Peroxynitrite Reaction with Carbon Dioxide/Bicarbonate: Kinetics and Influence on Peroxynitrite-Mediated Oxidations

Denicola, Ana; Freeman, Bruce Α.; Trujillo, Madia; Radí, Rafael

doi:10.1006/abbi.1996.0363

Cited by 553 publications

(433 citation statements)

References 3 publications

Supporting

Mentioning

407

Contrasting

Unclassified

Order By: Relevance

“…These reductions were more pronounced in the cytochrome c 2ϩ assay and less pronounced in the benzoate hydroxylation assay ( Fig. 1 and Table I), in agreement with the different oxidation mechanisms involved (54,55). Thus, the free thiol appears to be crucial to the inhibitory effect of mercaptoalkylguanidines on the peroxynitrite-induced oxidation of cytochrome c 2ϩ .…”

Section: Meg and Related Compounds Reduce Peroxynitrite-inducedsupporting

confidence: 76%

“…The peroxynitrite-dependent oxidation of cytochrome c 2ϩ was measured as described (54,55). Cytochrome c was reduced by sodium dithionite immediately before use and purified by chromatography on Sephadex G-25 using 100 mM potassium phosphate containing 0.1 mM DTPA, pH 7.2, as the elution buffer.…”

Section: Measurement Of Peroxynitrite-induced Oxidation Of Cytochromementioning

confidence: 99%

“…Measurement of Peroxynitrite-induced Hydroxylation of BenzoateThe peroxynitrite-dependent hydroxylation of benzoate was measured as described (55,56). Briefly, peroxynitrite (100 M initial concentration after mixing) was added to a buffer containing 1 mM sodium benzoate in 100 mM potassium phosphate containing 0.1 mM DTPA, pH 7.2, at 25°C in the absence or presence of MEG or related compounds (1 M to 3 mM).…”

Section: Measurement Of Peroxynitrite-induced Oxidation Of Cytochromementioning

confidence: 99%

See 2 more Smart Citations

Mercaptoethylguanidine and Guanidine Inhibitors of Nitric-oxide Synthase React with Peroxynitrite and Protect against Peroxynitrite-induced Oxidative Damage

Szabó

Ferrer-Sueta

Zingarelli

et al. 1997

Journal of Biological Chemistry

Self Cite

159

View full text Add to dashboard Cite

Nitric oxide (NO) produced by the inducible nitricoxide 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 ؊1 s ؊1 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.Nitric oxide (NO), 1,2 a free radical produced by a family of isoenzymes termed nitric-oxide synthases (NOS), has been implicated in a variety of physiological and pathophysiological processes. The cytotoxic effects of NO are mediated in part by peroxynitrite (ONOO Ϫ ), 3 a reactive oxidant species formed from NO and superoxide at an almost diffusion-controlled rate (1-4). Although the biological activity and decomposition of peroxynitrite are very much dependent on cellular or chemical environment (concentration of proteins, thiols, glucose, and carbon dioxide and the ratio of NO to superoxide) (1-11), peroxynitrite is now generally considered a more toxic species than either NO or superoxide anion alone (12-19). The cytotoxic processes triggered by peroxynitrite include initiation of lipid peroxidation (5, 15, 16), inhibition of mitochondrial respiration (5,12,(17)(18)(19), inhibition of membrane pumps (20), depletion of glutathione (21), and damage to DNA (22-25) with subsequent activation of poly(ADP-ribose) synthetase and concomitant cellular energy depletion (25)(26)(27).Under certain conditions, NO produced by each of the three major isoforms of NOS can react with superoxide to form peroxynitrite. The constitutive, endothelial NOS isoform mainly serves physiological functions and is necessary for maintaining normal vascular functions, but under conditions of hypoxia/ reoxygenation and ischemia/reperfusion injury and in atherosclerosis, peroxynitrite formed from endothelial NOS-derived NO can initiate cytotoxic processes (28 -33). Similarly, during neuroinjury in response ...

show abstract

Section: Meg and Related Compounds Reduce Peroxynitrite-inducedsupporting

confidence: 76%

Section: Measurement Of Peroxynitrite-induced Oxidation Of Cytochromementioning

confidence: 99%

Section: Measurement Of Peroxynitrite-induced Oxidation Of Cytochromementioning

confidence: 99%

See 1 more Smart Citation

Mercaptoethylguanidine and Guanidine Inhibitors of Nitric-oxide Synthase React with Peroxynitrite and Protect against Peroxynitrite-induced Oxidative Damage

Szabó

Ferrer-Sueta

Zingarelli

et al. 1997

Journal of Biological Chemistry

Self Cite

159

View full text Add to dashboard Cite

show abstract

“…The effects of UA on tyrosine nitration in the presence and absence of NaHCO 3 were compared, as the nitrating activity of ONOO Ϫ is enhanced in the presence of carbonyl anion, which is found in a biological milieu (29,30). At levels comparable to those found in the sera of normal humans (5 mg/dl), UA effectively inhibited the SIN-1-mediated nitration of tyrosine residues in BSA and various FBS proteins regardless of whether or not carbonyl anion was present (Fig.…”

