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Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis.

Abstract：

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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Hennenberg M,Trebicka J,Stark C,Kohistani AZ,Heller J,Sauerbruch T

doi

10.1111/j.1476-5381.2009.00158.x

subject

Has Abstract

pub_date

2009-05-01 00:00:00

pages

258-70

issue

eissn

0007-1188

issn

1476-5381

pii

BPH158

journal_volume

157

pub_type

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Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis.