Chang Ching-Chih, Lee Wen-Shin, Chuang Chiao-Lin, Hsin I-Fang, Hsu Shao-Jung, Chang Ting, Huang Hui-Chun, Lee Fa-Yauh, Lee Shou-Dong
Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
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.
Eur J Pharmacol. 2017 May 5;802:36-43. doi: 10.1016/j.ejphar.2017.02.039. Epub 2017 Feb 24.
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.
雷洛昔芬是一种选择性雌激素受体调节剂，已被广泛用于治疗骨质疏松症。除了治疗骨质疏松症的作用外，新出现的证据表明雷洛昔芬会影响不同组织的血管功能。肝硬化的特征是门静脉高压，并伴有肝性脑病。门静脉高压会影响门体分流，进而导致肝性脑病，而血管调节可能会影响肝性脑病的严重程度。在此，我们评估了雷洛昔芬对胆管结扎（BDL）诱导的肝硬化大鼠的影响。雌性Sprague-Dawley大鼠接受胆管结扎加卵巢切除术或假手术。四周后，大鼠分别分为2个亚组，接受雷洛昔芬（10mg/kg/天）或生理盐水（溶剂）治疗14天。在第43天，测量运动活动和血流动力学参数。测定肝脏和血管的mRNA和蛋白表达。检查肝脏的组织病理学变化。我们发现，给予或未给予雷洛昔芬的肝硬化大鼠之间的肝脏生化指标、氨水平和运动活动相似。除了雷洛昔芬减少门静脉流入量外，血流动力学参数没有显著差异。雷洛昔芬加剧了肝纤维化，并上调了肝脏内皮素-1和环氧化酶2蛋白的表达。此外，雷洛昔芬调节了肠系膜上动脉和侧支血管中内皮型一氧化氮合酶、环氧化酶和内皮素-1的mRNA表达。总之，雷洛昔芬会加重肝硬化大鼠的肝纤维化并减少门静脉流入量，而不会对门静脉高压和肝性脑病产生不利影响。肝脏和血管内皮素-1、内皮型一氧化氮合酶和环氧化酶表达的调节可能在这一机制中起作用。
