Article Text

Intrahepatic upregulation of RhoA and Rho-kinase signalling contributes to increased hepatic vascular resistance in rats with secondary biliary cirrhosis
  1. Q Zhou*,
  2. M Hennenberg*,
  3. J Trebicka,
  4. K Jochem,
  5. L Leifeld,
  6. E Biecker,
  7. T Sauerbruch,
  8. J Heller
  1. Department of Internal Medicine I, University of Bonn, Bonn, Germany
  1. Correspondence to:
    Martin Hennenberg
    Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str 25, D-53105 Bonn, Germany; Martin.Hennenberg{at}


Background and aims: Portal hypertension in cirrhosis is mediated in part by increased intrahepatic resistance, reflecting an increased sensitivity of the hepatic microvasculature to vasoconstrictors. Activation of the RhoA/Rho-kinase pathway is essential for contraction of vascular smooth muscle. The aim of this study was to investigate RhoA/Rho-kinase mediated regulation of the intrahepatic vascular tone in cirrhotic rats.

Methods: Cirrhosis was induced by bile duct ligation (BDL). Hepatic RhoA and Rho-kinase expressions were studied by real time reverse transcription polymerase chain reaction and western blot analysis. Hepatic Rho-kinase activity in rat and human livers was assessed as phosphorylation of the Rho-kinase substrate moesin. The effect of the Rho-kinase inhibitor Y-27632 on hepatic perfusion pressure was measured in livers perfused at constant flow. The in vivo effect of intravenous application of Y-27632 was studied by haemodynamic measurements.

Results: Hepatic expressions of RhoA and Rho-kinase were increased at mRNA and protein level in BDL rats. Intrahepatic moesin phosphorylation was increased in livers from cirrhotic rats and patients with alcohol induced cirrhosis. Y-27632 reduced the basal perfusion pressure of in situ perfused livers in BDL rats but not in sham operated rats. Y-27632 reduced the sensitivity to methoxamine in isolated perfused livers in sham operated rats more than in BDL rats. In vivo, Y-27632 reduced portal pressure to a greater extent in BDL rats than in sham operated rats. Intrahepatic vascular resistance was decreased in response to bolus injection of Y-27632 in BDL rats but not in sham operated rats.

Conclusions: Upregulation of RhoA and Rho-kinase contributes to increased intrahepatic resistance in cirrhotic rats and to an increased sensitivity of cirrhotic livers to vasoconstrictors.

  • BDL, bile duct ligation
  • EC50, concentration producing a half maximal effect
  • HSC, hepatic stellate cell
  • PSS, porto-systemic shunting
  • RT-PCR, real time reverse transcription polymerase chain reaction
  • Y-27632, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexane carboxamide dihydrochloride, monohydrate
  • cirrhosis
  • portal hypertension
  • intrahepatic vascular resistance
  • RhoA
  • Rho-kinase

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  • Published online first 21 February 2006

  • * QZ and MH contributed equally to this paper.

  • Conflict of interest: None declared.

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