KETAMINE SUPPRESSES ENDOTOXIN-INDUCED TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION IN MICE

Background: The cytokines play important roles in the pathophysiologic alterations associated with sepsis, but there are no reports about th e effect of anesthetics on their production. Therefore, the authors ex amined the effect of ketamine on lipopolysaccharide (LPS)-induced and calcium ionophore A23187-induced tumor necrosis factor alpha (TNF-alph a) production in thioglycolate (TGC)-elicited peritoneal macrophages ( MPs) in ddY mice. Methods: Ketamine was added to TGC-elicited MPs at v arious times after the stimulation with LPS or A23187. After the MPs w ere stimulated by LPS or A23187 and incubated, TNF-alpha activities in the supernatant of MPs were determined by an L929 cytotoxic assay. In vivo, the ddY mice were injected intraperitoneally with TGC. Four day s later, they were injected subcutaneously with ketamine and then inje cted intravenously with LPS. Two bouts after the LPS challenge, TNF-al pha activities of the sera were determined. Results: Ketamine suppress ed both LPS-induced and A23187-induced TNF-alpha production in a dose- dependent manner. The simultaneous addition of ketamine to LPS-stimula ted and A23187-stimulated MPs resulted in a 50% inhibition of TNF-alph a production at 20 mu g/ml and 12.5 mu g/ml, respectively. Ketamine al so caused a significant suppression of TNF-alpha production even when added to the MPs 2 h after the LPS challenge. There was a significant decrease in A23187-induced TNF-alpha production in TGC-elicited MPs in a calcium-depleted medium when compared with that in a calcium-contai ning medium. Conversely, LPS-induced TNF-alpha production did not caus e such a result. in addition, ketamine could suppress LPS-induced TNF- alpha production in TGC-pretreated mice in vivo. Conclusions: Ketamine suppresses LPS-induced TNF-alpha production in both TGC-elicited MPs and TGC-pretreated mice.