LOW-DOSE N-OMEGA-NITRO-L-ARGININE METHYL-ESTER TREATMENT IMPROVES SURVIVAL RATE AND DECREASES MYOCARDIAL INJURY IN A MURINE MODEL OF VIRAL MYOCARDITIS INDUCED BY COXSACKIEVIRUS B3

Recent reports demonstrated the expression of inducible-type NO syntha se in the heart of viral myocarditis. Since NO has multiple biological actions, a substantial amount of NO produced in the diseased heart ma y act either as a cytotoxic or as a cytoprotective molecule in the pro cess of myocarditis. In the present study, we examined the effect of i nhibition of NO synthesis on the mortality and the extent of myocardia l injury in a murine model of coxsackievirus B3-induced myocarditis. W e fed the infected mice drinking water containing a relatively low con centration (0.37 mmol/L) of N-omega-nitro-L-arginine methyl ester (L-N AME) for 14 days after virus inoculation. This dose of L-NAME did not change virus titers in the heart. However, L-NAME-fed mice showed a si gnificant reduction in mortality compared with those fed normal drinki ng water (nontreated mice). On the contrary, mice given a higher conce ntration of L-NAME (3.7 mmol/L) exhibited increased mortality, In addi tion, mice fed a low concentration of L-NAME showed reductions in the severity of heart failure and in the area of myocardial necrosis. Alth ough systemic blood pressure was reduced in nontreated mice, in mice f ed a low concentration of L-NAME, it was maintained at a level similar to that in uninfected control mice. L-NAME-treated mice also exhibite d a reduction in the degree of inflammatory cell infiltration associat ed with decreased production of tissue prostaglandin E-2 levels in the heart compared with nontreated mice. Therefore, NO is likely to be in volved in the pathogenic mechanisms of myocardial injury and resultant cardiac dysfunction in a murine model of coxsackievirus B3-induced vi ral myocarditis.