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Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis
Author(s) -
Hennenberg M,
Trebicka J,
Stark C,
Kohistani AZ,
Heller J,
Sauerbruch T
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00158.x
Subject(s) - sorafenib , medicine , portal venous pressure , cirrhosis , endocrinology , rho associated protein kinase , portal hypertension , kinase , protein kinase a , vascular resistance , mapk/erk pathway , cancer research , blood pressure , hepatocellular carcinoma , biology , microbiology and biotechnology
Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusions and implications: 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.