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CLINICAL STUDIES

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

Manuscript received October 2, 1996; revised manuscript received May 13, 1998, accepted May 14, 1998.

Address for correspondence: Dr. Akira Matsumori, Department of Cardiovascular Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606, Japan

Objectives. This study was designed to examine the effects of denopamine, a selective ß1-adrenergic agonist, in a murine model of congestive heart failure (CHF) due to viral myocarditis.

Background. Positive inotropic agents are used to treat severe heart failure due to myocarditis. However, sympathomimetic agents have not been found beneficial in animal models of myocarditis.

Methods. In vitro: The effects of denopamine on lipopolysaccharide-induced tumor necrosis factor- (TNF-) production was studied in murine spleen cells. In vivo: Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus (day 0). Denopamine (14 µmol/kg), denopamine (14 µmol/kg) with a selective ß1-blocker metoprolol (42 µmol/kg), or denopamine (14 µmol/kg) with metoprolol (84 µmol/kg) was given daily, and control mice received the vehicle only. Survival and myocardial histology on day 14 and TNF- levels in the heart on day 6 were examined.

Results. In the in vitro study, TNF- levels in treated cells were significantly lower than in controls (p < 0.05). In the in vivo study treatment with denopamine significantly improved the survival of the animals (14 of 25 (56%) treated, vs 5 of 25 (20%) control mice), attenuated myocardial lesions, and suppressed TNF- production (66.5 ± 7.5 pg/mg of heart in treated mice vs 113.5 ± 15.1 pg/mg of heart in control mice, mean ± SE). There was a strong linear relationship between mortality and TNF- levels (r = 0.98, n = 4, p < 0.05). These in vitro and in vivo effects of denopamine were significantly inhibited by metoprolol.

Conclusions. These results suggest that denopamine may exert its beneficial effects, in part, by suppressing the production of TNF- via ß1-adrenoceptors.

Abbreviations and Acronyms   CHF = congestive heart failure   EMCV = encephalomyocarditis virus   TNF- = tumor necrosis factor-   LPS = lipopolysaccharide   ELISA = enzyme-linked immunosorbent assay   BW = body weight   HW = heart weight

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