Skip to main content

Advertisement

SpringerLink
Log in

Arginine metabolism and nutrition in growth, health and disease

  • Review Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

l-Arginine (Arg) is synthesised from glutamine, glutamate, and proline via the intestinal-renal axis in humans and most other mammals (including pigs, sheep and rats). Arg degradation occurs via multiple pathways that are initiated by arginase, nitric-oxide synthase, Arg:glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine, and agmatine with each having enormous biological importance. Arg is also required for the detoxification of ammonia, which is an extremely toxic substance for the central nervous system. There is compelling evidence that Arg regulates interorgan metabolism of energy substrates and the function of multiple organs. The results of both experimental and clinical studies indicate that Arg is a nutritionally essential amino acid (AA) for spermatogenesis, embryonic survival, fetal and neonatal growth, as well as maintenance of vascular tone and hemodynamics. Moreover, a growing body of evidence clearly indicates that dietary supplementation or intravenous administration of Arg is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, as well as facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity. Additionally, Arg or l-citrulline may provide novel and effective therapies for obesity, diabetes, and the metabolic syndrome. The effect of Arg in treating many developmental and health problems is unique among AAs, and offers great promise for improved health and wellbeing of humans and animals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AA:

Amino acid

Arg:

l-arginine

ADMA:

Asymmetric dimethylarginine

BH4:

(6R)-5,6,7,8-tetrahydrobiopterin

BMI:

Body mass index

IUGR:

Intrauterine growth retardation

NAG:

N-acetylglutamate

NMMA:

N G-monomethy-l-arginine (NMMA)

NO:

Nitric oxide

NOS:

Nitric-oxide synthase

P5C:

Pyrroline-5-carboxylate

TPN:

Total parenteral nutrition

References

  • Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615

    Article  PubMed  CAS  Google Scholar 

  • Amin HJ, Zamora SA, McMillan DD et al (2002) Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr 140:425–431

    Article  PubMed  CAS  Google Scholar 

  • Arana V, Paz Y, Gonzalez A et al (2004) Healing of diabetic foot ulcers in -arginine-treated patients. Biomed Pharmacother 58:588–597

    Article  PubMed  CAS  Google Scholar 

  • Balercia G, Moretti S, Vignini A et al (2004) Role of nitric oxide concentrations on human sperm motility. J Androl 25:245–249

    PubMed  CAS  Google Scholar 

  • Bassit RA, Curi R, Costa Rosa LFBP (2008) Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids 35:425–431

    Article  PubMed  CAS  Google Scholar 

  • Baylis C (2008) Nitric oxide deficiency in chronic kidney disease. Am J Physiol Renal Physiol 294:F1–F9

    Article  PubMed  CAS  Google Scholar 

  • Becker RM, Wu G, Galanko JA et al (2000) Reduced serum amino acid concentrations in infants with necrotizing enterocolitis. J Pediatr 137:785–793

    Article  PubMed  CAS  Google Scholar 

  • Bellinghieri G, Santoro D, Mallamace A, Savica V (2006) l-arginine: a new opportunity in the management of clinical derangement in dialysis patients. J Renal Nutr 16:245–247

    Article  Google Scholar 

  • Böger RH, Bode-Böger SM, Brandes RP et al (1997) Dietary l-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits. Circulation 96:1282–1290

    PubMed  Google Scholar 

  • Brosnan JT, Brosnan ME (2007) Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr 27:241–261

    Article  PubMed  CAS  Google Scholar 

  • Brunton JA, Bertolo RFP, Pencharz PB, Ball RO (1999) Proline ameliorates arginine deficiency during enteral but not parenteral feeding in neonatal pigs. Am J Physiol Endocrinol Metab 277:E223–E231

    CAS  Google Scholar 

  • Buhimschi IA, Saade GR, Chwalisz K, Garfield RE (1998) The nitric oxide pathway in pre-eclampsia: pathophysiological implications. Hum Reprod Update 4:25–42

    Article  PubMed  CAS  Google Scholar 

  • Bush JA, Wu G, Suryawan A et al (2002) Somatotropin-induced amino acid conservation in pigs involves differential regulation of liver and gut urea cycle enzyme activity. J Nutr 132:59–67

    PubMed  CAS  Google Scholar 

  • Campisi R, Czernin J, Schoder H et al (1999) l-Arginine normalizes coronary vasomotion in long-term smokers. Circulation 99:491–497

    PubMed  CAS  Google Scholar 

  • Cardounel AJ, Cui H, Samouilov A et al (2007) Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem 282:879–887

    Article  PubMed  CAS  Google Scholar 

  • Castillo L, Chapman TE, Yu YM et al (1993) Dietary arginine uptake by the splanchnic region in adult humans. Am J Physiol Endocrinol Metab 265:E532–E539

    CAS  Google Scholar 

  • Clarkson P, Adams MR, Powe AJ et al (1996) Oral l-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 97:1989–1994

