Exercise training, in which the load did not affect energy metabolism efficacy of the heart, suppressed atherosclerosis by antioxidant effects via the vascular NO system.
In this study, we tested the hypothesis that MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one; edaravone), a novel free radical scavenger, protects against acute experimental autoimmune myocarditis (EAM) in rats by the radical scavenging action associated with the suppression of cytotoxic myocardial injury. Recent evidence suggests that oxidative stress may play a role in myocarditis. We administered MCI-186 intraperitoneally at 1, 3, and 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 to rats with EAM for 3 wk. The results were compared with untreated rats with EAM. MCI-186 treatment did not affect hemodynamics. MCI-186 treatment (3 and 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) reduced the severity of myocarditis as assessed by comparing the heart-to-body weight ratio and pathological scores. Myocardial interleukin-1 (IL-1)-positive cells and myocardial oxidative stress overload with DNA damage in rats with EAM given MCI-186 treatment were significantly less compared with those of the untreated rats with EAM. In addition, MCI-186 treatment decreased not only the myocardial protein carbonyl contents but also the myocardial thiobarbituric acid reactive substance products in rats with EAM. The formation of hydroxyl radicals in MCI-186-treated heart homogenates was decreased compared with untreated heart homogenates. Furthermore, cytotoxic activities of lymphocytes of rats with EAM treated with MCI-186 were significantly lower compared with those of the untreated rats with EAM. Hydroxyl radicals may be involved in the development of myocarditis. MCI-186 protects against acute EAM in rats associated with scavenging hydroxyl free radicals, resulting in the suppression of autoimmune-mediated myocardial damage associated with reduced oxidative stress state. lymphocytes; immune system; inflammation IN PATIENTS WITH HEART FAILURE, reactive oxygen species (ROS) have been found to be elevated in plasma (2). Acute myocarditis is a potentially lethal disease and frequently precedes the development of acute and chronic heart failure. Two mechanisms to explain how myocarditis develops into heart failure have been proposed: one is a persistent viral or etiologic agent infection, and the other is a progressive autoimmune myocardial injury. The autoimmune giant cell myocarditis in rats mimics human fulminant myocarditis with heart failure (12).Excess amount of cytokine induced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis (1,5,7,15,16,22,23). Also, recent reports indicated that myocardial injury was produced by ROS (18,19,29). Lipid peroxidation is also caused by ROS (20), resulting in cell membrane damage. As proposed, MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one; edaravone) is a novel free radical scavenger (8, 27, 28) and may be an effective agent for myocardial inflammation by inhibiting overproduced cytokines (24). The purpose of the present study was to examine the effects of MCI-186 on experimental autoimmune myocarditis (EAM), focusing on its inhibitory effects on the inflammatory cytokines and on free radical generation...
xercise is deters the development of cardiovascular disease. Its antiatherogenic effects have been described in different animal models, 1,2 and exercise can also influence risk factors that are associated with cardiovascular diseases (ie, hypertension, diabetes mellitus, obesity, hyperlipidemia, and endothelial dysfunction). [1][2][3] However, the mechanisms by which exercise is beneficial with regard to cardiovascular diseases are still unknown. Enzymes associated with antioxidant defense, such as manganese superoxide dismutase, endothelial nitric oxide synthase (eNOS), heme oxygenase, and catalase, 4-8 can be induced by oxidants in cell culture studies. There is significant evidence to indicate that exercise training increases coronary endothelium-dependent relaxation, 9,10 and that these effects are associated with increased NO production 9-12 and eNOS gene expression. 12,13 In the present study, using apolipoprotein-E (apoE)-deficient mice, we looked for evidence of induction of fatty and fibrofatty streaks in the arterial wall and the lessening of atherosclerotic lesions by exercise. We also investigated the effect of N G -nitro-L-arginine methylester (L-NAME) supplementation, an inhibitor of NOS, on atherosclerotic lesions in exercise-trained mice. Circulation Journal Vol.71, July 2007 Methods Experimental AtherosclerosisThe apoE-deficient 129ola × C57BL/6 hybrid mice were the generous gift of Dr Edward M. Rubin (University of California, Berkeley, CA, USA). They were mated with C57BL/6 mice to produce F1 hybrids. The F1 apoE +/-mice were then backcrossed to C57BL/6 mice for 10 generations. Mice homogeneous for the apoE-null allele on a C57BL/6 background were subsequently generated. Male mice were used in the present experiments. The mice were kept in a temperature-controlled facility on a 14:10-h light -dark cycle with free access to food and water.After being weaned at 4 weeks of age, the mice were fed a normal chow diet (Oriental Yeast) until 6 weeks of age, when they were switched to a high-fat diet (HFD) containing 20% fat and 0.3% cholesterol as previously described. 14 We performed the animal experiments in accordance with the Declaration of Helsinki, and they were approved by the institutional ethics committee for animal experiments of Kyoto University. Exercise ProtocolAt 6 weeks of age, the mice underwent an exercise protocol of swimming in a hot bath (37°C) for 30 min per day 3 times per week for 8 weeks. Exercise time was gradually increased up to 45 min in the first 2 weeks. These mice were divided into the following 4 groups, which on day 0 received HFD with and without L-NAME supplementation: HFD alone; n=9, HFD + Swimming; n=9, HFD + L-NAME; n=8, HFD + Swimming + L-NAME; n=9. L-NAME (100 g/ml) was administered orally via the drinking water 15 and daily fluid consumption was monitored. The estimated dose of L-NAME (25 mg·kg -1 ·body weight -1 ·day -1 ) was based on fluid consumption and drug concentration. The oral route Circ J 2007; 71: 1147 -1151 (Received April 5, 2006 revised manuscr...
It was previously shown that administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) aggravated murine viral myocarditis by increasing myocardial virus titres. Experimental autoimmune myocarditis in mice and rats mimics human fulminant myocarditis. The effects of L-arginine, a precursor of nitric oxide, upon heart failure in experimental autoimmune myocarditis were evaluated. Dietary L-arginine (L-arginine group) and L-arginine plus N(G)-nitro-L-arginine methyl ester (L-arginine + l-NAME group) were administered to C57BL/6 mice immunized with porcine cardiac myosin over 3 weeks. An untreated myocarditis group was prepared. Cardiac damage was less in the L-arginine group compared with the other two groups, as was incidence of heart failure. In addition, extracellular matrix change was less prominent in the L-arginine group. Plasma concentrations of nitric oxide were elevated in the L-arginine group. Cytotoxic activities of lymphocytes were lower in L-arginine group than in other two groups. L-arginine treatment may be effective in preventing the development of heart failure in experimental myocarditis by maintaining extracellular matrix and reducing the cytotoxic activity of lymphocytes.
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