Recent studies point to important interactions between proinflammatory cytokines and neurohumoral mediators in heart failure. Here we investigate the influence of the -adrenergic system on cytokines and neurohumoral factors and the sequelae of viral myocarditis. In an experimental model with virus-infected BALB/c mice, we tested the acute and chronic effects of adrenaline and propranolol on myocardial morphology, cytokine gene expression, arrhythmogenesis, and survival. BALB/c mice were inoculated with either the encephalomyocarditis virus (EMCV) or sham-incoculated with saline. The mice were then treated with adrenaline or propranolol. Histology and mortality were characterized during a follow-up period of 30 days. Adrenaline increased the severity of inflammatory cell infiltration and myocardial necrosis induced by EMCV myocarditis. The gene expression of tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6) and interleukin-10 (IL-10) were markedly enhanced by concomitant administration of adrenaline in EMCV-inoculated mice. Survival rate after 30 days was reduced from 70% for EMCV-only to 40% in adrenaline-treated EMCV- inoculated mice. Electrocardiograms indicated arrhythmias as the cause of death. A single dose of adrenaline, 0.6 mg/kg, administered 120 days after EMCV inoculation caused sudden death in 70% of the infected mice, but did not cause any mortality in non-infected control mice. Treatment with the b-blocker propranolol significantly decreased mortality, myocardial necrosis and infiltration of inflammatory cells in EMCV mice. Propranolol also protected EMCV-mice from lethal arrhythmias elicited by acute adrenaline administration and suppressed gene expression of TNF-, IL-6 and IL-10. These results indicate that both the acute and chronic stage of viral myocarditis are amenable to profound alterations by the -adrenergic system and its interactions with proinflammatory cytokines.