The pharmacological modulation of thrombin‐induced cerebral thromboembolism in the rabbit

Abstract

Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium‐labelled platelets and 125I‐labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. Thrombin (100 iu kg−1, i.c.) — induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg−1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg−1) 5 min prior to thrombin (100 iu kg−1, i.c.) had no effect on platelet accumulation. An inhibitor of NO biosynthesis, l‐NG‐nitro arginine methyl ester (l‐NAME; 100 mg kg−1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg−1, i.c.) when administered 5 min prior to thrombin. Defibrotide (32 or 64 mg kg−1 bolus i.c. followed by 32 or 64 mg kg−1 h−1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg−1, i.c.) did not significantly modify the cranial platelet accumulation response. Cranial platelet accumulation induced by thrombin (100 iu kg−1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg−1, i.e., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 μg kg−1, i.v. bolus) or recombinant tissue plasminogen activator (rt‐PA; 100 μg kg−1, i.c. bolus followed by 20 μg kg−1 min−1, i.c., infusion for 45 min) administered 20 min after thrombin. APSAC had no significant effect when administered 3 h after thrombin. APSAC (200 μg kg−1, i.v. bolus) significantly reversed thrombin (100 iu kg−1, i.c.) — induced intracranial accumulation of 125I‐fibrinogen when administered 20 min after thrombin. These results suggest that neither endogenous PAF nor NO modulate thrombin‐induced intracranial platelet accumulation in the rabbit. However, fibrin deposition appears to play an important role as shown by the ability of fibrinolytic agents to reverse platelet and fibrinogen accumulation induced by i.c. thrombin. 1992 British Pharmacological Society