Role of superoxide anion in the pathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo.
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 microns in diameter) with and without interleukin-1 beta (IL-1 beta) were injected into the left main coronary artery (control and IL-1 beta group). Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 week.


RESULTS
Immediately after the intracoronary injection of MS (10(6)/kg), LVEF equally decreased to approximately 30% in both the control and IL-1 beta group. While LVEF rapidly recovered within 2 days in the control group, it remained depressed in the IL-1 beta group until day 7 (p < 0.0001 vs. control group). Pretreatment with OPC-6535 (an inhibitor of superoxide production) before (2 mg/kg i.v.) and 1 and 2 days after IL-1 beta MS application (1 mg/kg i.v.) prevented the IL-1 beta-induced myocardial dysfunction. Superoxide production in the myocardium was significantly higher in the IL-1 beta group than in the control group at day 2 (p < 0.01), and OPC-6535 significantly suppressed the IL-1 beta-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-1 beta but not in that with control MS. OPC-6535 abolished the IL-1 beta-induced formation of myocardial nitrotyrosine.


CONCLUSIONS
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.
Cheng
X S
XS
Research Institute of Angiocardiology, Kyushu University School of Medicine, Fukuoka, Japan.
Shimokawa
H
H
Momii
H
H
Oyama
J
J
Fukuyama
N
N
Egashira
K
K
Nakazawa
H
H
Takeshita
A
A
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D004285:Dogs; D004452:Echocardiography; D005260:Female; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism; D011897:Random Allocation; D013318:Stroke Volume / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology
D000975:Antioxidants; D015415:Biomarkers; D007375:Interleukin-1; D009566:Nitrates; D013844:Thiazoles; D013481:Superoxides; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C108965:tetomilast