DENOPAMINE, A BETA-1-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

Objectives. This study was designed to examine the effects of denopami ne, a selective beta 1-adrenergic agonist, in a murine model of conges tive heart failure (CHF) due to viral myocarditis. Background. Positiv e inotropic agents are used to treat severe heart failure due to myoca rditis. However, sympathomimetic agents have not been found beneficial in animal models of myocarditis. Methods. In vitro: The effects of de nopamine on lipopolysaccharide-induced tumor necrosis factor-alpha (TN F-alpha) production was studied in murine spleen cells. In vivo: Four- week-old DBA/2 mice were inoculated with the encephalomyocarditis viru s (day 0). Denopamine (14 mu mol/kg), denopamine (14 mu mol/kg) with a selective beta 1-blocker metoprolol (42 mu mol/kg), of denopamine (14 mu mol/kg) with metoprolol (84 mu mol/kg) was given daily, and contro l mice received the vehicle only. Survival and myocardial histology on day 14 and TNF-alpha levels in the heart on day 6 were examined. Resu lts. In the in vitro study, TNF-alpha levels in treated cells were sig nificantly lower than in controls (p < 0.05). In the in vivo study tre atment with denopamine significantly improved the survival of the anim als (14 of 25 (56%) treated, vs 5 of 25 (20%) control mice), attenuate d 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 c ontrol mice, mean +/- SE). There was a strong linear relationship betw een mortality and TNF-alpha levels (r = 0.98, n = 4, p < 0.05). These in vitro and in vice effects of denopamine were significantly inhibite d by metoprolol. Conclusions. These results suggest that denopamine ma y exert its beneficial effects, in pact, by suppressing the production of TNF-alpha via beta 1-adrenoceptors. (J Am Coll Cardiol 1998;32:808 -15) (C)1998 by the American College of Cardiology.