The effect of late modulation of inducible-nitric oxide synthase on coxsackievirus B3-induced autoimmune myocarditis

Objective: This study investigates the effects of nitric oxide inhibition on the development of coxsackievirus B3 (CB3)-induced autoimmune myocarditis. Methods: Male and female B10.M mice were injected intraperitoneally with aminoguanidine (AG,400 mg/kg), a specific inducible-nitric oxide synthase (i-NOS) inhibitor, on days 10-20 and with CB3 virus on day 0. Control mice received CB3 virus or AG alone. Mice were sacrificed on day 21. Results: In female B10.M mice AG treatment resulted in a significant decrease in the intracardiac i-NOS expression, cardiac histopathologic score, and IgG1 antibody to murine cardiac myosin (MCM) compared to positive controls treated with CB3 virus alone. CB3-inoculated male mice showed a significantly lower lesion score, i-NOS expression and MCM IgG1 levels compared to females. AG treatment, though reducing i-NOS expression, had no effect on lesion score and MCM IgG1 levels in male mice. Intracardiac i-NOS expression and MCM IgG1 levels correlated positively with the development of myocarditis. Conclusions: In female B10.M mice, nitric oxide, through direct cytotoxicity and/or indirect immune modulation, enhances the development of CB3-induced autoimmune myocarditis.