Arginine, citrulline and nitric oxide metabolism in sepsis

Kao, Christina C.; Bandi, Venkata; Guntupalli, Kalpalatha K.; Wu, Miao; Castillo, Leticia; Jahoor, Farook

doi:10.1042/cs20080444

Cited by 104 publications

(99 citation statements)

References 35 publications

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“…However, in patients with CAD, baseline inflammation and circulating ADMA are higher, and acute inflammation has only a moderate effect on endothelial function and fails to change ADMA levels, despite the striking elevation of circulating IL-6. Although we demonstrate an effect of acute inflammation on both ADMA and FMD, the direct causal effect of ADMA on FMD can only be implied; other mechanisms, such as the inflammation-induced elevation of NADPH-oxidase 23 or the depletion of L-arginine because of reduced de novo synthesis 24 could also account for the effect of inflammation on endothelial function.…”

Section: Discussionmentioning

confidence: 98%

Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis

et al. 2011

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Abstract-We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (nϭ11 healthy and nϭ60 CAD) or placebo (nϭ11 healthy and nϭ10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (PϽ0.0001 for both). However, interleukin 6 was inversely correlated with FMD (PϽ0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (rϭ0.515; PϽ0.0001) compared with CAD (rϭ0.289; Pϭ0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (PϽ0.0001) and ADMA (Pϭ0.004) but lower FMD (Pϭ0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (PϽ0.001) and CAD (PϽ0.001) subjects. FMD was reduced in healthy subjects (PϽ0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (PϽ0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans. (Hypertension. 2011;58:93-98.) • Online Data Supplement Key Words: ADMA Ⅲ endothelium Ⅲ inflammation Ⅲ interleukin 6 Ⅲ atherosclerosis Ⅲ coronary artery disease T he development of endothelial dysfunction is considered to be the initial step in atherogenesis. 1 A healthy endothelium is responsible for NO generation through oxidation of L-arginine by endothelial NO synthase (eNOS). 1 NO maintains vascular tone and acts, per se, as an important intracellular messenger, inducing divergent anti-inflammatory, antithrombotic, and antiapoptotic effects. 1 Asymmetrical dimethylarginine (ADMA), an endogenous L-arginine analog, has been associated with impaired endothelial function in humans. 2 ADMA has also been associated with eNOS uncoupling that results in increased eNOSderived superoxide production in human vessels. 2 Clinical evidence suggests that ADMA plasma levels are associated with endothelial function, particularly in patients with coronary atherosclerosis 3 or atherosclerosis risk factors, 4 whereas this association is significant but weak in healthy individuals. 5 Furthermore, in prospective studies, plasma ADMA has been independently associated with clinical outcome and mortality in diabetic subjects and patients with atherosclerosis. 6 ADMA is derived from ...

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Section: Discussionmentioning

confidence: 98%

Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis

et al. 2011

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“…Tracer/tracee ratios of plasma arginine, citrulline, and ornithine were measured by liquid chromatography-tandem mass spectrometry. Rate of appearance or total flux and endogenous flux of arginine, citrulline, ornithine, and urea, the rate of conversion of citrulline to arginine, and the rate of NO synthesis were calculated as previously described (33,59). Details are provided in Supplemental Methods.…”

Section: Discussionmentioning

confidence: 99%

“…Increased mitochondrial arginine metabolism supports bioenergetics in asthma arginine synthesis was increased, individuals with asthma and healthy controls were studied using stable isotope-labeled arginine and citrulline tracers to determine the whole-body rate of metabolism of arginine and its de novo synthesis from citrulline (32,33). Arginine and other urea cycle amino acids are highly compartmentalized in various tissues, and their intracellular pools do not equilibrate rapidly with extracellular pools.…”

