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1 Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport, Louisiana 71130; and 2 Radiation Biology Branch, National Cancer Institute, Bethesda, Maryland 20892
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ABSTRACT |
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 Top
 Abstract
 Introduction
Physiological chemistry of no
Direct effects
Indirect effects
Conclusions
References
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The role of nitric oxide (NO) in inflammation represents one of the most studied yet controversial subjects in physiology. A number of reports have demonstrated that NO possesses potent anti-inflammatory properties, whereas an equally impressive number of studies suggest that NO may promote inflammation-induced cell and tissue dysfunction. The reasons for these apparent paradoxical observations are not entirely clear; however, we propose that understanding the physiological chemistry of NO and its metabolites will provide a blueprint by which one may distinguish the regulatory/anti-inflammatory properties of NO from its deleterious/proinflammatory effects. The physiological chemistry of NO is complex and encompasses numerous potential reactions. In an attempt to simplify the understanding of this chemistry, the physiological aspects of NO chemistry may be categorized into direct and indirect effects. This type of classification allows for consideration of timing, location, and rate of production of NO and the relevant targets likely to be affected. Direct effects are those reactions in which NO interacts directly with a biological molecule or target and are thought to occur under normal physiological conditions when the rates of NO production are low. Generally, these types of reactions may serve regulatory and/or anti-inflammatory functions. Indirect effects, on the other hand, are those reactions mediated by NO-derived intermediates such as reactive nitrogen oxide species derived from the reaction of NO with oxygen or superoxide and are produced when fluxes of NO are enhanced. We postulate that these types of reactions may predominate during times of active inflammation. Consideration of the physiological chemistry of NO and its metabolites will hopefully allow one to identify which of the many NO-dependent reactions are important in modulating the inflammatory response and may help in the design of new therapeutic strategies for the treatment of inflammatory tissue injury.
arthritis; colitis; leukocytes; free radicals; superoxide; cancer
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INTRODUCTION |
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Top
Abstract
Introduction
Physiological chemistry of no
Direct effects
Indirect effects
Conclusions
References
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THE LANDMARK DISCOVERY THAT nitric oxide (NO; nitrogen monoxide) is synthesized by mammalian cells initiated a tremendous number of studies over the past 10 years, demonstrating that this diatomic free radical plays crucial roles in the homeostatic regulation of the cardiovascular, neuronal, and immune systems (7, 14). Despite these important physiological functions, this oxidized metabolite of nitrogen is also a well-known toxic agent, being a constituent of air pollution and cigarette smoke. In addition to being an environmental toxin, endogenously formed NO is thought to promote a number of chronic inflammatory diseases such as arthritis, hepatitis, inflammatory bowel disease, septic and hemorrhagic shock, and certain autoimmune disorders (5, 6, 12, 15, 17). It is known, for example, that, in the presence of molecular oxygen (O2), NO can form reactive nitrogen oxide species that can damage DNA, inhibit a variety of enzymes, and initiate lipid peroxidation (27). The question then becomes: How can this molecule be so unstable in an aerobic environment, generating toxic intermediates, yet play such important roles in normal physiology?
The answer to this apparent paradox lies in understanding the
physiological chemistry of NO, which may be defined as the fundamental chemistry involved in specific biological processes. Consideration of
these chemical reactions provides a blueprint by which one may
distinguish the regulatory processes and/or anti-inflammatory effects of NO from its potential toxic and/or proinflammatory properties (Fig. 1). This brief overview
will discuss the basic physiological chemistry of NO and its
metabolites, with particular attention given to those interactions that
may modulate the inflammatory process.
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PHYSIOLOGICAL CHEMISTRY OF NO |
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Top
Abstract
Introduction
Physiological chemistry of no
Direct effects
Indirect effects
Conclusions
References
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The physiological chemistry of NO is a complex process encompassing
numerous potential reactions. However, the chemistry is, in fact, the
most important determinant for dictating which type of effect NO has on
biological systems. One may begin to decipher this chemistry by
understanding how different concentrations or different rates of
production of NO may influence certain reactions in a particular
chemical event. To help guide us through this maze of reactions, it is
convenient to separate NO chemistry into direct and
indirect effects (27) (Fig.
2). Direct effects are those reactions in
which NO interacts directly with a biological molecule or target,
whereas indirect effects are those reactions mediated by NO-derived
intermediates such as reactive nitrogen oxide species derived from the
reaction of NO with O2 or
superoxide (O
2). The
advantage of categorizing NO chemistry into these two types of
reactions is that the chemical reactions can be separated on the basis
of relative rates (i.e., fluxes) of NO production. For example, direct
effects may occur at lower concentrations or fluxes of NO, whereas
higher NO fluxes result in indirect effects. Cells containing
constitutive isoforms of nitric oxide synthase (NOS; i.e., endothelial
cell or neuronal NOS) generate relatively small fluxes of NO and thus
one would predict that direct effects of NO will predominate. Indeed,
under normal physiological conditions, cells produce small but
significant amounts of NO and only trace amounts of reactive oxygen
species dictating that direct NO chemistry will predominate in normal tissue. However, in tissues where the high-output, inducible isoform of
NOS (iNOS) has been upregulated, as in the case of chronic inflammation, indirect effects such as nitrosation, nitration, and
oxidation will prevail (Fig. 2). Therefore, understanding the timing,
location, and rates of NO production provides a guideline to the type
of chemistry and relevant targets most likely to be affected.
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DIRECT EFFECTS |
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Abstract
Introduction
Physiological chemistry of no
Direct effects
Indirect effects
Conclusions
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The direct interaction of NO with metal-containing proteins or with organic free radicals represents two of the best characterized direct effects of NO in biological systems.
Metal nitrosyl complexes. The reaction of NO with certain metals to form nitrosyl complexes occurs in vivo primarily with iron-containing proteins (26). The most facile reaction of NO to form stable nitrosyl adducts is with proteins that contain a heme moiety. The most notable of these is the reaction of NO and guanylate cyclase, which stimulates the formation of cGMP from GTP (7, 14). Synthesis of cGMP has several regulatory/anti-inflammatory effects such as regulation of vascular tone, inhibition of platelet aggregation, and leukocyte-endothelial cell interactions. Yet, this same type of chemistry can also inhibit other metalloproteins such as cytochrome P-450, NOS, cytochrome oxidase, and catalase (26).
In addition, it has been shown that small amounts of NO stimulate the production of prostaglandins (22). It is thought that O2 inhibits cyclooxygenase (COX) and
possibly other enzymes involved in prostaglandin synthesis by reducing the heme iron to its inactive ferrous
(Fe2+) state. The presence of
small amounts of NO would prevent this reduction of the heme iron by
interacting with and scavenging O2.
This would maintain the COX-associated heme iron in the ferric
(Fe3+) form, resulting in the
formation of potentially protective/anti-inflammatory prostaglandins.
It should be noted, however, that the sustained overproduction of
iNOS-derived NO will actually inhibit COX activity, which may, in and
of itself, promote rather than inhibit inflammation.
NO, metal complexes, and oxidative stress. It is becoming increasingly apparent that iron or hemoprotein-catalyzed oxidative reactions may mediate some of the pathophysiology associated with acute and chronic inflammation (5, 8, 27). This oxidative stress may enhance endothelial cell or leukocyte adhesion molecule expression, injure cells, induce apoptosis, damage DNA, promote inflammatory mediator synthesis, and regulate gene expression (4, 5, 27).
Several studies suggest that NO may modulate iron-catalyzed oxidation reactions such as the O2-driven Fenton reaction, which produces powerful oxidants such as the hydroxyl radical
(OH ·) and metalloxo complexes
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2-driven Fenton reaction in vitro. For example, generation of
O2 and H2O2
in the presence of small amounts of a redox-active
Fe3+ chelate produces substantial
amounts of the OH ·, as measured by the hydroxylation of
benzoic acid. Addition of varying fluxes of NO to this system
dramatically inhibited hydroxylation of benzoic acid such that
equimolar fluxes of NO inhibited the
O2- and
H2O2-dependent
hydroxylation of benzoic acid by ~80% (13). These data demonstrate
that, depending on the fluxes of the different reactive species, NO may
have remarkable antioxidant capabilities.
Another modulatory and possibly more physiologically relevant reaction
mediated by NO is its interaction with higher oxidation states of
hemoproteins such as hemoglobin, myoglobin, and certain cytochromes.
The reaction of the ferric forms of these pentacoordinate hemoproteins
(HP
Fe3+) with
H2O2
results in the formation of the ferryl pi cation radical species
(+·HPFe4+==O),
a potent and relatively stable oxidizing agent (8)
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Fe4+==O
to its original HPFe3+ oxidation
state
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NO and free radicals.
In addition to metal-nitrosyl formation, NO may react directly with
high-energy free radicals such as carbon-, oxygen-, and nitrogen-centered radicals. Because NO has an unpaired electron, it
will rapidly react with alkoxyl (RO ·) and alkyl hydroperoxyl (ROO ·) radicals at near diffusion-limited reaction rates
(k = 2 × 109
M1 · s1)
(16). These types of reactions may be critical in modulating metal or
enzyme-catalyzed lipid peroxidation (21). Peroxidation of
polyunsaturated lipids is thought to be an important pathophysiological event involved in the development of tissue injury and dysfunction in a
number of different inflammatory conditions. Recent studies demonstrate
that NO inhibits lipid peroxidation and thus may be important in
modulating the inflammatory response by inhibiting the formation of
proinflammatory lipids (21).
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INDIRECT EFFECTS |
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Abstract
Introduction
Physiological chemistry of no
Direct effects
Indirect effects
Conclusions
References
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In contrast to the direct effects of NO, the indirect effects of NO are
mediated by reactive nitrogen oxide species derived from the
interactions of NO with O2 or
O2 (Fig. 2). Indeed, reactive nitrogen
oxide species have been suggested as important mediators of the
pathophysiology associated with a variety of different models of
inflammation (5, 6, 15, 17, 27). The most prevalent reactive nitrogen
oxide species produced in vivo are dinitrogen trioxide
(N2O3)
and peroxynitrite (ONOO),
both of which can induce two types of chemical stresses: nitrosative and oxidative (27). Although oxidation and nitrosation may occur under
normal physiological conditions, these types of chemical stresses are
generally thought to be associated with certain pathophysiological situations (e.g., inflammation), where iNOS has been upregulated (27).
Nitrosative and oxidative stresses provide different chemical signatures in biological systems with effects that are essentially orthogonal to each other. These reactive nitrogen oxide
species-mediated reactions provide a balance in biological systems and
are the key to understanding the role of the indirect effects in
biological systems.
NO-O2 interactions. NO can react with O2 to yield reactive intermediates, which in turn may mediate additional nitrosative and/or oxidative reactions. The formation of these intermediates has been well studied in atmospheric chemistry due to their association with the deleterious effects of air pollution. It is well appreciated that the autoxidation of NO in an aqueous environment leads to the formation of reactive nitrogen oxide species such as N2O3, which is a potent nitrosating agent (25-27). However, due to the rapid reaction of NO with other biological substrates such as hemoproteins, this reaction has been suggested to occur too slowly to be of any consequence in vivo. Recent studies have shown, however, that hydrophobic environments, such as those found in the cellular membrane, can accelerate this reaction over 1,000 times (11). Subsequent studies by this same group have shown that the rate at which NO is scavenged by erythrocytes is approximately three orders of magnitude slower than the rate of the reaction between NO and purified oxyhemoglobin, suggesting that nitrosation reactions mediated by N2O3 may in fact play important roles in vivo. This nitrosating agent has been shown to N- and S-nitrosate a variety of biological targets to yield potentially carcinogenic nitrosamines and nitrosothiol (RSNO) derivatives (25, 27). N2O3 is primarily responsible for mediating nitrosative stress in vivo.
The chemistry of N2O3 has been actively investigated for a number of years. This intermediate can nitrosate as well as oxidize different substrates (25, 27). Nitrosation of amines to yield nitrosamines most probably takes place only through the interaction of N2O3 with amino compounds, thus providing the best indicator of nitrosative stress in the living organism. Indeed, a number of studies have shown that N-nitrosation does occur in vivo and may have important implications in the known association between chronic inflammation and malignant transformation (25, 27). S-nitrosothiol adducts (RSNO) are also readily formed during the autoxidation of NO via the interaction between N2O3 and certain thiols (26, 27). These complexes have been suggested to play an important role in NO transport, signal transduction pathways, and regulation of gene expression (23). Ignarro and co-workers showed that these adducts could stimulate the conversion of GTP to cGMP in guanylate cyclase and suggested that they are key intermediates in the action of various nitrovasodilating compounds such as sodium nitroprusside and nitroglycerin (reviewed in Ref. 7). In fact, it is thought that endothelium-derived relaxing factor may be an RSNO adduct. S-nitroso-albumin is thought to be the most abundant nitrosothiol in human plasma, with concentrations reported to be as high as 5 µM (23). Because many of the high- and low-molecular-weight RSNOs release NO either spontaneously or via metabolism, they are capable of mediating many of the biological functions of NO. In addition, Stamler and co-workers (24) have proposed that a specific cysteine residue located in the
-subunits of hemoglobin is
S-nitrosated in the lung, with the NO
group being subsequently released during the arterial-venous transit of
red blood cells. They propose that this type of reaction may enhance
blood flow during tissue oxygenation (24). The exact mechanism(s) by
which hemoglobin is S-nitrosated in
vivo and how S-nitrosohemoglobin may
affect smooth muscle relaxation are unclear at the present time.
