The effects of sarpogrelate on superoxide production by human neutrophils

Background and Objectives: Superoxide anion (O-2(-)) released from neutroph ils plays an important role in antibacterial host defense system and tissue auto-injury. Sarpogrelate, a serotonin-receptor antagonist, has been succe ssfully used for management of chronic pain caused by arterial occlusive or ischemic vascular diseases, or by microcirculation disturbances. Suppressi on of O-2(-) generation may be detrimental to infection or contribute to th e therapeutic approach to these diseases, the pathogenesis of which probabl y includes neutrophil activation. No data regarding the effects of sarpogre late on neutrophil functions are available despite the possible clinical co ncern. The purpose of this study was to determine whether sarpogrelate redu ces O-2(-) production by human neutrophils using an in vitro system. In add ition, we examined changes in concentrations of the intracellular calcium i on ([Ca2+]i), which is responsible for one of the mechanisms of the neutrop hils' O-2(-) production. Methods: The O-2(-) production by human neutrophils or the xanthine-xanthin e oxidase system and [Ca2+]i were measured in the absence and the presence (at clinically relevant concentrations: 0.1X, 10X, and 100x these concentra tions) of sarpogrelate. Results: Sarpogrelate inhibited O-2(-) production of neutrophils in a dose- dependent manner. The drug at a clinically relevant concentration suppresse d this neutrophil function. In contrast, sarpogrelate failed to inhibit O-2 (-) generation by the cell-free (xanthine-xanthine oxidase) system. Elevati on of [Ca2+]i in neutrophils stimulated by a chemotactic factor was dose-de pendently attenuated with sarpogrelate. Conclusions: These findings suggest that sarpogrelate (even at clinically r elevant concentrations) is able to inhibit O-2(-) production by neutrophils . However, the drug failed to quench an excessive amount of O-2(-) (similar to the level produced by neutrophils). There is a possibility that the inh ibitory effect of the drug on [Ca2+]i response in neutrophils may contribut e to impairment of the neutrophils' O-2(-) production. Further studies usin g in vivo systems are required to elucidate the inhibitory effects of sarpo grelate on O-2(-) in clinical settings.