Denopamine, a beta1-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-alpha production in the heart.
OBJECTIVE
This study was designed to examine the effects of denopamine, a selective beta1-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-alpha (TNF-alpha) 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 micromol/kg), denopamine (14 micromol/kg) with a selective beta1-blocker metoprolol (42 micromol/kg), or denopamine (14 micromol/kg) with metoprolol (84 micromol/kg) was given daily, and control mice received the vehicle only. Survival and myocardial histology on day 14 and TNF-alpha levels in the heart on day 6 were examined.


RESULTS
In the in vitro study, TNF-alpha 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-alpha 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-alpha 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-alpha via beta1-adrenoceptors.
Nishio
R
R
Department of Cardiovascular Medicine, Kyoto University, Japan.
Matsumori
A
A
Shioi
T
T
Wang
W
W
Yamada
T
T
Ono
K
K
Sasayama
S
S
D000318:Adrenergic beta-Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D018188:Cardiovirus Infections / Q000473:pathology*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004686:Encephalomyocarditis virus; D004983:Ethanolamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D006333:Heart Failure / Q000473:pathology*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D009205:Myocarditis / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D004983:Ethanolamines; D014409:Tumor Necrosis Factor-alpha; D008790:Metoprolol; C037293:denopamine