Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts

Ferdinándy, Péter; Panas, Donna; Schulz, Richard

doi:10.1152/ajpheart.1999.276.6.h1861

Cited by 52 publications

(41 citation statements)

References 30 publications

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“…Formation of dityrosine has been attributed mainly to the activation of the myeloperoxidase/H 2 O 2 system of neutrophils and macrophages (46), but other peroxidases (47) and peroxynitrite (36, 48) have been recognized as additional sources of dityrosine. The present results agree with previous studies suggesting that dityrosine formation together with increased NO synthase expression may be a useful marker for peroxynitrite formation in tissues (49,50).…”

Section: Peroxynitrite-mediated Tyrosine Modificationsupporting

confidence: 93%

Dityrosine Formation Outcompetes Tyrosine Nitration at Low Steady-state Concentrations of Peroxynitrite

Pfeiffer

Schmidt

Mayer

2000

Journal of Biological Chemistry

157

106

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Tyrosine nitration is a well established protein modification occurring in vivo in a number of inflammatory diseases associated with oxidative stress and increased activity of NO synthases (1, 2). Nitration of specific tyrosine residues has been reported to affect protein structure and function (3), suggesting that 3-nitrotyrosine formation may not only be a disease marker but could be causally involved in the pathogenesis of certain disease states.Peroxynitrite, formed in a nearly diffusion-controlled reaction from NO and O 2 . , is considered a potent pathophysiologically relevant cytotoxin. Besides oxidation reactions resulting in dysfunction of various biomolecules, nitration of free and protein-bound tyrosine to yield 3-nitrotyrosine is a well established reaction of peroxynitrite that may contribute to NO cytotoxicity (1). The nitration reaction has been extensively studied in vitro by bolus addition of synthetic peroxynitrite to tyrosine-containing samples including purified proteins, cells, and tissues (3-6) . In situ, 3-nitrotyrosine was most frequently visualized with monoclonal or polyclonal antibodies (2), but the identity of the product has been confirmed by several laboratories using sophisticated gas chromatography/mass spectroscopy and HPLC 1 methods (7,8). Thus, there is general agreement that (i) authentic peroxynitrite is a potent nitrating agent that converts free and proteinbound tyrosine to the corresponding 3-nitro derivative, and that (ii) 3-nitrotyrosine does occur in vivo. The conclusion that peroxynitrite is the main cause for in vivo nitration may thus seem obvious, but is not supported by experimental data. In fact, several recent studies have identified alternative pathways of tyrosine nitration (9), and we found that nitration by simultaneously generated NO and O 2 . is much less efficient than the reaction triggered by authentic peroxynitrite (10). The interpretation of the latter results has been disputed, and a number of points have been raised questioning their validity. One point was related to the possibility that urate formed in the XO reaction might have scavenged peroxynitrite and thus prevented tyrosine nitration in long term (12 h) experiments. Concerning data interpretation, we had suggested that NO and O 2 . may combine to trans-peroxynitrite, the rapid protonation of which prevents formation of the nitrating CO 2 . adduct. However, thermodynamic calculations have unambiguously identified the cis-rotamer as the more stable conformation of peroxynitrite in both gas phase (11) and aqueous solution, 2 rendering our initial hypothesis untenable. We hope to settle both issues with the present study in which we extend our earlier findings to other, urate-free NO/O 2 .-generating systems and demonstrate that the low nitrating efficiency of NO/O 2 . is explained by an unexpected dependence of nitration yields on peroxynitrite steady-state concentrations. It is shown that the reaction between tyrosine and peroxynitrite yields almost exclusively dityrosine at peroxynitrit...

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Section: Peroxynitrite-mediated Tyrosine Modificationsupporting

confidence: 93%

Dityrosine Formation Outcompetes Tyrosine Nitration at Low Steady-state Concentrations of Peroxynitrite

Pfeiffer

Schmidt

Mayer

2000

Journal of Biological Chemistry

157

106

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“…Activity of xanthine oxidase and xanthine dehydrogenase is increased by nitrite during ischemic conditions, where oxygen and pH are reduced, but not during aerobic conditions. Increased xanthine oxidoreductase activity as a consequence of ischemia has been reported previously [33][34][35][36]. Alternately, ischemia may repair the inactive desulfo form of the enzyme to the fully active form as previously suggested [25].…”

Section: Discussionmentioning

confidence: 55%

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

Baker

et al. 2007

Journal of Molecular and Cellular Cardiology

120

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Reduction of nitrite to nitric oxide during ischemia protects the heart against injury from ischemia/ reperfusion. However the optimal dose of nitrite and the mechanisms underlying nitrite-induced cardioprotection are not known. We determined the ability of nitrite and nitrate to confer protection against myocardial infarction in two rat models of ischemia/reperfusion injury and the role of xanthine oxidoreductase, NADPH oxidase, nitric oxide synthase and K ATP channels in mediating nitrite-induced cardioprotection. In vivo and in vitro rat models of myocardial ischemia/reperfusion injury were used to cause infarction. Hearts (n=6/group) were treated with nitrite or nitrate for 15 min prior to 30 min regional ischemia and 180 min reperfusion. Xanthine oxidoreductase activity was measured after 15 min aerobic perfusion and 30 min ischemia. Nitrite reduced myocardial necrosis and decline in ventricular function following ischemia/reperfusion in the intact and isolated rat heart in a dose or concentration-dependent manner with an optimal dose of 4 mg/kg in vivo and concentration of 10 μM in vitro. Nitrate had no effect on protection. Reduction in infarction by nitrite was abolished by inhibition of flavoprotein reductases and the molybdenum site of xanthine oxidoreductase, and was associated with an increase in activity of xanthine dehydrogenase and xanthine oxidase during ischemia. Inhibition of nitric oxide synthase had no effect on nitrite-induced cardioprotection. Inhibition of NADPH oxidase and K ATP channels abolished nitrite-induced cardioprotection. Nitrite but not nitrate protects against infarction by a mechanism involving xanthine oxidoreductase, NADPH oxidase and K ATP channels.

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“…There are many studies which demonstrate a concentration-dependent biphasic effect of peroxynitrite on basal myocardial contractility, but the majority of these studies did not address these effects on β-adrenergic responsiveness [10][11][12][13][14][15][16][17][18]26,28]. In our study, SIN-1 (source of peroxynitrite) had a biphasic effect on murine cardiomyocyte contractility that was not only dependent on concentration, but also on the contractile state of the cardiomyocyte.…”

Section: Discussionmentioning

confidence: 60%

“…For instance, numerous studies have shown high concentrations of peroxynitrite to be detrimental to myocardial contractility [10][11][12][13][14][15], while at low concentrations peroxynitrite appears to act as a positive inotropic agent [16][17][18]. However, the majority of these studies examined effects on basal contractility and did not address the effects of peroxynitrite as they relate to β-adrenergic responsiveness.…”

Section: Introductionmentioning

confidence: 99%

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high SIN-1 (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, while the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz and [Ca 2+ ] i transients and shortening were recorded. Following submaximal ISO (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, while cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. 10 μmol/L SIN-1 also increased basal contractility. Interestingly, SIN-1 only produced a contractile effect under one condition in phospholamban knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

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Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts

Cited by 52 publications

References 30 publications

Dityrosine Formation Outcompetes Tyrosine Nitration at Low Steady-state Concentrations of Peroxynitrite

Dityrosine Formation Outcompetes Tyrosine Nitration at Low Steady-state Concentrations of Peroxynitrite

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

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