The formation of RSNO may also play an important role in leukocyte
adhesion to the microvascular endothelium. For example, RSNOs are known
to inhibit leukocyte adhesion to microvascular endothelial cells in
vivo, presumably via the release of NO. However, it is also known that
SH groups are essential for normal leukocyte-endothelial cell
adhesion (5). S-nitrosation of these
critical SH groups on the surface of endothelial cells and/or
polymorphonuclear neutrophils (PMNs) could decrease adhesion, thereby
limiting leukocyte infiltration. Furthermore, the formation of
endogenous antiadhesive RSNOs by NO-derived nitrosating agents may be
inhibited by O2, suggesting that
during inflammation enhanced O2 production may promote PMN-endothelial cell adhesion (26). Indeed, it
is well established that exogenous NO donors are very effective at
inhibiting PMN adhesion in vivo (4, 5). In addition, because reduced
glutathione (GSH) has such an unusually high affinity for
N2O3,
it is likely to play a critical role in inhibiting the toxicity of NO
produced during times of enhanced NO production (27). Depletion of GSH
by buthionine sulfoximine (BSO) renders cells considerably
more susceptible to NO-mediated toxicity (27). Formation of RSNOs may,
on the other hand, promote or perpetuate chronic inflammation. Lander
and colleagues (10) have demonstrated that
S-nitrosation of one specific cysteine
residue on the p21 Ras protein in lymphocytes is critical for guanine
nucleotide exchange and downstream signaling resulting in the formation
of proinflammatory cytokines such as tumor necrosis factor.
NO-O2 interactions.
Much of the vascular and tissue injury observed in different models of
inflammation have been shown to be inhibited by either SOD or NOS
inhibitors, suggesting that both O2 and NO are important mediators of tissue injury and organ dysfunction (4-6, 15). Because neither O2 nor
NO is a particularly potent oxidant or cytotoxin, it has been suggested that O2 and NO may rapidly interact to
produce the potent cytotoxic oxidants
ONOO and its conjugate acid
ONOOH (1). Indeed, this hypothesis has generated an astonishing amount
of interest because it has provided a biochemical rationale to account
for the remarkable yet perplexing protective effects of intravenous
administration of L-arginine
analogs (NO synthase inhibitors) or SOD in models of inflammatory
tissue injury. Numerous studies have been published describing the
physicochemical and cytotoxic properties of preformed, chemically
synthesized ONOO (1, 20).
Peroxynitrite in neutral solution is a powerful oxidant, oxidizing
thiols or thioethers, nitrating tyrosine residues, nitrating and
oxidizing guanosine, degrading carboydrates, initiating lipid
peroxidation, and cleaving DNA. It is thought that the oxidant primarily responsible for these oxidative reactions is an
electronically excited isomer of ONOOH that has both OH ·-
and NO2-like properties (1, 20).
Peroxynitrite exists in equilibrium with ONOOH, and in the absence of
substrate this protonated form decomposes to yield nitrate
(NO3) via the
intermediate formation of the excited isomer (ONOOH*)
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2 without the concomitant formation
of
H2O2 (4, 27). Only relatively recently have investigators attempted to
quantitatively characterize the interaction between
O2 and NO under physiological
conditions. We, as well as others, have attempted to systemically
quantify the interaction between NO and
O2 and have made some rather
surprising observations (13, 19, 21).
