Brief Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 28, 2013; 19(36): 6069-6076
Published online Sep 28, 2013. doi: 10.3748/wjg.v19.i36.6069
Glycyrrhizinate reduces portal hypertension in isolated perfused rat livers with chronic hepatitis
Xin Zhao, Bo Deng, Xue-Yan Xu, Shi-Jun Yang, Tao Zhang, Yi-Jun Song, Xiao-Ting Liu, Yue-Qi Wang, Da-Yong Cai
Xin Zhao, Bo Deng, Xue-Yan Xu, Shi-Jun Yang, Tao Zhang, Da-Yong Cai, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China
Yi-Jun Song, Xiao-Ting Liu, Yue-Qi Wang, School of Basic Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
Author contributions: Zhao X and Deng B contributed equally to this work; Zhao X, Deng B, Xu XY, Yang SJ, Zhang T, Song YJ and Liu XT acquired, analyzed, and interpreted data; Cai DY designed the study; Cai DY and Wang YQ did final approval of the version to be published.
Supported by The National Natural Science Foundation of China, No. 30873464; the Research Foundation from Ministry of Education of China, No. 108019; and the Natural Science Foundation of Beijing, China, No. 7132150
Correspondence to: Da-Yong Cai, Professor, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. dycai@implad.ac.cn
Telephone: +86-10-57833218 Fax: +86-10-62899715
Received: March 16, 2012
Revised: May 30, 2012
Accepted: June 8, 2012
Published online: September 28, 2013
Abstract

AIM: To investigate the effects of diammonium glycyrrhizinate (Gly) on portal hypertension (PHT) in isolated portal perfused rat liver (IPPRL) with carbon tetrachloride (CCl4)-induced chronic hepatitis.

METHODS: PHT model was replicated with CCl4 in rats for 84 d. Model was identified by measuring the ascetic amounts, hepatic function, portal pressure in vivo, splenic index, and pathological alterations. Inducible nitric oxide synthase (iNOS) in liver was assessed by immunohistochemistry. IPPRLs were performed at d0, d28, d56, and d84. After phenylephrine-induced constriction, Gly was geometrically used to reduce PHT. Gly action was expressed as median effective concentration (EC50) and area under the curve (AUC). Underlying mechanism was exploited by linear correlation between AUC values of Gly and existed iNOS in portal triads.

RESULTS: PHT model was confirmed with ascites, splenomegaly, serum biomarkers of hepatic injury, and elevated portal pressure. Pathological findings had shown normal hepatic structure at d0, degenerations at d28, fibrosis at d56, cirrhosis at d84 in PHT rats. Pseudo lobule ratios decreased and collagen ratios increased progressively along with PHT development. Gly does dose-dependently reduce PHT in IPPRLs with CCl4-induced chronic hepatitis. Gly potencies were increased gradually along with PHT development, characterized with its EC50 at 2.80 × 10-10, 3.03 × 10-11, 3.77 × 10-11 and 4.65×10-11 mol/L at d0, d28, d56 and d84, respectively. Existed iNOS was located at hepatocyte at d0, stellate cells at d28, stellate cells and macrophages at d56, and macrophages in portal triads at d84. Macrophages infiltrated more into portal triads and expressed more iNOS along with PHT development. AUC values of Gly were positively correlated with existed iNOS levels in portal triads.

CONCLUSION: Gly reduces indirectly PHT in IPPRL with CCl4-induced chronic hepatitis. The underlying mechanisms may relate to rescue NO bioavailability from macrophage-derived peroxynitrite in portal triads.

Keywords: Chronic hepatitis, Portal hypertension, Isolated portal perfused rat liver, Diammonium glycyrrhizinate, Inducible nitric oxide synthase