L-N6-(1-iminoethyl)-lysine potently inhibits inducible nitric oxide synthase and is superior to NG-monomethyl-arginine in vitro and in vivo.
L-N6-(1-iminoethyl)-lysine is a novel inhibitor of nitric oxide (NO) synthase, which similar to aminoguanidine but unlike NG-monomethyl-L-arginine is 30-fold more selective for the inducible than for the constitutive 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-N6-(1-iminoethyl)-lysine potently inhibited the activity of inducible NO-synthase in primary macrophages. After stimulation by interferon-gamma the IC50 of L-N6-(1-iminoethyl)-lysine was 0.4 +/- 0.1 mu M and 10- or 30-fold lower than that of NG-monomethyl-L-arginine or aminoguanidine, respectively. In vivo, L-N6-(1-iminoethyl)-lysine (0.4-9 mM in the drinking water) suppressed inducible NO-synthase activity and caused a dramatic exacerbation of leishmaniasis, despite a counterregulatory increase of inducible NO-synthase protein in the tissue. In contrast, considerably higher concentrations of NG-monomethyl-L-arginine (20-50 mM) were required in order to achieve comparable effects. NG-monomethyl-L-arginine, but not L-N6-(1-imino-ethyl)-lysine led to weight loss, reduced water and food consumption. We conclude that L-N6-(1-iminoethyl)-lysine should be used instead of NG-monomethyl-L-arginine for potent suppression of inducible NO-synthase in vitro and in vivo.
Stenger
S
S
Institute of Clinical Microbiology and Immunology, University of Erlangen, Germany.
Thuring
H
H
Rollinghoff
M
M
Manning
P
P
Bogdan
C
C
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007896:Leishmaniasis / Q000188:drug therapy / Q000201:enzymology; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019323:omega-N-Methylarginine
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D008239:Lysine