Phorbol esters induce nitric oxide synthase and increase arginine influx in cultured peritoneal macrophages

Incubation of peritoneal macrophages with beta-phorbol 12,13-dibutyrate promotes a time-dependent release of NO to the incubation medium. This effect was antagonized by LPS, a well known inducer of nitric oxide synthase (NOS) expression in macrophages, and was inhibited by NG-methyl-L-arginine and N omega-nitro-L-arginine. An increase in intracellular cGMP and NOS activity was observed in parallel with NO release. The induction of NOS was accompanied by a stimulation of arginine influx within the cell. These results suggest that activation of protein kinase C by phorbol esters is sufficient to promote NOS induction in macrophages.