Improvement of Portal Hypertension and Hepatic Blood Flow in Liver Cirrhosis by Estrogen

背景：在本研究中，我们研究了雌激素对肝硬化大鼠肝脏一氧化氮合酶活性和一氧化氮生成的影响。材料与方法：二甲基亚硝胺诱导肝硬化。二甲基亚硝胺治疗后第4周皮下注射戊酸雌二醇2次。此外，皮下注射雌激素受体拮抗剂ICI-182.780，给药前2天戊酸雌二醇。测量门静脉压和肝血流。用l -瓜氨酸生成法测定一氧化氮合酶活性。从肝硬化大鼠肝脏中分离并培养窦状内皮细胞。细胞用雌二醇和/或ICI-182.780孵育24小时。使用双醋酸二氨基荧光素-2获得血管内皮细胞一氧化氮的图像。结果：与对照组相比，经戊酸雌二醇治疗的肝硬化大鼠门静脉压力明显降低，肝脏血流量明显增加。然而，用ICI-182.780治疗的肝硬化大鼠，门静脉压的降低和肝血流量的升高被完全抑制。在用戊酸雌二醇治疗的肝硬化大鼠中，与对照肝硬化大鼠相比，一氧化氮合酶活性增加。在雌二醇刺激下培养的内皮细胞中，细胞内一氧化氮的荧光水平高于未处理的内皮细胞。结论：本研究提示雌激素在肝硬化大鼠肝窦内皮细胞一氧化氮生成增强和降低门脉压力中起重要作用。

Background : In this study, we investigated the effects of estrogen on nitric oxide synthase activity and nitric oxide production using the cirrhotic rat liver.Material and Methods : Cirrhosis was induced by dimethylnitrosamine. Estradiol valerate was subcutaneously injected 2 times at week 4 after dimethylnitrosamine treatment. Furthermore, subcutaneous injection of an estrogen receptor antagonist, ICI-182.780, was performed 2 days before administration of estradiol valerate. Portal pressure and hepatic blood flow were measured. Nitric oxide synthase activity was assessed by L-citrulline generation. Sinusoidal endothelial cells were isolated from the cirrhotic rat liver and cultured. The cells were incubated with estradiol and/or ICI-182.780 for 24 hours. Images for nitric oxide in sinusoidal endothelial cells were obtained using diaminofluorescein-2 diacetate.Results : Cirrhotic rats treated with estradiol valerate showed a significant decrease in portal pressure and a significant increase in hepatic blood flow compared to those of control cirrhosis rats. However, in cirrhotic rats treated with ICI-182.780, the reduction of portal pressure and elevation of hepatic blood flow were completely inhibited. In cirrhotic rats treated with estradiol valerate, nitric oxide synthase activity was increased compared to that in control cirrhotic rats. The fluorescent level of intracellular nitric oxide in estradiol-stimulated cultured sinusoidal endothelial cells was higher than that in non-treated sinusoidal endothelial cells.Conclusions : The present study indicated that estrogen plays an important role in the enhancement of nitric oxide production in sinusoidal endothelial cells of cirrhotic liver and reduces the portal pressure in cirrhotic rats.