Angiotensin II (AngII) increases oxidative stress and is associated with increased risk of sudden cardiac death. The cardiac Na⁺ channel promoter contains elements that confer redox sensitivity. We tested the hypothesis that AngII-mediated oxidative stress may modulate Na⁺ channel current through altering channel transcription. In H9c2 myocytes treated for 48 h with AngII (100 nmol/L) or H₂O₂ (10 µmol/L) showed delayed macroscopic inactivation, increased late current, and 59.6% and 53.8% reductions in Na⁺ current, respectively (P0.01). By quantitative real-time RT-PCR, the cardiac Na⁺ channel (scn5a) mRNA abundance declined by 47.3% (P<0.01) in H9c2 myocytes treated for 48 h with 100 nmol/L AngII. A similar change occurred with 20 µmol/L H₂O₂ (46.9%, P<0.01) after 48 h. Comparable effects were seen in acutely isolated ventricular myocytes. The effects of AngII could be inhibited by prior treatment of H9c2 cells with scavengers of reactive oxygen species or an inhibitor of the NADPH oxidase. Mutation of the scn5a promoter NF-B binding site prevented decreased activity in response to AngII and H₂O₂. Gel shift and chromosomal immunoprecipitation assays confirmed that NF-B bound to the scn5a promoter in response to AngII and H₂O₂. Overexpression of the p50 subunit of NF-B in H9c2 cells reduced scn5a mRNA (77.3%, P<0.01). In conclusion, AngII can decrease scn5a transcription and current. This effect appears to be through production of H₂O₂ resulting in NF-B binding to the Na⁺ channel promoter.