Section: Introductionmentioning

confidence: 99%

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

Xu¹,

Ghosh²,

Comhair³

et al. 2016

Journal of Clinical Investigation

104

119

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“…Normally the most abundant amino acid in human plasma and muscle (3), glutamine becomes conditionally essential during sepsis, because the need for glutamine exceeds its endogenous rate of synthesis (18). Low plasma glutamine concentrations are found in patients with sepsis (16), and in critically ill patients, low glutamine concentrations are correlated with mortality (4,28). At present there is a paucity of data on the mechanism(s) responsible for this reduction of glutamine in sepsis.…”

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confidence: 97%

“…In addition, citrulline is a modulator of protein anabolism (7) and is the only precursor for de novo synthesis of arginine in the body. Low plasma citrulline concentrations in sepsis are the result of decreased citrulline production (16,22). This decrease in citrulline synthesis may be caused by reduced availability of glutamine or impaired metabolic conversion of glutamine to citrulline within the enterocyte.…”

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confidence: 99%

Alterations in glutamine metabolism and its conversion to citrulline in sepsis

Kao

Hsu

Bandi

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Alterations in glutamine metabolism and its conversion to citrulline in sepsis. Am J Physiol Endocrinol Metab 304: E1359 -E1364, 2013. First published April 23, 2013 doi:10.1152/ajpendo.00628.2012.-In enterocytes, glutamine serves as the major source of energy; another metabolic fate of glutamine is conversion to citrulline. Because sepsis can affect gut function and integrity, alterations in glutamine metabolism may exist and lead to decreased citrulline production. This study aimed to investigate how sepsis affects glutamine metabolism, including its conversion to citrulline, by measuring glutamine and citrulline flux, fractional splanchnic extraction of glutamine and leucine, and the contribution of glutamine nitrogen to citrulline in septic patients and healthy controls. Eight patients with severe sepsis and 10 healthy controls were given primed, constant intravenous infusion of [ 2 H2]citrulline and sequential administration of intravenous and enteral [␣-15 N]glutamine and [ 13 C]leucine in the postabsorptive state. The results showed that, compared with healthy controls, septic patients had a significantly lower whole body citrulline flux and plasma concentration, higher endogenous leucine flux, and higher glutamine clearance. Fractional splanchnic extraction of leucine was higher in septic patients than in controls, but fractional extraction of glutamine was not different. The majority of the 15 N label transferred from glutamine to citrulline was found at the ␣-position. These results demonstrate that lower glutamine plasma concentrations in sepsis were a result of increased glutamine clearance. Despite adequate splanchnic uptake of glutamine, there is decreased production of citrulline, suggesting a defect in the metabolic conversion of glutamine to citrulline, decreased uptake of glutamine by the enterocyte but increased uptake by the liver, and/or shunting of glutamine to other metabolic pathways. severe sepsis; stable isotopes; enterocyte THE GUT IS BELIEVED TO PLAY an important role in sepsis. In fact, it has been postulated that the gut can initiate, perpetuate, or exacerbate the systemic inflammatory response syndrome (SIRS) and lead to the development of multiorgan dysfunction syndrome (MODS) (29). Sepsis can affect gut function and mucosal integrity via a variety of mechanisms, including ischemia-reperfusion injury, mitochondrial dysfunction, and increased intestinal permeability (9). Because maintenance of gut mucosal integrity depends almost exclusively on an adequate enteral supply of amino acids both as primary source of fuel and as substrate for protein synthesis, more information is needed about the metabolic fates of enterally administered amino acids in sepsis.In health, the gastrointestinal tract is the major organ of glutamine utilization (32). Glutamine is the major source of energy for proliferating enterocytes, providing energy for ATP-dependent processes, including rapid intracellular protein turnover and nutrient transport (39). Adult rat enterocytes extract 25-33% of arterial g...

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Arginine, citrulline and nitric oxide metabolism in sepsis

Cited by 104 publications

References 35 publications

Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis

Role of Asymmetrical Dimethylarginine in Inflammation-Induced Endothelial Dysfunction in Human Atherosclerosis

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

Alterations in glutamine metabolism and its conversion to citrulline in sepsis

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