Increased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation

doi:10.1016/0270-9139(95)90189-2

Hepatology

Volume 22, Issue 6, December 1995, Pages 1666-1673

https://doi.org/10.1016/0270-9139(95)90189-2 Get rights and content

Abstract

An increased release of nitric oxide (NO), a powerful vasodilating agent, has been proposed to play a role in the pathogenesis of vasodilation and hyperdynamic circulation associated with advanced cirrhosis. We evaluated NO synthase (NOS) activity in peripheral leukocytes of 12 cirrhotic patients and 9 healthy subjects together with plasma endotoxin levels and systemic hemodynamic (by a noninvasive echocardiographic method). NOS activity was evaluated by (1) measuring the capacity of isolated polymorphonuclear cells (PMNs) and monocytes to convert [³[H]arginine to [³[H]citrulline; (2) measuring the ability of neutrophils and monocytes to inhibit thrombin-induced platelet aggregation and to increase guanosine 3′-5′-cyclic monophosphate content in coincubated platelets, an expression of NO release from these cells. Both neutrophils and monocytes from cirrhotic patients produced significantly higher amounts of [³h]citrulline than cells obtained from healthy subjects (P < .001 and P < .02 for neutrophils and monocytes, respectively) and were more effective than control cells in inhibiting platelet aggregation (P < .05 and P < .001, respectively for 2 ×10⁶ cells) and in increasing guanosine 3′-5′-cyclic monophosphate content in coincubated platelets (P < .05 and P < .001, respectively). The anti-aggregating activity expressed by leukocytes has a pharmacological profile similar to that described for NO, because it increased after addition of superoxide dismutase, a superoxide anion scavenger, and markedly decreased after inhibition of nitric oxide synthesis with N^G-monomethyl-l-arginine (L-NMMA) and N^G-nitro-l-arginine-methyl ester (LNAME). Cirrhotic patients had significantly higher plasma endotoxin levels (P < .001) and cardiac index (P < .01) when compared with controls. These data support the contention that the NO synthetic pathway is activated in cirrhotic patients with ascites, hyperdynamic circulation, and endotoxemia.

