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Center for Translational Research on Aging and Longevity, Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205
* To whom correspondence should be addressed. E-mail: deutznep{at}uams.edu.
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ABSTRACT |
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In this article, we focus on the metabolism of arginine and NO and the rationale for and effects of arginine supplementation, especially in relation to sepsis. Because the amino acid lysine uses the same transport system as arginine for intracellular transport, intracellular arginine availability can potentially be affected by lysine. Therefore, biomarkers for both arginine and lysine excess are discussed.
Metabolism of arginine and NO
Arginine metabolism, especially as a source for NO, and factors that can affect arginine metabolism in health and disease are described below.
Arginine-NO metabolism in health.
Under normal physiological conditions, arginine is a semiessential amino acid that is derived both from endogenous and dietary sources (Fig. 1). The average daily arginine dietary intake is 
5 g (9), whereas the total arginine whole-body production and consumption are 82 µmol·kg–1·min–1 (equals 25 g/d) (10). Protein breakdown is a major endogenous source of arginine, but arginine synthesis from citrulline supplies 10–15% of the total arginine flux, with a daily average of 9.2 µmol·kg–1·min–1 (10). This so-called de novo arginine production is catalyzed by the enzymes argininosuccinate synthetase and argininosuccinate lyase and occurs mainly in the proximal renal tubule (11–15). The largest endogenous source of citrulline is via intestinal conversion of arterial and luminal derived glutamine through the glutamate-to-ornithine pathway (12,16–19). This results in a total whole-body citrulline production of 9.5 µmol·kg–1·min–1 (10). Arginine is metabolized via several pathways of which protein synthesis and conversion to urea and ornithine by the enzyme arginase are the major ones. In the liver, catabolism of arginine via the hepatic urea cycle is isolated from the metabolism of arginine within the cytosolic free amino acid pool (20–22). Ornithine can subsequently be converted to polyamines (for cell growth and differentiation) (23) and proline (for collagen synthesis and wound healing). Other pathways for arginine catabolism are synthesis of creatine (source of energy for muscle), agmatine (regulates a number of ligand-gated calcium channels and therefore affects brain, heart, and vasculature), and NO, the latter formed via the NO synthase (NOS) enzymes [see reviews (6,8,24)]. Although NO production is only 1.2 µmol·kg–1·min–1 and comprises 1–2% of arginine catabolism (10), arginine is the only source for NO production, which makes this an important metabolic pathway. Three different NOS isozymes exist and are related to specific functions of NO. First, NO produced via NOS-1 (or nNOS) is present in central and peripheral nervous system and acts as a neurotransmitter. Second, NO produced via NOS-2 (or iNOS) is induced by inflammatory mediators in all cells in the body. Third, NO produced via NOS-3 (or eNOS) is mainly present in endothelial cells and is essential for smooth muscle relaxation with related vasodilatation. The latter is also the main counterregulatory system against vasoconstriction produced by the sympathetic nervous system and the renin-angiotensin system (4,25–27). In addition to its vasodilator properties, endothelial NO also has vasoprotective and antiatherosclerotic properties (27). NO has a very short half-life and is rapidly oxidized to nitrite and nitrate, the latter being excreted in the urine (4).
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In a quiescent state, intracellular arginine transport is mostly through the CAT-1 transporter. Arginine uptake in activated macrophages is increased through induction of the CAT-2 transporter (30,31). Activation by Th1-cytokines (e.g., IFN-
) and LPS stimulates the uptake of arginine and activates NOS-2 with subsequent NO production, whereas Th2-type cytokines (e.g., IL-4 and IL-10) stimulate the uptake of arginine and activation of arginase with subsequent ornithine and polyamine formation (30,32). In proliferating macrophages, arginine is mainly used for enhanced protein synthesis, and only a modest increase in (probably) CAT-1–dependent arginine transport occurs (30). The regulation of CAT proteins may also differ between organs, as was demonstrated for CAT-2 isozymes in the lung and liver after LPS treatment in a rat model (33). The presence of constitutive NOS-2 expression may be of importance (34). LPS stimulates arginine transport activity in undifferentiated intestinal epithelial cells by increasing the levels of arginine transporter CAT1 mRNA and protein, and this stimulation of arginine transport is regulated by intracellular NO availability (35). In vivo administration of LPS augments glomerular arginine transport by up-regulating CAT-2 mRNA while down-regulating CAT-1 mRNA (36).
Thus, concomitant induction of transport proteins and metabolic enzymes facilitates substrate availability to the specific enzyme, and this transport protein induction seems also organ or cell specific.
Factors that affect arginine-NO metabolism. Several factors are considered important in the regulation of arginine-NO metabolism and probably also contribute to the so-called "arginine-paradox": high intracellular arginine levels that exceed the Km for NOS still limit NO production, but increasing extracellular arginine levels can increase NO production (37). These factors include intracellular compartmentalization (different arginine pools accessible for NOS) (38,39), coupling between specific NOS enzymes on the 1 hand and specific arginine transporters (e.g., NOS-3 and CAT-1 or NOS-2 and CAT-2) (36,40) or endogenous arginine-synthesizing enzymes on the other hand (e.g., NOS-3 and argininosuccinate synthase and lyase) (41). Alternatively, it has been hypothesized that extracellular arginine regulates the activity of intracellular NOS-2 by regulating its translation (42).
Arginine analogs such as N
-monomethyl-L-arginine (L-NMMA) and asymmetric dimethylarginine (ADMA) can compete with L-arginine for intracellular uptake. The ratio between the availability of these arginine analogs and arginine as a substrate can affect NO production (43). Moreover, other cationic amino acids that share the same protein for intracellular transport, such as lysine [see review (44)], can affect NO production (39,45). In addition, glutamine competes with citrulline for intracellular uptake and can therefore affect the conversion of intracellular citrulline to arginine (28), which can affect NO production (46). Moreover, a regulatory role for arginase on NO synthesis by intracellular substrate depletion has been suggested (32). Therefore, several factors that reduce NO synthesis, but also factors such as superoxide anion that increase the degradation or inactivation of (NOS specific) NO (27), may cause NO deficiency, with functional consequences that can be related to disease.
Arginine-NO metabolism in disease: sepsis. Sepsis is a major complication of an acute infection and is triggered by a systemic inflammatory reaction (47). Sepsis occurs often in intensive care units, causing high morbidity and mortality, the latter varying between 20 and 50% within the first month of disease (48,49).
NOS-1 and NOS-3 are considered the major sources of NO under normal physiological conditions, although NOS-2 is responsible for the increase in NO production during sepsis (50). In a pig model of sepsis, whole-body arginine production increased, and, although NO production increased in the gut and liver, this could not be detected at whole-body level when using a stable isotope technique to measure arginine to citrulline conversion (51,52).
Septic patients display reduced plasma and tissue arginine levels when compared with healthy individuals, and also when compared with other critically ill patient groups (53–56). Whole-body arginine production remains unchanged, but production of de novo arginine and citrulline decreases in septic patients to 30% of normal levels (56). Arginase activity and urea production increased 4-fold (Y. C. Luiking, M. Poeze, G. Ramsay, and N. E. P. Deutz, unpublished results), whereas, similar to the observation in the pig model of sepsis, NO production did not increase, even though plasma nitrate levels were greatly enhanced (Y. C. Luiking, M. Poeze, G. Ramsay, and N. E. P. Deutz, unpublished results). In contrast to adult patients, the decrease in de novo arginine production was not present in children with sepsis, although NO production was increased in this population (57). This suggests that changes in arginine metabolism during disease, at least during sepsis, may be age specific.
The changes in arginine metabolism in sepsis and related metabolic dysfunctions suggest that sepsis is an arginine-deficient state (1). Supplementation of arginine has therefore been suggested as being beneficial.
In summary, arginine is an important substrate in several metabolic pathways, including the synthesis of NO. Changes in arginine metabolism during disease can result in arginine deficiency.
Supplementation of arginine
Related to its metabolic pathways, potential benefits of arginine supplementation are hypothesized, and application of arginine supplementation in sepsis is discussed.
Potential situations that may benefit from arginine supplementation. Based on its metabolic pathways, supplementation of arginine could stimulate the arginase pathway, with subsequent enhanced production of ornithine and polyamines for cell growth and differentiation. Stimulation of NO production could be bacteriocidal, improve microcirculation, reduce superoxide production, and improve NO-mediated neural inhibition in, for example, the intestine. Stimulated protein synthesis and preserved muscle mass could benefit immune defense and muscle function. Hormonal stimulation of insulin release could improve glucose regulation [see Luiking (1) for review].
Arginine supplementation in sepsis. Arginine supplementation in a LPS-induced hyperdynamic pig model of sepsis stimulated NO production (52). In this study, arginine was supplied continuously from 8 h after LPS infusion in a dose of 5.3 µmol·kg–1·min–1 by intravenous infusion (during fasting) and by the oral route from 24 h thereafter (during feeding) (52). In addition, net protein loss from muscle was prevented by arginine supplementation during LPS infusion in the fasted state (58). No effects were measured on gut protein kinetics, but the increased protein turnover in the liver during sepsis was attenuated with arginine (58). Moreover, the intestinal contractility pattern (the migrating motor complex or MMC) that is disturbed during sepsis and is characterized by an increase in MMC frequency and enhanced MMC migration velocity (59) was completely restored to normal during arginine supplementation (60). When arginine was supplied in this septic pig model begining 8 h before the start of LPS infusion, NO production was already stimulated before induction of sepsis. In this latter study, arginine supplementation also increased portal blood flow, whereas the blood flow to the liver remained unchanged (M. Poeze, Y. C. Luiking, W. H. Lamers, and N. E. P. Deutz, unpublished results).
Little is known about the effect of arginine supplementation as a monotherapy in septic humans. In a recent dose-response study in 8 patients with severe sepsis, arginine was supplemented intravenously in doses ranging from 0.6 to 1.8 µmol·kg–1·min–1, each dose for 2 h, resulting in plasma levels that reached 4 times baseline levels (61). Moreover, a 6-fold increase in plasma ornithine was observed, which indicates the large conversion of arginine to ornithine via arginase, the activity of which is increased in sepsis (Y. C. Luiking, M. Poeze, G. Ramsay, and N. E. P. Deutz, unpublished results). In addition, NO production seemed to increase, whereas protein breakdown, which is related to the high catabolic state of sepsis, was less during arginine supplementation at the highest doses (Y. C. Luiking, M. Poeze, G. Ramsay, and N. E. P. Deutz, unpublished results). A subsequent placebo-controlled randomized study with 3-d intravenous arginine infusion at 1.2 µmol·kg–1·min–1 in patients with severe sepsis confirmed that arginine could be supplied without (further) hemodynamic instability (62). These data in animals and humans therefore suggest that arginine supplementation at doses for clinical use does not have harmful effects and may be considered beneficial. However, based on the suggested increased mortality in patients with sepsis treated with arginine-containing immunonutrition (63), the use of arginine in sepsis has been extensively debated (64–67).
In summary, arginine supplementation can increase NO production in sepsis without further hemodynamic instability in septic patients. Improved blood flow has been demonstrated in animal models of sepsis, but more evidence in humans is needed.
Biomarkers of arginine and lysine excess
Regarding the role of arginine in metabolism, potential markers of arginine excess related to its metabolic pathways are discussed. Because lysine can compete with arginine for intracellular transport, excess of lysine may indirectly affect arginine metabolism.
Potential markers of arginine excess: related to metabolism. Regarding the large contribution of the arginase pathway to arginine catabolism (3), enhanced plasma levels of ornithine and urea can be expected during excess arginine consumption. In patients with renal failure and related impaired renal urea excretion, blood urea (nitrogen) levels could potentially increase as a consequence. Secondly, overstimulation of the NOS pathway could result in enhanced nitrotyrosine production, which is a marker of oxidative stress. Nitrotyrosine is formed through biochemical interactions of NO or NO-derived secondary products with reactive oxygen species and subsequent nitration of the tyrosine residues in proteins (68). In addition, overstimulation of the NOS pathway may induce hypotension and increase hemodynamic instability resulting from systemic NO-mediated vasodilatation (69). Finally, when the renal threshold for reabsorption is exceeded, which can occur with intravenous arginine infusion, arginine is excreted in urine (70). All these factors may therefore be considered as markers of arginine excess. In septic patients supplied with intravenous arginine, neither plasma nitrotyrosine levels nor hemodynamic instability (62) nor plasma urea levels (Y. C. Luiking, M. Poeze, G. Ramsay, and N. E. P. Deutz, unpublished results) were enhanced, which suggests that arginine was not supplied in excess.
