Safety of long-term dietary supplementation with L-arginine in rats

This study was conducted with rats to determine the safety of long-term dietary supplementation with L-arginine. Beginning at 6 weeks of age, male and female rats were fed a casein-based semi-purified diet containing 0.61 % L-arginine and received drinking water containing L-arginine-HCl (0, 1.8, or 3.6 g L-arginine/kg body-weight/day; n = 10/group). These supplemental doses of L-arginine were equivalent to 0, 286, and 573 mg L-arginine/kg body-weight/day, respectively, in humans. After a 13-week supplementation period, blood samples were obtained from rats for biochemical analyses. Supplementation with L-arginine increased plasma concentrations of arginine, ornithine, proline, homoarginine, urea, and nitric oxide metabolites without affecting those for lysine, histidine, or methylarginines, while reducing plasma concentrations of ammonia, glutamine, free fatty acids, and triglycerides. L-Arginine supplementation enhanced protein gain and reduced white-fat deposition in the body. Based on general appearance, feeding behavior, and physiological parameters, all animals showed good health during the entire experimental period; Plasma concentrations of all measured hormones (except leptin) did not differ between control and arginine-supplemented rats. L-Arginine supplementation reduced plasma levels of leptin. Additionally, L-arginine supplementation increased L-arginine:glycine amidinotransferase activity in kidneys but not in the liver or small intestine, suggesting tissue-specific regulation of enzyme expression by L-arginine. Collectively, these results indicate that dietary supplementation with L-arginine (e.g., 3.6 g/kg body-weight/day) is safe in rats for at least 91 days. This dose is equivalent to 40 g L-arginine/kg body-weight/day for a 70-kg person. Our findings help guide clinical studies to determine the safety of long-term oral administration of L-arginine to humans.