Recent evidence suggests that the hepatic expression of heme oxygenase–1 (HO–1) may preserve hepatocellular integrity after hemorrhagic shock and resuscitation (HR). Because nitric oxide (NO) has been shown to modulate HO–1 expression in cultured cells in vitro, we determined its potential role in the regulation of HO–1 expression after HR in the rat liver in vivo. HO–1 mRNA and protein were highly induced and HO enzyme activity was higher after HR when compared with time–matched sham controls. Administration of the NO donor, molsidomine (MOL) (3 mg · kg-1), during resuscitation attenuated the accumulation of HO–1 mRNA and protein and the rise in HO activity. In addition, MOL prevented the shock–induced increase in DNA binding activity of the transcription factor, activator protein–1 (AP–1), but did not alter the activity of nuclear factor–erythroid 2 related factor (Nrf–2), nuclear transcription factor–κB (NF–κB), and hypoxia–inducible factor–1 (HIF–1). The suppressing action of MOL was not confined to HO–1, because the hepatic expression of the 70–kd major heat shock protein (HSP) in response to HR was also diminished. Moreover, MOL prevented the HR–induced increase in the serum activity of alanine transaminase (ALT) and α–glutathione–S–transferase (α–GST) that could otherwise be observed after HR. In contrast, the NO synthase inhibitor, Nω–nitro–l–arginine methyl ester (l–NAME) (1 mg · kg-1), had either no or only minor effects on the primary experimental endpoints. These findings would be consistent with a reduction of shock–induced liver damage by exogenous NO, which in turn prevents the subsequent activation of injury–sensitive transcription factors, thus attenuating the expression of stress–inducible proteins such as HO–1.