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

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Abstract

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.

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Abbreviations

ADMA:

Asymmetrical dimethylarginine

AGAT:

l-Arginine:glycine amidinotransferase

Arg:

l-Arginine

BW:

Body weight

hArg:

l-Homoarginine

HPLC:

High-performance liquid chromatography

NMMA:

NG-monomethylarginine

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOx:

Nitrate plus nitrite

SDMA:

Symmetrical dimethylarginine

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Acknowledgments

This research was supported by a grant from the International Council of Amino Acid Science (Brussels, Belgium). We thank our graduate students and technicians for assistance in this work. Ying Yang was supported by a Fellowship from the China Scholarship Council.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The use of animals for this research was approved by the Institutional Animal Care and Use Committee of Texas A&M University.

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Authors and Affiliations

  1. Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA

    Ying Yang, Sichao Jia, Sudath Dahanayaka & Guoyao Wu

  2. State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, People’s Republic of China

    Ying Yang & Zhenlong Wu

  3. Department of Statistics, Texas A&M University, College Station, TX, 77843, USA

    Shuo Feng

  4. Department of Medical Physiology, Texas A&M University, College Station, TX, 77843, USA

    Cynthia J. Meininger & Guoyao Wu

  5. Department of Internal Medicine, Scott & White Healthcare, Temple, TX, 76508, USA

    Catherine J. McNeal

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  1. Ying Yang
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  2. Zhenlong Wu
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  3. Sichao Jia
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  4. Sudath Dahanayaka
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  5. Shuo Feng
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  7. Catherine J. McNeal
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  8. Guoyao Wu
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Correspondence to Guoyao Wu.

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Yang, Y., Wu, Z., Jia, S. et al. Safety of long-term dietary supplementation with l-arginine in rats. Amino Acids 47, 1909–1920 (2015). https://doi.org/10.1007/s00726-015-1992-3

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