In vitro and in vivo TNF alpha synthesis modulation by methylguanidine, anuremic catabolyte

This study was performed in order to examine whether the uraemic toxin, met hylguanidine (MG), can modulate tumor necrosis factor alpha (TNF alpha) rel ease by activated macrophages. In this study we have evaluated the ability of MG to influence TNFa release in vitro, in Escherichia coli lypopolysacch aride- (LPS)-stimulated J774 cells preincubated overnight with MG, and in v ivo in rats treated with MG before and after LPS challenge. Parallel experi ments employing N-G-nitro-L-arginine methyl esther (L-NAME) were also carri ed out for comparison. The effect of LPS (6 x 10(3) u/ml) on TNF alpha rele ase by J774, following overnight incubation with MG or L-NAME (1 mM), was e xamined 3 hours after LPS challenge. LPS-stimulated J774 released 287.83 +/ - 88 u/ml TNF alpha. into the culture medium. MG(I mM) significantly inhibi ted TNF alpha release by 73 % (P<0.05). L-NAME (1 mM) significantly inhibit ed TNF alpha release too by 72.88 % (P<0.05). The effect of MG and L-NAME h ave been also studied in vivo. Serum TNFa levels in LPS treated rats 2 h af ter LPS challenge were 88.33+/-31.7 u/ml as compared to the serum TNF alpha levels of control rats (undetectable). Treatment of rats with MG (30 mg/kg , i.p.) strongly and significantly reduced TNF alpha release (98.71 % inhib ition; with P<0.001); in the same experimental setting L-NAME (10 mg/kg, i. p.) also significantly reduced TNF alpha serum levels (76.47 % inhibition; with P<0.01). These results could indicate that immunodisfunction related t o uremia may be related to the inhibitory capability of uremic catabolyte, MG, on TNF alpha synthesis and release. (C) 1999 Elsevier Science Inc.