Conclusion and Hypothesis
In sepsis, arginine availability is reduced by increased arginine catabolism, mainly through arginase pathways, and reduced availability through diminished endogenous arginine synthesis and food intake (Fig. 2). This makes arginine a near essential amino acid in sepsis, as was suggested before, and limits arginine availability for NO production and other arginine-consuming pathways. This is illustrated by the observation that exogenous arginine administration can increase NO production.
Although increased NO production by NOS-2 in sepsis is linked to systemic hypotension, many characteristics of sepsis could be linked to locally diminished NO availability. For example, impaired NO synthesis by NOS-3 may be related to loss of ability to autoregulate microcirculation. Increased NO from NOS-2 could then be regarded as a compensatory mechanism to improve blood flow. This could also explain why nonselective NOS inhibitors, which inhibit both NOS-3 and NOS-2, are not beneficial. Arginine might improve microcirculation by increasing NO production, mainly by delivering adequate amounts of substrate for NOS-3. The fact that in our hypothesis the reduction of NOS-3 expression is important in the pathophysiology of sepsis makes the supplementation of arginine a more logical step than selective inhibition of NOS-2. Although this latter therapy may reduce the exaggerated induction of NOS-2 and therefore treat the sepsis-induced hypotension, it will not compensate for the prolonged reduction in arginine availability, which causes a considerable number of sepsis-related features.
The importance of adequate arginine levels and NO production is further supported by the observations that marked reduction in serum arginine is a predictor of mortality in patients with sepsis and that patients surviving septic shock had higher plasma nitrate levels than nonsurvivors. However, debate exists concerning this last argument.[27,55] Adequate arginine levels may also reduce the production of superoxide and peroxynitrite by NOS, as this occurs in conditions of reduced levels of arginine or cofactor tetrahydrobiopterin. Moreover, arginine has anabolic effects and contributes to protein synthesis (e.g., acute phase proteins). Although arginine-containing immunonutrition did not improve survival, further studies are needed with arginine supplementation as a monotherapy. It would be interesting to focus on the effect of arginine supplementation (both intravenously and enterally) on microcirculation and subsequent organ function, on protein metabolism, and ultimately, on survival. Well-designed and controlled studies are therefore needed.
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Crit Care Med. 2004;32(10) © 2004 Lippincott Williams & Wilkins
Cite this: Sepsis: An Arginine Deficiency State? - Medscape - Oct 01, 2004.