ENHANCING EFFECT OF STAUROSPORINE ON NO PRODUCTION IN RAT PERITONEAL-MACROPHAGES VIA A PROTEIN-KINASE C-INDEPENDENT MECHANISM

Staurosporine (3-100 nM), frequently used as a protein kinase C (PKC) inhibitor, increased accumulation of nitrite in the culture medium of rat peritoneal macrophages up to 6 times above the control level. More over, when used in combination with the stable analogue of cyclic AMP, dibutyryl-cyclic AMP (db cyclic AMP; 0.1 mM), and/or a cytokine, tumo ur necrosis factor-alpha (TNF alpha; 100 u ml(-1)), staurosporine syne rgistically potentiated, up to 30 times, nitrite accumulation. On the other hand, the other PKC inhibitors, calphostin C and H-7 (10 nM-10 m u M) were not effective under the same conditions. The staurosporine-i nduced nitrite accumulation, in both the presence and the absence of T NF alpha and/or db cyclic AMP was effectively inhibited by the protein synthesis inhibitor, cycloheximide, or by the nitric oxide (NO) synth esis inhibitor, N-G-monomethyl-L-arginine (L-NMMA). Thus our data sugg est that staurosporine may enhance NO production in macrophages via in tracellular mechanisms unrelated to the PKC inhibition.