Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis

Lluch, Paloma; Torondel, Belén; Medina, Pascual; Segarra, Gloria; Olmo, Juan A. del; Serra, Miguel; Rodrigo, José

doi:10.1016/j.jhep.2004.03.016

Cited by 95 publications

(98 citation statements)

References 25 publications

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“…Similarly, acute NOS inhibition increases systemic vascular resistance in patients with decompensated cirrhosis and decreases plasma renin activity and urinary prostaglandin E2 excretion (56). Patients with cirrhosis and ascites have higher NO plasma concentrations than normal individuals or those with compensated cirrhosis, and high serum NO level correlates with high plasma RAAS activity and antidiuretic hormone levels as well as low urinary sodium excretion (57,58). The concentration of NO is higher in portal venous plasma than in peripheral venous plasma, suggesting increased splanchnic production of NO (59).…”

Section: Cytokines and Vasoactive Mediatorsmentioning

confidence: 99%

Hepatorenal Syndrome

Wadei

Martin

Ahsan

et al. 2006

Clinical Journal of the American Society of Nephrology

229

194

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Section: Cytokines and Vasoactive Mediatorsmentioning

confidence: 99%

Hepatorenal Syndrome

Wadei

Martin

Ahsan

et al. 2006

Clinical Journal of the American Society of Nephrology

229

194

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“…• synthesis and serum levels in various cirrhotic conditions [29][30][31][32] . Our study, including only alcoholic patients of different Child classes, strengthens previous investigations and adds further information with respect to the second messenger cGMP and its relationship with the redox state of GSH.…”

Section: Nomentioning

confidence: 99%

“…Recent studies by Lluch et al [29] suggest that the serum concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase is elevated in patients with alcoholic cirrhosis. This finding may offer an alternative compensatory mechanism to counteract the excessive visceral vasodilatation caused by excess production of NO…”

Section: Nomentioning

confidence: 99%

Elevated nitric oxide and 3',5' cyclic guanosine monophosphate levels in patients with alcoholic cirrhosis

Siqueira

Moura²,

Pedro³

et al. 2008

WJG

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AIM:To evaluate whether serum levels of nitric oxide (NO • ) and plasma levels of cyclic guanosine monophosphate (cGMP) and total glutathione (GSH) are altered in patients with alcoholic cirrhosis and to examine their correlation with the severity of liver disease. METHODS:Twenty-six patients with alcoholic liver cirrhosis were studied. Serum levels of NO• and plasma levels of cGMP and GSH were measured in 7 patients with compensated alcoholic cirrhosis (Child-Pugh A) and 19 patients with advanced cirrhosis (Child-Pugh B and C). The model for end-stage liver disease (MELD) score was evaluated. Sixteen healthy volunteers served as controls. Liver enzymes and creatinine levels were also tested. RESULTS: NO• and cGMP levels were higher in patients with Child-Pugh B and C cirrhosis than in Child-Pugh A cirrhosis or controls (NO • : 21.70 ± 8.07 vs 11.70 ± 2.74; 21.70 ± 8.07 vs 7.26 ± 2.47 µmol/L, respectively; P < 0.001) and (cGMP: 20.12 ± 6.62 vs 10.14 ± 2.78; 20.12 ± 6.62 vs 4.95 ± 1.21 pmol/L, respectively; P < 0.001). Total glutathione levels were lower in patients with Child-Pugh B and C cirrhosis than in patients with Child-Pugh A cirrhosis or controls (16.04 ± 6.06 vs 23.01 ± 4.38 or 16.04 ± 6.06 vs 66.57 ± 26.23 µmol/L, respectively; P < 0.001). There was a significant correlation between NO• and cGMP levels in all patients with alcoholic cirrhosis. A significant negative correlation between reduced glutathione/glutathione disulfide and the MELD score was found in all cirrhotic patients. CONCLUSION:Our results suggest a role for oxidative stress in alcoholic liver cirrhosis, which is more significant in decompensated patients with higher levels of NO• and cGMP and lower GSH levels than in compensated and control patients. Altered mediator levels in decompensated patients may influence the hemodynamic changes in and progression of liver disease.

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“…The levels of V-PYRRO/NO used in these studies (500 or 1000 μM) produced levels of NO (as measured by extracellular nitrite-see below) that are approximately 2∼ to 8∼ fold higher than the normal plasma levels of NO observed in control human subjects [21].…”

Section: Metabolic Integrity Assaymentioning

confidence: 92%

The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

Liu

Fuquay

et al. 2007

Cancer Letters

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Arsenite is an important cancer chemotherapeutic. The liver is a major target tissue of arsenic toxicity and hepatotoxicity may limit its chemotherapeutic efficacy. O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a liver-selective nitric oxide (NO)-producing prodrug metabolized by hepatic P450 enzymes to release NO locally. V-PYRRO/NO protects against various organic or inorganic hepatotoxicants but any role in arsenic hepatotoxicity is undefined. Thus, we studied the effects of V-PYRRO/NO (0-1000 μM) pretreatment on inorganic arsenic-induced toxicity in cultured rat liver (TRL 1215) cells. These cells metabolized the prodrug to release NO, producing extracellular nitrite levels to 41.7-fold above control levels (7.50 ± 0.38 μM) after 24 h V-PYRRO/ NO (1000 μM) exposure. The effect of pretreatment with V-PYRRO/NO (24 h) on the cytolethality of arsenic (as NaAsO 2 ) exposure (24 h) was assessed. Arsenic was markedly less toxic in V-PYRRO/ NO pretreated cells (LC 50 = 30.3 μM) compared to control (LC 50 = 20.1 μM) and the increases in LC 50 showed a direct relationship to the level of NO produced (measured as nitrite). Consistent with the cytolethality data, V-PYRRO/NO pretreatment markedly reduced arsenic-induced apoptosis as assessed by DNA fragmentation. Activation of the c-Jun N-terminal kinase (JNK) pathway can be critical to apoptosis and pretreatment with V-PYRRO/NO suppressed arsenic-induced JNK activation. V-PYRRO/NO pretreatment modestly increased metallothionein (MT), a metal-binding protein, but greatly enhanced arsenic induction of MT. Thus, V-PYRRO/NO pretreatment directly mitigates arsenic toxicity in cultured liver cells, reducing cytolethality, apoptosis and related JNK pathway activation, apparently through generation of NO. The role of NO in reducing the hepatotoxicity of arsenical chemotherapeutics in vivo deserves additional study.

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Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis

Cited by 95 publications

References 25 publications

Hepatorenal Syndrome

Hepatorenal Syndrome

Elevated nitric oxide and 3',5' cyclic guanosine monophosphate levels in patients with alcoholic cirrhosis

The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

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