Studies on the hepatic sinusoidal circulation and bile secretion in portal hypertension

门脉高压症肝窦循环及胆汁分泌的研究

• 批准号: 10670509
• 负责人: WATANABE Norihito
• 金额: $ 2.05万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670509/
• 关键词: hepatic hemodynamics; hepatic microcirculation; portal hypertension; sinusoidal endothelial cell; SEF; endothelin-1; endothelin receptors; ethanol; 肝循環; 肝硬変; エンドセリン; BQ-123; video-enhanced microscopy

Endothelin (ET)-1, a potent vasoconstrictor is increased in liver cirrhosis, indicating that ET-1 may be involved in the pathophysiology of portal hypertension. Here we examined effects of ET (ET_A and ET_B) receptors antagonists on hepatic hemodynamics and SEF in normal and portal hypertensive rats. Methods : BQ-123, an ET_A receptor antagonist, or BQ-788, an ET_B receptor antagonist was infused to normal and cirrhotic rats at the rate of 10 nmol/min for 10 min. Ethanol was infused at the rate of 8 mg/min for 60 min. Portal pressure and hepatic tissue blood flow were measured using a hydromanometer and a laser Doppler blood flowmeter, respectively. Plasma ET-1 levels were determined by RIA.The sinusoids fixed by the perfusion technique were observed SEM.The expression of ET_A and ET_B receptors was examined by the indirect immunoperoxidase method. Results : Acute ethanol infusion caused a significant increase in portal pressure and decrease in hepatic tissue blood flow, and SEF were m … More arkedly decreased in number and in diameter. These ethanol-induced changes were inhibited by BQ-123. In cirrhotic rats, the portal pressure was markedly increased to be 16.6±1.5 cm H_2O, and plasma ET-1 levels became higher than those in normal. When BQ-123 was infused, the portal pressure showed a marked reduction by more than 2 cm H_2Oin both normal and cirrhotic rats. On the other hand, the decrease in portal pressure was not found in the BQ-788 infused groups. BQ-123 induced marked dilatation of SEF in zone 1 and zone 3. The diameter of SEF was almost three times longer than that of normal SEF.SEF were extremely decreased and almost disappeared in cirrhosis. However, SEF could be observed in some sinusoids by treatment with BQ-123. Immunohistochemically, ET-1 was evenly distributed alpng the sinusoidal walls in normal rats, and remarkably enhanced in cirrhosis. The expression of ET_A and ET_B were found to be augmented in cirrhosis. Conclusions : The action of ET-1 via ET_A receptors rather than ET_B receptors may be associated with the regulation of portal pressure as well as the motion of SEF in the hepatic microcirculation and in the mechanisms of portal hypertension. Less

内皮素（ET）-1是一种强有力的血管收缩剂，在肝硬化时升高，提示ET-1可能参与了门静脉高压症的病理生理过程。本文观察了ET_A和ET_B受体拮抗剂对正常和门脉高压大鼠肝脏血流动力学和SEF的影响。研究方法：正常大鼠和肝硬化大鼠分别以10 nmol/min的速率输注ET_A受体拮抗剂BQ-123或ET_B受体拮抗剂BQ-788 10 min，以8 mg/min的速率输注乙醇60 min，用液体压力计和激光多普勒血流计测定门静脉压力和肝组织血流量。采用放射免疫法测定血浆ET-1水平，扫描电镜观察灌流固定的血窦，间接免疫过氧化物酶法检测ET_A、ET_B受体表达。结果：急性乙醇灌注引起门静脉压力显著升高，肝组织血流量显著减少，SEF显著降低。 ...更多信息 数量和直径显著减少。这些乙醇诱导的变化被BQ-123抑制。实验组门静脉压力明显升高，达16.6± 1.5cmH_2O，血浆ET-1水平明显高于正常组。BQ-123可使正常大鼠和肝硬化大鼠的门静脉压力明显降低2cm H_2O以上。另一方面，在BQ-788输注组中未发现门静脉压力降低。BQ-123诱导1区和3区的SEF显著扩张。SEF直径约为正常SEF直径的3倍，肝硬化时SEF明显缩小，几乎消失。然而，用BQ-123处理可以在一些窦状隙中观察到SEF。免疫组化显示，正常大鼠肝窦壁ET-1分布均匀，肝硬化大鼠肝窦壁ET-1表达明显增强。ET_A、ET_B在肝硬化时表达增强。结论：ET-1通过ET_A受体而不是ET_B受体发挥作用，可能与门静脉压力的调节以及SEF在肝微循环中的运动有关，并参与了门静脉高压症的发病机制。少

项目成果

高清水眞二,渡辺勲史ら: "急性エタノール投与による肝微小循環障害機構-特に類洞内皮細胞小孔の変化について-" アルコールと医学生物学. 18. 75-83 (1998)

Shinji Takashimizu、Isao Watanabe 等人：“急性乙醇给药引起的肝脏微循环损伤的机制 - 特别是肝窦内皮细胞孔的变化”《酒精与医学生物学》18. 75-83 (1998)。

Shinji Takashimizu,Norihito Watanabe, et al: "Mechanisms of hepatic microcirculatory disturbances induced by acute ethanol administration in rats, with special reference to alterations of sinusoidal endothelial fenestrae."Alcohol Clin Exp Res. 23(4). 39s-

Shinji Takashimizu、Norihito Watanabe 等人：“大鼠急性乙醇给药诱导肝脏微循环紊乱的机制，特别是肝窦内皮窗孔的改变。”Alcohol Clin Exp Res。

Shinji Takashimizu, Norihito Watanabe, Yasuhiro Nishizaki, Kazuya Kawazoe, Koichi Shiraishi, Masayoshi Tokunaga, Akira Akatsuka and Shohei Matsuzaki: "Hepatic microcirculatory disturbances induced by acute ethanol administration in rats, with special refe

Shinji Takashimizu、Norihito Watanabe、Yasuhiro Nishizaki、Kazuya Kawazoe、Koichi Shiraishi、Masayoshi Tokunaga、Akira Akatsuka 和 Shohei Matsuzaki：“大鼠急性乙醇给药引起的肝微循环障碍，特别参考

Shinji Takashimizu,Norihito Watanabe, et al.: "Scanning electron microscopic studies on morphological abnormalities of erythrocytes in alcoholic liver diseases."Alcohol Clin Exp Res. 24(4). 81s-86s (2000)

Shinji Takashimizu、Norihito Watanabe 等人：“酒精性肝病中红细胞形态异常的扫描电子显微镜研究。”酒精临床实验研究。

Shinji Takashimizu, et al: "Mechanisms of hepatic microcirculatory disturbances induced by acute ethanol administration in rats"A lcoholism: Clinical and Experimental Research. 23・4. 39s-46s (1999)

Shinji Takashimizu 等人：“大鼠急性乙醇给药引起的肝脏微循环紊乱的机制”酒精中毒：临床和实验研究 23・4（1999）。