    Article  PubMed  CAS  Google Scholar 

  • Creager MA, Gallagher SJ, Girerd XJ et al (1992) l-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 90:1248–1253

    Article  PubMed  CAS  Google Scholar 

  • Crenn P, Messing B, Cynober L (2008) Citrulline as a biomarker of intestinal failure due to enterocytes mass reduction. Clin Nutr 27:328–339

    Article  PubMed  CAS  Google Scholar 

  • Davis TA, Nguyen HV, Garciaa-Bravo R et al (1994) Amino acid composition of human milk is not unique. J Nutr 124:1126–1132

    PubMed  CAS  Google Scholar 

  • De Jonge WJ, Kwikkers KL, Te Velde AA et al (2002) Arginine deficiency affects early B cell maturation and lymphoid organ development in transgenic mice. J Clin Invest 110:1539–1548

    PubMed  Google Scholar 

  • Dekaney CM, Wu G, Yin YL, Jaeger LA (2008) Regulation of ornithine aminotransferase gene expression and activity by all-trans retinoic acid in CaCo2 intestinal epithelial cells. J Nutr Biochem 19:674–681

    Article  PubMed  CAS  Google Scholar 

  • Dillon EL, Knabe DA, Wu G (1999) Lactate inhibits citrulline and arginine synthesis from proline in pig enterocytes. Am J Physiol Gastrointest Liver Physiol 276:G1079–G1086

    CAS  Google Scholar 

  • Durante W, Johnson FK, Johnson RA (2007) Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol 34:906–911

    Article  CAS  Google Scholar 

  • Eremin O (1997) l-Arginine: biological aspects and clinical applications. RG Landes Company, Georgetown

    Google Scholar 

  • Facchinetti F, Neri I, Genazzani AR (1996) l-Arginine infusion reduces preterm uterine contractions. J Perinat Med 24:283–285

    PubMed  CAS  Google Scholar 

  • Facchinetti F, Saade GR, Neri I et al (2007) l-Arginine supplementation in patients with gestational hypertension: a pilot study. Hypertens Pregnancy 26:121–130

    Article  PubMed  CAS  Google Scholar 

  • Fang YZ, Yang S, Wu G (2002) Free radicals, antioxidants, and nutrition. Nutrition 18:872–879

    Article  PubMed  CAS  Google Scholar 

  • Flynn NE, Wu G (1996) An important role for endogenous synthesis of arginine in maintaining arginine homeostasis in neonatal pigs. Am J Physiol Regul Integr Comp Physiol 271:R1149–R1155

    CAS  Google Scholar 

  • Flynn NE, Wu G (1997) Enhanced metabolism of arginine and glutamine in enterocytes of cortisol-treated pigs. Am J Physiol Gastrointest Liver Physiol 272:G474–G480

    CAS  Google Scholar 

  • Flynn NE, Meininger CJ, Kelly K et al (1999) Glucocorticoids mediate the enhanced expression of intestinal type II arginase and argininosuccinate lyase in postweaning pigs. J Nutr 129:799–803

    PubMed  CAS  Google Scholar 

  • Flynn NE, Meininger CJ, Haynes TE, Wu G (2002) The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother 56:427–438

    Article  PubMed  CAS  Google Scholar 

  • Flynn NE, Bird JG, Guthrie AS (2008) Glucocorticoid regulation of amino acid and polyamine metabolism in the small intestine. Amino Acids. doi:10.1007/s00726-008-0206-7

  • Frank JW, Escobar J, Hguyen HV et al (2007) Oral N-carbamylglutamate supplementation increases protein synthesis in skeletal muscle of piglets. J Nutr 137:315–319

    PubMed  CAS  Google Scholar 

  • Fricke O, Baecker N, Heer M et al (2008) The effect of l-arginine administration on muscle force and power in postmenopausal women. Clin Physiol Funct Imaging 28:307–311

    Article  PubMed  CAS  Google Scholar 

  • Fu WJ, Haynes TE, Kohli R et al (2005) Dietary l-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J Nutr 135:714–721

    PubMed  CAS  Google Scholar 

  • Gaur U, Roberts SC, Dalvi RP et al (2007) An effect of parasite-encoded arginase on the outcome of murine cutaneous Leishmaniasis. J Immunol 179:8446–8453

    PubMed  CAS  Google Scholar 

  • Gobert AP, McGee DJ, Akhtar M et al (2001) Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc Natl Acad Sci USA 98:13844–13849

    Article  PubMed  CAS  Google Scholar 

  • Gookin JL, Foster DM, Coccaro MR, Stauffer SH (2008) Oral delivery of l-arginine stimulates prostaglandin-dependent secretory diarrhea in Cryptosporidium parvum-infected neonatal piglets. J Pediatr Gastroenterol Nutr 46:139–146

