Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation

Oberti, Frédéric; Pilette, Christophe; Rifflet, H; Maïga, M. Y.; Moreau, Alain; Gallois, Yves; Girault, A; Bouil, Anne Le; Jeune, Jean‐Jacques Le; Saumet, J. L.; Feldmann, Gérard; Calès, Paul

doi:10.1016/s0168-8278(97)80473-4

Cited by 57 publications

(58 citation statements)

References 31 publications

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“…32,42 We recently showed that spironolactone decreased portal pressure and prevented PSS in BDL rats without reducing liver fibrosis. 9 In the present study, octreotide was shown to decrease portocollateral blood flow in two models of PHT caused by liver fibrosis. Octreotide may have two advantages over spironolactone: it limits the development of liver fibrosis, and it has fewer side-effects.…”

Section: Discussionsupporting

confidence: 51%

“…Indeed, we have previously shown that several parameters of PHT were correlated with the degree of liver fibrosis in the BDL model. 9 In rats with PHT, the main PSS is the splenorenal shunt, while the collateral esophageal venous network is poorly developed. 10 In this study, to measure splenorenal shunt blood flow, we used transit-time ultrasound (TTU), a technique that provides volumetric blood measurement flow using perivascular flow probes.…”

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confidence: 99%

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Antifibrotic and Hemodynamic Effects of the Early and Chronic Administration of Octreotide in Two Models of Liver Fibrosis in Rats

et al. 1998

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The aim of this study was to assess the effect of the early and chronic administration of octreotide in the prevention of hepatic fibrosis and portal hypertension (PHT). Two experimental models of liver fibrosis caused by bile duct ligation (BDL) or CCl 4 were divided into 4 rat groups: sham, placebo, and octreotide (10 and 100 g/kg twice daily, subcutaneously). Liver fibrosis was assessed by the area of fibrosis (image analysis), liver hydroxyproline and fibronectin mRNA contents, and serum hyaluronate. Systemic and splanchnic hemodynamic changes were also evaluated, including the splenorenal shunt blood flow by the transittime ultrasound (TTU) technique. In both models, splenorenal shunt blood flow was significantly lower in the octreotide groups than in the placebo group (P F .05), while portal pressure was not significantly decreased. There was a significant decrease in fibrosis by octreotide in the CCl 4 model only: area of fibrosis: 13.9% ؎ 3.7% vs. 9.8% ؎ 2.5% (P F .01), hydroxyproline: 1.8 ؎ 0.6 vs. 1.3 ؎ 0.4 mg/g wet liver (P F .05), respectively, placebo vs. octreotide 10 g/kg. There was a significant correlation between the area of fibrosis and hydroxyproline liver content (r ‫؍‬ .87 in the biliary model and r ‫؍‬ .91 in the CCl 4 model; P F .0001). The early and chronic administration of octreotide prevents the development of portocollateral blood flow without reducing portal pressure in two models of liver fibrosis and the development of liver fibrosis in the CCl 4 model. (HEPATOLOGY 1998;28:1525-1531

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Section: Discussionsupporting

confidence: 51%

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confidence: 99%

Antifibrotic and Hemodynamic Effects of the Early and Chronic Administration of Octreotide in Two Models of Liver Fibrosis in Rats

et al. 1998

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“…48 Another experimental study investigated the effect of simvastatin in BDL rats. 49 In this study, simvastatin (2.5 mg/kg body weight) administered for 4 weeks had no effect on the hemodynamics and fibrosis of cirrhotic rats. Simvastatin is a prodrug activated in the liver.…”

Section: Discussionmentioning

confidence: 55%

Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

Trebicka

Hennenberg

Laleman³

et al. 2007

Hepatology

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In cirrhosis, increased RhoA/Rho-kinase signaling and decreased nitric oxide (NO) availability contribute to increased intrahepatic resistance and portal hypertension. Hepatic stellate cells (HSCs) regulate intrahepatic resistance. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit synthesis of isoprenoids, which are necessary for membrane translocation and activation of small GTPases like RhoA and Ras. Activated RhoA leads to Rho-kinase activation and NO synthase inhibition. We therefore investigated the effects of atorvastatin in cirrhotic rats and isolated HSCs. Rats with secondary biliary cirrhosis (bile duct ligation, BDL) were treated with atorvastatin (15 mg/kg per day for 7 days) or remained untreated. Hemodynamic parameters were determined in vivo (colored microspheres). Intrahepatic resistance was investigated in in situ perfused livers. Expression and phosphorylation of proteins were analyzed by RT-PCR and immunoblots. Three-dimensional stress-relaxed collagen lattice contractions of HSCs were performed after incubation with atorvastatin. Atorvastatin reduced portal pressure without affecting mean arterial pressure in vivo. This was associated with a reduction in intrahepatic resistance and reduced responsiveness of in situ-perfused cirrhotic livers to methoxamine. Furthermore, atorvastatin reduced the contraction of activated HSCs in a 3-dimensional stress-relaxed collagen lattice. In cirrhotic livers, atorvastatin significantly decreased Rho-kinase activity (moesin phosphorylation) without affecting expression of RhoA, Rho-kinase and Ras. In activated HSCs, atorvastatin inhibited the membrane association of RhoA and Ras. Furthermore, in BDL rats, atorvastatin significantly increased hepatic endothelial nitric oxide synthase (eNOS) mRNA and protein levels, phospho-eNOS, nitrite/nitrate, and the activity of the NO effector protein kinase G (PKG). Conclusion: In cirrhotic rats, atorvastatin inhibits hepatic RhoA/Rhokinase signaling and activates the NO/PKG-pathway. This lowers intrahepatic resistance, resulting in decreased portal pressure. Statins might represent a therapeutic option for portal hypertension in cirrhosis. (HEPATOLOGY 2007;46:242-253.)

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“…In addition, attempts to verify this possibility in animal models of liver fibrosis have led to controversial findings. [19][20][21] The aim of this study was to evaluate the possible direct antifibrotic effects of canrenone, the active metabolite of spironolactone, in activated human HSC. This potential activity was evaluated by the well-established mitogenic and chemotactic effects exerted by platelet-derived growth factor (PDGF) 22,23 and the increased de novo synthesis of different extracellular matrix (ECM) components induced by transforming growth factor-␤1 (TGF-␤1).…”

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Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

et al. 2003

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Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation

Cited by 57 publications

References 31 publications

Antifibrotic and Hemodynamic Effects of the Early and Chronic Administration of Octreotide in Two Models of Liver Fibrosis in Rats

Antifibrotic and Hemodynamic Effects of the Early and Chronic Administration of Octreotide in Two Models of Liver Fibrosis in Rats

Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

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