In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis

Villalpando, Salvador; Gopal, Jayashree; Balasubramanyam, Ashok; Bandi, Venkata; Guntupalli, Kalpalatha K.; Jahoor, Farook

doi:10.1093/ajcn/84.1.197

Cited by 52 publications

(61 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inflammatory processes are likely to affect L-arginine homeostasis in patients with malaria. Studies with critically ill children have shown an increase in the oxidation of L-arginine (2), with no change in flux compared to that for healthy adults, and in contrast to that for adults with sepsis, who had a decreased flux (29). In these studies, NO production accounted for 6% of L-arginine consumption in acutely ill children, compared to approximately 2 to 3% in septic adults and 4 to 5% in healthy adult controls.…”

Section: Discussionmentioning

confidence: 79%

“…Increased oxidation without a compensatory increase in the de novo synthesis of endogenous L-arginine has been described for sepsis (2,29). This work led investigators to postulate that L-arginine becomes a conditionally essential amino acid during acute inflammatory states (2) and therefore may be required as part of standard nutritional therapy in severely ill patients with infections or burns.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of l -Arginine in Adults with Moderately Severe Malaria

Yeo

Rooslamiati

Gitawati

et al. 2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g, L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] ‫؍‬ 52%) and a volume of distribution of 24 liters (CV ‫؍‬ 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the K m of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.The treatment of severe malaria currently relies on antimalarial drugs and supportive treatments, but the early case fatality rate remains high (8). Adjunctive therapies targeting underlying pathogenic processes early in the treatment of severe malaria may reduce mortality further, but to date none have proven efficacious (10). L-Arginine has been proposed as a potential adjunctive therapy for severe malaria because of its ability to increase nitric oxide (NO) production in endothelial and other cells (16, 34).We have previously described impaired production of NO (1, 34); low plasma concentrations of its precursor, L-arginine (16); and impaired NO-dependent endothelial function in cases of severe malaria (34). Endothelial dysfunction is a measure of endothelial activation and may play a role in the pathogenesis of severe malaria by increasing the adhesion of parasitized erythrocytes to the endothelium and thereby worsening microcirculatory obstruction and oxygen delivery (9). NO downregulates endothelial inflammation (7) and reduces the cytoadherence of parasitized erythrocytes in vitro (20,23). Endothelial NO production is dependent on the intracellular movement of extracellular L-arginine by cationic amino acid transporter protein-1 (CAT-1) (35). Estimates for the halfsaturating concentration (K m ) of extracellular L-arginine for CAT-1 are 100 to 150 mol/liter (32), within the estimated range of the K m of extracellular L-arginine for intracellular NO production (73 to 150 mol/liter) (11, 14). In severe malaria, plasma L-arginine concen...

show abstract

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of l -Arginine in Adults with Moderately Severe Malaria

Yeo

Rooslamiati

Gitawati

et al. 2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Many previous studies on pregnancy have used plasma NOx level and urinary NOx excretion as indirect measures of NO production (Maul et al, 2003). However, sources of NOx, in addition to production from NO synthesis (Helmke and Duncan, 2007), may include diet and the environment, and plasma concentrations will be affected by renal clearance (Villalpando et al, 2006). These influences on NOx levels may explain the differing findings of studies using these indirect approaches to investigate NO kinetics in pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma concentrations of NO metabolites nitrite and nitrate (NOx) were measured by in vitro isotope dilution as previously described by us (Villalpando et al, 2006). Briefly, 0.5 ml of the baseline plasma sample was spiked with a known quantity of Na 15 NO 3 , the internal standard and the nitrate reduced to nitrite.…”

Section: Analysis Of Blood Samplesmentioning

confidence: 99%

In vivo arginine production and nitric oxide synthesis in pregnant Indian women with normal and low body mass indices

et al. 2009

View full text Add to dashboard Cite

Background/Objectives: Nitric oxide (NO) has been proposed as a mediator of vascular expansion during pregnancy. Inability to increase NO synthesis and/or production of its precursor, arginine, may be a contributor to pregnancy-induced hypertension or preeclampsia. Because maternal weight is associated with blood pressure and risk of preeclampsia during pregnancy, it may also influence arginine and/or NO production. The purpose of this study was to determine the in vivo arginine production and NO synthesis rate in pregnant women with normal (n ¼ 10) and low (n ¼ 10) body mass indices (BMIs). Subjects/Methods: Arginine flux and NO synthesis rate were measured in the postabsorptive state with constant infusions of 15 N 2 -arginine and 13 C, 2 H 4 -citrulline. Plasma concentrations of arginine and NO metabolites were also measured. Kinetic parameters were correlated to maternal variables, gestational age, birth weight and blood pressure. Results: Endogenous arginine flux was significantly faster in the low-BMI compared with normal-BMI women in the first trimester (63.1 ± 3.4 vs 50.2 ± 2.0 mmol/kg per h, Po0.01), but not in the second. Plasma NO concentration was higher (44.7 ± 5.3 vs 30.4 ± 1.9 mmol/l, P ¼ 0.03) and its rate of synthesis trended faster in the low-BMI compared with normal-BMI group in the second trimester. Maternal weight and BMI were negatively correlated with arginine flux in both trimesters and NO synthesis in the second trimester. Conclusions: These findings suggest, but do not prove, that maternal BMI may be a factor in the ability to produce NO during pregnancy and may be one way by which BMI influences blood pressure during pregnancy.

show abstract

“…Both NOS1 and NOS3 are calcium-dependent enzymes expressed constitutively, whereas NOS2 is expressed in response to acute inflammatory stimuli (54). NO has been related to numerous pathological conditions, including artery disease (55), cerebrovascular stroke (56), sepsis (57), and ischemic injury (58).…”

Section: Nitric Oxidementioning

confidence: 99%

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

et al. 2016

View full text Add to dashboard Cite

cOver 200 million people worldwide suffer from malaria every year, a disease that causes 584,000 deaths annually. In recent years, significant improvements have been achieved on the treatment of severe malaria, with intravenous artesunate proving superior to quinine. However, mortality remains high, at 8% in children and 15% in adults in clinical trials, and even worse in the case of cerebral malaria (18% and 30%, respectively). Moreover, some individuals who do not succumb to severe malaria present longterm cognitive deficits. These observations indicate that strategies focused only on parasite killing fail to prevent neurological complications and deaths associated with severe malaria, possibly because clinical complications are associated in part with a cerebrovascular dysfunction. Consequently, different adjunctive therapies aimed at modulating malaria pathophysiological processes are currently being tested. However, none of these therapies has shown unequivocal evidence in improving patient clinical status. Recently, key studies have shown that gaseous therapies based mainly on nitric oxide (NO), carbon monoxide (CO), and hyperbaric (pressurized) oxygen (HBO) alter vascular endothelium dysfunction and modulate the host immune response to infection. Considering gaseous administration as a promising adjunctive treatment against severe malaria cases, we review here the pathophysiological mechanisms and the immunological aspects of such therapies. Malaria exerts a heavy burden over human populations, with an estimated 124 to 283 million cases and 584,000 deaths in 2013 (1). Currently, intravenous (i.v.) artesunate is the treatment of choice in severe malaria cases in children and adults (2, 3). However, despite the efficacy of intravenous artesunate, mortality from severe malaria in general and from cerebral malaria (CM) in particular remains high, at 18% for African children and 30% for adults in Southeast Asia (2, 3). In addition, 11% of children who survive CM show severe neurological deficits, and up to 25% can maintain long-term cognitive deficits (4-8). Therefore, strategies focusing only on parasite killing may not be sufficient to prevent neurological complications and deaths related to severe malaria. Accordingly, adjunctive therapies-defined as therapies administered in combination with antiparasitic drugs that modify pathophysiological processes caused by malaria-are being sought in order to mitigate complications caused by severe malaria (9). Considering the fact that currently administered antimalarial drugs often take 12 to 18 h to kill parasites, adjunctive therapies could reduce the risk of neurocognitive sequelae and mortality, particularly in patients with CM (10).Different adjunctive therapies have been or are being tested, including treatments aimed at modulation of the immune response to infection (dexamethasone, intravenous immunoglobulin), reduction of iron burden, reduction of oxidative stress, modulation of the prothrombotic state, and reduction of parasitemia (blood transfusion), amon...

show abstract

In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis

Abstract: 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.

Cited by 52 publications

References 34 publications

Pharmacokinetics of l -Arginine in Adults with Moderately Severe Malaria

Pharmacokinetics of l -Arginine in Adults with Moderately Severe Malaria

In vivo arginine production and nitric oxide synthesis in pregnant Indian women with normal and low body mass indices

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

Contact Info

Product

Resources

About