Hepatic and splanchnic nitric oxide activity in patients with cirrhosis

Sarela, Abeezar; Mihaimeed, F.; Batten, J.; Davidson, Brian R; Mathie, Robert T.

doi:10.1136/gut.44.5.749

Cited by 106 publications

(64 citation statements)

References 41 publications

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“…Thus, plasma NO x Ϫ levels in the systemic circulation do not reflect well on the profound alterations in NO metabolism detected in liver parenchyma of patients with viral hepatitis, alcoholic cirrhosis, and cholestasis. Indeed, blood sampling from portal venous circulation may be necessary to get an insight into the changes in NO generation in the liver (14). In contrast to cirrhosis, a reduction of NO x Ϫ was observed in patients with acute liver necrosis, emphasizing the devastating effects of this syndrome on the generation of NO by NOS.…”

Section: Discussionmentioning

confidence: 99%

“…As with most proteins, the presence of mRNA for NOS isoforms provides indicative but not definitive evidence for the expression of enzyme activity. A recent study (14) reported that the activity of constitutive NOS in liver biopsies from cirrhotic patients was reduced. However, NOS proteins were not identified in this study, nor were there any correlations made between the activity of NOS and the underlying liver disorders.…”

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confidence: 99%

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Distribution of nitric oxide synthase in normal and cirrhotic human liver

McNaughton

Puttagunta

Martínez-Cuesta

et al. 2002

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

153

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Chronic liver disorders represent a serious health problem, considering that 300 million people worldwide are hepatitis B virus carriers, and 8,000 -10,000 patients per year, in the U.S. alone, die as a result of liver failure caused by hepatitis C infection. Nitric oxide synthase (NOS) regulates hepatic vasculature; however, the patterns of expression and activity of NOS proteins in healthy and diseased human livers are unknown. Sections of diseased (n ‫؍‬ 42) and control livers (n ‫؍‬ 14) were collected during orthotopic liver transplants and partial hepatectomy. The diseased sections included alcoholic cirrhosis, viral hepatitis, cholestasis, acute necrosis, and uncommon pathologies including ␣1-anti-trypsin disorder. The endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) were studied by using the citrulline assay, Western immunoblot, immunohistochemistry, and in situ hybridization. The systemic generation of plasma NO metabolites was measured by HPLC. In control livers, Ca 2؉ -dependent and -independent NOS activities were identified by Western analysis as eNOS and iNOS, respectively. The eNOS was uniformly distributed in the hepatocytes and also detected in the endothelium of hepatic arteries, terminal hepatic venules, sinusoids, and in biliary epithelium. The iNOS was detected in hepatocytes and localized mainly in the periportal zone of the liver acinus. This pattern of distribution of eNOS and iNOS in normal liver was confirmed by in situ hybridization. In diseased livers, there was a significant increase in Ca 2؉ -independent NOS with the corresponding strong appearance of iNOS in the cirrhotic areas. The eNOS was translocated to hepatocyte nuclei. Thus, eNOS and iNOS proteins are differentially expressed in healthy human liver, and this expression is significantly altered in cirrhotic liver disorders.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Distribution of nitric oxide synthase in normal and cirrhotic human liver

McNaughton

Puttagunta

Martínez-Cuesta

et al. 2002

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

153

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“…9 Studies on human cirrhosis have revealed that the activity of constitutive NO synthases is reduced in cirrhotic livers. 26 Even though the expression of endothelial NO synthases (eNOS) is increased in livers with cirrhosis, the activity of eNOS is reduced by promoting caveolin-eNOS binding, and NO production is impaired. 27 In our study, using the fluorescent dye, we were able to directly visualize the release of NO in the liver.…”

