Local anesthetics potentiate nitric oxide synthase type 2 expression in rat glial cells

Expression of the calcium-independent nitric oxide synthase (NOS2) contribu tes to damage in neurologic disease and trauma. The effects of local anesth etics on NOS2 expression have not been examined. The authors tested the eff ects of four local anesthetics on the expression of NOS2 in immunostimulate d rat C6 glioma cells. Incubation with local anesthetics alone did not indu ce nitrite accumulation: however, the nitrite production induced by stimula tion with bacterial endotoxin lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was increased in a dose-dependent manner by bupivacaine (maxim al 3-fold at 360 muM). tetracaine (maximal 7-fold at 360 muM), and lidocain e at higher doses (5-fold increase at 3.3 mM). Significant increases in nit rite production were observed in concentrations of bupivacaine or tetracain e as low as 120 muM, which correspond to 30 mug/mL (.003% weight/volume). I n contrast, ropivacaine had little effect on nitrite production (160% of co ntrol values) and only at the highest concentration (3.3 mM, corresponding to 890 mug/mL or 0.089% w/v) tested. Increased nitrite production was not c aused by cytotoxic effects of the drugs used, as assessed by release of int racellular lactate dehydrogenase. Increased nitrite production was accompan ied by increased NOS2 catalytic activity, steady state mRNA levels, and pro moter activation. These results demonstrate that submillimolar doses of two commonly used local anesthetics can increase glial NOS2 expression.