Inhibitory effects of vesnarinone in the progression of myocardial damage in experimental autoimmune myocarditis in rats.
OBJECTIVE
Vesnarinone, a positive inotropic and immunomodulatory agent, diminishes nitric oxide (NO) levels by suppressing the induction of inducible NO synthase (iNOS) expressed in cytokine-stimulated macrophages and cardiomyocytes. We examined whether vesnarinone exerts inhibitory effects on the progression of myocardial damage in experimental autoimmune myocarditis in rats through suppression of iNOS.


METHODS
Myocarditis was induced in 30 Lewis rats by injection of porcine cardiac myosin and vesnarinone was orally administered to 20 of the 30 rats. On day 21 after immunization (the climax of inflammation), the hemodynamics were examined and the severity of myocarditis was evaluated by determining the area ratio (%) [affected/entire area] of myocardial lesions in histological sections. Levels of serum CK-MB, NOx (NO2(-)+NO3-), TNF-alpha and IL-1 beta, and cyclic GMP, iNOS mRNA, TNF-alpha and IL-1 beta in heart tissues were determined. Expression of iNOS and TNF-alpha protein were examined by immunohistochemical methods.


RESULTS
Histopathological examination revealed extensive myocardial destruction and massive infiltration of inflammatory cells in the vesnarinone-untreated rats. The area ratio of the lesions in the treated rats was significantly lower than that in the untreated ones. Levels of CK-MB, NOx, cyclic GMP, cytokines and iNOS mRNA were significantly lower in the vesnarinone-treated rats. Infiltrating macrophages and cardiomyocytes in the untreated rats showed much higher levels of expression of iNOS and TNF-alpha than those in the vesnarinone-treated rats.


CONCLUSIONS
Vesnarinone may prove to be useful in the treatment of myocarditis by attenuating NO production through suppression of iNOS induced by cytokines.
Ishiyama
S
S
Department of Pathology, Tokyo Women's Medical University School of Medicine, Japan.
Hiroe
M
M
Nishikawa
T
T
Shimojo
T
T
Hosokawa
T
T
Ikeda
I
I
Toyozaki
T
T
Kasajima
T
T
Marumo
F
F
D000704:Analysis of Variance; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D015152:Blotting, Northern; D005260:Female; D007375:Interleukin-1 / Q000032:analysis / Q000097:blood; D009205:Myocarditis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011719:Pyrazines; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015415:Biomarkers; D007375:Interleukin-1; D011719:Pyrazines; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C041667:vesnarinone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat