Nitric oxide and murine coxsackievirus B3 myocarditis: aggravation of myocarditis by inhibition of nitric oxide synthase.
OBJECTIVE
This study sought to investigate the effects of nitric oxide inhibition in a murine model of coxsackievirus B3 myocarditis.


BACKGROUND
Little is known about the contribution of nitric oxide to the pathophysiology of myocarditis.


METHODS
Antiviral activity was tested in vitro using nitric oxide inhibition by treatment with activated macrophages of NG-nitro-L-arginine methyl ester. In the in vivo experiments, NG-nitro-L-arginine methyl ester and NG-nitro-D-arginine methyl ester (both at 100 micrograms/ml) were administered to C3H/He mice early (days 0 to 14) and late (days 14 to 35) after infection with coxsackievirus B3.


RESULTS
In the in vitro experiments with interferon-gamma- and lipopolysaccharide-induced activated murine macrophages, treatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, but not its inactive enantiomer NG-nitro-D-arginine methyl ester, restored coxsackievirus B3 titers. In the in vivo experiments in the early treatment group, myocardial virus titers were higher in NG-nitro-L-arginine methyl ester-treated than infected untreated animals, and both inflammatory cell infiltration and necrosis were more severe. In the late treatment group, more severe necrosis and more dense myocardial and perivascular fibrosis were observed in NG-nitro-L-arginine methyl ester-treated than in infected untreated animals. NG-Nitro-D-arginine methyl ester administration was ineffective.


CONCLUSIONS
Nitric oxide inhibition increases myocardial virus titers, resulting in the aggravation of cardiac pathology in the early stage of coxsackievirus B3 myocarditis. In the late stage, it induces more severe cardiomyopathic lesions. Nitric oxide plays a defensive role in the pathogenesis of coxsackievirus B3 myocarditis.
Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Japan.
Y
Y
Hiraoka
C
C
Kishimoto
H
H
Takada
M
M
Nakamura
M
M
Kurokawa
H
H
Ochiai
K
K
Shiraki
D000818:Animals; D003384:Coxsackievirus Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology*; D029822:Enterovirus B, Human / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D008264:Macrophages / Q000821:virology; D051379:Mice; D009205:Myocarditis / Q000188:drug therapy / Q000201:enzymology / Q000821:virology*; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014766:Viremia / Q000188:drug therapy / Q000201:enzymology; D014779:Virus Replication
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester