The effects of combination therapy with the immunomodulators OK432 (derived from the Su strain of Streptococcus pyogenes A3; 1 unit corresponds to 0.1 mg of dried streptococci dissolved in 0.1 ml of saline) and human recombinant interferon-alpha A/D (IFN) on cardiac atrial natriuretic peptide (ANP) gene expression and myocardial hypertrophy were examined in a murine model of viral myocarditis with congestive heart failure. Therapy was started 24 h after inoculation with encephalomyocarditis virus and was continued for 14 days. The plasma ANP concentration in untreated infected mice was significantly (P < .01) increased on day 10 (115 +/- 48 pg/ml) and day 30 (43 +/- 22 pg/ml) after inoculation relative to that in uninfected controls (5 +/- 4 pg/ml), whereas plasma ANP levels in treated mice were significantly (P < .01) reduced on day 10 (14 +/- 13 pg/ml) and day 30 (11 +/- 9 pg/ml) in comparison with untreated infected mice. The atrial and ventricular ANP messenger RNA (mRNA) concentrations in untreated mice showed increases of approximately 1.4- and 29.3-fold, respectively, on day 10 and increases of 1.8- and 34-fold, respectively, on day 30 compared with the concentration in uninfected controls. Combined OK432 and IFN significantly (P < .01) reduced the increase in ANP mRNA concentration in ventricles to 6.0- and 6.7-fold on days 10 and 30, respectively. Neither OK432 nor IFN monotherapy reduced the ANP mRNA concentrations in atria and ventricles compared with those in untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS)