Antiplatelet Drugs and Endothelial Function

Antiplatelets drugs, particularly cilostazol, an inhibitor of phosphodiesterase (PDE), are widely used for the treatment of ischemic stroke, transient ischemic attack, and peripheral arterial disease (PAD). The use of cilostazol reduces cardiovascular morbidity and mortality in patients with PAD as well as in patients with coronary artery disease (CAD) 1). Although the mechanisms underlying the antiathero-genic effects of cilostazol remain unclear, cilostazol-induced improvement in endothelial function should contribute to the reduction in cardiovascular events. Endothelial dysfunction is the initial step in the patho-genesis of atherosclerosis, leading to cardiovascular events 2). CAD is also associated with endothelial dys-function mediated through reduced nitric oxide (NO) bioavailiability 3). In a pathophysiological state of endothelial function, disruption of a balance between antithrombosis and pro-thrombosis leads to platelet aggregation. The use of cilostazol is expected to prevent cardiovascular events through an improvement in endothelial function. Indeed, previous studies have shown that cilostazol improves endothelial function both in smokers and patients with silent cerebral lacu-nar infarcts with hypercholesterolemia 4, 5). Although the precise mechanism of cilostazol-induced improvement in endothelial function has not been fully clarified, it is believed that cilostazol increases NO production by an increase in endothelial NO synthase (eNOS) activity and decreases NO inac-tivation by a decrease in oxidative stress. Under a physiological condition, a normal interaction between platelets and endothelial cells is maintained by vasoac-tive agents and cytokines derived from cells and binding of their receptors. Cilostazol inhibits PDE in platelets through an increase in adenosine 3´,5´-cyclic monophosphate (cAMP) content and activation of protein kinase A, resulting in antiplatelet aggregation. It is expected that cilostazol restores an abnormal interaction between platelets and endothelial cells. Inhibition of PDE by cilostazol in vascular smooth muscle cells induces peripheral vasodilation through an increase in cAMP content and activation of protein kinase A, resulting in an increase in shear stress. Shear stress increases NO production through the activation of the Akt/PI3 pathway in endothelial cells. In addition , Kawabe-Tako et al. 6) reported that cilostazol promoted the mobilization of endothelial progenitor cells (EPCs) from bone marrow and endothelial regenera-tion in a rat carotid balloon injury model. In a clinical setting, Ueno et al. 7) showed a cilsotazol-induced increase in the number of circulating EPCs in patients with diabetes who had cerebral ischemia. Repair and regeneration of endothelial cells induce an increase in NO production from endothelial cells, and increased NO contributes to an increase in the number …