mg/kg + 0.2 mg/kg/hr), or the thrombin inhibitor D-phenyl alanyl-L-prolyl-L-arginyl chloromethyl ketone (PPACK, 52 micrograms/kg/min) decreased average thrombus weight by 35, 50, 57 and 94%, respectively. Each of these drugs also reduced the frequency of occlusion to < 25%. In contrast, thrombus weight and vessel occlusion were not decreased by a serotonin antagonist (ketanserin, 0.3 mg/kg, i.v.), or after 14 days of oral dosing with either the calcium antagonist diltiazem (60 mg/kg) or SQ 33,351 (30 mg/kg).