    Article  PubMed  CAS  Google Scholar 

  • Goud PT, Goud AP, Diamond MP et al (2008) Nitric oxide extends the oocyte temporal window for optimal fertilization. Free Radic Biol Med 45:453–459

    Article  PubMed  CAS  Google Scholar 

  • Grasemann H, Kurtz F, Ratjen F (2006a) Inhaled l-arginine improves exhaled nitric oxide and pulmonary function in patients with cystic fibrosis. Am J Respir Crit Care Med 174:208–212

    Article  PubMed  CAS  Google Scholar 

  • Grasemann H, Schwiertz R, Grasemann C et al (2006b) Decreased systemic bioavailability of l-arginine in patients with cystic fibrosis. Respir Res 7:1–7

    Article  CAS  Google Scholar 

  • Greenberg SS, Lancaster JR, Xie J et al (1997) Effects of NO synthase inhibitors, arginine-deficient diet, and amiloride in pregnant rats. Am J Physiol Regul Integr Comp Physiol 273:R1031–R1045

    CAS  Google Scholar 

  • Grillo MA, Lanza A, Colombatto S (2008) Transport of amino acids through the placenta and their role. Amino Acids 34:517–523

    Article  PubMed  CAS  Google Scholar 

  • Grimble GK (2007) Adverse gastrointestinal effects of arginine and related amino acids. J Nutr 137:1693S–1701S

    PubMed  CAS  Google Scholar 

  • Gualano B, Novaes RB, Artioli GG et al (2008) Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids 34:245–250

    Article  PubMed  CAS  Google Scholar 

  • Han J, Liu YL, Fan W et al. (2008) Dietary l-arginine supplementation alleviates immunosuppression induced by cyclophosphamide in weaned pigs. Amino Acids. doi:10.1007/s00726-08-0184-9

  • Hayashi T, Juliet PAR, Matsui-Hirai H et al (2005) l-citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci USA 102:13681–13686

    Article  PubMed  CAS  Google Scholar 

  • He QH, Kong XF, Wu G et al. (2008) Metabolomic analysis of the response of growing pigs to dietary l-arginine supplementation. Amino Acids. doi:10.1007/s00726-008-0192-9

  • Heird WC, Nicholson JF, Driscoll JM et al (1972) Hyperammonemia resulting from intravenous alimentation using a mixture of synthetic l-amino acids: a preliminary report. J Pediatr 81:162–165

    Article  PubMed  CAS  Google Scholar 

  • Helmbrecht GD, Farhat MY, Lochbaum L et al (1996) l-arginine reverses the adverse pregnancy changes induced by nitric oxide synthase inhibition in the rat. Am J Obstet Gynecol 175:800–805

    Article  PubMed  CAS  Google Scholar 

  • Hnia K, Gayraud J, Hugon G et al (2008) l-Arginine decreases inflammation and modulates the nuclear factor-kB/matrix metalloproteinase cascade in Mdx muscle fibers. Am J Pathol 172:1509–1519

    Article  PubMed  CAS  Google Scholar 

  • Holt LE Jr, Albanese AA (1944) Observations on amino acid deficiencies in man. Trans Assoc Am Physicians 58:143–156

    CAS  Google Scholar 

  • Hou ZP, Yin YL, Huang RL et al (2008) Rice protein concentrate partially replaces dried whey in the diet for early-weaned piglets and improves their growth performance. J Sci Food Agric 88:1187–1193

    Article  CAS  Google Scholar 

  • Hu CA, Khalil S, Zhaorigetu S et al (2008a) Human ∆1-pyrroline-5-carboxylate synthase: function and regulation. Amino Acids 35:665–672

    Article  PubMed  CAS  Google Scholar 

  • Hu CA, Williams DB, Zhaorigetu S et al (2008b) Functional genomics and SNP analysis of human genes encoding proline metabolic enzymes. Amino Acids 35:655–664

    Article  PubMed  CAS  Google Scholar 

  • Ito K, Chen J, Seshan SV et al (2005) Dietary arginine supplementation attenuates renal damage after relief of unilateralureteral obstruction in rats. Kidney Int 68:515–528

    Article  PubMed  CAS  Google Scholar 

  • Jeyabalan G, Klune JR, Nakao A et al (2008) Arginase blockade protects against hepatic damage in warm ischemia-reperfusion. Nitric Oxide 19:29–35

    Article  PubMed  CAS  Google Scholar 

  • Jobgen WS (2007) Dietary l-arginine supplementation reduces fat mass in diet-induced obese rats, PhD dissertation, Texas A&M University, College Station, Texas

  • Jobgen WS, Fried SK, Fu WJ et al (2006) Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem 17:571–588

    Article  PubMed  CAS  Google Scholar 

  • Kamada Y, Nagaretani H, Tamura S et al (2001) Vascular endothelial dysfunction resulting from l-arginine deficiency in a patient with lysinuric protein intolerance. J Clin Invest 108:717–724

