Pharmacologic Levels of Dietary Arginine in CB6F1 Mice Increase Serum Ammonia in the Healthy State and Serum Nitrite in Endotoxemia

Background: Therapeutic or pharmacologic doses of arginine are used to enhance blood flow and immune function despite the lack of dose‐response studies and the potential for adverse effects. This study determined the optimal level of oral arginine supplementation required to elevate serum arginine concentrations yet limit adverse effects in healthy and endotoxemic mice. Methods: Male CB6F1 mice were fed one of the following diets: The standard AIN93G (3 g arginine/100 g of protein) or this diet modified to provide 10 g, 20 g, or 30 g arginine/100 g of protein. On day 14, mice were injected with lipopolysaccharide (endotoxemic) or saline (healthy) and 4 hours later were exsanguinated. Results: Weight gain was reduced 50% in the group fed the 30 g arginine vs standard diet. Serum arginine, ornithine, citrulline, histidine, lysine, serine, threonine, tyrosine, and phenylalanine were greater and glutamate levels were lower in healthy supplemented mice; lipopolysaccharide treatment negated these changes. Serum ammonia concentration was 52% greater in healthy mice fed the 30 g arginine vs standard diet. Serum nitrite and urea were unaffected by supplementation in healthy mice. Serum nitrite was 37% greater in endotoxemic mice fed 30 g vs 10 g arginine, and serum urea was 27% greater in mice fed 20 g or 30 g vs 10 g arginine. Conclusions: Changes in serum arginine or its metabolites were observed with all of the modified diets; however, a 30‐g arginine diet was associated with an initial impairment of growth and potential adverse effects.