Arginine, citrulline and nitric oxide metabolism in sepsis (original) (raw)
Related papers
American Journal of Clinical Nutrition, 2008
Background: L-Arginine is an important precursor of nitric oxide (NO) and protein synthesis. Arginine is produced in the body (mainly kidney) by de novo production from citrulline and by protein breakdown. Arginine availability appears to be limited in sepsis. Objective: The objective was to compare arginine and citrulline metabolism in septic patients and nonseptic control patients in an intensive care unit (ICU) and in healthy control subjects. Design: Ten patients with septic shock, 7 critically ill control patients, and 16 healthy elderly subjects were studied. Metabolism was measured by using a primed continuous (2 h) stable-isotope infusion protocol. NO production was calculated as the conversion rate of arginine to citrulline; de novo arginine production was calculated as the conversion rate of citrulline to arginine. Arterial blood (arterialized venous blood in healthy subjects) was collected for the measurement of amino acid enrichment and concentrations. Data are reported as means 6 SDs. Results: Whole-body citrulline production was significantly lower in septic patients (4.5 6 2.1 lmol Á kg 21 Á h 21 ) than in ICU control patients (10.1 6 2.9 lmol Á kg 21 Á h 21 ; P , 0.01) and in healthy control subjects (13.7 6 4.1 lmol Á kg 21 Á h 21 ; P , 0.001). Accordingly, de novo arginine production was lower in patients with sepsis (3.3 6 3.7 lmol Á kg 21 Á h 21 ) than in healthy controls (11.9 6 6.6 lmol Á kg 21 Á h 21 ; P , 0.01) and tended to be lower in septic patients than in ICU control patients (10.9 6 9.4 lmol Á kg 21 Á h 21 ; P ¼ 0.05). NO production was lower in septic patients than in healthy control subjects (P , 0.01), whereas a larger part of arginine was converted to urea in sepsis. Conclusions: Citrulline production is severely low in patients with sepsis and is related to diminished de novo arginine and NO production. These metabolic alterations contribute to reduced citrulline and arginine availability, and these findings warrant further studies of therapeutic nutritional interventions to restore arginine metabolism in sepsis.
In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis
The American Journal of Clinical Nutrition, 2006
Background: Arginine is important in the response to infections and is a precursor for the synthesis of the vasodilator nitric oxide (NO). Low plasma arginine is correlated with a worse prognosis in patients with sepsis, and increased NO has been implicated in the hypotension of sepsis. Data on in vivo arginine and NO kinetics are lacking in hypotensive septic adults. Objective: We aimed to measure in vivo arginine production and the intravascular NO synthesis rate in hypotensive septic patients. Design: Arginine flux and the fractional and absolute synthesis rates of plasma NO were measured in fasted healthy (n ҃ 10) and hypotensive septic (n ҃ 6) adults by using a 6-h constant infusion of [ 15 N 2-guanidino]arginine. Urinary excretion of the NO metabolites nitrite and nitrate (NOx) and plasma concentrations of NOx, arginine, and creatinine were also measured. Results: All patients had hyperdynamic septic shock and impaired renal function. Compared with the control subjects, the patients had slower arginine flux (99 Ȁ 8 compared with 50 Ȁ 7 mol • kg Ҁ1 • h Ҁ1 ; P 0.01), lower plasma arginine concentrations (75 Ȁ 8 compared with 40 Ȁ 11 mol/L; P 0.01), higher plasma NOx concentrations (30 Ȁ 4 compared with 65 Ȁ 1.8 mol/L), and a slower fractional synthesis rate of NOx. There was no significant difference in the absolute synthesis rate of NOx between groups. In patients with sepsis, the plasma NOx concentration correlated with the glomerular filtration rate and plasma creatinine but not with mean arterial pressure. Conclusions: Patients with septic shock have a shortage in the availability of arginine associated with a slower production. Impaired renal excretion of NOx is a contributor to the high plasma NOx in these patients.
Activation of the L-arginine nitric oxide pathway in severe sepsis
Archives of Disease in Childhood, 1997
Aims-To determine in children with sepsis syndrome and septic shock the time course of nitric oxide metabolites: nitrate and nitrite (nitrogen oxides). To determine whether serum concentrations of nitrogen oxides distinguished those children who died from sepsis from those who survived; those who required prolonged inotropic support compared with those who did not; and whether there was any relationship of the levels of nitrogen oxides to markers of tissue perfusion. Methods-Nitrogen oxides were measured in 30 children with sepsis syndrome or septic shock at admission, 12, 24, and 48 hours. A non-septic control group had serum nitrogen oxides measured at admission. Markers of haemodynamics and tissue perfusion measured were mean arterial pressure, blood lactate, base deficit, gastric intramucosal pH, and del-taCO 2 (DCO 2 : the diVerence between arterial and gastric intraluminal carbon dioxide tensions). Inotrope doses, number of organ systems failing at 48 hours, and outcome as survival were recorded. Results-Children with sepsis had increased nitrogen oxide concentrations at presentation compared with a group of non-septic controls. Children with organ failure at 48 hours had higher serum nitrogen oxide concentrations than those with sepsis uncomplicated by organ failure at 48 hours. There was no diVerence in nitrogen oxide when patients were subgrouped according to the receipt of inotropes at 48 hours, and no association with markers of tissue perfusion, or survival.
