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Circulation Research. 2000;87:241-247

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(Circulation Research. 2000;87:241.)
© 2000 American Heart Association, Inc.


Integrative Physiology

Peroxynitrite Is a Major Contributor to Cytokine-Induced Myocardial Contractile Failure

Péter Ferdinandy, Hajira Danial, Ildikó Ambrus, Richard A. Rothery, Richard Schulz

From the Cardiovascular Research Group, Departments of Pediatrics (R.S.), Pharmacology (P.F., H.D., I.A., R.S.), and Biochemistry (R.A.R.), Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada, and Department of Biochemistry (P.F., I.A.), University of Szeged, Hungary.

Correspondence to Dr Richard Schulz, Cardiovascular Research Group, 4-62 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. E-mail richard.schulz{at}ualberta.ca

Abstract—Proinflammatory cytokines depress myocardial contractile function by enhancing the expression of inducible NO synthase (iNOS), yet the mechanism of iNOS-mediated myocardial injury is not clear. As the reaction of NO with superoxide to form peroxynitrite markedly enhances the toxicity of NO, we hypothesized that peroxynitrite itself is responsible for cytokine-induced cardiac depression. Isolated working rat hearts were perfused for 120 minutes with buffer containing interleukin-1ß, interferon-{gamma}, and tumor necrosis factor-{alpha}. Cardiac mechanical function and myocardial iNOS, xanthine oxidoreductase (XOR), and NAD(P)H oxidase activities (sources of superoxide) were measured during the perfusion. Cytokines induced a marked decline in myocardial contractile function accompanied by enhanced activity of myocardial XOR, NADH oxidase, and iNOS. Cardiac NO content, myocardial superoxide production, and perfusate nitrotyrosine and dityrosine levels, markers of peroxynitrite, were increased in cytokine-treated hearts. The peroxynitrite decomposition catalyst FeTPPS (5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III]), the NO synthase inhibitor NG-nitro-L-arginine, and the superoxide scavenger tiron each inhibited the decline in myocardial function and decreased perfusate nitrotyrosine levels. Proinflammatory cytokines stimulate the concerted enhancement in superoxide and NO-generating activities in the heart, thereby enhancing peroxynitrite generation, which causes myocardial contractile failure.


Key Words: cytokines • nitric oxide synthase • xanthine • oxidoreductases • NADPH oxidase




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Am. J. Physiol. Heart Circ. Physiol.Home page
T. Csont, C. Csonka, A. Onody, A. Gorbe, L. Dux, R. Schulz, G. F. Baxter, and P. Ferdinandy
Nitrate tolerance does not increase production of peroxynitrite in the heart
Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H69 - H76.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
V. Adams, B. Nehrhoff, U. Spate, A. Linke, P. C Schulze, A. Baur, S. Gielen, R. Hambrecht, and G. Schuler
Induction of iNOS expression in skeletal muscle by IL-1{beta} and NF{kappa}B activation: an in vitro and in vivo study
Cardiovasc Res, April 1, 2002; 54(1): 95 - 104.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al.
Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart
Circ. Res., February 22, 2002; 90(3): 297 - 304.
[Abstract] [Full Text] [PDF]


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DiabetesHome page
P. Pacher, L. Liaudet, F. G. Soriano, J. G. Mabley, E. Szabo, and C. Szabo
The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes
Diabetes, February 1, 2002; 51(2): 514 - 521.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
V. Stangl, G. Baumann, K. Stangl, and S. B Felix
Negative inotropic mediators released from the heart after myocardial ischaemia-reperfusion
Cardiovasc Res, January 1, 2002; 53(1): 12 - 30.
[Abstract] [Full Text] [PDF]


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CirculationHome page
M. T. Ziolo, H. Katoh, and D. M. Bers
Expression of Inducible Nitric Oxide Synthase Depresses {beta}-Adrenergic-Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes
Circulation, December 11, 2001; 104(24): 2961 - 2966.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
H. Chen, D. Li, T. Saldeen, and J. L. Mehta
TGF-{beta}1 modulates NOS expression and phosphorylation of Akt/PKB in rat myocytes exposed to hypoxia-reoxygenation
Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1035 - H1039.
[Abstract] [Full Text] [PDF]


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CirculationHome page
Q. Feng, X. Lu, D. L. Jones, J. Shen, and J. M. O. Arnold
Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice
Circulation, August 7, 2001; 104(6): 700 - 704.
[Abstract] [Full Text] [PDF]


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Eur. J. Cardiothorac. Surg.Home page
D. Pevni, I. Frolkis, A. Iaina, Y. Wollman, T. Chernichovski, I. Shapira, G. Uretzky, and R. Mohr
Protamine cardiotoxicity and nitric oxide
Eur. J. Cardiothorac. Surg., July 1, 2001; 20(1): 147 - 152.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
G. Merrill, P. McConnell, K. Vandyke, and S. Powell
Coronary and myocardial effects of acetaminophen: protection during ischemia-reperfusion
Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2631 - H2638.
[Abstract] [Full Text] [PDF]


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Journal of Renin-Angiotensin-Aldosterone SystemHome page
M.-S. Zhou, A. Adam, and L. Raij
Review: Interaction among angiotensin II, nitric oxide and oxidative stress
Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S59 - S63.
[PDF]


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Circ. Res.Home page
P. Ferdinandy and R. Schulz
Peroxynitrite: Toxic or Protective in the Heart?
Circ. Res., February 2, 2001; 88 (2): e12 - e13.
[Full Text] [PDF]


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Circ. Res.Home page
J. Vinten-Johansen
Physiological Effects of Peroxynitrite : Potential Products of the Environment
Circ. Res., August 4, 2000; 87(3): 170 - 172.
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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
A. U. Khan, R. L. Delude, Y. Y. Han, P. L. Sappington, X. Han, J. A. Carcillo, and M. P. Fink
Liposomal NAD+ prevents diminished O2 consumption by immunostimulated Caco-2 cells
Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L1082 - L1091.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al.
Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart
Circ. Res., February 22, 2002; 90(3): 297 - 304.
[Abstract] [Full Text] [PDF]