Article Text
Abstract
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
Statistics from Altmetric.com
Footnotes
-
Published online first 21 February 2006
-
↵* QZ and MH contributed equally to this paper.
-
Conflict of interest: None declared.