Hennenberg M, Trebicka J, Stark C, Kohistani A Z, Heller J, Sauerbruch T
Department of Internal Medicine I, University of Bonn, Germany.
Br J Pharmacol. 2009 May;157(2):258-70. doi: 10.1111/j.1476-5381.2009.00158.x. Epub 2009 Mar 26.
Extrahepatic vasodilation and increased intrahepatic vascular resistance represent attractive targets for the medical treatment of portal hypertension in liver cirrhosis. In both dysfunctions, dysregulation of the contraction-mediating Rho kinase plays an important role as it contributes to altered vasoconstrictor responsiveness. However, the mechanisms of vascular Rho kinase dysregulation in cirrhosis are insufficiently understood. They possibly involve mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-dependent mechanisms in extrahepatic vessels. As the multikinase inhibitor sorafenib inhibits ERK, we tested the effect of sorafenib on haemodynamics and dysregulated vascular Rho kinase in rats with secondary biliary cirrhosis.
Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Sorafenib was given orally for 1 week (60 mg.kg(-1).d(-1)). Messenger RNA levels were determined by quantitative real time polymerase chain reaction, protein expressions and protein phosphorylation by Western blot analysis. Aortic contractility was studied by myographic measurements, and intrahepatic vasoregulation by using livers perfused in situ. In vivo, haemodynamic parameters were assessed invasively in combination with coloured microspheres.
In BDL rats, treatment with sorafenib decreased portal pressure, paralleled by decreases in hepatic Rho kinase expression and Rho kinase-mediated intrahepatic vascular resistance. In aortas from BDL rats, sorafenib caused up-regulation of Rho kinase and an improvement of aortic contractility. By contrast, mesenteric Rho kinase remained unaffected by sorafenib.
Intrahepatic dysregulation of vascular Rho kinase expression is controlled by sorafenib-sensitive mechanisms in rats with secondary biliary cirrhosis. Thus, sorafenib reduced portal pressure without affecting systemic blood pressure.
肝外血管舒张和肝内血管阻力增加是肝硬化门静脉高压症药物治疗的有吸引力的靶点。在这两种功能障碍中，介导收缩的Rho激酶的失调起着重要作用，因为它导致血管收缩反应性改变。然而，肝硬化中血管Rho激酶失调的机制尚未完全了解。它们可能涉及肝外血管中丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）依赖性机制。由于多激酶抑制剂索拉非尼抑制ERK，我们测试了索拉非尼对继发性胆汁性肝硬化大鼠血流动力学和失调的血管Rho激酶的影响。
通过胆管结扎（BDL）诱导继发性胆汁性肝硬化。索拉非尼口服给药1周（60mg·kg⁻¹·d⁻¹）。通过定量实时聚合酶链反应测定信使核糖核酸水平，通过蛋白质印迹分析测定蛋白质表达和蛋白质磷酸化。通过肌电图测量研究主动脉收缩性，并使用原位灌注的肝脏研究肝内血管调节。在体内，结合彩色微球有创地评估血流动力学参数。
在BDL大鼠中，索拉非尼治疗降低了门静脉压力，同时肝Rho激酶表达和Rho激酶介导的肝内血管阻力降低。在BDL大鼠的主动脉中，索拉非尼导致Rho激酶上调和主动脉收缩性改善。相比之下，肠系膜Rho激酶不受索拉非尼影响。
在继发性胆汁性肝硬化大鼠中，血管Rho激酶表达的肝内失调受索拉非尼敏感机制控制。因此，索拉非尼降低了门静脉压力而不影响全身血压。
