Hemodynamic characterization of chronic bile duct-ligated rats: effect of pentobarbital sodium

Lee, S. S.; Girod, Catherine; Braillon, Alain; Hadengue, A.; Lebrec, Didier

doi:10.1152/ajpgi.1986.251.2.g176

Cited by 87 publications

(91 citation statements)

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“…40 Furthermore atorvastatin reduces in vitro contraction of activated hepatic stellate cells and inhibits hepatic RhoA/Rho-kinase and activates hepatic NO/cGMP/PKG signaling.…”

Section: Discussionmentioning

confidence: 99%

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

276

338

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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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“…40 Furthermore atorvastatin reduces in vitro contraction of activated hepatic stellate cells and inhibits hepatic RhoA/Rho-kinase and activates hepatic NO/cGMP/PKG signaling.…”

Section: Discussionmentioning

confidence: 99%

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

276

338

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“…The surgical procedure was performed under pentobarbital anesthesia, as previously described. 19 The hemodynamic study was performed 4 weeks after the surgical procedure. The fourth group contained 16 rats with carbon tetrachloride (CCl 4 )-induced cirrhosis.…”

Section: Methodsmentioning

confidence: 99%

Beneficial hemodynamic effects of bosentan, a mixed ETA and ETB receptor antagonist, in portal hypertensive rats

et al. 1998

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In patients with cirrhosis, the plasma level of endothelin, a potent vasoconstrictor peptide, is elevated, and endothelin plays a role in increased intrahepatic vascular resistance. Thus, the aim of this study was to evaluate the hemodynamic effects of bosentan, a mixed ET A and ET B endothelin receptor antagonist in three models of portal hypertension. In all groups of rats, endothelin (2 g/kg intravenously) administration significantly increased intrahepatic vascular resistance. In rats with secondary biliary cirrhosis, bosentan (30 mg/kg) significantly reduced portal pressure from 14.6 ؎ 1.2 to 12.1 ؎ 0.6 mm Hg, while portal blood flow and cardiac output increased by 45% and 57%, respectively. Thus, hepatocollateral vascular resistance decreased significantly from 177 ؎ 19 to 101 ؎ 9 dyn · s · cm ؊5 ؋ 10 ؊3 . Similar results were observed in rats with CCl 4 -induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 mol/L) had no significant effect on hepatic vascular resistance. In portal vein-stenosed rats, bosentan administration significantly decreased portal pressure from 13.1 ؎ 0.6 to 11.4 ؎ 0.5 mm Hg by reducing portosystemic vascular resistance, because bosentan had no effect on vascular resistance of normal rat liver. In conclusion, bosentan administration decreased portal pressure in vivo by reducing hepatocollateral vascular resistance in rats with cirrhosis. Thus, mixed endothelin receptor antagonists might be a new approach in the pharmacological treatment of portal hypertension. (HEPATOLOGY 1998;28:655-659.)Numerous studies have found that plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) are increased in patients with cirrhosis and are related to the severity of the liver disease. 1-8 Despite this, these patients have low arterial pressure and systemic vascular resistance. This discrepant finding may be caused, at least in part, by a vascular hyporesponsiveness to endothelins that has been identified in cirrhotic rats. 9,10 Moreover, it has been shown that endothelins induce sinusoidal vasoconstriction through both ET A and ET B receptors and increase intrahepatic vascular resistance in the normal and perfused cirrhotic liver. [11][12][13][14][15] These results suggest that endothelins play a role in the mechanism of intrahepatic portal hypertension. Thus, administration of the mixed ET A and ET B receptor antagonist, 16,17 bosentan, may decrease intrahepatic vascular resistance and decrease portal hypertension. The aim of this study was to evaluate the acute hemodynamic effect of both bosentan and endothelin in two animal models of cirrhosis and in one model with extrahepatic portal hypertension. MATERIALS AND METHODSAnimals. Sixty-four male Sprague-Dawley rats (Charles River Laboratories, Saint-Aubin-lès-Elbeuf, France) were divided into four groups. The first group contained 16 normal rats. The second group contained 16 rats with portal hypertension induced by the partial ligation of the portal vein, as previously described. 18 The hemodynamic study w...

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“…Estudos prévios têm demonstrado que no modelo equivalente de cirrose biliar secundária à ligadura do ducto biliar comum se estabelecem as características próprias da doença em torno de vinte e oito dias 12,13 . Neste período, encontram-se alterações provenientes da reação inflamatória causada pelo refluxo biliar, desorganização da arquitetura natural do parênquima com áreas inflamatórias presentes e, outras já com fibrose e deposição colágena, que são características que determinam a cirrose hepática.…”

Section: Fp Discussãounclassified

Uso de quercetina a longo prazo em ratos cirróticos

Miltersteiner

Filho

et al. 2003

Acta Cir. Bras.

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Hemodynamic characterization of chronic bile duct-ligated rats: effect of pentobarbital sodium

Cited by 87 publications

References 0 publications

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

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

Beneficial hemodynamic effects of bosentan, a mixed ETA and ETB receptor antagonist, in portal hypertensive rats

Uso de quercetina a longo prazo em ratos cirróticos

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