Abstract
Succinobucol is a derivative of probucol with improved partitioning into cells and potent extracellular antioxidant activity. It has antiplatelet effects ex vivo in human blood but it is unclear if this is due to antioxidant activity. We aimed to study the effect of succinobucol on free radical-modulated platelet aggregation and generation of vascular tone. We also studied platelet aggregation ex vivo in rats following acute administration of succinobucol. Rabbit blood was collected and aggregation in whole blood and platelet-rich plasma (PRP) measured using dual-wire impedance. Rabbit iliac arteries were mounted in a small artery wire myograph to measure vessel tone and the effect of free radicals and succinobucol. Rat carotid and jugular vessels were cannulated in anaesthetised animals prior to administration of succinobucol. Blood was withdrawn to measure platelet aggregation 45 minutes following injection of succinobucol. In whole blood and PRP, succinobucol (10-100μM) caused a dose-dependent reduction in collagen-induced platelet aggregation. Aggregation to collagen in PRP was significantly increased by the superoxide-generating system xanthine/xanthine oxidase (X/XO; 29.8% increase, n=4; p<0.05 vs. control) and succinobucol abolished this effect. In denuded rabbit iliac arteries incubated with excess xanthine, addition of XO (3-9mU/mL) induced a dose-dependent relaxation and this was largely abolished by succinobucol at both 10 and 100μM. Injection of 3 doses of succinobucol (50-150mg/kg) in vivo had no effect on mean arterial pressure or heart rate. However, blood removed 45minutes following the last dose of succinobucol showed a significant reduction in aggregation to collagen (reduction of 40.4% compared to control with 5μg/mL collagen; n=5, p<0.05 vs. control). The results of the current study demonstrate that the antiplatelet effects of succinobucol may be attributed to an antioxidant effect in rabbit blood and that succinobucol exerts an antiplatelet effect in vivo for at least 45mins after administration. Furthermore, the antioxidant effects may be able to influence vascular tone at sites of free radical generation in the vascular tree.
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