P100	Dose-dependent effects of the AT1-receptor antagonist losartan on vascular NO/cGMP- and RhoA/Rho-kinase-mediated signaling in cirrhotic rats.
M.Hennenberg, J.Trebicka, T.Sauerbruch, J.Heller
Department of Internal Medicine I, University of Bonn, Bonn, DE.

Background: Cirrhosis is associated with vasodilation and hypotension (hyperdynamic circulatory syndrom), leading to increased splanchnic flow and portal hypertension. These hemodynamic changes are responsible for the main causes of death in cirrhosis. Angiotensin-II type1- (AT1-) receptor antagonists have been proposed for the pharmacological treatment of portal hypertension, however, this is discussed controversely. In the animal model of rats with secondary biliary cirrhosis, treatment of cirrhotic rats with low-doses of the AT1-receptor antagonist losartan partially reverses hyperdynamic circulation via improvement of vascular contractility and subsequent normalization of vascular resistance, without hypotensive side-effects. Contrary, high doses further worsens hypotension and hyperdynamic circulation. To study the molecular mechanisms underlying these dose-dependent losartan-actions in cirrhotic rats, we investigated the effect of chronic low- and high-dose losartan on vascular NO/cGMP- (mediating vasorelaxation) and RhoA/Rho-kinase-signaling (mediating vasocontraction) in cirrhotic rats. Methods: Cirrhosis was induced by bile duct ligation (BDL). Cirrhotic rats were treated with low-dose (0.5 mg/kg/d, one week) or high-dose (10 mg/kg) losartan, or remained untreated. Sham-operated rats served as controls. Aortic eNOS-mRNA and –protein levels were studied by RT-PCR and Western-blot. Activities of cGMP-dependent kinase (PKG) and Rho-kinase were assessed as phosphorylation of their substrates, vasodilator-stimulated phosphoprotein (VASP, ser-239), and moesin (thr-558)(Western-blot, immunohistochemistry, phospho- and total VASP and moesin). Results: Aortic levels of eNOS-mRNA, –protein and phospho-VASP were elevated in BDL rats compared to controls, but decreased after chronic low-dose losartan. High-dose losartan was without effect on aortic eNOS- and phospho-VASP-levels. VASP-phosphorylation in intrahepatic branches of hepatic artery and portal venules was increased in BDL rats, but virtually abolished after low-dose losartan. Aortic moesin-phosphorylation was decreased in BDL rats, but restored after low-dose losartan. High-dose losartan further decreased moesin-phosphorylation, even below levels of untreated BDL rats. Discussion: Normalization of vascular PKG- and Rho-kinase-activity might account for the improvement of vascular contractility after low-dose losartan-treatment of cirrhotic rats.

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