Peroxynitrite (ONOO−) reacts with superoxide dismutase to give the reactive nitronium ion (NO2+)

Ischiropoulos, Harry; Tsai, Jyh-Hsin Michael; Martin, J. C.; Smith, Craig D.; Beckman, Joseph S.

doi:10.1016/0891-5849(90)90643-w

Cited by 13 publications

(3 citation statements)

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“…H20 2 NO+O2-~2N02-NQ + NO + 2 H [2] H20 N02+NO ±N2 3-2 NO2 + 2 H [3] Analyses of the metabolites of NO in vivo also fail to prove that reaction la is significant. Although peroxynitrite (ONOO-) can decompose to NO2 and 0OH in the absence of SOD (9) or may convert to NO' in its presence (10), nitrate (NO-) is still a major product of reaction la (5,9). Therefore, when reaction la is significant, SOD should not only protect NO but should also decrease NO production in favor of NO and NO-.…”

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confidence: 99%

Reversible conversion of nitroxyl anion to nitric oxide by superoxide dismutase.

Murphy

Sies

1991

Proc. Natl. Acad. Sci. U.S.A.

281

126

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Superoxide dismutase (SOD) rapidly scavenges superoxide (O°) and also prolongs the vasorelaxant effects of nitric oxide (NO), thought to be the endotheliumderived relaxing factor. This prolongation has been ascribed to prevention of the reaction between°2-with NO. We report that SOD supports a reversible reduction of NO to NO-. When cyanamide and catalase were used to generate NO-in the presence of SOD, NO was measured by the conversion of HbO2 to MetHb. When SOD[Cu(I)] was exposed to NO anaerobicafly, NO-was trapped by MetHb forming nitrosylmyoglobin. When NO was generated by 3-morpholinosydnonimine hydrochloride in the presence of SOD, NO-or a similar reductant was formed, which reduced catalase compound II and promoted the formation of the catalase[Fe(H)J-NO complex. It is, therefore, conceivable that SOD may protect NO and endothelium-derived relaxing factor by a mechanism in addition toO°scavenging and that NO-may be a physiologically important form of endothelium-derived relaxing factor.Nitric oxide is thought to be the endothelium-derived relaxing factor (EDRF), a vasodilator produced from arginine. The similar chemical properties of NO and EDRF, including their apparent reactivity with°2, support this proposal (1-4). The reaction of NO with O2 (reactions la and b) has been directly observed by using pulse-radiolysis (5), but evidence of the reaction of EDRF with°2 is indirect. Namely, superoxide dismutase (SOD) prolongs the effects of both EDRF and exogenous NO, whether or not there is a simultaneous addition of compounds thought to generate O°. This consistent effect of SOD has been attributed (1-4) to its known ability to catalyze 0°dismutation (6).One report (5) suggests the rate constant for reaction la may be much slower than diffusion limited (-56 x 106 M-1 s-1 at 370C). Also, the intracellular concentration of°2 is estimated to be quite low [e.g., in liver <66 pM (7) Analyses of the metabolites of NO in vivo also fail to prove that reaction la is significant. Although peroxynitrite (ONOO-) can decompose to NO2 and 0OH in the absence of SOD (9) or may convert to NO' in its presence (10), nitrate (NO-) is still a major product of reaction la (5, 9). Therefore, when reaction la is significant, SOD should not only protect NO but should also decrease NO production in favor of NO and NO-. However, product analyses have failed to meet the latter expectation (11, 12) and led us to examine reactions involving SOD and NO in more detail. METHODS 3-Morpholinosydnonimine hydrochloride (SIN-1) was from Cassella AG (Frankfurt), CuZn-SOD (from bovine erythrocytes), cyanamide, and hydroxylamine were from Sigma, and catalase (from bovine liver) was from Boehringer Mannheim. HbO2 was prepared by reduction of MetHb (Aldrich) with dithionite, oxygenation, and purification on a Sephadex G-25 column (in Krebs/Hepes buffer containing 140mM NaCl, 2.7 mM KCl, 0.42 mM NaH2PO4, 1 mM MgCl2, 1.8 mM CaCI2, 20 mM Hepes, adjusted to pH 7.4 at 37°C by adding NaOH) and measured at 415 nm (e = 131 mM-1-cm-1) (13). Metmyoglob...

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mentioning

confidence: 99%

Reversible conversion of nitroxyl anion to nitric oxide by superoxide dismutase.

Murphy

Sies

1991

Proc. Natl. Acad. Sci. U.S.A.

281

126

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“…Another possibility has recently been advanced that proposes an interaction between peroxynitrite radicals and SOD leading to the production of a highly reactive nitronium radical that could exhaust endogenous antioxidants. 43 It is important to note that although protection is lost at high doses of PEG-SOD, recovery does not fall below that of the PEG-SOD-free controls; i.e., we have no evidence of drug-induced detrimental effects. Whatever the mechanisms involved, our results once again stress the importance of undertaking dose-response studies for any potentially therapeutic agent.…”

Section: Dose-response Characteristics For the Efficacy Of Peg-sodmentioning

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PEG-SOD and myocardial protection. Studies in the blood- and crystalloid-perfused rabbit and rat hearts.

et al. 1992

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BACKGROUND Polyethylene glycol, covalently linked to superoxide dismutase (PEG-SOD), has a long plasma half-life (greater than 30 hours) and has been proposed as an effective agent for reducing free radical-mediated injury ischemia and reperfusion. METHODS AND RESULTS Using an isolated rabbit heart perfused with arterial blood from a support rabbit, we have demonstrated that pretreatment with PEG-SOD (30,000 units/kg, intravenous bolus, 12-24 hours before 60 minutes of normothermic global ischemia), combined with addition of PEG-SOD to the blood perfusion circuit (30,000 units/kg to the support rabbit) and inclusion of PEG-SOD (150 micrograms/ml) in a cardioplegic solution, enhanced the postischemic recovery of left ventricular developed pressure (LVDP) from 51 +/- 6 to 74 +/- 9 mm Hg (p less than 0.05; n = 9 per group). In further studies we showed that, whereas maximum protection was obtained when PEG-SOD was given as a combined pretreatment and additive to both the cardioplegic and the reperfusate solutions (postischemic LVDP recovery increased from 44 +/- 4% in the control group to 70 +/- 3% in the PEG-SOD group), the administration of PEG-SOD during pretreatment plus cardioplegia or during reperfusion alone also resulted in a significant improvement in postischemic function (62 +/- 7% and 60 +/- 3%, respectively). However, the use of PEG-SOD as a cardioplegic additive alone failed to afford protection (47 +/- 4% recovery of LVDP). In dose-response studies (with 0, 3,000, 6,000, 12,000, 30,000, or 60,000 units/kg; n = 8 per group), maximum recovery of LVDP was obtained with the administration of 12,000 units/kg of PEG-SOD. Studies of the plasma activity of PEG-SOD confirmed its long half-life and showed that the treatment with PEG-SOD either 1 hour or 12-24 hours before the study resulted in similar levels of plasma activity. In an attempt to assess any involvement of blood-borne elements in the protection afforded by PEG-SOD, studies were also carried out in the crystalloid-perfused rabbit heart, and no protection was observed. Similarly, no protection was observed at any one of a variety of doses in the crystalloid-perfused rat heart. CONCLUSIONS PEG-SOD can afford protection in the blood-perfused rabbit heart; this protection is dose dependent and probably involves some action of PEG-SOD on blood-borne elements, possibly leukocytes.

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“…Igualmente que en la variable anterior observamos la alta agresividad del modelo aplicado y un mantenimiento de la función orgánica en los animales tratados. Este mantenimiento de la función orgánica ha sido puesto de manifiesto por otros autores, en diferentes modelos experimentales (24,53,60,74,90,94,124,190,274,317,332,364,379) .…”

Section: -Discusión De Los Resultadosunclassified

Síndrome de la respuesta inflamatoria sistémica experimental inducida por Zymosan A, su regulación con Celecoxib®

Casanueva¹,

Antonio²

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XI ÍNDICE: Página I. ESTADO ACTUAL DEL PROBLEMA 1 1.-Inflamación 3 1.1.-Mediadores químicos de la inflamación 6 1.2.-Interacción Leucocito-Endotelio 23 2.-Translocación Bacteriana (TB) e Infección 35 2.1.-Concepto de TB 36 2.2.-Fisiopatología de la TB 37 2.3.-Factores que alteran la barrera intestinal 38 2.4.-Factores que modifican la tendencia bacteriana a la TB 44 2.5.-Mecanismos de TB 46 3.-Celecoxib 48 Tesis Doctoral XII 3.-Estudios de la Función Renal 91 4.-Mieloperoxidasa 93 5.-Radicales libres del oxígeno 95 6.-Citocinas 100 7.-Óxido Nítrico 105 8.-Expresión CAMs 108 9.-Activación NFkB 112 V. DISCUSIÓN 113 1.-Discusión del diseño experimental 115 2.-Discusión de los resultados 119 VI. CONCLUSIONES 127

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Peroxynitrite (ONOO−) reacts with superoxide dismutase to give the reactive nitronium ion (NO2+)

Cited by 13 publications

References 0 publications

Reversible conversion of nitroxyl anion to nitric oxide by superoxide dismutase.

Reversible conversion of nitroxyl anion to nitric oxide by superoxide dismutase.

PEG-SOD and myocardial protection. Studies in the blood- and crystalloid-perfused rabbit and rat hearts.

Síndrome de la respuesta inflamatoria sistémica experimental inducida por Zymosan A, su regulación con Celecoxib®

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