It has been demonstrated, for example, that simultaneous generation of
equivalent amounts of O2 and NO
synergize to yield a potent oxidant (presumably
ONOO). We found that,
when the flux of one radical exceeded the other, oxidant production was
significantly reduced (13). We speculate that the decreased production
of ONOO/ONOOH in the
presence of either excess NO or O2 may
be due to secondary chemical interactions occurring between NO or
O2 and
ONOO/ONOOH. Although the
interaction between NO or O2 and
ONOO is thermodynamically
possible, recent work by Pfeiffer et al. (18) suggests that the rate
constant for the interaction between NO and
ONOO may be too slow to
compete with the spontaneous decomposition of
ONOO. It may be that NO
reacts with and decomposes a specific isomer of HOONO, thereby
effectively reducing steady-state concentrations of this potent oxidant
(Wink and Grisham, unpublished observations).
The reaction rate constant for the interaction between
O2 and NO (6 × 109
M1 · s1)
has been used to suggest that
ONOO/ONOOH may be formed in
vivo. One of the most important considerations for whether a chemical
reaction occurs in vivo is the relative pseudo first-order rate
constant and not just the rate constant itself. The extent of
participation of a particular reaction is determined by the
concentrations of the reactants as well as by the rate constant (27).
The cellular concentrations of O2 and
NO under normal conditions have been estimated to be 0.1-1 nM and
0.1-1 µM, respectively (27). This suggests that the production of O2 determines the location of the
reaction between these radicals as well as the amount of
ONOO formed. The
concentration and diffusion coefficient of NO determine whether the
reaction occurs at any specific location. To illustrate this concept,
it is useful to consider a model with two point sources of NO and
O2 (Fig.
3). Simultaneous production of
O2 and NO by these two point sources would produce maximal nitrosative stress (i.e.,
NO-O2 interactions) near the
source of NO. As NO diffuses away from its source, its concentration
dilutes proportionally to distance, thereby enhancing the direct
effects of NO as it diffuses from its source. As NO approaches the
source of O2, it reacts to form ONOO. However, as
ONOO diffuses into areas of
O2 or NO excess, it decomposes,
thereby limiting ONOO
production (and its oxidative stress) to sites close to the
O2 source (Fig. 3).
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2 and NO may act to control the
steady-state concentration of
ONOO in vivo. Situations
and cell types that could produce the optimal amounts of
O2 and NO to generate
ONOO would be macrophages
and possibly endothelial cells. Neutrophils on the other hand when
fully activated would produce 100-1,000 times more
O2 than NO, suggesting that PMNs would
produce little or no
ONOO/ONOOH and indeed this
is exactly what we observe (Grisham and Jourd'heuil, unpublished
data). The occurrence of this reaction also depends on the competing
reaction of O2 with SOD. For example,
SOD reacts with O2 at a similar rate
constant to that of the reactions of
O2 with NO, thereby representing the
most important competing reaction to consider. For 10% of the
O2 formed to be converted to
ONOO, the concentration of
NO would have to be 0.4-5 µM. The intracellular concentration of
SOD is thought to be between 4 and 10 µM, whereas the mitochondrial
SOD is probably as high as 20 µM in the organelle in which most of
the O2 is produced. Therefore, the
reaction of O2 with NO, despite the
high rate constant, is probably confined to specific sites, i.e.,
site-specific generation in much the same way as OH ·.
In addition to oxidation reactions,
ONOO has been demonstrated
in vitro to nitrate certain phenolic compounds such as tyrosine to
yield primarily 3-nitrotyrosine (3-NT). Indeed, nitration of certain
tyrosine residues may exert dramatic physiological effects by altering
kinase reactions and subsequent signaling pathways. Some investigators
have also suggested that the presence of 3-NT in tissues obtained from
inflamed tissues is evidence for the formation of
ONOO formation in vivo. Two
recent studies suggest that this may not be necessarily the case.
Eiserich et al. (2) have recently reported that 3-NT may be formed by
activated human PMNs via the myeloperoxidase-catalyzed
H2O2-dependent
oxidation of NO2 and tyrosine without
the intermediate formation of
ONOO. These data would
suggest that 3-NT may not necessarily reflect the formation of
ONOO but may more likely
indicate the production of NO-derived
NO2. A second study by Pfeiffer and
Mayer (19) demonstrated that, when NO and
O2 are generated at equal rates, little or no significant nitrosation of tyrosine occurs. Indeed, they demonstrated that nitration was most efficient with an NO donor
alone, and, when O2 fluxes exceeded
those of NO, 3-NT formation was undetectable. These investigators
concluded that 3-NT formation may not necessarily arise from
ONOO formation in vivo.
