The Impact of a Nitric Oxide Synthase Inhibitor (L-NAME) on Ischemia⁻Reperfusion Injury of Cholestatic Livers by Pringle Maneuver and Liver Resection after Bile Duct Ligation in Rats

• Published in: International journal of molecular sciences 2019-04, Vol.20 (9), p.2114
• Main Authors: Iwasaki, Junji, Afify, Mamdouh, Bleilevens, Christian, Klinge, Uwe, Weiskirchen, Ralf, Steitz, Julia, Vogt, Michael, Yagi, Shintaro, Nagai, Kazuyuki, Uemoto, Shinji, Tolba, Rene H
• Format: Article
• Language: English
• Subjects: Arginine; Bile; bile duct ligation; Bile ducts; Cholestasis; Endothelial cells; Gallbladder diseases; Hepatectomy; Hepatocytes; Inflammation; Inhibitors; Ischemia; ischemia–reperfusion injury; Lipid peroxidation; Liver; NG-Nitroarginine methyl ester; Nitric oxide; Nitric-oxide synthase; Pringle maneuver; Reperfusion
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20092114

The Pringle maneuver (PM) has been widely used to control blood loss during liver resection. However, hepatic inflow occlusion can also result in hepatic ischemia-reperfusion injury (IRI), especially in patients with a cholestatic, fibrotic, or cirrhotic liver. Here we investigate a nitric oxide synthase (NOS) inhibitor N-Nitroarginine methyl ester (L-NAME) on IRI after the PM and partial hepatectomy of cholestatic livers induced by bile duct ligation (BDL) in rats. Control group (non-BDL/no treatment), BDL + T group (BDL/L-NAME treatment) and BDL group (BDL/no treatment) were analyzed. Cholestasis was induced by BDL in the L-NAME and BDL group and a 50% partial hepatectomy with PM was performed. L-NAME was injected before PM in the BDL + T group. Hepatocellular damage, portal venous flow, microcirculation, endothelial lining, and eNOS, iNOS, interleukin (IL)-6, and transforming growth factor-β (TGF-β) were evaluated. Microcirculation of the liver in the BDL + T group tended to be higher. Liver damage and apoptotic index were significantly lower and Ki-67 labeling index was higher in the BDL + T group while iNOS and TGF-β expression was decreased. This was corroborated by a better preserved endothelial lining. L-NAME attenuated IRI following PM and improved proliferation/regeneration of cholestatic livers. These positive effects were considered as the result of improved hepatic microcirculation, prevention of iNOS formation, and TGF-β mRNA upregulation.