Cardioprotective effect of NO-metoprolol in murine coxsackievirus B3-induced myocarditis.
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.
Glück
Brigitte
B
Department of Virology and Antiviral Therapy, Jena University Hospital, Jena, Germany. Brigitte.Glueck@med.uni-jena.de
Dahlke
Katja
K
Zell
Roland
R
Krumbholz
Andi
A
Decker
Michael
M
Lehmann
Jochen
J
Wutzler
Peter
P
D058671:Adrenergic beta-1 Receptor Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D029822:Enterovirus B, Human / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000821:virology; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D016896:Treatment Outcome
D058671:Adrenergic beta-1 Receptor Antagonists; D009569:Nitric Oxide; D008790:Metoprolol