    PubMed  CAS  Google Scholar 

  • Kaul DK, Zhang XQ, Dasgupta T, Fabry ME (2008) Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilator, hemolysis, and oxidative stress. Am J Physiol Heart Circ Physiol 295:H39–H47

    Article  PubMed  CAS  Google Scholar 

  • Kepka-Lenhart D, Mistry SK, Wu G, Morris SM Jr (2000) Arginase I: a limiting factor for nitric oxide and polyamine synthesis by activated macrophages? Am J Physiol Regul Integr Comp Physiol 279:R2237–R2242

    PubMed  CAS  Google Scholar 

  • Kim SW, Wu G (2004) Dietary arginine supplementation enhances the growth of milk-fed young pigs. J Nutr 134:625–630

    PubMed  CAS  Google Scholar 

  • Kim SW, Wu G (2008) Regulatory role for amino acids in mammary gland growth and milk synthesis. Amino Acids. doi:10.1007/s00726-008-0151-5

  • Kim YJ, Parks HS, Lee HY et al (2006) Reduced l-arginine level and decreased placental eNOS activity in preeclampsia. Placenta 27:438–444

    Article  PubMed  CAS  Google Scholar 

  • King DE, Mainous AG, Geesey ME (2008) Variation in l-arginine intake follow demographics and lifestyle factors that may impact cardiovascular disease risk. Nutr Res 28:21–24

    Article  CAS  PubMed  Google Scholar 

  • Kohli R, Meininger CJ, Haynes TE et al (2004) Dietary l-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J Nutr 134:600–608

    PubMed  CAS  Google Scholar 

  • Kwon H, Spencer TE, Bazer FW, Wu G (2003a) Developmental changes of amino acids in ovine fetal fluids. Biol Reprod 68:1813–1820

    Article  PubMed  CAS  Google Scholar 

  • Kwon H, Wu G, Bazer FW, Spencer TE (2003b) Developmental changes in polyamine levels and synthesis in the ovine conceptus. Biol Reprod 69:1626–1634

    Article  PubMed  CAS  Google Scholar 

  • Lassala A (2008) Arginine and fetal growth in ovine models of intrauterine growth restriction, PhD dissertation, Texas A&M University, College Station, Texas

  • Lee J, Ryu H, Ferrante RJ et al (2003) Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 100:4843–4848

    Article  PubMed  CAS  Google Scholar 

  • Li H, Meininger CJ, Hawker JR Jr, Haynes TE et al (2001) Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab 280:E75–E82

    PubMed  CAS  Google Scholar 

  • Li H, Meininger CJ, Kelly KA et al (2002) Activities of arginase I and II are limiting for endothelial cell proliferation. Am J Physiol Regul Integr Comp Physiol 282:R64–R69

    PubMed  CAS  Google Scholar 

  • Li P, Yin YL, Li DF et al (2007) Amino acids and immune function. Br J Nutr 98:237–252

    Article  PubMed  CAS  Google Scholar 

  • Li P, Kim SW, Li XL et al (2008a) Dietary supplementation with cholesterol and docosahexaenoic acid increases the activity of the arginine-nitric oxide pathway in tissues of young pigs. Nitric Oxide 19:259–265

    Article  PubMed  CAS  Google Scholar 

  • Li P, Mai KS, Trushenski J, Wu G (2008b) New developments in fish amino acid nutrition: towards functional and environmentally oriented aquafeeds. Amino Acids. doi:10.1007/s00726-008-0171-1

  • Li P, Kim SW, Li XL et al. (2008c) Dietary supplementation with cholesterol and docosahexaenoic acid affects concentrations of amino acids in tissues of young pigs. Amino Acids. doi:10.1007/s00726-008-0196-5

  • Ligthart-Melis GC, van de Poll MCG, Boelens PG et al (2008) Glutamine is an important precursor for de novo synthesis of arginine in humans. Am J Clin Nutr 87:1282–1289

    PubMed  CAS  Google Scholar 

  • Lin CC, Tsai WC, Chen JY et al (2008) Supplements of l-arginine attenuate the effects of high-fat meal on endothelial function and oxidative stress. Int J Cardiol 127:337–341

    Article  PubMed  Google Scholar 

  • Lubec B, Hoeger H, Kremser K et al (1996) Decreased tumor incidence and increased survival by one year oral low dose arginine supplementation in the mouse. Life Sci 58:2317–2325

    Article  PubMed  CAS  Google Scholar 

  • Lucotti P, Setola E, Monti LD et al (2006) Beneficial effect of a long-term oral l-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients. Am J Physiol Endocrinol Metab 291:E906–E912

    Article  PubMed  CAS  Google Scholar 

  • Lupi A, Tenni R, Rossi A et al (2008) Human prolidase and prolidase deficiency. Amino Acids 35:739–752

    Article  PubMed  CAS  Google Scholar 

  • Ma Q, Williamson KE, O’Rourke D, Rowlands BJ (1999) The effects of l-arginine on crypt cell hyperproliferation in colorectal cancer. J Surg Res 81:181–188

    Article  PubMed  CAS  Google Scholar 

  • Mannick JB (2007) Regulation of apoptosis by protein S-nitrosylation. Amino Acids 32:523–526

    Article  PubMed  CAS  Google Scholar 

  • Marliss EB, Chevalier S, Gougeon R et al (2006) Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover. Diabetologia 49:351–359

    Article  PubMed  CAS  Google Scholar 

  • Mateo RD, Wu G, Bazer FW et al (2007) Dietary l-arginine supplementation enhances the reproductive performance of gilts. J Nutr 137:652–656

    PubMed  CAS  Google Scholar 

  • Mateo RD, Wu G, Moon HK et al (2008) Effects of dietary arginine supplementation during gestation and lactation on the performance of lactating primiparous sows and nursing piglets. J Anim Sci 86:827–835

    Article  PubMed  CAS  Google Scholar 

  • McCaffrey MJ, Bose CL, Reiter PD, Stiles AD (1995) Effect of l-arginine infusion on infant with persistent pulmonary hypertension of the newborn. Biol Neonate 67:240–243

    Article  PubMed  CAS  Google Scholar 

  • Moinard C, Nicolis I, Neveux N et al (2008) Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the citrudose pharmacokinetic study. Br J Nutr 99:855–862

    Article  PubMed  CAS  Google Scholar 

  • Montanez R, Rodriguez-Caso C, Sanchez-Jimenez F, Medina MA (2008) In silico analysis of arginine catabolism as a source of nitric oxide or polyamines in endothelial cells. Amino Acids 34:223–229

    Article  PubMed  CAS  Google Scholar 

  • Morris SM Jr (2007) Arginine metabolism: boundaries of our knowledge. J Nutr 137:1602S–1609S

    PubMed  CAS  Google Scholar 

  • Morris CR, Kato GJ, Poijakovic M et al (2005) Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294:81–90

    Article  PubMed  CAS  Google Scholar 

  • Nagasaka H, Yorifuji T, Murayama K et al (2006) Effect of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency. Eur J Pediatr 165:618–624

    Article  PubMed  CAS  Google Scholar 

  • Nguyen RHN, Wilcox AJ, Skjaerven R, Baird DD (2007) Men’s body mass index and infertility. Hum Reprod 22:2488–2493

    Article  PubMed  Google Scholar 

  • Nikolic J, Stojanovic I, Pavlovic R et al (2007) The role of l-arginine in toxic liver failure: interrelation of arginase, polyamine catabolic enzymes and nitric oxide synthase. Amino Acids 32:127–131

    Article  PubMed  CAS  Google Scholar 

  • O’Quinn PR, Knabe DA, Wu G (2002) Arginine catabolism in lactating porcine mammary tissue. J Anim Sci 80:467–474

    PubMed  CAS  Google Scholar 

  • Odenlund M, Holmqvist B, Baldetorp B et al. (2008) Polyamine synthesis inhibition induces S phase cell cycle arrest in vascular smooth muscle cells. Amino Acids. doi:10.1007/s00726-008-0060-7

  • Orlando GF, Wolf G, Engelmann M (2008) Role of neuronal nitric oxide synthase in the regulation of the neuroendocrine stress response in rodents: insights from mutant mice. Amino Acids 35:17–27

    Article  PubMed  CAS  Google Scholar 

  • Peters H, Border WA, Noble NA (1999) l-Arginine supplementation increased mesangial cell injury and subsequent tissue fibrosis in experimental glomerulonephritis. Kidney Int 55:2264–2273

    Article  PubMed  CAS  Google Scholar 

  • Phang JM, Donald SP, Pandhare J, Liu YM (2008) The metabolism of proline, a stress substrate, modulates carcinogenic pathways. Amino Acids 35:681–690

    Article  PubMed  CAS  Google Scholar 

  • Pieper GM (1997) Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol 29:8–15

    Article  PubMed  CAS  Google Scholar 

  • Reid KM, Tsung A, Kaizu T et al (2007) Liver I/R injury is improved by the arginase inhibitor, N-ω-Hydroxy-Nor-L-arginine (Nor-NOHA). Am J Physiol Gastrointest Liver Physiol 292:G512–G517

    Article  PubMed  CAS  Google Scholar 

  • Rhoads JM, Chen W, Gookin J et al (2004) l-Arginine stimulates intestinal cell migration through a focal adhesion kinase-dependent mechanism. Gut 53:514–522

    Article  PubMed  CAS  Google Scholar 

  • Rhoads JM, Plunkett E, Galanko J et al (2005) Serum citrulline correlates with enteral tolerance and bowel length in infants with short bowel syndrome. J Pediatr 146:542–547

