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Denopamine, a ß1-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor- production in the heart

^a Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan

View larger version (25K): [in a new window]   Figure 1 (A) Effect of increasing concentrations of denopamine on 1 µg/mL LPS-induced TNF- production in murine spleen cells. LPS-induced TNF- production was suppressed by denopamine in a concentration-dependent manner. Values are means ± SE of 9 cultures. *p < 0.05 versus the control culture stimulated by LPS. (B) Effect of denopamine and metoprolol on 1 µg/mL LPS-induced TNF- production in murine spleen cells. LPS-induced TNF- production was significantly suppressed by denopamine, 1 µmol/L. Metoprolol blocked the suppression of TNF- production in a concentration-dependent manner. Values are means ± SE of 4 cultures. *p < 0.05 versus the control stimulated by LPS, denopamine with metoprolol concentration of 10 µmol/L, or metoprolol alone (10 µmol/L).

View larger version (20K): [in a new window]   Figure 2 (A) Significant improvement by denopamine in survival of mice to day 14 after EMCV inoculation. = control group (n = 30); = 14 µmol/kg denopamine treatment group (n = 28). *p < 0.05 (B) Effect of denopamine on TNF- levels in the heart on day 7 and day 14. TNF- in the hearts of mice treated with denopamine (n = 17 on day 7; n = 7 on day 14) was significantly lower than in those of control animals (n = 11 on day 7; n = 6 on day 14). Solid bars = day 7; clear bars = day 14. Values are means ± SE. *p < 0.05 versus control group.

View larger version (127K): [in a new window]   Figure 3 Effects of denopamine on histopathologic changes at day 14. Myocardial lesions in mice treated with denopamine were significantly less than in control animals. (A) control animals. (B) denopamine-treated animals. Hematoxylin-eosin stain; original magnification: x12.

View larger version (22K): [in a new window]   Figure 4 (A) Effects of denopamine and metoprolol on survival of mice to day 14 after EMCV inoculation. Denopamine significantly improved the survival; the effect was significantly blocked by metoprolol at a concentration of 84 µmol/kg. = control group (n = 25); = denopamine, 14 µmol/kg + metoprolol, 84 µmol/kg treatment group (n = 20); = denopamine, 14 µmol/kg + metoprolol, 42 µmol/kg treatment group (n = 10); = denopamine alone, 14 µmol/kg treatment group (n = 25). *p < 0.05 versus control, or versus denopamine, 14 µmol/kg + metoprolol, 84 µmol/kg treatment group. (B) Effect of denopamine and metoprolol on TNF- levels in the heart on day 6. TNF- in the hearts of mice treated with denopamine was significantly lower than in those of control animals. The effect of denopamine was significantly blocked by metoprolol at a concentration of 84 µmol/kg. Values are means ± SE. N = 5 in each group. Deno = denopamine, 14 µmol/kg; low Meto = metoprolol, 42 µmol/kg; high Meto = metoprolol, 84 µmol/kg. *p < 0.05 versus control or 14 µmol/kg denopamine with 84 µmol/kg metoprolol treatment group.

View larger version (14K): [in a new window]   Figure 5 Significant, linear relationship between mortality from day 6 to day 14 and TNF- levels measured on day 6 (R = 0.98, n = 4, p < 0.05).