Differing Effects of Cilostazol and Aspirin on Thrombus Formation and Microvascular Permeability

Abstract

Cilostazol is a unique antiplatelet drug as it has been shown to reduce the recurrence of vascular events without exacerbating a risk of bleeding complication, although mechanisms for such effects are unknown. We examined its effects on changes in formation of platelet thrombus and compared those with aspirin. Microhemorrhage was induced by laser ablation on a rat mesenteric venule to observe a spatiotemporal process of non‐occlusive thrombus formation. Platelet thrombi in both cilostazol‐ and aspirin‐treated rats were examined to choose the doses of reagents resulting in comparable anti‐platelet effects. Surprisingly, cilostazol, but not aspirin, was found to reduce erythrocyte extravasation under these conditions. To test if such an effect is attributed to modulation of endothelial barrier properties, we measured changes in water permeability (Lp) and reflection coefficient to albumin (σ) in single‐perfused venules. Cilostazol significantly abolished a transient increase in Lp and a decrease in σ when vessels were challenged by histamine. Furthermore the reagent attenuated baseline Lp under a control state. These results indicate that cilostazol not only acts on the platelet to reduce the size of developing thrombus, but also acts on endothelium to tighten up the endothelial barrier at least in part by inhibiting the cAMP‐degrading enzyme in the endothelium that differs from aspirin. Supported by MEXT.