Arginine and Citrulline and the Immune Response in Sepsis
Nutrients, 2015
Arginine, a semi-essential amino acid is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs. In the immune response, arginine metabolism and availability is determined by the nitric oxide synthases and the arginase enzymes, which convert arginine into nitric oxide (NO) and ornithine, respectively. Limitations in arginine availability during inflammatory conditions regulate macrophages and T-lymfocyte activation. Furthermore, over the past years more evidence has been gathered which showed that arginine and citrulline deficiencies may underlie the detrimental outcome of inflammatory conditions, such as sepsis and endotoxemia. Not only does the immune response contribute to the arginine deficiency, also the impaired arginine de novo synthesis in the kidney has a key role in the eventual observed arginine deficiency. The complex interplay between the immune response and the arginine-NO metabolism is further underscored by recent data of our group. In this review we give an overview of physiological arginine and citrulline metabolism and we address the experimental and clinical studies in which the arginine-citrulline NO pathway plays an essential role in the immune response, as initiator and therapeutic target.
The role of arginine in infection and sepsis
JPEN. Journal of parenteral and enteral nutrition
Sepsis is a systemic response to an infection, with high morbidity and mortality rates. Metabolic changes during infection and sepsis could be related to changes in metabolism of the amino acid L-arginine. In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery because both endogenous de novo arginine production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine via the arginase and nitric oxide pathways. As a result, lowered plasma arginine levels are usually found. Arginine may therefore be considered as an essential amino acid in sepsis, and supplementation could be beneficial in sepsis by improving microcirculation and protein anabolism. L-Arginine supplementation in a hyperdynamic pig model of sepsis prohibits the increase in pulmonary arterial blood pressure, improves muscle and liver protein metabolism, and restores the intestinal motility pattern. Argum...
Production of arginine by the kidney is impaired in a model of sepsis: early events following LPS
AJP: Regulatory, Integrative and Comparative Physiology, 2004
Lipopolysaccharide (LPS) is used experimentally to elicit the innate physiological responses observed in human sepsis. We have previously shown that LPS causes depletion of plasma arginine before inducible nitric oxide synthase (iNOS) activity, indicating that changes in arginine uptake and/or production rather than enhanced consumption are responsible. Because the kidney is the primary source of circulating arginine and renal failure is a hallmark of septicemia, we determined the time course of changes in arginine metabolism and kidney function relative to iNOS expression. LPS given intravenously to anesthetized rats caused a decrease in mean arterial blood pressure after 120 min that coincided with increased plasma nitric oxide end products (NOx) and iNOS expression in lung and liver. Interestingly, impairment of renal function preceded iNOS activity by 30–60 min and occurred in tandem with decreased renal arginine production. The baseline rate of renal arginine production was ∼60...
In vivo (Athens, Greece)
Nitric oxide (NO) pathway plays a major role in the development and advancement of inflammation. We aimed to design a study and investigate its feasibility to show the changes of L-arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), which are important regulators of the NO pathway. Concentrations of L-arginine, ADMA and SDMA were measured by liquid chromatography-tandem mass spectrometry. Seventeen septic survival patients were enrolled and blood samples were obtained on the first, third and fifth day after the diagnosis of sepsis. Sixteen non-septic matched controls were recruited. ADMA levels on admission correlated well with sequential organ failure assessment (SOFA) score. During the follow-up, L-arginine/ADMA ratio increased significantly from day 1 to day 3 (p=0.005), then decreased from day 3 to day 5 (p=0.023). This study design seems feasible to investigate changes of L-Arginine, ADMA and SDMA in sepsis survival patients.
Time course of endogenous nitric oxide inhibitors in severe sepsis in humans
Minerva anestesiologica, 2010
Asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) are protein breakdown markers; both compete with arginine for cellular transport and both are excreted in urine. Moreover, ADMA is a non-selective inhibitor of nitric oxide (NO) synthase that is metabolized by a specific hydrolase in which the activity during stress remains controversial. While an increase in ADMA is known to be associated with adverse events, little is known about SDMA. We investigated plasma ADMA and SDMA levels during ICU stay to reveal the time course of endogenous NO inhibition in patients with sepsis. A post hoc analysis from a prospective random controlled trial conducted in three ICUs was performed to study the pathophysiological pathways of sepsis. ADMA, SDMA, the ratio of ADMA/SDMA (a marker of ADMA catabolism), arginine, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C reactive protein (CRP) were measured on days 1, 3, 6, 9, 12 and at discharge in 72 consecutive s...
Critical Care Medicine, 2011
Objective-Arginine deficiency may contribute to microvascular dysfunction, but previous studies suggest that arginine supplementation may be harmful in sepsis. Systemic arginine availability can be estimated by measuring the ratio of arginine to its endogenous inhibitors, asymmetric and symmetric dimethylarginine. We hypothesized that the arginine to dimethylarginine (Arg/DMA) ratio is reduced in patients with severe sepsis and associated with severity of illness and outcomes. Design-Case-control and prospective cohort study Setting-Medical and surgical intensive care units of an academic medical center Patients and Subjects-109 severe sepsis and 50 control subjects Measurements and Main Results-Plasma and urine were obtained in control subjects and within 48 hours of diagnosis in severe sepsis patients. The Arg/DMA ratio was higher in control subjects vs. sepsis patients ((median = 95 [inter-quartile range = 85-114]) vs. 34 [24-48], p <
Markers of nitric oxide are associated with sepsis severity: an observational study
Critical Care
Background: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity. Method: This single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression. Results: lArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30-2.29) μmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36-1.44) μmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46-0.65) μmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56-1.39) μmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA. Conclusions: In patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense.