DIFFERENTIAL-EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITORS ON ENDOTOXIN-INDUCED LIVER-DAMAGE IN RATS

Background & Aims: During endotoxemia, expression of inducible nitric oxide synthase (iNOS) and nitric oxide production in the liver is incr eased, NO has been suggested to have a hepatoprotective function. The aim of this study was to investigate the distribution of iNOS and the effect of different NO synthase inhibitors on liver damage and hemodyn amics during endotoxemia. Methods: Rats were injected with lipopolysac charide (LPS) and received the NOS-inhibitor S-methylisothiourea (SMT) or NG-nitro-L-arginine methyl ester (L-NAME). iNOS induction was asse ssed by Western blot, immunohistochemistry, and measurement of NO meta bolites in plasma and bile. Liver damage was determined by aspartate a minotransferase and alanine aminotransferase and by histology. The eff ects of both inhibitors on systemic and portal pressure were measured in normal and LPS-treated rats. Results: LPS treatment strongly induce d iNOS in inflammatory cells, macrophages, bile duct epithelium, and h epatocytes, especially at the canalicular membrane, LPS-induced liver damage strongly increased after L-NAME. SMT caused a similar reduction of NO production without enhancing liver damage. In LPS-treated rats, SMT increased the systemic and portal pressure significantly more tha n L-NAME. Conclusions: During endotoxemia, administration of the NOS-i nhibitor L-NAME aggravates liver damage. This liver damage does not se em to be caused by hemodynamic changes, In contrast, SMT caused signif icant hemodynamic changes but did not increase LPS-induced liver damag e.