Ikutaro Okada

Beneficial effects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis. A possible mechanism through inhibition of nitric oxide production.

BACKGROUND Although calcium channel blockers have not been shown to be beneficial for the treatment of patients with heart failure, a recent clinical trial demonstrated a favorable effect of amlodipine on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy. We investigated the effects of amlodipine on a murine model of congestive heart failure induced by the M variant of encephalomyocarditis virus (EMCV). METHODS AND RESULTS Four-week-old male DBA/2 mice were inoculated with EMCV and administered amlodipine, diltiazem, or vehicle PO for 2 weeks. The heart weight-to-body weight ratio and the histopathological grades of myocardial lesions were significantly lower and survival was significantly increased in the amlodipine-treated group (P < .01, P < .05, and P < .05, respectively) than in the control group. In vitro, amlodipine added to murine J774A.1 macrophages concomitant with EMCV inhibited nitrite formation in a concentration-dependent manner, but diltiazem did not. Furthermore, NG-monomethyl-L-arginine, an inhibitor of NO synthesis, decreased myocardial lesions significantly in this murine model. Immunohistochemistry revealed that the number of cells stained with antibody against an inducible NO synthase decreased significantly in the amlodipine-treated group compared with that in the control group (P < .01). CONCLUSIONS Amlodipine appears to have a protective effect against myocardial injury in this animal model of congestive heart failure. The therapeutic effect of amlodipine may be in part resulting from inhibition of overproduction of NO.

Beta-blocker treatment of dilated cardiomyopathy. Beneficial effect of carteolol in mice.

BackgroundThe effects of carteolol, a nonselective P-adrenergic receptor blocker with intrinsic sympathomimetic activity, were compared with those of metoprolol in a murine model of viral myocarditis and dilated cardiomyopathy caused by encephalomyocarditis virus. Methods and ResultsIn the acute experiment, BALB/c and DBA/2 mice were inoculated with encephalomyocarditis virus. BALB/c mice were then given carteolol at 1 (n =10), 10 (n =10), 30 (n =11), or 100 mg/kg (n =9) daily, and DBA/2 mice were given carteolol at 1 (n =9) or 10 mg/kg (n =9) daily starting the day of inoculation. Controls were given distilled water (n =23 for BALB/c mice and n = 8 for DBA/2 mice). BALB/c mice were killed on day 7, and DBA/2 mice were killed on day 14. In the subacute experiment, DBA/2 mice were inoculated with the virus and then given carteolol at 1 (n =12) or 10 mg/kg (n =16), or distilled water (n =27) daily, starting on day 14. Mice were killed on day 28. Virus replication, murine survival, heart weight to body weight ratio, and histopathological findings were similar in each group in the acute and subacute experiments. In the chronic experiment, DBA/2 mice were inoculated with the virus and were then given carteolol at 1 (n =13) or 10 mg/kg (n =9), metoprolol at 30 mg/kg (n =9), or distilled water (n =31) daily, starting on day 14. Mice were killed on day 104. Heart weight to body weight ratio and histopathological scores were significantly lower in mice given carteolol than in the infected control group. Furthermore, left ventricular cavity dimension, left ventricular wall thickness, and myocardial fiber diameter of the left ventricle were significantly reduced in mice given carteolol compared with the control group. Metoprolol did not cause any significant changes compared with the control group. ConclusionsThis study suggests that carteolol prevents the development of myocardial lesions similar to those in dilated cardiomyopathy after myocarditis in the chronic stage. (Circulation 1991;83:2021—2028)

Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditis.

The myocardial uptake of 125I- and 131I-antimyosin monoclonal antibody Fab in experimental myocarditis in BALB/c mice induced by encephalomyocarditis virus was studied. The biodistribution of 125I-antimyosin demonstrated that the highest ratio of radioactivity appears in the heart of infected mice on day 14 (the ratio of percent dose per gram for the organ to percent dose per milliliter for blood; 9.75 +/- 2.79 vs. 1.27 +/- 0.78 at 24 hours in inoculated mice vs. control mice). There was no statistically significant difference between the mean activity ratios of tissues other than the heart in control and inoculated mice. The uptake ratio for the heart increased significantly 3 days after virus inoculation and reached a maximum on day 14 when myocardial lesions were most extensive and prominent. The uptake ratio decreased significantly, but it still remained high compared with controls on day 28 when cellular infiltration had decreased and fibrosis was evident. The scintigraphic images obtained with 131I-antimyosin monoclonal antibody clearly demonstrated that visualization of the heart in experimental myocarditis was possible 24 hours after administration of radiotracer, and localized activity was still observed in the 48-hour image. We conclude that antimyosin monoclonal antibodies localize selectively in the heart from the acute to subacute stage of viral myocarditis. These findings indicate that antimyosin scintigraphy is a reliable noninvasive method for the evaluation of patients suspected of having myocarditis.

Animal Models for Therapeutic Trials of Viral Myocarditis: Effect of Ribavirin and Alpha Interferon on Coxsackievirus B3 and Encephalomyocarditis Virus Myocarditis

Currently, the treatment of viral myocarditis is symptomatic and supportive, no specific therapy having yet been found. Therefore, we investigated the effects of antiviral agents, ribavirin and recombinant alpha interferon (IFN-α) on viral myocarditis using animal models of encephalomyocarditis (EMC) virus and coxsackievirus B3 myocarditis in mice (Matsumori and Kawai 1982, a, b).