Identification of N‐iminoethyl‐ l ‐ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells

Identification of N‐iminoethyl‐ l ‐ornithine as an irreversible inhibitor of nitric oxide... 1 The synthesis of nitric oxide (NO) from l‐arginine by rat peritoneal neutrophils (PMN) and the murine macrophage cell‐line J774 and the inhibition of this synthesis by N‐iminoethyl‐l‐ornithine (l‐NIO), NG‐monomethyl‐l‐arginine (l‐NMMA), NG‐nitro‐l‐arginine (l‐NNA) and its methyl ester (l‐NAME) were investigated. 2 l‐NIO was the most potent inhibitor in both types of cells while l‐NMMA was less active. l‐NNA and l‐NAME had no significant effect in PMN and l‐NNA produced only approximately 40% inhibition of the generation of NO in the J774 cells at the highest concentration tested (300 μm). 3 The inhibitory effect of l‐NIO was rapid in onset, requiring 10 min pre‐incubation to achieve its full inhibitory activity, while the other compounds required 20–60 min pre‐incubation to achieve their full effect. 4 The inhibitory effect of l‐NIO (10 μm) on intact cells could not be reversed by l‐arginine (300 μm) but could be prevented by concomitant incubation with this compound (300 μm), while the effect of the other inhibitors could be reversed by a 3–5 fold molar excess of l‐arginine. 5 The NO synthase from both PMN and J774 cells was cytosolic and NADPH‐ but not Ca2+‐dependent, with Km values for l‐arginine of 3.3 ± 0.8 and 4.2 ± 1.1 μm respectively. 6 l‐NIO was the most potent inhibitor of the neutrophil and J774 enzymes with IC50 values of 0.8 ± 0.1 and 3 ± 0.5 μm respectively. Furthermore, the effect of l‐NIO was irreversible. The other three compounds were less potent, reversible inhibitors. 7 The inhibitory effects of all these compounds were enantiomerically specific. 8 These data indicate that l‐NIO is a novel, potent, rapid in onset and irreversible inhibitor of NO synthase in phagocytic cells. The rapid uptake of l‐NIO compared with the other compounds indicates that phagocytic cells have different uptake mechanisms for l‐arginine analogues. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Identification of N‐iminoethyl‐ l ‐ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells

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Publisher
Wiley
Copyright
1991 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1111/j.1476-5381.1991.tb12159.x
Publisher site
See Article on Publisher Site

Abstract

1 The synthesis of nitric oxide (NO) from l‐arginine by rat peritoneal neutrophils (PMN) and the murine macrophage cell‐line J774 and the inhibition of this synthesis by N‐iminoethyl‐l‐ornithine (l‐NIO), NG‐monomethyl‐l‐arginine (l‐NMMA), NG‐nitro‐l‐arginine (l‐NNA) and its methyl ester (l‐NAME) were investigated. 2 l‐NIO was the most potent inhibitor in both types of cells while l‐NMMA was less active. l‐NNA and l‐NAME had no significant effect in PMN and l‐NNA produced only approximately 40% inhibition of the generation of NO in the J774 cells at the highest concentration tested (300 μm). 3 The inhibitory effect of l‐NIO was rapid in onset, requiring 10 min pre‐incubation to achieve its full inhibitory activity, while the other compounds required 20–60 min pre‐incubation to achieve their full effect. 4 The inhibitory effect of l‐NIO (10 μm) on intact cells could not be reversed by l‐arginine (300 μm) but could be prevented by concomitant incubation with this compound (300 μm), while the effect of the other inhibitors could be reversed by a 3–5 fold molar excess of l‐arginine. 5 The NO synthase from both PMN and J774 cells was cytosolic and NADPH‐ but not Ca2+‐dependent, with Km values for l‐arginine of 3.3 ± 0.8 and 4.2 ± 1.1 μm respectively. 6 l‐NIO was the most potent inhibitor of the neutrophil and J774 enzymes with IC50 values of 0.8 ± 0.1 and 3 ± 0.5 μm respectively. Furthermore, the effect of l‐NIO was irreversible. The other three compounds were less potent, reversible inhibitors. 7 The inhibitory effects of all these compounds were enantiomerically specific. 8 These data indicate that l‐NIO is a novel, potent, rapid in onset and irreversible inhibitor of NO synthase in phagocytic cells. The rapid uptake of l‐NIO compared with the other compounds indicates that phagocytic cells have different uptake mechanisms for l‐arginine analogues.

Journal

British Journal of PharmacologyWiley

Published: Jan 1, 1991

References

  • Characterization of three inhibitors of endothelial nitric oxide synthase in vivo and in vitro
    REES, REES; PALMER, PALMER; SCHULZ, SCHULZ; HODSON, HODSON; MONCADA, MONCADA
  • Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium‐derived relaxing factor and the chemical reactivity of nitric oxide
    STUEHR, STUEHR; GROSS, GROSS; SAKUMA, SAKUMA; LEVI, LEVI; NATHAN, NATHAN

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