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 the effect of anesthetics on their production. Therefore, the authors examined the effect of ketamine on lipopolysaccharide (LPS)-induced and calcium ionophore A23187-induced tumor necrosis factor alpha (TNF-alpha) production in thioglycolate (TGC)-elicited peritoneal macrophages (MPs) in ddY mice. Methods: Ketamine was added to TGC-elicited MPs at various times after the stimulation with LPS or A23187. After the MPs were 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 days later, they were injected subcutaneously with ketamine and then injected intravenously with LPS. Two bouts after the LPS challenge, TNF-alpha activities of the sera were determined. Results: Ketamine suppressed both LPS-induced and A23187-induced TNF-alpha production in a dose-dependent manner. The simultaneous addition of ketamine to LPS-stimulated and A23187-stimulated MPs resulted in a 50% inhibition of TNF-alpha production at 20 mu g/ml and 12.5 mu g/ml, respectively. Ketamine also 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-containing medium. Conversely, LPS-induced TNF-alpha production did not cause 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.