L-N-6-(1-IMINOETHYL)-LYSINE POTENTLY INHIBITS INDUCIBLE NITRIC-OXIDE SYNTHASE AND IS SUPERIOR TO N-G-MONOMETHYL-ARGININE IN-VITRO AND IN-VIVO

L-N-6-(1-Iminoethyl)-lysine is a novel inhibitor of nitric oxide (NO) synthase, which similar to aminoguanidine but unlike N-G-monomethyl-L- arginine is 30-fold more selective for the inducible than for the cons titutive isoform of the enzyme. Here, we characterized this inhibitor for the first time in intact cells and during infection of mice with a NO-sensitive parasite (Leishmania major). L-N-6-(1-Iminoethyl)-lysine potently inhibited the activity of inducible NO-synthase in primary m acrophages. After stimulation by interferon-gamma the IC50 of L-N-6-(1 -iminoethyl)-lysine was 0.4 +/- 0.1 mu M and 10- or 30-fold lower than that of N-G-monomethyl-L-arginine or aminoguanidine, respectively. In vivo, L-N-6-(l-imino-ethyl)-lysine (0.4-9 mM in the drinking water) s uppressed inducible NO-synthase activity and caused a dramatic exacerb ation of leishmaniasis, despite a counterregulatory increase of induci ble NO-synthase protein in the tissue. In contrast, considerably highe r concentrations of N-G-monomethyl-L-arginine (20-50 mM) were required in order to achieve comparable effects. N-G-Monomethyl-L-arginine, bu t not L-N-6-(1-imino-ethyl)-lysine led to weight loss, reduced water a nd food consumption. We conclude that L-N-6-(1-iminoethyl)-lysine shou ld be used instead of N-G-monomethyl-L-arginine for potent suppression of inducible NO-synthase in vitro and in vivo.