Recent evidence indicates that inhibition of the Na+/H + exchanger improves heart and brain injuries induced by l/R. Studies were performed to investigate whether FR183998, a Na+/H+ exchanger inhibitor, has protective effects on hepatic l/R injury in rats. Male Sprague-Dawley rats were subjected to 70% hepatic ischemia by occluding the hepatic artery, portal vein, and bile duct associated with the left and median liver lobes with a microvascular clip for 2 h. FR183998 (1 mg/kg) was administered i.v. 10 min before the hepatic ischemia. Hepatic l/R increased the serum levels of aspartate transaminase, alanine transaminase, and lactate dehydrogenase, which peaked at 9 h after reperfusion. FR183998 reduced these injury markers and recovered liver functions. Histopathologic analysis revealed that FR183998 prevented the incidences of hepatic necrosis, apoptosis, and neutrophil infiltration at 6 and 9 h (P< 0.05). FR183998 reduced the increases in proinflammatory cytokines such as TNF-α (1-6 h), IL-6 (1-12 h), interferon-γ (6-12 h), IL-1β (1-3 h), and cytokine-induced neutrophil chemoattractant 1 (1-3 h), but enhanced the anti-inflammatory cytokine IL-10 (1 h). FR183998 inhibited the hepatic l/R-induced activation of the transcription factor nuclear factor-κB at 1 to 6 h and reduced the induction of iNOS at 6 to 12 h, followed by inhibition of nitric oxide production. Furthermore, FR183998 decreased the expression of the iNOS gene antisense transcript, which is involved in the stability of iNOS messenger RNA, at 9 to 12 h in the liver of hepatic l/R rats. These results demonstrate that FR183998 reduces the induction of proinflammatory cytokines and iNOS at least in part through inhibition of nuclear factor-κB activation and iNOS antisense transcript expression, thereby preventing hepatic l/R injury.
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