Detrimental effect of nitric oxide synthase inhibition during endotoxemia may be caused by high levels of tumor necrosis factor and interleukin-6

Background. Nitric oxide (NO) production increases during sepsis and endotoxemia. Inhibition of NO synthase has been suggested as a therapeutic modality in sepsis and endotoxemia, but in recent reports NO synthase inhibition increased mortality rate. The mechanism of this phenomenon is not known. Other studies have shown that high levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) contribute to death during sepsis and endotoxemia. We tested the effect of NO synthase inhibition on survival in endotoxemic rats and hypothesized that inhibition of NO synthase during endotoxemia increases circulating levels of TNF and IL-6. Methods. Rats were treated with subcutaneous injection of saline solution or 100 mg/kg of the NO synthase inhibitor N-nitro-L-arginine 1 hour before intravenous injection of endotoxin (15 mg/kg) or saline solution. Survival was followed for 24 hours. Plasma nitrite-nitrate (NO₂/NO₃), TNF, and IL-6 levels were determined at intervals. Results. Endotoxin caused a significant increase in levels of plasma NO₂/^-/NO₃/^-, TNF, and IL-6 and a 33% mortality rate. Pretreatment with N-nitro-L-arginine increased mortality rate to 74%, decreased NO₂/NO₃, and substantially increased TNF and IL-6 levels. Conclusions. Inhibition of NO synthase increases mortality rate during endotoxemia. The detrimental effect of NO synthase inhibition during endotoxemia may be caused by excessive production of TNF and IL-6.