The role of prostacyclin in the protective effects of pentoxifylline and other xanthine derivatives in endotoxin action in mice.

ABSTRACT

The xanthine derivative pentoxifylline (POF, Trental) and its metabolically more stable structural analogues, HWA 138 and HWA 448, were compared for their capacity to prevent leukopenia provoked in mice by injection of bacterial lipopolysaccharide (LPS). It was found that HWA 138 and HWA 448 counteracted LPS-induced leukopenia more effectively than POF. Indomethacin diminished the action of HWA 138 and HWA 448, and the stable prostacyclin analogue CG-4203 (Taprosten) mimicked the effect of the xanthine derivatives. Since pentoxifylline and its structural analogues induced synthesis of PGI2 in endothelial cell cultures, it is suggested that its effect on LPS leukopenia is mediated by endogenous prostacyclin production. All of the xanthine derivatives tested and CG-4203 blocked the leukopenia induced by recombinant tumor necrosis factor, which is a major endogenous mediator for endotoxin toxicity.