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Patients with cirrhosis and ascites have higher plasma NO concentration compared with control subjects, and it is higher in the portal venous plasma than in peripheral venous blood22. The activity of nitric oxide synthetase (NOS) in polymorphonuclear cells and monocytes was increased in patients with cirrhosis with ascites23, suggesting a potential role of the inducible NOS (iNOS). Other studies rather suggested a pathogenic role of the endothelial NOS (eNOS)24.
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Experimental data suggest that in liver cirrhosis splanchnic and systemic vasculature exhibit marked endothelial Carbon monoxide (CO) overproduction, while recent data demonstrated heme oxygenase (HO) hyperactivity in the liver of rats with cirrhosis. No data are so far available on CO levels in the hepatic veins of cirrhotic patients. We aimed at evaluating whether plasma CO levels differ between systemic (peripheral vein) and hepatic (hepatic vein) circulation in patients with viral cirrhosis with and without ascites.
We enrolled 31 consecutive non-smoking in- or outpatients with liver cirrhosis. We measured wedge (occluded, WHVP) and free hepatic venous pressures (FHVP) and hepatic-vein pressure gradient (HVPG) was the calculated. Plasma level of NO and plasma CO concentration were determined both in peripheral vein and in the hepatic vein in cirrhotics.
In cirrhotic patients plasma CO levels were significantly higher in the hepatic vein (16.66 ± 10.71 p.p.m.) than in the peripheral vein (11.71 ± 7.00 p.p.m). Plasma NO levels were significantly higher in peripheral vein (97.02 ± 21.11 μmol/ml) than in the hepatic vein (60.76 ± 22.93 μmol/ml).
In patients with liver cirrhosis we documented a hepato-systemic CO gradient as inferred by the higher CO values in the hepatic vein than in the peripheral vein. In cirrhotic patients, CO and NO exhibit opposite behavior in the liver, while both molecules show increased values in the systemic circulation. It can be speculated that increased intra-hepatic CO levels might represent a counterbalancing response to reduced NO intra-hepatic levels in human liver cirrhosis.
Ascites
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Citation Excerpt :
Die NO-Konzentrationen im portalvenösen Blut sind höher als im peripheren venösen Kreislauf, was eine gesteigerte NO-Synthese in der splanchnischen Zirkulation nahelegt [18]. Patienten mit Leberzirrhose und Aszites zeigen sowohl eine gesteigerte Endotoxin-induzierte Freisetzung von NO als auch eine vermehrte Aktivität der NO-Synthase in neutrophilen Granulozyten und Monozyten [19]. Die derzeitige Datenlage spricht dafür, dass NO eine wichtige Rolle in der Pathogenese des zirrhotischen Aszites hat.
Aszites bezeichnet die pathologische Ansammlung von Flüssigkeit in der Peritonealhöhle. Ätiologisch können verschiedene Aszitesformen unterschieden werden: portaler (z.B. bei Leberzirrhose), kardialer (z.B. bei Rechtsherzinsuffizienz), maligner (z.B. bei Peritonealkarzinose), inflammatorischer/infektiöser (z.B. bei Tuberkulose) und chylöser Aszites (bei Schädigung der Lymphgefäße). Die Leberzirrhose ist die häufigste Ursache des Aszites. Bei der Anamnese sollte gezielt nach einer Vergrößerung des Bauchumfangs gefragt werden. Der abdominelle Ultraschall ist das bildgebende Verfahren der Wahl, um auch kleinste Aszitesmengen darzustellen. Die Parazentese ist der Goldstandard zur weiteren Beurteilung des Aszites mit biochemischen, zytologischen und bakteriologischen Verfahren. Komplikationen des Aszites sind vor allem die spontane bakterielle Peritonitis (SBP), das hepatorenale Syndrom und der hepatische Hydrothorax. Therapie und Prognose des Aszites richten sich nach der Grunderkrankung.
Ascites denotes the accumulation of fluid in the peritoneal cavity. Different types of ascites can be distinguished depending on its aetiology: portal (e.g. in liver cirrhosis), cardial (e.g. in right heart failure), malignant (e.g. in peritoneal carcinosis), inflammatory or infectious (e.g. in tuberculosis), and chylous ascites (due to injury to the lymphatic vessels). Liver cirrhosis is the most common cause of ascites. During anamnesis the patient should be asked if there has been an increase of the abdominal girth. Abdominal ultrasound is the medical imaging of choice in order to discover even the smallest amount of ascites. Paracentesis is the gold standard for further analysis of ascites through biochemical, cytological and bacteriological procedures. Complications of ascites include primarily spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, and hepatic hydrothorax. Treatment and prognosis of ascites depend on the underlying disease.
Superimposed Coagulopathic Conditions in Cirrhosis: Infection and Endogenous Heparinoids, Renal Failure, and Endothelial Dysfunction
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First, endotoxins lead to an increase in portal pressure by contracting hepatic stellate cells through the induction of endothelin.14 Second, the release of nitric oxide (NO)15–17 and prostacyclin18,19 inhibits platelet aggregation. Indeed, infection may lead to abnormalities in coagulation through multiple pathways.
In this article, the authors discuss three pathophysiologic mechanisms that influence the coagulation system in patients who have liver disease. First, bacterial infections may play an important role in the cause of variceal bleeding in patients who have liver cirrhosis, affecting coagulation through multiple pathways. One of the pathways through which this occurs is dependent on endogenous heparinoids, on which the authors focus in this article. Secondly, the authors discuss renal failure, a condition that is frequently encountered in patients who have liver cirrhosis. Finally, they review dysfunction of the endothelial system. The role of markers of endothelial function in cirrhotic patients, such as von Willebrand factor and endothelin-1, is discussed.

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^☆: This study was supported in part by The Italian Ministry of University and Scientific and Technological Research, Rome, Italy, and the Italian Liver Foundation, Florence, Italy.

^☆☆: Portions of this work were presented in abstract form at the annual meeting of the American Association for the Study of Liver Disease, Chicago, IL, November 3–7, 1993.

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Other clinical studyIncreased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation☆,☆☆

Abstract

Lancet

Cell

Biochem Biophys Res Commun

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

FEBS Lett

J Biol Chem

J Hepatol

Gastroenterology

Nitric oxide: physiology, pathophysiology, and pharmacology

Pharmacol Rev

The L-arginine-nitric oxide pathway

N Engl J Med

Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences

Hepatology

The nitric oxide hypothesis and the hyperdynamic circulation in cirrhosis

Hepatology

Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis

Hepatology

Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia

Hepatology

Other clinical study
Increased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation☆,☆☆