Potential markers of arginine excess: toxicity. In general, arginine is well tolerated at intravenous, intraarterial, or oral doses not exceeding 30 g/d. Intravenous arginine at high doses may cause local phlebitis or irritation from the high osmolality of the solution. Allergic reactions, including anaphylaxis, are also possible. Oral arginine may cause nausea and vomiting and abdominal cramps and bloating in cystic fibrosis patients. Patients receiving intravenous arginine should be monitored for cardiac arrhythmias and electrolyte disturbances [see Boger and Bode-Boger (5) for review]. Other side effects of arginine that may occur are largely related to the HCl group that is often linked to arginine to improve its solubility. These side effects include a sudden drop in blood pH, which may cause metabolic acidosis as well as hyperkalemia from displacement of intracellular potassium by arginine [see Boger and Bode-Boger (5) for review]. In vitro studies in caco-2 cells reported cytotoxic effects at 7% solution, related to the decrease in mitochondrial dehydrogenase activity (71). In vivo studies in rats, however, showed no cytotoxic effects of oral arginine administration at 250 mg·kg–1, which was ascribed to the protective action of the intestinal mucosal layer (71).
Potential markers of lysine excess: inhibition of arginine transport. Because lysine uses the same intracellular transporter system as arginine, competition of transport can be hypothesized. In human umbilical endothelial cells, lysine as well as leucine and phenylalanine inhibited intracellular arginine transport, whereas cysteine and alanine had no effect (72). In vivo studies in a rat model of early diabetes also showed inhibition of glomerular arginine uptake by lysine (73). However, excess dietary lysine in young pigs reduced growth via amino acid imbalance rather than antagonism, and plasma and tissue amino acid levels including arginine were elevated (74).
When the arginine/lysine plasma ratio was calculated in patients with sepsis as a surrogate marker for competition, arginine/lysine ratio was lower in patients with sepsis than in other ICU patients with moderate inflammation or in healthy subjects (Y. C. Luiking, M. Poeze, G. Ramsay, and N. E. P. Deutz, unpublished results; Fig. 2). This ratio was significantly related to whole-body citrulline production and plasma taurine and inversely related to plasma phenylalanine (Y. C. Luiking, M. Poeze, G. Ramsay, and N. E. P. Deutz, unpublished results; Fig. 3). These findings need further investigation but seem to indicate competition of transport between arginine and lysine in sepsis. A strong correlation between plasma arginine and lysine was observed in a group of trauma patients that consecutively developed sepsis both before and during parenteral nutrition with 10.4% of amino acids supplied by arginine (75).
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Lysine reduced resting blood flow and NO levels and inhibited the increase in blood flow in endothelial cells (45), which suggests that transport of extracellular arginine via (CAT-1) amino acid transporter is required during in vivo endothelial NO production. This is also confirmed by a study in which exhaled NO from isolated lungs was used as a marker of NO production, with a dose-related inhibition of NO production by lysine both under normal and LPS treated conditions (76). In a rat model of heart failure, the effect of arginine on NO production could be blocked by lysine, which suggests that arginine transport plays an important role in enhanced NO production in heart failure (77). In lysinuric protein intolerance, impaired dibasic amino acid transport probably contributes to decreased arginine efflux and increased NO production (78). However, diminished intracellular arginine levels and reduced NO production have also been reported in a patient suffering from this disorder (79).
In summary, biomarkers of arginine excess can be related to NO as a primary marker and to hemodynamics, metabolism, and oxidative stress as secondary markers. NO production can also be related to lysine excess through inhibition of arginine transport.
Arginine stimulates NO production, but effects of arginine depend on the condition in which it is tested: in the condition of an arginine-deficient state, supplementation of arginine will benefit arginine metabolism and related functions. Possible markers for arginine and lysine excess in relation to NO production are NO production, hemodynamics, and metabolism.
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FOOTNOTES |
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2 Author disclosures: Y. C. Luiking, no conflicts of interest; and N. E. P. Deutz, travel expenses to the meeting paid by the ICAAS.
3 Supported by: Work presented on arginine supplementation in sepsis by Luiking et al. was supported by Novartis Consumer Health.
4 Abbreviations used: ADMA, asymmetric dimethylarginine; CAT, cationic amino acid transport; L-NMMA, N-monomethyl-L-arginine; MMC, migrating motor complex; NO, nitric oxide; NOS, nitric oxide synthase.
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