The hepatic circulation in health and disease: Report of a single-topic symposium

Shah, Vijay H.; García‐Cardeña, Guillermo; Sessa, William C.; Groszmann, Roberto J.

doi:10.1002/hep.510270141

Cited by 69 publications

(51 citation statements)

References 112 publications

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“…A close relationship occurs between the progression of liver fibrosis and development of portal hypertension. In particular, the development of portal-central anastomosis and arterialization͞ capillarization of liver sinusoids represents the hallmark of the fibrogenic process as well as the key determinant for increased intrahepatic vascular resistance (2). Portal-central anastomoses are embedded in developing scar tissue where a complex interplay between several cell types and soluble mediators occurs.…”

Section: Portal Hypertension Resulting From Increased Intrahepatic Rementioning

confidence: 99%

“…This active contraction is caused mainly by an impaired production of NO that acts in the liver as an endogenous vasodilator (2). In experimental models of liver cirrhosis, as well as in cirrhotic patients, simultaneously with the excessive synthesis of NO in the systemic vasculature there is an impaired enzymatic function of liver eNOS despite the fixed expression of eNOS mRNA and protein (11,13).…”

Section: Discussionmentioning

confidence: 99%

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NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension

Fiorucci

Antonelli

Morelli

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

118

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Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension

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Section: Portal Hypertension Resulting From Increased Intrahepatic Rementioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension

Fiorucci

Antonelli

Morelli

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

118

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“…Mesenteric arteriolar vasodilatation and increased portal inflow play a major role in the development of portal hypertension in cirrhosis (Vorobioff et al, 1984;Shah et al, 1998). Various vasodilator compounds, including glucagon, adenosine, prostacyclin, NO, ␣-calcitonin gene-related peptide, and adrenomedullin have been proposed as mediators of the mesenteric vascular abnormalities that occur both in cirrhosis and in prehepatic portal hypertension (Shah et al, 1998;Gatta et al, 1999).…”

mentioning

confidence: 99%

“…Various vasodilator compounds, including glucagon, adenosine, prostacyclin, NO, ␣-calcitonin gene-related peptide, and adrenomedullin have been proposed as mediators of the mesenteric vascular abnormalities that occur both in cirrhosis and in prehepatic portal hypertension (Shah et al, 1998;Gatta et al, 1999). In cirrhotic rats, inhibition of NO synthesis greatly reduced mesenteric blood flow and hyporeactivity of the mesenteric circulation to vasoconstrictor agents (Sieber et al, 1993).…”

mentioning

confidence: 99%

Role of the Heme Oxygenases in Abnormalities of the Mesenteric Circulation in Cirrhotic Rats

Sacerdoti

Abraham²,

Oyekan³

et al. 2003

J Pharmacol Exp Ther

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Carbon monoxide (CO), a product of heme metabolism by heme-oxygenase (HO), has biological actions similar to those of nitric oxide (NO). The role of CO in decreasing vascular responses to constrictor agents produced by experimental cirrhosis induced by carbon tetrachloride was evaluated before and after inhibition of HO with tin-mesoporphyrin (SnMP) in the perfused superior mesenteric vasculature (SMV) of cirrhotic and normal rats and in normal rats transfected with the human HO-1 (HHO-1) gene. Perfusion pressure and vasoconstrictor responses of the SMV to KCl, phenylephrine (PE), and endothelin-1 (ET-1) were decreased in cirrhotic rats. SnMP increased SMV perfusion pressure and restored the constrictor responses of the SMV to KCl, PE, and ET-1 in cirrhotic rats. The relative roles of NO and CO in producing hyporeactivity of the SMV to PE in cirrhotic rats were examined. Vasoconstrictor responses to PE were successively augmented by stepwise inhibition of CO and NO production, suggesting a complementary role for these gases in the regulation of reactivity of the SMV. Expression of constitutive but not of inducible HO (HO-1) was increased in the SMV of cirrhotic rats as was HO activity. Administration of adenovirus containing HHO-1 gene produced detection of HHO-1 RNA and increased HO activity in the SMV within 7 days. Rats transfected with HO-1 demonstrated reduction in both perfusion pressure and vasoconstrictor responses to PE in the SMV. We propose that HO is an essential component in mechanisms that modulate reactivity of the mesenteric circulation in experimental hepatic cirrhosis in rats.

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“…Endothelin-1 (ET-1) and ET-3 were also measured because these vasoactive peptides can be released from the splanchnic circulation, 11 they are elevated in patients with cirrhosis, 11,12 and they may play a role in the local regulation of HBF. 13 …”

mentioning

confidence: 99%

Hepatic blood flow and splanchnic oxygen consumption in patients with liver failure. Effect of high-volume plasmapheresis

Clemmesen

Gerbes²,

Gülberg³

et al. 1999

Hepatology

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Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO 2,sp ) and oxygen consumption (VO 2,sp ) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 ؎ 0.78 L/min) and VO 2,sp (3.9 ؎ 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 ؎ 0.19 L/min, P F .01) and (2.3 ؎ 0.7 mmol/min, P F .001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 ؎ 1.19 L/min) and VO 2,sp (3.9 ؎ 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 ؎ 0.36 L/min, P F .005; and 2.0 ؎ 0.6 mmol/min, P F .005). During HVP, HBF increased from 1.67 ؎ 0.72 to 2.07 ؎ 1.11 L/min (n‫)11؍‬ in ALF, and from 1.89 ؎ 1.32 to 2.34 ؎ 1.54 L/min (n‫)7؍‬ in AOCLD, P F .05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 ؎ 2.5 vs. 6.6 ؎ 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 ؎ 650 vs. 2,020 ؎ 806 Dyne · s · cm ؊5 · m 2 , P F .01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 ؎ 2.8 to 10.1 ؎ 2.9 L/min (P F .01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n‫,)81؍‬ DO 2,sp increased by 15% (P F .05) whereas VO 2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P F .005) and VO 2,sp (P F .05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P F .05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO 2,sp . HVP further increased HBF and DO 2,sp but VO 2,sp was unchanged, indicating that splanchnic hypoxia was not present.(HEPATOLOGY 1999;29: 347-355.)A basic requirement for organ function is adequate blood flow and oxygen delivery. Hepatic blood flow (HBF) and splanchnic oxygenation in patients with liver failure (in the present study, defined as having developed hepatic encephalopathy [HE] grade II or more) have not been assessed because a method to estimate HBF in such patients has not been available until recently. 1,2 Knowledge in this field, therefore, rests on indirect evidence and animal experiments. The observation that whole-body (systemic) oxygen consumpti...

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The hepatic circulation in health and disease: Report of a single-topic symposium

Cited by 69 publications

References 112 publications

NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension

NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension

Role of the Heme Oxygenases in Abnormalities of the Mesenteric Circulation in Cirrhotic Rats

Hepatic blood flow and splanchnic oxygen consumption in patients with liver failure. Effect of high-volume plasmapheresis

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