P327	Arterial hypotension and vascular hypocontractility in cirrhotic rats is associated with impairment of RhoA/Rho-kinase-mediated vasocontraction.
M.Hennenberg, J.Trebicka, K.Jochem, E.Biecker, T.Sauerbruch, J.Heller
Department of Internal Medicine I, University of Bonn, Bonn, DE.

Background: Cirrhosis of the liver is associated with impaired vascular reactivity to vasoconstrictors. This results in a decreased systemic and splanchnic vascular resistance, hyperdynamic circulation and portal hypertension. Complications resulting from portal hypertension are the main reasons for death in cirrhosis. The mechanisms of persistent vasodilation and decreased responsiveness to vasoconstrictors are not entirely understood so far. Using the animal model of rats with secondary biliary cirrhosis, we investigated the role of the RhoA/Rho-kinase pathway in impaired vasocontraction, which is associated with cirrhosis. Methods: Cirrhosis was induced by bile duct ligation (BDL), sham-operated rats served as controls. Contraction and relaxation of aortic rings were determined myographically. Aortic expressions of RhoA, Rho-kinase, and α-subunits of heterotrimeric G-proteins were analyzed by RT-PCR and immunoblots. Aortic RhoA-activation was examined by pull-down (GTP-RhoA) and membrane translocation. Rho-kinase activity was assessed as phosphorylation of its substrate, moesin (thr-558). The in vivo effect of Y-27632 (Rho-kinase inhibitor) was determined by hemodynamic measurements. Results: Methoxamine- (α1-adrenoceptor agonist) induced contraction of aortic rings from BDL rats was impaired, even after preincubation with L-NAME (inhibitor of NO-sythases). Aortic RhoA-expression was unchanged, whereas Rho-kinase was down-regulated posttranscriptionally. Methoxamine-induced RhoA-activation as well as methoxamine-induced and basal moesin-phosphorylation were reduced in aortas from BDL rats. Precontracted aortic rings from BDL rats showed increased sensitivity to relaxation with Y-27632, also after NOS-inhibition, endothelium-removal and chronic L-NAME-treatment (30 mg/kg/d,7d). Aortic protein-levels Gαq/11, Gα12 and Gα13 were unchanged. Systemic vascular resistance was lowered in BDL rats. The relative drop in SVR induced by Y-27632 (1mg/kg, i.v.) was larger in BDL rats than in controls. Conclusions: Impaired RhoA-activation and down-regulation of Rho-kinase contribute (independent from endogenous NO-production) to vascular hypocontractility and hypotension in rats with secondary biliary cirrhosis.

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