간경변증 쥐 모델에서 산화질소 조절인자가 간내 산화질소의 활성에 미치는 영향

Abstract

Background: It is known that increased NO level in hepatic cirrhosis is closely related with the complications of hepatic cirrhosis such as ascites and hemorrhage at the esophageal varices. An interesting fact was that intraheptic vasodilation was not found in comparison to the increased NO level while the increased portal blood pressure was maintained. Some studies reported that the endothelial damage was very frequently accompanied and the reaction to vasodilators was reduced in the patients with hepatic cirrhosis. Thus, the reduced NO activity in tissues despite the excessive vasodilation in the general circulation blood is described as uncoupling. We investigate the changes of NO bioavailability in a hepatic cirrhosis model, and if an oxide modulator to enhance the NO bioavailability in tissues can also enhance that in intraheptic tissues. Method: The TAA was administered for 24 weeks to establish the hepatic cirrhosis model. (1) Control (normal chow, n=10); (2) TAA (thioacetoamide 24 weeks, n=10); (3) NOD (TAA 24 weeks with last one week Isosorbide mononitrate (Imdur®): 30mg in DW x 2 times/ day); (4) NAME (TAA 24 weeks with last one week NOS non-specific inhibitor : L-NAME (N-nitro-Larginine methyl ester, 30mg/kg in DW) x1 time/ day); (5) Statin (TAA 24 weeks with last one week HMG CoA reductase inhibitor (Simvastatin®): 10mg in DW x 1 time/ day); (6) BH4 (TAA 24 weeks with last one week tetrahydrobiopterin (BH4) (10mg/kg in DW) x 1 time/ day). All animal were allowed unrestricted access to water and to the standard chow. All animal were housed in a room under controlled temperature (23±2 ), ℃ humidity (45±5%), and lighting (12-hour artificial light and dark cycle). The weights and food intakes in each group of rats were recorded every week. Liver histology, realtime polymerase chain reaction (PCR) for eNOS, citrulline assay, and renal cGMP concentration were measured. Results: Expression of eNOS mRNA was significantly increased in the cirrhosis group than in the control group (p<0.05). Expression of eNOS mRNA was significantly higher in the NO donor group than in control group and cirrhosis group (p<0.05). Expression of eNOS mRNA was increased in the cirrhosis with BH4 than that of the control group (p<0.05). NO bioavailability was 467.2 pg/ml in the case group with NAME, and was lower than that of the control group. BH4 increased NO bioavailability significantly. In the statin group, NO activity was significantly lower than that of the cirrhosis group, being similar to that of the control group (71,326 vs. 50,450 cpm respectively, p<0.05). In the BH4 group, cGMP concentration was significantly increased when compared with that of the cirrhosis group (respectively, 11.6±2.3 vs. 20.1±1.4, p<0.05). Conclusion: Intraheptic NO bioavailability in the tissue was decreased in the cirrhosis and BH4 administration could increase intraheptic NO activity. Further study will be needed that increase of intraheptic NO bioavailability can be reduced intraheptic portal pressure.