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Heller J, Trebicka J, Shiozawa T, Schepke M, Neef M, Hennenberg M, Sauerbruch T. Vascular, hemodynamic and renal effects of low-dose losartan in rats with secondary biliary cirrhosis.Liver International 2005: DOI: 10.1111/j.1478-3231.2005.01053.x.© Blackwell Munksgaard 2005In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response toα1-adrenoceptor agonists. Recently, the angiotensin II type 1-receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive toα1-adrenoceptor agonists.We studied, in rats with secondary biliary cirrhosis and sham-operated rats, the effect of 0.5 and 10 mg losartan/kg× day on aortic responsiveness toα1-adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function.In cirrhotic rats, 10 mg losartan/kg× day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg× day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis.In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness toα1-adrenoceptor agonists. [ABSTRACT FROM AUTHOR]

Biecker E, Neef M, Sägesser H, Shaw S, Koshy A, Reichen J. Nitric oxide synthase 1 is partly compensating for nitric oxide synthase 3 deficiency in nitric oxide synthase 3 knock-out mice and is elevated in murine and human cirrhosis. Liver International 2004: DOI: 10.1111/j.1478-3231.2004.0933.x. © Blackwell Munksgaard 2004 The role of endothelial nitric oxide synthase 3 (NOS-3) in the hyperdynamic circulation associated with cirrhosis is established but not that of the neuronal (NOS-1) isoform. We therefore investigated aortic NOS-1 levels in NOS-3 knock-out (KO) and wildtype (WT) mice and in hepatic arteries of patients. Mice rendered cirrhotic by bile duct ligation (BDL) were compared with sham-operated controls. Hepatic arteries of cirrhotic patients were collected during liver transplantation; donor vessels served as controls. mRNA levels were quantified by real-time PCR, protein levels by Western blotting and NO production by Nω-nitro- l-arginine methyl ester inhibitable arginine–citrulline assay. Aortae of NOS-3 KO mice exhibited higher NOS-1mRNA (5.6-fold, P<0.004) and protein levels (8.8-fold) compared with WT. NO production in aortae of NOS-3 KO mice was 52% compared with WT ( P=0.002). BDL increased NOS-1 mRNA (2.4-fold, P=0.01) and protein (7.1-fold) levels in aortae of WT, but no further in the NOS-3 KO mice. Hepatic artery NOS-1 mRNA levels in cirrhotic patients were markedly increased compared with controls (24.5-fold, P=0.0007). Increased NOS-1 mRNA and protein levels and partially maintained in vitro NO-production in aortae of NOS-3 KO mice suggest that NOS-1 may partially compensate for NOS-3 deficiency. BDL-induced increase in aortic NOS-1 mRNA and protein levels hint that not only NOS-3, but also NOS-1 may be involved in the regulation of systemic hyperdynamic circulation and portal hypertension. Upregulation of NOS-1 mRNA levels in hepatic arteries of portal hypertensive patients suggests possible clinical significance for these experimental findings. [ABSTRACT FROM AUTHOR]