    Article  PubMed  CAS  Google Scholar 

  • Rhoads JM, Corl BA, Harrell R et al (2007) Intestinal ribosomal p70s6 k signaling is increased in piglet rotavirus enteritis. Am J Physiol Gastrointest Liver Physiol 292:G913–G922

    Article  PubMed  CAS  Google Scholar 

  • Rhoads JM, Niu XM, Surendran S et al (2008) Arginine stimulates intestinal epithelial cell migration via a mechanism requiring both nitric oxide and p70s6 k signaling. J Nutr 138:1652–1657

    PubMed  CAS  Google Scholar 

  • Roberts JM (1999) Objective evidence of endothelial dysfunction in preeclampsia. Am J Kidney Dis 33:992–997

    Article  PubMed  CAS  Google Scholar 

  • Romero JR, Suzuka SM, Nagel RL, Fabry ME (2002) Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity. Blood 99:1103–1108

    Article  PubMed  CAS  Google Scholar 

  • Rytlewski K, Olszanecki R, Lauterbach R et al (2006) Effects of oral l-arginine on the foetal condition and neonatal outcome in preeclampsia: a preliminary report. Basic Clin Pharmacol Toxicol 99:146–152

    Article  PubMed  CAS  Google Scholar 

  • Rytlewski K, Olszanecki R, Lauterbach R et al (2008) Effects of oral l-arginine on the pulsatility indices of umbilical artery and middle cerebral artery in preterm labor. Eur J Obstet Gynecol Reprod Biol 138:23–28

    Article  PubMed  CAS  Google Scholar 

  • Satriano J (2007) Kidney growth, hypertrophy and the unifying mechanism of diabetic complications. Amino Acids 33:331–339

    Article  PubMed  CAS  Google Scholar 

  • Shantz LM, Levin VA (2007) Regulation of ornithine decarboxylase during oncogenic transformation: mechanisms and therapeutic potential. Amino Acids 33:213–223

    Article  PubMed  CAS  Google Scholar 

  • Shao A, Hathcock JN (2008) Risk assessment for the amino acids taurine, l-glutamine and l-arginine. Regul Toxicol Pharmacol 50:376–399

    Article  PubMed  CAS  Google Scholar 

  • Shi W, Meininger CJ, Haynes TE et al (2004) Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells. Cell Biochem Biophys 41:415–433

    Article  PubMed  CAS  Google Scholar 

  • Siasos G, Tousoulis D, Vlachopoulos C et al (2008) Short-term treatment with l-arginine prevents the smoking-induced impairment of endothelial function and vascular elastic properties in young individuals. Int J Cardiol 126:394–399

    Article  PubMed  Google Scholar 

  • Snyderman SE, Boyer A, Holt LE Jr (1959) The arginine requirement of the infant. AMA J Dis Child 97:192–195

    PubMed  CAS  Google Scholar 

  • Sotgia S, Zinellu A, Pinna GA et al (2008) A new selective pre-column ninhydrin-based derivatization for a RP-HPLC determination of plasma asymmetric dimethyl-l-arginine (ADMA) by fluorescence detection. Amino Acids 34:677–682

    Article  PubMed  CAS  Google Scholar 

  • Starbuck MJ, Dailey RA, Inskeep EK (2004) Factors affecting retention of early pregnancy in dairy cattle. Anim Reprod Sci 84:27–39

    Article  PubMed  Google Scholar 

  • Tan BE, Li XG, Kong XF et al. (2008a) Dietary l-arginine supplementation enhances the immune status in early-weaned piglets. Amino Acids. doi:10.1007/s00726-008-0155-1

  • Tan BE, Yin YL, Liu ZQ et al. (2008b) Dietary L-arginine supplementation increases muscle gain and reduces body fat mass in growing-finishing pigs. Amino Acids. doi:10.1007/s00726-008-0148-0

  • Tanimura J (1967) Studies on arginine in human semen. Part II. the effects of medication with l-arginine-HCl on male infertility. Bull Osaka Med School 13:84–89

    CAS  Google Scholar 

  • Tiboni GM, Giampietro F (2000) Inhibition of nitric oxide synthesis causes preterm delivery in the mouse. Hum Reprod 15:838–1842

    Article  Google Scholar 

  • van de Poll MCG, Siroen MPC, van Leeuwen PAM et al (2007) Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism. Am J Clin Nutr 85:167–172

    PubMed  Google Scholar 

  • Veleva Z, Tiitinen A, Vilska S et al (2008) High and low BMI increases the risk of miscarriage after IVF/ICSI and FET. Hum Reprod 23:878–884

    Article  PubMed  Google Scholar 

  • Vosatka RJ, Hassoun PM, Harvey-Wilkes KB (1998) Dietary l-arginine prevents fetal growth restriction in rats. Am J Obstet Gynecol 178:242–246

