Abstract
The effect of NO‐metoprolol, that is, 3‐nitrooxypivaloyl metoprolol‐amide, a novel NO‐releasing derivative of the β1‐blocking drug metoprolol was investigated in A.CA/SnJ mice infected with coxsackievirus B3 (CVB3) and compared to metoprolol and placebo. Daily treatment of mice with the respective drug started immediately (experiment A) or 3 days after virus infection (experiment B) and was continued until day 13 post‐infection (p.i.). Two doses of NO‐metoprolol were administered. Body mass differences, viral load, and histopathological signs of myocarditis were compared between the several groups. As a result, NO‐metoprolol diminished significantly the body weight loss, the viral load and the histopathology, whereas metoprolol treatment led solely to a significant attenuation of myocardial damage. In experiment A, low dose NO‐metoprolol decreased significantly enteroviral copy numbers. Both doses of NO‐metoprolol had a significant effect on reduction of myocardial infiltrates and fibrosis. The data suggest that delayed drug administration might more advantageous. Both doses of NO‐metoprolol reduced significantly the scores of four tested parameters compared to placebo. Body weight loss, virus titers, plus‐strand as well as minus‐strand enteroviral RNA levels, infiltration and fibrosis scores were diminished significantly when NO‐metoprolol was given 3 days p.i. In addition, a significant difference regarding the enteroviral copy numbers was observed between low dose NO‐metoprolol‐ and metoprolol‐treated mice. Treatment with metoprolol reduced insignificantly the viral load and body weight loss (experiment A and B) but led to a significant reduction of myocardial histopathology in experiment A. The results indicate that NO‐metoprolol treatment has a greater therapeutic benefit than metoprolol. J. Med. Virol. 82:2043–2052, 2010. © 2010 Wiley‐Liss, Inc.