Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure.
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-1 beta, 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 N(G)-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.
Cardiovascular Research Group, Department of Pharmacology, Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada.
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P
Ferdinandy
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Danial
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I
Ambrus
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Rothery
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R
Schulz
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D019335:Nitroarginine / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010477:Perfusion; D011166:Porphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000378:metabolism
D016166:Free Radical Scavengers; D007375:Interleukin-1; D009124:Muscle Proteins; D009566:Nitrates; D011166:Porphyrins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D019335:Nitroarginine; C039642:peroxynitric acid; D009569:Nitric Oxide; C016136:tetraphenylporphine sulfonate; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014969:Xanthine Oxidase; D019255:NADPH Oxidases