1 The antithrombotic action of argatroban, a synthetic thrombin inhibitor, was studied in three models of thrombosis in the rat, and in the tail transection bleeding time test. Heparin was studied as a reference anticoagulant. 2 In the model of venous thrombosis induced by thromboplastin followed by stasis of the abdominal vena cava, argatroban had an ED(50) of 125 mu g kg(-1), when administered as an i.v. bolus 5 min prior to the thromboplastin injection: the ED(50) Of heparin was 42 mu g kg(-1), where ED(50) is the dose which reduces the weight of the thrombus by 50% compared with that of the control animals. When the two compounds were administered by continuous i.v. infusion, argatroban (ED(50) = 1.5 mu g kg(-1) min(-1)) had the same potency as heparin (ED(50) = 1.2 mu g kg(-1) min(-1)). 3 Argatroban was active in the arterio-venous shunt model with an ED(50) of 0.6 mg kg(-1) when the compound was given as a bolus. The ED(50) of herapin was 0.04 mg kg(-1) under the same conditions. The two compounds had ED(50) values of 6 mu g kg(-1) min(-1)(argatroban) and 3 mu g kg(-1) min(-1)(heparin), when administered by continuous i.v. infusion. 4 When tested against occlusive arterial thrombus formation by electrical stimulation of the left carotid artery, both compounds given as either an i.v. bolus or a continuous infusion led to dose-dependent increases in the duration of post-lesion vessel patency. Heparin bolus was more active than argatroban on a weight basis, in that 2 mg kg(-1) gave a similar increase in the time to occlusion as 8 mg kg(-1) argatroban. As in the other models, when given as continuous infusions, argatroban (111% increase in time to occlusion at 20 mu g kg(-1), min(-1)) had similar activity to, that of heparin (180% increase at 25 mu g kg(-1) min(-1)) on a weight basis. Hoever, the antithrombotic effects of argatroban were accompanied by only moderate changes in the coagulation parameters (thrombin time and activated partial thromboplastin time, APTT), whereas, even at a subthreshold dose of heparin (12.5 mu g kg(-1) min(-1)), both the thrombin time and the APTT were greater than 150 s. 5 Infusions of both compounds caused dose-dependent increases in the tail transection bleeding time, with the dose of argatroban that doubles the bleeding time (11 mu g kg(-1) min(-1)) being five times greater than that of heparin (ED(100) = 2.2 mu g kg(-1) min(-1)). 6 These data show that, when administered as an intravenous infusion, argatroban is a potent antithrombotic agent in rat models of venous 'mixed' and arterial thrombosis, this effect can be obtained with a lower degree of systemic anticoagulation than with heparin in the arterial model, and argatroban has a lower haemorrhagic potential than that of heparin.
