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Mercaptoethylguanidine and Guanidine Inhibitors of Nitric-oxide Synthase React with Peroxynitrite and Protect against Peroxynitrite-induced Oxidative Damage
Nitric oxide (NO) produced by the inducible nitric-oxide synthase (iNOS) is responsible for some of the pathophysiological alterations during inflammation. Part of NO-related cytotoxicity is mediated by peroxynitrite, an oxidant species produced from NO and superoxide. Aminoguanidine and mercaptoeth...
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Published in: | The Journal of biological chemistry 1997-04, Vol.272 (14), p.9030-9036 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Nitric oxide (NO) produced by the inducible nitric-oxide synthase (iNOS) is responsible for some of the pathophysiological
alterations during inflammation. Part of NO-related cytotoxicity is mediated by peroxynitrite, an oxidant species produced
from NO and superoxide. Aminoguanidine and mercaptoethylguanidine (MEG) are inhibitors of iNOS and have anti-inflammatory
properties. Here we demonstrate that MEG and related compounds are scavengers of peroxynitrite. MEG caused a dose-dependent
inhibition of the peroxynitrite-induced oxidation of cytochrome c 2+ , hydroxylation of benzoate, and nitration of 4-hydroxyphenylacetic acid. MEG reacts with peroxynitrite with a second-order
rate constant of 1900 ± 64 M â1 s â1 at 37°C. In cultured macrophages, MEG reduced the suppression of mitochondrial respiration and DNA single strand breakage
in response to peroxynitrite. MEG also reduced the degree of vascular hyporeactivity in rat thoracic aortic rings exposed
to peroxynitrite. The free thiol plays an important role in the scavenging effect of MEG. Aminoguanidine neither affected
the oxidation of cytochrome c 2+ nor reacted with ground state peroxynitrite, but inhibited the peroxynitrite-induced benzoate hydroxylation and 4-hydroxyphenylacetic
acid nitration, indicating that it reacts with activated peroxynitrous acid or nitrogen dioxide. Compounds that act both as
iNOS inhibitors and peroxynitrite scavengers may be useful anti-inflammatory agents. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.272.14.9030 |