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CONCLUSIONS |
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Top
Abstract
Introduction
Physiological chemistry of no
Direct effects
Indirect effects
Conclusions
References
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NO has numerous potential reactions that may greatly influence a variety of physiological and pathophysiological processes. Consideration of the timing, location, and rates of production of NO and reactive nitrogen oxide species may help identify which of the many NO-dependent reactions are important in modulating the inflammatory response. A basic understanding of the physiological chemistry of NO may also help in the design of new therapeutic strategies for the treatment of inflammatory tissue injury.
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ACKNOWLEDGEMENTS |
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We wish to thank F. Stephen Laroux for his helpful discussions and preparation of the figures.
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FOOTNOTES |
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* First in a series of invited articles on Nitric Oxide.
Some of this work was supported by a grant from National Institute of Diabetes and Digestive and Kidney Diseases (DK-43785), the Crohn's and Colitis Foundation of America, and the Arthritis Center of Excellence at LSU Medical Center in Shreveport.
Address for reprint requests: M. B. Grisham, Dept. of Molecular and Cellular Physiology, LSU Medical Center, PO Box 33932, Shreveport, LA 71130-3932.
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REFERENCES |
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Top
Abstract
Introduction
Physiological chemistry of no
Direct effects
Indirect effects
Conclusions
References
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1.
Beckman, J. S.,
and
W. H. Koppenol.
Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.
Am. J. Physiol.
271 (Cell Physiol. 40):
C1424-C1437,
1996
2.
Eiserich, J. P.,
M. Hristova,
C. E. Cross,
A. D. Jones,
B. A. Freeman,
B. Halliwell,
and
A. van der Vliet.
Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils.
Nature
391:
393-397,
1998[Medline].
3.
Gow, A. J.,
and
J. S. Stamler.
Reactions between nitric oxide and haemoglobin under physiological conditions.
Nature
391:
169-173,
1998[Medline].
4.
Granger, D. N.,
and
P. Kubes.
Nitric oxide as anti-inflammatory agent.
Methods Enzymol.
369:
434-442,
1996.
5.
Grisham, M. B.,
D. N. Granger,
D. Neil,
and
D. J. Lefer.
Modulation of leukocyte-endothelial interactions by reactive metabolites of oxygen and nitrogen: relevance to ischemic heart disease.
Free Radic. Biol. Med.
25:
404-433,
1998[Medline].
6.
Hierholzer, C.,
B. Harbrecht,
J. M. Menezes,
J. Kane,
J. MacMicking,
C. F. Nathan,
A. B. Peitzman,
T. R. Billiar,
and
D. J. Tweardy.
Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock.
J. Exp. Med.
187:
917-928,
1998
7.
Ignarro, L. J.
Biosynthesis and metabolism of endothelium-derived nitric oxide.
Annu. Rev. Pharmacol. Toxicol.
30:
535-560,
1990[Medline].
8.
Jourd'heuil, D.,
L. Mills,
A. M. Miles,
and
M. B. Grisham.
Effect of nitric oxide on hemoprotein-catalyzed oxidative reactions.
Nitric Oxide
2:
37-44,
1998.[Medline]
9.
Kanner, J.,
S. Harel,
and
R. Granit.
Nitric oxide as an antioxidant.
Arch. Biochem. Biophys.
289:
130-136,
1991[Medline].
10.
Lander, H. M.,
A. J. Milbank,
J. M. Tauras,
D. P. Hajjar,
B. L. Hempstead,
G. D. Schwartz,
R. T. Kraemer,
U. A. Mirza,
B. T. Chait,
S. C. Burk,
and
C. Quillia.
Redox regulation of cell signaling.
Nature
381:
380-381,
1996[Medline].
11.
Liu, X.,
M. J. S. Miller,
M. S. Joshi,
D. D. Thomas,
and
J. R. J. Lancaster.
Accelerated reaction of nitric oxide with O2 within the hydrophobic interior of biological membranes.
Proc. Natl. Acad. Sci. USA
95:
2175-2179,
1998
12.
