title: Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats.
abstract: Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal-systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)-induced cirrhotic rats. The female Sprague-Dawley rats received BDL plus ovariectomy or sham-operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up-regulated hepatic endothelin-1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin-1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin-1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism.
authors.affiliation: Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Ching-Chih
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chiao-Lin
authors.initials: CL
authors.lastname: Chuang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Hsin
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Shao-Jung
authors.initials: SJ
authors.lastname: Hsu
authors.affiliation: Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ting
authors.initials: T
authors.lastname: Chang
authors.affiliation: Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: hchuang2@vghtpe.gov.tw.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: fylee@vghtpe.gov.tw.
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Cheng-Hsin General Hospital, Taipei, Taiwan.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000641:Ammonia / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006501:Hepatic Encephalopathy / Q000150:complications* / Q000188:drug therapy*; D006975:Hypertension, Portal / Q000150:complications* / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D012333:RNA, Messenger; D020849:Raloxifene Hydrochloride; D000641:Ammonia
keywords: Hepatic encephalopathy; Liver cirrhosis; Portal hypertension; Raloxifene