Pyrrolidine dithiocarbamate, an antioxidant and a potent inhibitor of nuclear factor-kappa B (NF-kappaB), is known to have protective effect against ischemia and reperfusion injury. This study examined the cytoprotective mechanism of pyrrolidine dithiocarbamate against the microcirculatory failure caused by hepatic ischemia and reperfusion. Rats were subjected to 60 min of hepatic ischemia followed by 5 h of reperfusion. Pyrrolidine dithiocarbamate (100 mg/kg) or the vehicle was administered intraperitoneally 24 h before ischemia. The level of serum aminotransferases and hepatic lipid peroxides significantly increased, and the glutathione contents fell in the ischemia/reperfusion group. Pyrrolidine dithiocarbamate prevented the increase in the level of serum enzymes and hepatic lipid peroxides, and the decrease in the glutathione contents. The NF-kappaB DNA-binding activity was inhibited by a pre-treatment with pyrrolidine dithiocarbamate. Ischemia and reperfusion significantly increased the mRNA expression of the endothelin-1 and endothelin ET(B) receptor, which was prevented by pyrrolidine dithiocarbamate. There were significant increases in the mRNA expressions of inducible nitric oxide synthase, tumor necrosis factor-alpha, and cyclooxygenase-2, in the livers after ischemia and reperfusion. These increases were attenuated by the pyrrolidine dithiocarbamate treatment. In a rat model of hepatic ischemia and reperfusion, our results suggest that the hepatoprotective actions of pyrrolidine dithiocarbamate may be mediated in part through the modulation of imbalanced expression of vascular stress genes.