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Research ArticleCARDIOVASCULAR

Peroxynitrite, a Two-Edged Sword in Post-Ischemic Myocardial Injury—Dichotomy of Action in Crystalloid- Versus Blood-Perfused Hearts

Xin-Liang Ma, Feng Gao, Bernard L. Lopez, Theodore A. Christopher and Jakob Vinten-Johansen
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 912-920;
Xin-Liang Ma
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Feng Gao
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Bernard L. Lopez
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Theodore A. Christopher
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Jakob Vinten-Johansen
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Abstract

Peroxynitrite (ONOO−) is widely recognized as a mediator of NO· toxicity, but recent studies have indicated that this compound may also have physiologic activity and induces vascular relaxation as well as inhibition of platelet aggregation and neutrophil adhesion. The present experiment was designed to determine whether ONOO− may exert different effects on postischemic myocardial injury in a crystalloid perfusion environment versus a blood perfusion environment and, if it does, to clarify the mechanisms causing any differences. In Krebs-Henseleit buffer-perfused rabbit hearts, administration of ONOO− at the onset of reperfusion enhanced myocardial injury in a concentration-dependent fashion with a significant effective concentration of 30 μM. In contrast, in blood-perfused hearts, administration of ONOO− (1 to 30 μM) significantly attenuated postmyocardial injury as evidenced by improved cardiac function recovery, preserved endothelial function, decreased myocardial creatine kinase loss, and reduced necrotic size. The minimal and maximal protective concentrations were determined to be 1 and 3 μM, respectively. When a high concentration of ONOO− (i.e., 100 μM) was administered, a detrimental effect was observed. Administration of ONOO− decreased neutrophil accumulation in the ischemic-reperfused myocardial tissue in a concentration-dependent manner in blood-perfused hearts and inhibited neutrophil adhesion to cultured endothelial cells exposed to hypoxia/reoxygenation. Taken together, these results demonstrate that ONOO− may act as a “double-edged sword” in postischemic myocardial injury. This compound is directly toxic to the cardiac tissue at a relatively high concentration, but it can indirectly protect myocardial cells from neutrophil-induced injury at a much lower concentration.

Footnotes

  • Send reprint requests to: Dr. Xin L. Ma, Division of Emergency Medicine, Jefferson Medical College, 1020 Walnut St., Philadelphia, PA 19107-5004. E-mail:Xin.Ma{at}mail.tju.edu

  • ↵1 This work was supported in part by National Science Foundation of China Grants 39970807, 39925013, and 39970302. F.G. is a visiting professor and is supported in part by National Science Foundation of China Grants.

  • Abbreviations:
    PMN
    neutrophil
    CF
    coronary flow
    CK
    creatine kinase
    KH
    Krebs-Henseleit
    LVDP
    left ventricular developed pressure
    LVP
    left ventricular pressure
    LVSP
    left ventricular systolic pressure
    MPO
    myeloperoxidase
    PRP
    pressure rate product
    SNAP
    S-nitroso-N-acetylpenicillamine
    EC
    endothelial cell
    HR
    heart rate
    ACh
    acetylcholine
    • Received July 22, 1999.
    • Accepted November 5, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleCARDIOVASCULAR

Peroxynitrite, a Two-Edged Sword in Post-Ischemic Myocardial Injury—Dichotomy of Action in Crystalloid- Versus Blood-Perfused Hearts

Xin-Liang Ma, Feng Gao, Bernard L. Lopez, Theodore A. Christopher and Jakob Vinten-Johansen
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 912-920;

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Research ArticleCARDIOVASCULAR

Peroxynitrite, a Two-Edged Sword in Post-Ischemic Myocardial Injury—Dichotomy of Action in Crystalloid- Versus Blood-Perfused Hearts

Xin-Liang Ma, Feng Gao, Bernard L. Lopez, Theodore A. Christopher and Jakob Vinten-Johansen
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 912-920;
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