Section: Discussionmentioning

confidence: 99%

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

et al. 2004

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Metastases rarely occur in human livers with cirrhosis in clinical studies. We postulated that this phenomenon would also occur in experimental cirrhosis. Cirrhosis was established in C57BL/6 mice by carbon tetrachloride (CCl 4 ) gastrogavage. B16F1 melanoma cells were injected into the mesenteric vein to induce hepatic metastases. Contrary to our postulate, there was greater than 4-fold increase in metastasis in animals with cirrhosis compared to controls. Intravital videomicroscopy showed that the hepatic sinusoids were narrower and more tumor cells were retained in the terminal portal vein ( T he liver is a common site of metastatic tumor growth. Interestingly, the liver with cirrhosis has been reported to inhibit metastasis. 1 In clinical studies, colorectal cancers rarely metastasize to livers with cirrhosis. 2,3 Autopsy studies have shown that the rate of metastasis to such livers is lower than that to normal livers. 4,5 However, the mechanisms responsible for this result are not clear. Vanbockrijck and Kloppel suggested that the lower incidence of metastasis is due to a shorter life expectancy of patients with cirrhosis. 6 Seymour and Charnley considered that venovenous shunting in cirrhosis may prevent tumor cells from reaching the liver, and that changes in the architecture of cirrhotic sinusoids may reduce metastasis. 5 The activation of Kupffer cells in cirrhosis may also inhibit the formation of hepatic metastases. 7 Based on previous studies, the fate of metastatic cells in the liver is determined by the expression of hepatic microvasculature adhesion molecules and the release of endothelial-derived nitric oxide (NO). Specifically, the expression of inducible vascular adhesion molecules can cause tumor cell arrest in terminal portal vein (TPV) and increase metastasis. 8 Alternatively, tumor cell arrest in hepatic sinusoids can induce endothelial and hepatic NO release, causing tumor cell apoptosis and inhibiting metastasis. 9,10 We predicted these mechanisms would apply in a cirrhotic model. To examine this possibility, we established cirrhosis in C57BL/6 mice, using carbon tetrachloride (CCl 4 ) gastrogavage. Liver metastasis was induced by injecting B16F1 melanoma cells into the portal venous system. Surprisingly, we found a significant increase in metastasis of B16F1 melanoma cells in animals with cirrhosis. Our studies demonstrated that alterations

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“…Whole-body NO synthesis was increased in patients with cirrhosis and this is believed to be important in modulating the hyperdynamic circulation in these patients (Vallance & Moncada, 1991). Hepatic NO synthesis was, paradoxically, reported to be reduced in the diseased liver (Sarela et al 1999). Furthermore, it has been demonstrated that vascular responses to vasopressor agents were also impaired in these patients, and that this may be mediated through NO (Helmy et al 2003).…”

Section: Liver Failurementioning

confidence: 99%

“…In spite of a complex system of regulation (Rockey, 2003) and increased whole-body NO production in patients with cirrhosis (Vallance & Moncada, 1991), hepatic NO synthesis is, paradoxically, thought to be reduced in the diseased liver (Sarela et al 1999). Moreover, since impaired liver function decreases the hepatic breakdown of ADMA, liver failure results in increased concentrations of ADMA (Nijveldt et al 2003a,b), thereby potentially limiting hepatic NO production further.…”

Section: Liver Failurementioning

confidence: 99%

Pros and cons of L-arginine supplementation in disease

et al. 2004

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The amino acid arginine and one of its metabolites NO have gathered broad attention in the last decade. Although arginine is regarded as a conditionally essential amino acid in disease, L-arginine supplementation in severe illness has not found its way into clinical practice. This might be due to the invalid interpretation of results from studies with immune-enhancing diets containing L-arginine amongst other pharmaconutrients. However, not much attention is given to research using L-arginine as a monotherapy and the possibility of the alternative hypothesis: that L-arginine supplementation is beneficial in disease. The present review will discuss data from studies in healthy and diseased animals and patients with monotherapy of L-arginine to come to an objective overview of positive and negative aspects of L-arginine supplementation in disease with special emphasis on sepsis, cancer, liver failure and wound healing.

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Hepatic and splanchnic nitric oxide activity in patients with cirrhosis

Cited by 106 publications

References 41 publications

Distribution of nitric oxide synthase in normal and cirrhotic human liver

Distribution of nitric oxide synthase in normal and cirrhotic human liver

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

Pros and cons of L-arginine supplementation in disease

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