Ranitidine Reduces Ischemia/Reperfusion-Induced Liver Injury in Rats by Inhibiting Neutrophil Activation

Abstract

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-␣ (TNF-␣) in monocytes stimulated with lipopolysaccharide in vitro, whereas famotidine did not. Although hepatic ischemia/reperfusion-induced increases in hepatic tissue levels of TNF-␣, 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-␣, 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.

Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-Like Liver Injury in Rats

“…Interestingly, RAN attenuates liver injury after ischemia-reperfusion, probably by inhibiting release of cytotoxic factors by PMNs (Okajima et al, 2002). Previous studies demonstrated that RAN was nontoxic to hepatocytes even at high (e.g., 5 mM) concentrations (Zimmerman et al, 1986), and our results confirmed these findings (Fig.…”

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

“…Accordingly, PMNs require a secondary signal provided by RAN treatment to be activated and cause damage. RAN itself does not activate PMNs directly; in fact, it inhibits PMN activation both in vitro and in vivo (Okajima et al, 2000(Okajima et al, , 2002. This suggests that RAN acts indirectly through other inflammatory mediators produced during LPS exposure.…”

Histamine H 2 -Receptor Antagonist Ranitidine Protects Against Neural Death Induced by Oxygen-Glucose Deprivation

“…The possibility that ranitidine might act through other receptors besides HA-H 2 could not be excluded. 21 It is also possible that HA released from microglia or astroglia 22 during OGD could directly potentiate glutamate receptor-mediated cell death by interacting with the polyamine-binding site of the NMDA receptor complex. 8 Ranitidine could then be able to antagonize HA interaction with NMDA receptors.…”