Role of superoxide anion in the pathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo

Xiao Shu Cheng, Hiroaki Shimokawa, Hidetoshi Momii, Jun Ichi Oyama, Naoto Fukuyama, Kensuke Egashira, Hiroe Nakazawa, Akira Takeshita

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Objective: Although studies in vitro have implicated oxygen-derived free radicals as possible mediators of inflammatory cytokine-induced cell injury, the role of the radicals in the cytokine-induced myocardial dysfunction in vivo remains unclear. The present study was designed to address this point in our novel canine model of cytokine-induced myocardial dysfunction in vivo. Methods: Studies were performed in mongrel dogs, in which microspheres (MS, 15 μm in diameter) with and without interleukin-1β (IL-1β) were injected into the left main coronary artery (control and IL-1β group). Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 week. Results: Immediately after the intracoronary injection of MS (106/kg), LVEF equally decreased to approximately 30% in both the control and IL-1β group. While LVEF rapidly recovered within 2 days in the control group, it remained depressed in the IL-1β group until day 7 (p<0.0001 vs. control group). Pretreatment with OPC-6535 (an inhibitor of superoxide production) before (2 mg/kg IV) and 1 and 2 days after IL-1β MS application (1 mg/kg IV) prevented the IL-1β-induced myocardial dysfunction. Superoxide production in the myocardium was significantly higher in the IL-1β group than in the control group at day 2 (p<0.01), and OPC-6535 significantly suppressed the IL-1β-induced superoxide production (p<0.01). An HPLC assay showed that nitrotyrosine, a marker of the formation of peroxynitrite by superoxide anion and nitric oxide, was present in the myocardium treated with IL-1β but not in that with control MS. OPC-6535 abolished the IL-1β-induced formation of myocardial nitrotyrosine. Conclusion: These results indicate that superoxide anion and the resultant formation of peroxynitrite may substantially be involved in the pathogenesis of the cytokine-induced myocardial dysfunction in dogs in vivo.

Original languageEnglish
Pages (from-to)651-659
Number of pages9
JournalCardiovascular research
Issue number3
Publication statusPublished - Jun 1 1999


All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cheng, X. S., Shimokawa, H., Momii, H., Oyama, J. I., Fukuyama, N., Egashira, K., ... Takeshita, A. (1999). Role of superoxide anion in the pathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo. Cardiovascular research, 42(3), 651-659.