Ranitidine reduces ischemia/reperfusion-induced liver injury in rats by inhibiting neutrophil activation.

We previously reported that ranitidine, an H(2) receptor antagonist, inhibited neutrophil activation in vitro and in vivo, contributing to reduce stress-induced gastric mucosal injury in rats. In this study, we examined whether ranitidine would reduce ischemia/reperfusion-induced liver injury, in which activated neutrophils are critically involved, in rats. We also examined the effect of famotidine, another H(2) receptor antagonist, on leukocyte activation in vitro and after ischemia/reperfusion-induced liver injury in rats to know whether inhibition of neutrophil activation by ranitidine might be dependent on its blockade of H(2) receptors. Ranitidine inhibited the activation of neutrophils in vitro as reported previously, whereas famotidine significantly enhanced it. Ranitidine inhibited the production of tumor necrosis factor-alpha (TNF-alpha) in monocytes stimulated with lipopolysaccharide in vitro, whereas famotidine did not. Although hepatic ischemia/reperfusion-induced increases in hepatic tissue levels of TNF-alpha, cytokine-induced neutrophil chemoattractant, and hepatic accumulation of neutrophils were inhibited by intravenously administered 30 mg/kg ranitidine, these increases were significantly enhanced by 5 mg/kg i.v. famotidine. The decreases in both hepatic tissue blood flow and bile secretion and the increases in serum levels of transaminases seen after reperfusion were significantly inhibited by ranitidine, whereas these changes were more marked in animals given famotidine than in controls. These observations strongly suggested that ranitidine could reduce ischemia/reperfusion-induced liver injury by inhibiting neutrophil activation directly, or indirectly by inhibiting the production of TNF-alpha, which is a potent activator of neutrophils. Furthermore, the therapeutic efficacy of ranitidine might not be explained solely by its blockade of H(2) receptor.