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(Received for publication, September 30, 1996, and in revised form, January 9, 1997)
From the 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
c2+, hydroxylation of benzoate, and nitration
of 4-hydroxyphenylacetic acid. MEG reacts with peroxynitrite with a
second-order rate constant of 1900 ± 64 M
Volume 272, Number 14,
Issue of April 4, 1997
pp. 9030-9036
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
,
and
Division of Critical Care, Children's
Hospital Medical Center, Cincinnati, Ohio 45229 and the
¶ Department of Biochemistry, Facultad de Medicina, Universidad de
la Republica, 11800 Montevideo, Uruguay
1 s1 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 c2+ 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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