Protective effect of S-nitrosylated α1-protease inhibitor on hepatic ischemia-reperfusion injury

Norisato Ikebe, Takaaki Akaike, Yoichi Miyamoto, Kazuyuki Hayashida, Jun Yoshitake, Michio Ogawa, Hiroshi Maeda

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53 Citations (Scopus)


S-Nitrosylated compounds (nitrosothiols; RS-NOs) function as nitric oxide (NO) reservoirs and preserve the antioxidant activities of NO. We found remarkable cytoprotection by an S-nitrosylated protease inhibitor from human plasma, S-nitroso-α1-protease inhibitor (S-NO-α1-PI) that possesses a completely nitrosylated SH group, in hepatic ischemia-reperfusion injuries in rats. Liver ischemia was induced in rats by occluding both the portal vein and hepatic artery for 30 min and was followed by reperfusion. S-NO-α1-PI and control compounds such as native α1-PI, an NO synthase (NOS) inhibitor, and standard RS-NOs were given via the portal vein just after reperfusion was initiated. Liver injury was evaluated by measuring the extracellular release of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). Infiltration of neutrophils and induction of apoptosis and heme oxygenase-1 (HO-1) in the liver were also examined. Maximal liver injury occurred at 3 h after reperfusion and then decreased gradually. Not only did S-NO-α1-PI treatment (0.1 μmol; 5.3 mg/rat) greatly reduce elevation of liver enzymes in plasma, as well as neutrophil accumulation and apoptotic change in liver, it also improved the impaired hepatic blood flow as assessed by laser Doppler flowmetry and potentiated the induction of HO-1 in the liver. Although native α1-PI moderately reduced liver injury, low molecular weight RS-NOs such as S-nitroso-glutathione and S-nitroso-N-acetyl penicillamine produced no obvious protective effect. An NOS inhibitor exacerbated the hepatic ischemia-reperfusion injuries. These results suggest that S-NO-α1-PI exerts a potent cytoprotective effect on ischemia-reperfusion liver injury by maintaining tissue blood flow, inducing HO-1, and suppressing neutrophil-induced liver damage and apoptosis.

Original languageEnglish
Pages (from-to)904-911
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - 2000


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