Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
Liver Int. 2015 Mar;35(3):704-12. doi: 10.1111/liv.12527. Epub 2014 Apr 12.
BACKGROUND & AIMS: Cirrhosis is characterized by increased intrahepatic vascular resistance and enhanced vasocontractile responsiveness that impedes portal inflow and elevates portal pressure, in which endothelin-1 (ET-1) plays a role. Diabetes and glucose influence vasoresponsiveness but their impact on the intrahepatic vascular bed in cirrhosis is unknown. To investigate intrahepatic ET-1 vasoresponsiveness in cirrhotic rats with and without diabetes and to explore the underlying mechanisms.
Spraque-Dawley rats received common bile-duct ligation (BDL) to induce cirrhosis. Streptozotocin was injected to induce diabetes in the BDL rats (BDL/STZ). In situ liver perfusion was performed to obtain the ET-1 concentration-response curves. The basic hemodynamics and hepatic protein expressions of ET-1 receptors, pERK, ERK, pAkt, Akt, iNOS, eNOS, peNOS and calmodulin were evaluated. The circulating concentrations of N-terminal pro-brain natriuretic peptide (NT-ProBNP), blood urea nitrogen (BUN) and creatinine were also determined.
Body weight, mean arterial pressure, heart rate and survival rate were significantly decreased in the BDL/STZ rats. The perfusion pressure changes in response to ET-1 were higher in the BDL/STZ group for all perfusates. ETA receptor and pERK expressions were enhanced in the BDL/STZ group. The circulating concentrations of NT-ProBNP, BUN and creatinine, as well as SMA flow, were not significantly different between the BDL and BDL/STZ groups.
Cirrhotic rats with diabetes showed higher intrahepatic ET-1 vasoresponsiveness than normoglycemic cirrhotic rats. This effect is not affected by changes in perfused glucose concentration and may be related, at least in part, to intrahepatic ETA R receptor and pERK over-expression.
肝硬化的特征是肝内血管阻力增加和血管收缩反应增强，这会阻碍门脉流入并升高门脉压，其中内皮素-1（ET-1）发挥作用。糖尿病和葡萄糖会影响血管反应性，但它们对肝硬化患者肝内血管床的影响尚不清楚。本研究旨在探讨糖尿病合并肝硬化大鼠肝内 ET-1 血管反应性，并探讨其潜在机制。
Spraque-Dawley 大鼠接受胆总管结扎（BDL）以诱导肝硬化。链脲佐菌素（Streptozotocin，STZ）注射于 BDL 大鼠以诱导糖尿病（BDL/STZ）。原位肝脏灌注以获得 ET-1 浓度-反应曲线。评估基本血流动力学和 ET-1 受体、pERK、ERK、pAkt、Akt、iNOS、eNOS、peNOS 和钙调蛋白的肝蛋白表达。还测定了循环中 N 端脑利钠肽前体（N-terminal pro-brain natriuretic peptide，NT-ProBNP）、血尿素氮（blood urea nitrogen，BUN）和肌酐的浓度。
BDL/STZ 大鼠的体重、平均动脉压、心率和存活率明显下降。BDL/STZ 组对所有灌注液的 ET-1 反应性灌注压变化更高。BDL/STZ 组 ETA 受体和 pERK 表达增强。BDL 和 BDL/STZ 组之间循环 NT-ProBNP、BUN 和肌酐浓度以及 SMA 流量无显著差异。
糖尿病合并肝硬化大鼠肝内 ET-1 血管反应性高于非糖尿病肝硬化大鼠。这种作用不受灌注葡萄糖浓度变化的影响，可能至少部分与肝内 ETA R 受体和 pERK 过度表达有关。