Section: Capacity Of Ua To Inhibit Onoo ϫ Reactivity In Vitromentioning

confidence: 99%

The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

Kean

Spitsin

Mikheeva

et al. 2000

The Journal of Immunology

144

113

View full text Add to dashboard Cite

Uric acid (UA), a product of purine metabolism, is a known scavenger of peroxynitrite (ONOO−), which has been implicated in the pathogenesis of multiple sclerosis and experimental allergic encephalomyelitis (EAE). To determine whether the known therapeutic action of UA in EAE is mediated through its capacity to inactivate ONOO− or some other immunoregulatory phenomenon, the effects of UA on Ag presentation, T cell reactivity, Ab production, and evidence of CNS inflammation were assessed. The inclusion of physiological levels of UA in culture effectively inhibited ONOO−-mediated oxidation as well as tyrosine nitration, which has been associated with damage in EAE and multiple sclerosis, but had no inhibitory effect on the T cell-proliferative response to myelin basic protein (MBP) or on APC function. In addition, UA treatment was found to have no notable effect on the development of the immune response to MBP in vivo, as measured by the production of MBP-specific Ab and the induction of MBP-specific T cells. The appearance of cells expressing mRNA for inducible NO synthase in the circulation of MBP-immunized mice was also unaffected by UA treatment. However, in UA-treated animals, the blood-CNS barrier breakdown normally associated with EAE did not occur, and inducible NO synthase-positive cells most often failed to reach CNS tissue. These findings are consistent with the notion that UA is therapeutic in EAE by inactivating ONOO−, or a related molecule, which is produced by activated monocytes and contributes to both enhanced blood-CNS barrier permeability as well as CNS tissue pathology.

show abstract

“…PDHC and α-ketoglutarate dehydrogenase complex may also be important sources of superoxide and, consequently, peroxynitrite [48,49]. The free radical pathways leading to nitration are initiated secondary to the reaction of peroxynitrite with carbon dioxide [50] and PDHC is one of the main sources of carbon dioxide within the mitochondria [51]. The relative sensitivity of PDHC to tyrosine nitration after cerebral ischemia and reperfusion is at this juncture unknown.…”

mentioning

confidence: 99%

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

View full text Add to dashboard Cite

The pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate and represents the sole bridge between anaerobic and aerobic cerebral energy metabolism. Previous studies demonstrating loss of PDHC enzyme activity and immunoreactivity during reperfusion after cerebral ischemia suggest that oxidative modifications are involved. This study tested the hypothesis that hyperoxic reperfusion exacerbates loss of PDHC enzyme activity, possibly due to tyrosine nitration or S-nitrosation. We used a clinically relevant canine ventricular fibrillation cardiac arrest model in which, after resuscitation and ventilation on either 100% O 2 (hyperoxic) or 21-30% O 2 (normoxic), animals were sacrificed at 2 h reperfusion and the brains removed for enzyme activity and immunoreactivity measurements. Animals resuscitated under hyperoxic conditions exhibited decreased PDHC activity and elevated 3-nitrotyrosine immunoreactivity in the hippocampus but not the cortex, compared to nonischemic controls. These measures were unchanged in normoxic animals. In vitro exposure of purified PDHC to peroxynitrite resulted in a dose-dependent loss of activity and increased nitrotyrosine immunoreactivity. These results support the hypothesis that oxidative stress contributes to loss of hippocampal PDHC activity during cerebral ischemia and reperfusion and suggest that PDHC is a target of peroxynitrite. KeywordsMitochondria; Hyperoxia; Nitrotyrosine; Normoxia; Oxidative stress; Global ischemia; Selective vulnerability; Free radicals Global cerebral ischemia and reperfusion cause severe neurochemical alterations, including oxidative modifications to lipids, proteins, and DNA. These and other covalent modifications can impair enzyme activities, including those necessary for energy metabolism. Alterations in these enzyme activities can limit postischemic aerobic metabolism and cellular ATP regeneration, thereby contributing to the pathophysiology of delayed neuronal cell death [1][2][3][4]. One enzyme known to be targeted and inactivated by reactive oxygen species is the pyruvate dehydrogenase complex (PDHC) [5]. Effects of ischemia/reperfusion on the PDHC can be particularly devastating because this enzyme forms the bridge between glycolysis and the Krebs cycle and can be the rate-limiting step in aerobic cerebral energy metabolism. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2008 October 21. Published in final edited form as:Free Radic Biol Med. 2006 June 1; 40(11): 1960-1970. doi:10.1016/j.freeradbiomed.2006.01.022. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe PDHC is located exclusively in the mitochondrial matrix and catalyzes the oxidative decarboxylation of pyruvate to form NADH and acetyl coenzyme A-the primary form of carbon that enters the Krebs cycle in the adult brain. Several laboratories have shown that PDHC enzyme activity is lost during cerebral ischemia/reperfusion [6][7][8]. PDHC im...

show abstract

Peroxynitrite Reaction with Carbon Dioxide/Bicarbonate: Kinetics and Influence on Peroxynitrite-Mediated Oxidations

Cited by 553 publications

References 3 publications

Mercaptoethylguanidine and Guanidine Inhibitors of Nitric-oxide Synthase React with Peroxynitrite and Protect against Peroxynitrite-induced Oxidative Damage

Mercaptoethylguanidine and Guanidine Inhibitors of Nitric-oxide Synthase React with Peroxynitrite and Protect against Peroxynitrite-induced Oxidative Damage

The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Contact Info

Product

Resources

About