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 e ndotoxemia. Inhibition of NO Synthase has been suggested as a therapeu tic modality in sepsis and endotoxemia, but in recent reports NO synth ase inhibition increased mortality rate. The mechanism of this phenome non is not known. Other studies have shown that high levels of tumor n ecrosis factor (TNF) and interleukin-6 (IL-6) contribute to death duri ng sepsis and endotoxemia. We tested the effect of NO synthase inhibit ion on survival in endotoxemic rats and hypothesized that inhibition o f NO synthase during endotoxemia increases circulating levels of TNF a nd IL-6. Methods. Rats were treated with subcutaneous injection of sal ine solution or 100 mg/kg of the NO synthase inhibitor N-nitro-L-argin ine 1 hour before intravenous injection of endotoxin (15 mg/kg) or sal ine solution. Survival was followed for 24 hours. Plasma nitrite-nitra te (NO2/NO3), TNF, and IL-6 levels were determined at intervals. Resul ts. Endotoxin caused a significant increase in levels of plasma NO2-/N O3-, TNF, and IL-6 and a 33% mortality rate. Pretreatment with N-nitro -L-arginine increased mortality rate to 74%, decreased NO2/NO3, and su bstantially increased TNF and IL-6 levels. Conclusions. Inhibition of NO synthase increases mortality rate during endotoxemia. The detriment al effect of NO synthase inhibition during endotoxemia may be caused b y excessive production of TNF and IL-6.