    Article  PubMed  CAS  Google Scholar 

  • Wakabayashi Y, Yamada E, Yoshida T, Takahashi H (1994) Deficiency of endogenous arginine synthesis provokes hypertension by exhausting substrate arginine for nitric oxide synthesis. Biochem Biophys Res Commun 205:1391–1398

    Article  PubMed  CAS  Google Scholar 

  • Wang WW, Qiao SY, Li DF (2008) Amino acids and gut function. Amino Acids. doi: 10.1007/s00726-008-0152-4

  • Wascher TC, Graier WF, Dittrich P et al (1997) Effects of low-dose l-arginine on insulin-mediated vasodilation and insulin sensitivity. Eur J Clin Invest 27:690–695

    Article  PubMed  CAS  Google Scholar 

  • Waugh WH, Daeschner CW, Files BA et al (2001) Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc 93:363–371

    PubMed  CAS  Google Scholar 

  • Wei LH, Wu G, Morris SM Jr, Ignarro LJ (2001) Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation. Proc Natl Acad Sci USA 98:9260–9264

    Article  PubMed  CAS  Google Scholar 

  • Wei LH, Yang Y, Wu G, Ignarro LJ (2008) IL-4 and IL-13 upregulate ornithine decarboxylase expression by PI3 K and MAP kinase pathways in vascular smooth muscle cells. Am J Physiol Cell Physiol 294:C1198–C1205

    Article  PubMed  CAS  Google Scholar 

  • Wessagowit V, Mallipeddi R, McGrath JA, South AP (2004) Altered expression of l-arginine metabolism pathway genes in chronic wounds in recessive dystrophic epidermolysis bullosa. Clin Exp Dermatol 29:664–668

    Article  PubMed  CAS  Google Scholar 

  • Witte MB, Barbul A (2008) Arginine physiology and its implications for wound healing. Wound Repair Regen 11:419–423

    Article  Google Scholar 

  • Wood KC, Hsu LL, Gladwin MT (2008) Sickle cell disease vasculopathy: a state of nitric oxide resistance. Free Radic Biol Med 44:1506–1528

    Article  PubMed  CAS  Google Scholar 

  • Wu G (1995) Urea synthesis in enterocytes of developing pigs. Biochem J 312:717–723

    PubMed  CAS  Google Scholar 

  • Wu G (1997) Synthesis of citrulline and arginine from proline in enterocytes of postnatal pigs. Am J Physiol Gastrointest Liver Physiol 272:G1382–G1390

    CAS  Google Scholar 

  • Wu G, Brosnan JT (1992) Macrophages can convert citrulline into arginine. Biochem J 281:45–48

    PubMed  CAS  Google Scholar 

  • Wu G, Knabe DA (1994) Free and protein-bound amino acids in sow’s colostrum and milk. J Nutr 124:2437–2444

    PubMed  CAS  Google Scholar 

  • Wu G, Knabe DA (1995) Arginine synthesis in enterocytes of neonatal pigs. Am J Physiol Regul Integr Comp Physiol 269:R621–R629

    CAS  Google Scholar 

  • Wu G, Meininger CJ (1993) Regulation of l-arginine synthesis from l-citrulline by l-glutamine in endothelial cells. Am J Physiol Heart Circ Physiol 265:H1965–H1971

    CAS  Google Scholar 

  • Wu G, Meininger CJ (2000) Arginine nutrition and cardiovascular function. J Nutr 130:2626–2629

    PubMed  CAS  Google Scholar 

  • Wu G, Meininger CJ (2002) Regulation of nitric oxide synthesis by dietary factors. Annu Rev Nutr 22:61–86

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Tuo W, Flynn SP (1996a) Unusual abundance of arginine and ornithine in porcine allantoic fluid. Biol Reprod 54:1261–1265

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Knabe DA, Flynn NE et al (1996b) Arginine degradation in developing porcine enterocytes. Am J Physiol Gastrointest Liver Physiol 271:G913–G919

    CAS  Google Scholar 

  • Wu G, Flynn NE, Flynn SP et al (1999) Dietary protein or arginine deficiency impairs constitutive and inducible nitric oxide synthesis by young rats. J Nutr 129:1347–1354

    PubMed  CAS  Google Scholar 

  • Wu G, Flynn NE, Knabe DA (2000a) Enhanced intestinal synthesis of polyamines from proline in cortisol-treated piglets. Am J Physiol Endocrinol Metab 279:E395–E402

    PubMed  CAS  Google Scholar 

  • Wu G, Flynn NE, Knabe DA, Jaeger LA (2000b) A cortisol surge mediates the enhanced polyamine synthesis in porcine enterocytes during weaning. Am J Physiol Regul Integr Comp Physiol 279:R554–R559

    PubMed  CAS  Google Scholar 

  • Wu G, Meininger CJ, Kelly K et al (2000c) A cortisol surge mediates the enhanced expression of pig intestinal pyrroline-5-carboxylate synthase during weaning. J Nutr 130:1914–1919

