Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis

Zafra, Carmen; Abraldes, Juan G.; Turnés, Juan; Berzigotti, Annalisa; Fernández, Mercedes; García‐Pagán, Juan Carlos; Rodés, Juan; Bosch, Jaime

doi:10.1053/j.gastro.2003.12.007

Cited by 262 publications

(197 citation statements)

References 49 publications

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“…A previous study investigated the acute effect on portal hypertension of simvastatin, a prodrug activated after the liver first pass. 48 Patients with cirrhosis showed decreased intrahepatic resistance. 48 Another experimental study investigated the effect of simvastatin in BDL rats.…”

Section: Discussionmentioning

confidence: 99%

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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

277

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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Section: Discussionmentioning

confidence: 99%

“…48 Patients with cirrhosis showed decreased intrahepatic resistance. 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.…”

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

277

338

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“…24 However, the number of patients in the present and previous studies was too small for making final conclusions regarding drug tolerance in a rare condition such as PBC. Of note, statins have recently been suggested to be useful for the treatment of portal hypertension, 49 and further studies will have to explore their safety in patients with advanced PBC and cirrhosis. Our results indicate that patients with PBC should be closely monitored with serial liver function tests during atorvastatin therapy.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

et al. 2007

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Statin therapy may target both hypercholesterolemia and cholestasis in primary biliary cirrhosis (PBC). However, little is known about the efficacy and safety of statins in PBC. The aim of this single-center study was therefore to prospectively examine the effects of atorvastatin on serum markers of cholestasis, aminotransferases, and lipid and bile acid metabolism as well as inflammatory and immunological markers in patients with PBC. Fifteen patients with early-stage PBC and an incomplete biochemical response to ursodeoxycholic acid (UDCA) therapy (defined as alkaline phosphatase 1.5-fold above the upper limit of normal after 1 year) were treated with atorvastatin 10 mg/day, 20 mg/day, and 40 mg/day for 4 weeks, respectively. Serum levels of alkaline phosphatase increased during atorvastatin 20 mg and 40 mg (P < 0.05), whereas leucine aminopeptidase and ␥-glutamyltransferase remained unchanged. No statistical differences in overall serum ALT, AST, bilirubin, and IgM levels were observed. However, atorvastatin was discontinued in 1 out of 15 patients because of ALT 2-fold above baseline, and 2 patients showed ALT elevations 3-fold above the upper limit of normal at the end of the atorvastatin treatment period. Serum total cholesterol and low-density lipoprotein cholesterol levels decreased by 35% and 49%, respectively (P < 0.001). Precursors of cholesterol biosynthesis (lanosterol, desmosterol, lathosterol) showed a similar pattern. No changes in serum bile acid levels and composition were observed during treatment. Conclusion: Atorvastatin does not improve cholestasis in PBC patients with an incomplete biochemical response to UDCA but effectively reduces serum cholesterol levels. (HEPATOLOGY 2007;46:776-784.)

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“…8 Recent studies have shown that such increase can be attenuated by increasing hepatic NO delivery. 8,9 Altogether these data suggest an insufficient NO bioavailability as the cause of the impaired vasorelaxation in response to blood flow, which define what is known as endothelial dysfunction.…”

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confidence: 99%

Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension

et al. 2006

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Patients with cirrhosis show intrahepatic endothelial dysfunction, characterized by an impaired flow-dependent vasorelaxation. This alteration is responsible for the marked postprandial increase in portal pressure and is attributed to an insufficient release of nitric oxide (NO). Ascorbic acid reverts endothelial dysfunction in other vascular disorders, via the increase of NO bioavailability through the neutralization of superoxide anions, thus preventing the scavenging of NO by superoxide. This study examined whether acute ascorbic acid administration might improve endothelial dysfunction in cirrhosis. Thirty-seven portal hypertensive patients with cirrhosis had measurements of hepatic and systemic hemodynamics, ascorbic acid, and malondialdehyde (MDA). Patients were randomly allocated to receive ascorbic acid (3 g, intravenously, n ‫؍‬ 15) or placebo (n ‫؍‬ 12) followed by a liquid meal. A third group received ascorbic acid followed by a sham meal (n ‫؍‬ 10). Measurements were repeated after 30 minutes (hepatic venous pressure gradient at 15 and 30 minutes). Patients with cirrhosis had significantly lower ascorbic acid levels and higher MDA than healthy controls. Ascorbic acid significantly reduced MDA levels and markedly attenuated the postprandial increase in the hepatic venous pressure gradient (4% ؎ 7% vs. 18% ؎ 10% in placebo at 30 minutes, P < .001). Ascorbic acid followed by sham meal did not modify hepatic or systemic hemodynamics. In conclusion, patients with cirrhosis exhibited intrahepatic endothelial dysfunction, associated with decreased levels of ascorbic acid and increased levels of MDA. Ascorbic acid improved intrahepatic endothelial dysfunction, blunting the postprandial increase in portal pressure. These results encourage the performance of further studies testing antioxidants as adjunctive therapy in the treatment of portal hypertension. (HEPATOLOGY 2006;43:485-491.) P ortal hypertension is a serious consequence of cirrhosis and can result in life-threatening complications with increased mortality and morbidity. 1 Portal hypertension is determined by an increased resistance to portal-collateral blood flow and aggravated by an increased portal venous inflow, caused by splanchnic vasodilatation. 2 The primary factor in the pathophysiology of portal hypertension is increased resistance. 3 In cirrhosis, the increase in resistance occurs at the level of the hepatic microcirculation and is promoted by the morphological changes occurring in chronic liver diseases. In addition, the active contraction of different cell types that are able to constrict or relax in a reversible and graded manner in response to several stimuli promote a further increase or decrease in the intrahepatic resistance. 4 Insufficient nitric oxide (NO) production is considered a major pathogenic factor increasing intrahepatic vascular tone in cirrhosis. [5][6][7] The increased vascular tone is From the

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Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis

Cited by 262 publications

References 49 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

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension

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