Loscalzo, J.,
and
G. Welch.
Nitric oxide and its role in the cardiovascular system.
Prog. Cardiovasc. Dis.
38:
87-104,
1995[Medline].
13.
Miles, A. M.,
D. S. Bohle,
P. A. Glassbrenner,
B. Hansert,
D. A. Wink,
and
M. B. Grisham.
Modulation of superoxide-dependent oxidation and hydroxylation reactions by nitric oxide.
J. Biol. Chem.
271:
40-47,
1996
14.
Moncada, S.,
R. M. J. Palmer,
and
E. A. Higgs.
Nitric oxide: physiology, pathophysiology, and pharmacology.
Pharmacol. Rev.
43:
109-142,
1991[Medline].
15.
Nathan, C.
Inducible nitric oxide synthase: what difference does it make?
J. Clin. Invest.
100:
2417-2423,
1997[Medline].
16.
Padmaja, S.,
and
R. E. Huie.
The reaction of nitric oxide with organic peroxyl radicals.
Biochem. Biophys. Res. Commun.
195:
539-544,
1993[Medline].
17.
Palombella, V. J., E. M. Conner, J. W. Fuseler, A. Destree, J. M. Davis, F. S. Laroux, R. E. Wolf, J. Huang, S. Brand, P. J. Elliott, D. Lazarus, T. McCormack, L. Parent, R. Stein, J. Adams, and
M. B. Grisham. Role of the proteasome and NF-kB in
streptococcal cell wall-induced polyarthritis. Proc
Natl Acad Sci. USA In press.
18.
Pfeiffer, S.,
A. C. F. Gorren,
K. Schmidt,
E. R. Werner,
B. Hansert,
D. S. Bohle,
and
B. Mayer.
Metabolic fate of peroxynitrite in aqueous solution. Reaction with nitric oxide and pH-dependent decomposition to nitrite and oxygen in a 2:1 stoichiometry.
J. Biol. Chem.
272:
3465-3470,
1997
19.
Pfeiffer, S.,
and
B. Mayer.
Lack of tyrosine nitration by peroxynitrite generated at physiological pH.
J Biol Chem.
273:
27280-27285,
1998
20.
Pryor, W. A.,
and
G. L. Squadrito.
The chemistry of peroxynitrite and peroxynitrous acid: products from the reaction of nitric oxide with superoxide.
Am. J. Physiol.
268 (Lung Cell. Mol. Physiol. 12):
L699-L721,
1995
21.
Rubbo, H.,
R. Radi,
M. Trujillo,
R. Telleri,
B. Kalyanaraman,
S. Barnes,
M. Kirk,
and
A. Freeman.
Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation.
J. Biol. Chem.
269:
26066-26075,
1994
22.
Salvemini, D.,
T. P. Misko,
J. L. Masferrer,
K. Seibert,
M. G. Currie,
and
P. Needleman.
Nitric oxide activates cyclooxygenase enzymes.
Proc. Natl. Acad. Sci. USA
90:
7240-7244,
1993
23.
Stamler, J. S.
Redox signaling: nitrosylation and related target interactions of nitric oxide.
Cell
78:
931-936,
1994[Medline].
24.
Stamler, J. S.,
L. Jia,
J. P. Eu,
T. J. McMahon,
I. T. Demchenko,
J. Bonaventura,
K. Gernert,
and
C. A. Piantadosi.
Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient.
Science
276:
2034-2037,
1997
25.
Tamir, S.,
and
S. R. Tannenbaum.
The role of nitric oxide in the carcinogenic process.
Biochim. Biophys. Acta
1288:
F31-F36,
1996[Medline].
26.
Wink, D. A.,
J. A. Cook,
S. Kim,
Y. Vodovotz,
R. Pacelli,
M. C. Kirshna,
A. Russo,
J. B. Mitchell,
D. Jourd'heuil,
A. M. Miles,
and
M. B. Grisham.
Superoxide modulates the oxidation and nitrosation of thiols by nitric oxide derived reactive intermediates.
J. Biol. Chem.
272:
11147-11151,
1997
27.
Wink, D. A.,
and
J. B. Mitchell.
The chemical biology of nitric oxide: insights into regulatory, cytotoxic and cytoprotective mechanisms of nitric oxide.
Free Radic. Biol. Med.
25:
434-456,
1998[Medline].
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