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Cudd TA et al (2004a) Maternal nutrition and fetal development. J Nutr 134:2169–2172

    PubMed  CAS  Google Scholar 

  • Wu G, Jaeger LA, Bazer FW, Rhoads JM (2004b) Arginine deficiency in premature infants: biochemical mechanisms and nutritional implications. J Nutr Biochem 15:442–451

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Knabe DA, Kim SW (2004c) Arginine nutrition in neonatal pigs. J Nutr 134:2390S–2783S

    Google Scholar 

  • Wu G, Bazer FW, Hu J et al (2005) Polyamine synthesis from proline in the developing porcine placenta. Biol Reprod 72:842–850

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Wallace JM, Spencer TE (2006) Intrauterine growth retardation: implications for the animal sciences. J Anim Sci 84:2316–2337

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Cudd TA et al (2007a) Pharmacokinetics and safety of arginine supplementation in animals. J Nutr 137:1673S–1680S

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Kim SW (2007b) New developments in amino acid research. In: Rosati A, Tewolde A, Mosconi C et al (eds) Animal Production and Animal Science Worldwide: WAAP Book of the Year 2006. Wageningen Academic Publishers, The Netherlands, pp 299–315

    Google Scholar 

  • Wu G, Bazer FW, Davis TA et al (2007c) Important roles for the arginine family of amino acids in swine nutrition and production. Livest Sci 112:8–22

    Article  Google Scholar 

  • Wu G, Collins JK, Perkins-Veazie P et al (2007d) Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr 137:2680–2685

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Datta S et al (2008a) Proline metabolism in the conceptus: implications for fetal growth and development. Amino Acids 35:691–702

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Datta S et al (2008b) Intrauterine growth retardation in livestock: implications, mechanisms and solutions. Arch Fur Tierzucht-Arch Anim Breed 51(Special Issue 1):4–10

    Google Scholar 

  • Wu G, Meininger CJ (2009) Nitric oxide and vascular insulin resistance. BioFactors (in press)

  • Xiao XM, Li LP (2005) l-arginine treatment for asymmetric fetal growth restriction. Int J Gynecol Obstet 88:15–18

    Article  CAS  Google Scholar 

  • Yamasaki K, Edington HDJ, McClosky C et al (1998) Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Invest 101:967–971

    Article  PubMed  CAS  Google Scholar 

  • Yao K, Yin YL, Chu WY et al (2008) Dietary arginine supplementation increases mTOR signaling activity in skeletal muscle of neonatal pigs. J Nutr 138:867–872

    PubMed  CAS  Google Scholar 

  • Yeo TW, Lampah DA, Gitawati R et al (2007) Impaired nitric oxide bioavailability and l-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med 204:2693–2704

    Article  PubMed  CAS  Google Scholar 

  • Yu YM, Ryan CM, Castillo L et al (2001) Arginine and ornithine kinetics in severely burned patients: increased rate of arginine disposal. Am J Physiol Endocrinol Metab 280:E509–E517

    PubMed  CAS  Google Scholar 

  • Zeng XF, Wang FL, Fan X et al (2008) Dietary arginine supplementation during early pregnancy enhances embryonic survival in rats. J Nutr 138:1421–1425

    PubMed  CAS  Google Scholar 

  • Zou CH, Shao JH (2008) Role of adipocytokines in obesity-associated insulin resistance. J Nutr Biochem 19:277–286

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported, in part, by grants from National Institutes of Health (1R21 HD049449), National Research Initiative Competitive Grants (2006-35203-17283, 2008-35206-18762, 2008-35206-18764, and 2008-35203-19120) from the USDA Cooperative State Research, Education, and Extension Service, American Heart Association (0655109Y and 0755024Y), Texas AgriLife Research (H-8200), National Natural Science Foundation of China (30371038 and 30528006), and the Outstanding Overseas Chinese Scholars Fund of The Chinese Academy of Sciences (2005-1-4). We thank Drs. Nick Flynn and Nancy Turner for helpful comments on the paper.

Author information

Authors and Affiliations

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

    Guoyao Wu, Fuller W. Bazer, Peng Li, M. Carey Satterfield, Stephen B. Smith & Thomas E. Spencer

  2. Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, 41012, China

    Guoyao Wu & Yulong Yin

  3. Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA

    Teresa A. Davis

  4. North Carolina State University, Raleigh, NC, 27695, USA

    Sung Woo Kim

  5. Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, 77030, USA

    J. Marc Rhoads

Authors
  1. Guoyao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fuller W. Bazer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teresa A. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sung Woo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Marc Rhoads
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Carey Satterfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stephen B. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas E. Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yulong Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guoyao Wu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, G., Bazer, F.W., Davis, T.A. et al. Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37, 153–168 (2009). https://doi.org/10.1007/s00726-008-0210-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-008-0210-y

Keywords

Search

Navigation