Sepsis: An Arginine Deficiency State?

Yvette C. Luiking, PhD; Martijn Poeze, MD, PhD; Cornelis H. Dejong, MD, PhD; Graham Ramsay, MD, PhD; Nicolaas E. Deutz, MD, PhD

Crit Care Med. 2004;32(10) 

In This Article

Arginine Catabolism in Sepsis

Arginine catabolism involves multiple organs and compartmentalization of different catabolic pathways[14,18,47] as described above. Substrate availability for arginine-requiring catabolic enzymes also depends on arginine transport systems. Several arginine transporters exist, of which system y+ is the most important and high-affinity transport mechanism, ascribed on the molecular level to cationic amino acid transporters (CATs). Of these CATs, CAT-1, CAT-2(B), and CAT-3 have been identified and differ in their tissue distribution.[18] These transport systems are often co-localized with the catabolic enzymes and can thereby modulate cellular arginine metabolism.[18] For example, CAT-1 arginine transporter and endothelial NOS enzyme are co-localized in plasma membrane caveolae.[48] By this way, arginine is specifically channelled to NO production and does not mix with the total intracellular pool.[47] The arginine transport systems can be modulated by bacterial endotoxins and inflammatory cytokines, which can up-regulate CAT-2 arginine transporters[49,50] and down-regulate CAT-1 arginine transporters.[50] As a result, transport of arginine to NOS-2 (inducible NOS) is increased, whereas transport to NOS-3 (endothelial NOS) is decreased. Lysine, ornithine, and certain endogenous NOS inhibitors use the same transporter as arginine and may thereby compete for transporter capacity in conditions of low arginine.[47] These mechanisms may control arginine catabolic pathways in sepsis and may also explain the arginine paradox[51,52]: the fact that endothelial NO synthesis can be regulated by varying extracellular arginine concentrations despite the fact that intracellular arginine concentration far exceeds the Km of NOS-3 for arginine.[18] This, in fact, may also explain some of the contradictory results seen in the experimental intervention studies. Therefore, the question arises of how the different arginine catabolic pathways are affected in sepsis?

The enzyme arginase is a large arginine consumer. Because arginase activity is increased in sepsis, arginase activity may be an important regulatory factor for arginine availability and function.[53] In septic children, the fraction of urea produced from plasma arginine was increased three-fold, which indicates enhanced arginase activity in sepsis.[40]

By depleting the body of arginine, arginase activity is an important determining factor regarding the availability of arginine for NO synthesis and for other metabolic pathways of arginine.[18,53] The arginase-dependent depletion of arginine in interferon-γ/lipopolysaccharide-stimulated macrophages causes an anti-inflammatory cytokine interleukin-13-mediated down-regulation of NOS-2 protein, which can be restored by l-arginine administration.[54] Because not only macrophages but also bacteria express arginase, this may be a mechanism whereby infectious pathogens might shut down an important effector arm of the immune response locally and prolong their own survival.[54]

Elevated NO synthesis has been suggested in sepsis, based on elevated plasma levels of the elimination products nitrate/nitrite,[55,56,57,58,59,60,61,62,63] and has been ascribed to NOS-2 stimulation by endotoxins and cytokines.[64,65,66] However, discrepancies between the degree of plasma nitrate/nitrite elevation and actual NO production have been described,[39,61,67,68] which may partly be due to an effect of renal failure on plasma nitrate levels.[69] Using stable isotope techniques to measure arginine to citrulline conversion as a measure of NO production,[70] a 1.6-fold increase in NO synthesis rate in critically ill septic pediatric patients was described,[40] which we recently confirmed in adult septic patients when compared with healthy control values.[36] Interestingly, such an increase could not be detected when comparing septic patients with nonseptic intensive care unit controls with moderate inflammation.[36] In hyperdynamic septic pigs, increased NO synthesis was quantitatively matched by increased arginine disposal,[39] which confirms the link between arginine availability and NO synthesis.

Reduced arginine availability may limit NO synthesis because provision of the arginine pool for NO synthesis depends for >50% on extracellular sources of arginine.[14,66,67,71,72,73] Although NOS-2 activity increases during sepsis, activity of the other NOS isoforms seems down-regulated.[69,74,75,76,77] This may reduce NO production enzyme specifically.

Asymmetric dimethylarginine (ADMA) is the most powerful endogenous and competitive NOS inhibitor because it competes with l-arginine for the active site of NOS (not NOS isoform specific) and for y+-mediated uptake into cells (refer to Leiper and Vallance[78] for review). ADMA is derived from the catabolism of posttranslationally modified proteins that contain methylated arginine residues. ADMA is metabolized by dimethylaminohydrolase to citrulline and methylamines, and it is excreted in urine.[79] Increased protein catabolism and impaired renal function could therefore contribute to elevated ADMA levels. High expression of dimethylaminohydrolase in the liver makes this organ important in the metabolism of ADMA and hepatic dysfunction a prominent determinant of ADMA concentration.[79,80,81,82]

In critically ill patients, elevated ADMA levels have been described and were considered a strong and independent risk factor for intensive care unit mortality.[80] Accumulation of ADMA therefore was hypothesized to be a causative factor in the development of multiple organ failure by interfering with physiologic functions of NO production.[82] Through this pathway, ADMA may contribute to impaired blood flow in sepsis.[79] NO production could benefit from increasing the l-arginine/ADMA ratio by additional l-arginine supplementation.

Arginine is also an important constituent of proteins and therefore is required for protein synthesis. Increased synthesis of acute-phase proteins and up-regulated enzymes occurs in sepsis. Elevated muscle protein synthesis was also observed in an experimental model of sepsis in pigs.[83] Moreover, increased arginine oxidation is observed during sepsis in pediatric patients[40] and indicates increased use of arginine as an energy source, at least in children with sepsis.

In conclusion, arginine consumption is enhanced in sepsis, mainly due to increased catabolism by arginase and NOS enzymes and increased protein synthesis. Due to the limited arginine availability and competition for arginine transporter or enzyme activity (e.g., by the endogenous NOS inhibitor ADMA), arginine is to an important extent the limiting factor for NO production.

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