INHIBITION OF NITRIC-OXIDE SYNTHASE ATTENUATES LIPOPOLYSACCHARIDE-INDUCED FEVER WITHOUT REDUCTION OF CIRCULATING CYTOKINES IN GUINEA-PIGS

It was recently demonstrated that the diffusible messenger molecule ni tric oxide (NO) is involved in the febrile response of rats and rabbit s to exogenous or endogenous pyrogens. In this study we have investiga ted the effects of systemic administration of the NO-synthase inhibito r N-nitro-L-arginine-methylester (L-NAME) on abdominal temperature and on lipopolysaccharide(LPS-) induced fever in guinea-pigs. We further studied the effects of L-NAME on the LPS-induced circulating cytokine network by measurement of tumor necrosis factor alpha (TNF) and interl eukin-6 (IL-6) in blood plasma during the time course of fever. At a d ose of 10 mg/kg, intra-arterial injection of L-NAME per se had no infl uence on the abdominal temperature of guinea-pigs, while administratio n of 50 mg/kg L-NAME evoked a pronounced fall of body temperature whic h lasted about 12 h. When injected simultaneously with 10 mu g/kg LPS into the arterial circulation, the lower dose of L-NAME that did not d ecrease abdominal temperature per se caused a significant attenuation of LPS-induced fever due to suppression of the second phase of the bip hasic febrile response. The LPS-induced cytokine network remained unim paired by the treatment with L-NAME. Peak activity of TNF in plasma (m easured 60 min after LPS injection) was 20,596+/-2368 pg/ml in control animals and 18,900+/-4778 pg/ml in guinea-pigs treated with L-NAME. I n addition, circulating levels of IL-6 were not statistically differen t between both groups of animals 60 min or 180 min after administratio n of LPS along with L-NAME or vehicle. The results confirm that endoge nous NO formation has a role in the generation of LPS-induced fever an d demonstrate that the attenuation of fever by inhibition of NO-syntha se is independent of the circulating LPS-induced cytokine network.