In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis (original) (raw)
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Arginine, citrulline and nitric oxide metabolism in sepsis
Clinical Science, 2009
Arginine has vasodilatory effects, via its conversion by NO synthase into NO, and immunomodulatory actions which play important roles in sepsis. Protein breakdown affects arginine availability and the release of asymmetric dimethylarginine, an inhibitor of NO synthase, may therefore affect NO synthesis in patients with sepsis. The objective of the present study was to investigate whole-body in vivo arginine and citrulline metabolism and NO synthesis rates, and their relationship to protein breakdown in patients with sepsis or septic shock and in healthy volunteers. Endogenous leucine flux, an index of whole-body protein breakdown rate, was measured in 13 critically ill patients with sepsis or septic shock and seven healthy controls using an intravenous infusion of [1-13C]leucine. Arginine flux, citrulline flux and the rate of conversion of arginine into citrulline (an index of NO synthesis) were measured with intravenous infusions of [15N2]guanidino-arginine and [5,5-2H2]citrulline....
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...
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.
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.
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.
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.
Nitrite/nitrate (NOx) levels and hemodynamics during septic shock
Surgery Today, 2000
This study was carried out with the informed consent of the patients involved and/or their families, and the approval of the Ethics Committee of Iwate Medical University. The subjects were 21 patients who suffered septic shock, with a mean age of 56.7 Ϯ 17.6 years, including 14 men with a mean age of 53.9 Ϯ 17.9 years and 7 women with a mean age of 62.4 Ϯ 16.7 years. No significant differences in age were observed between the men and the women. The clinical characteristics of these patients are shown in . Of the total 21 patients, 13 survived and 8 died, the mean ages of the survivors and nonsurvivors being 54.8 Ϯ 18.1 years and Abstract Nitric oxide (NO) acts as a vasorelaxant. We investigated the relationship between nitrite/nitrate (NOx), which are the final metabolites of NO, and hemodynamics during septic shock. We also examined tumor necrosis factor α (TNF-α), interleukin-8 (IL-8), and endotoxin. A significant negative correlation was observed between NOx levels and pulmonary capillary wedge pressure (PCWP; r ϭ Ϫ0.6075, P ϭ 0.0028). A significant positive correlation was noted between NOx levels and the cardiac index (CI; r ϭ 0.5934, P ϭ 0.0038). A significant negative correlation was found between NOx levels and the systemic vascular resistance index (SVRI; r ϭ Ϫ0.4354, P ϭ 0.0485). A significant positive correlation was observed between NOx levels and the stroke volume index (SVI; r ϭ 0.5040, P ϭ 0.0186). A significantly close positive correlation was also observed between TNF-α levels and NOx levels (r ϭ 0.7848, P Ͻ 0.0001). These findings suggest that NOx levels are closely associated with hemodynamics during septic shock, resulting in a vascular relaxing effect.
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...
Nitric Oxide Synthase Inhibition in Sepsis? Lessons Learned from Large-Animal Studies
Anesthesia & Analgesia, 2005
Nitric Oxide (NO) plays a controversial role in the pathophysiology of sepsis and septic shock. Its vasodilatory effects are well known, but it also has pro-and antiinflammatory properties, assumes crucial importance in antimicrobial host defense, may act as an oxidant as well as an antioxidant, and is said to be a "vital poison" for the immune and inflammatory network. Large amounts of NO and peroxynitrite are responsible for hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis, and ultimately multiorgan failure. Therefore, NO synthase (NOS) inhibitors were developed to reverse the deleterious effects of NO. Studies using these compounds have not met with uniform success however, and a trial using the nonselective NOS inhibitor N G -methyl-l-arginine hydrochloride was terminated prematurely because of increased mortality in the treatment arm despite improved shock resolution. Thus, the issue of NOS inhibition in sepsis remains a matter of debate. Several publications have emphasized the differences concerning clinical applicability of data obtained from unresuscitated, hypodynamic rodent models using a pretreatment approach versus resuscitated, hyperdynamic models in high-order species using posttreatment approaches. Therefore, the present review focuses on clinically relevant large-animal studies of endotoxin or living bacteria-induced, hyperdynamic models of sepsis that integrate standard day-today care resuscitative measures. (Anesth Analg 2005;101:488 -98)
Role of active nitrogen molecules in progression of septic shock
Acta Anaesthesiologica Scandinavica, 2011
Introduction: Active nitrogen molecules are formed as a result of cell metabolism. They are essential for cell metabolism, but when produced in excess, they contribute to the pathogenesis of several disease processes. These nitrogen molecules play an important role in vascular instability of septic shock. This study was planned to detect the role of active nitrogen molecules in the progression of septic shock. Materials and methods: Blood samples were collected from 118 critically ill patients admitted in ICU and from 95 healthy relatives accompanying the patients. Patients were categorized into three groups: systemic inflammatory response syndrome (n = 54), sepsis (n = 35) and septic shock (n = 29). Plasma total nitrite (nitrites and nitrates), cytokines like tumour necrosis factor-a (TNF-a) and plasma lactate were measured to assess inflammatory activity and severity of septic shock. Results: High plasma levels of nitrite and nitrate (No2-/No3-) were observed in critically ill patients (mean level 78.92 mmol/l in sepsis and 97.20 mmol/l in septic shock). Mean plasma TNF-a level in sepsis was 213.50 pg/ml and septic shock was 227.38 pg/ml. Conclusion: Plasma No2-/No3-and TNF-a levels were high in patients with sepsis and septic shock, which increased with severity of sepsis.