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Arginine

Nutrient Name: Arginine.
Synonym:L-Arginine.

Summary Table
nutrient description

Chemistry and Forms

Arginine is a complex amino acid often found at the active (or catalytic) site in proteins and enzymes because of its amine-containing side chain. With four nitrogen atoms per molecule, it is the most abundant nitrogen carrier in humans and animals.

Physiology and Function

Arginine's primary function is generally considered to be the transport, storage, detoxification, and excretion of nitrogen, in particular, and metabolism of protein, in general, through the urea cycle. Arginine is also the substrate for nitric oxide synthase and arginase, two important metabolic pathways. Nitric oxide (NO), a key vasodilator, neurotransmitter, and cell-signaling molecule, is formed by the three different nitric oxide synthases from the N-guanido terminal of the amino acidL-arginine and from molecular oxygen. Nitric oxide synthase (NOS) also converts arginine to citrulline. Arginase converts arginine to ornithine and urea. Arginase I and arginase II control the transformation of arginine into ornithine, which subsequently forms proline and polyamines, which exert multiple effects on connective tissue, smooth muscle, and mucus synthesis. The NOS and arginase pathways interfere with each other through substrate competition.

As the precursor to NO, arginine plays a key role in the circulatory and respiratory systems, particularly endothelial function, vasodilation, and airway physiology. Arginine also functions as a key immunomodulator, particularly increasing the number of T cells, enhancing T cell function, and supporting tissue regeneration. Recent studies have reported increases in arginase in conditions including reperfusion injury, asthma, psoriasis, arthritis, and human breast cancer. Helper T cell type 2 (Th2) cytokines induce arginase expression. During allergic inflammation, increased interleukin-4 (IL-4) and/or IL-13 expression results in increased expression of arginase and amplification of the arginase-dependent pathway, with concomitant suppression of NO generation. Furthermore, in relation to neuroendocrine function, arginine strongly influences adrenal and pituitary functions, especially through stimulation of catecholamines, norepinephrine, insulin and glucagon, prolactin, and growth hormone (GH). Lastly, arginine is involved in synthesis of spermine and spermidine, polyamines required for cell division and growth, and numerous aspects of reproductive function. Hepatic metabolism of arginine produces hydrogen ions (H+).

Arginine is generally considered a conditionally essential amino acid because adult humans can generally synthesize it de novo from ornithine, glutamine, glutamate, and proline. However, arginine must be obtained through the diet during the juvenile period in humans and in those not synthesizing adequate amounts to meet metabolic demands, especially after acute trauma, burns, or surgery and during infections, chronic illness, or wound healing. In all situations, dietary intake remains the primary determinant of plasma arginine levels, since the rate of arginine biosynthesis does not increase to compensate for depletion or inadequate supply.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Arginine's central role in promoting NO formation forms the basis of its therapeutic effect in the treatment of cardiovascular disease, asthma, interstitial cystitis, female sexual dysfunction, and male erectile dysfunction. In particular, a growing body of research has focused on arginine's ability to induce vasodilation and improve endothelial function through its role as a substrate for NO synthesis. Arginine hydrochloride has been used clinically in correcting severe metabolic alkalosis because of its high chloride content. Findings from preliminary double-blind trials indicate the efficacy of arginine in the treatment of acquired immunodeficiency syndrome (AIDS) cachexia, angina, congestive heart failure (CHF), endothelial function in type 1 diabetes, erectile dysfunction, hypertension, and other conditions. Arginine has also been used therapeutically to enhance several aspects of healthy function, including supporting wound healing and resistance to infection; elevating production of GH and related hormones; increasing exercise tolerance, lean muscle mass, and total strength; improving sperm motility and sexual vitality; and reducing low-density lipoprotein (LDL) cholesterol.

Historical/Ethnomedicine Precedent

Arginine has not been used historically as an isolated nutrient.

Possible Uses

Angina, athletic performance, burns, chronic renal failure, congestive heart failure, cystic fibrosis, enhancing formation of muscle mass, erectile dysfunction, female infertility (in vitro fertilization), gastritis, hepatic insufficiency, human immunodeficiency virus (HIV) support, hypercholesterolemia, hypertension, inflammatory bowel disease, immunity enhancement, intermittent claudication (intravenous only), interstitial cystitis, male infertility (oligospermia), metabolic alkalosis, peripheral vascular disease, surgery preparation and recovery, trauma, wound healing enhancement.

Deficiency Symptoms

Arginine deficiency is uncommon and is usually related to overall protein malnutrition (especially protein deficiency), compromised health status or elevated physiological stress (e.g., burns, injury, infection), excessive ammonia production, or enzyme deficiency. Primary symptoms include rash, hair loss, poor wound healing, constipation, fatty liver, and cirrhosis.

Dietary Sources

The best dietary sources of arginine are meat (especially lamb), peanuts, soybeans, hazelnuts, shrimp, eggs, and milk products. Other foods containing significant mounts of arginine include: almonds, cashews, Brazil nuts, filberts, pecans, sesame and sunflower seeds, walnuts, raisins, coconut, gelatin, chicken, chocolate, brown rice, barley, buckwheat, corn, and oats.

Lysine competes with arginine for absorption, so a diet low in lysine may enhance the effects of arginine intake.

Dosage Forms Available

Capsules, powder, or tablets, containing a salt ofL-arginine, such asL-arginine hydrochloride, or arginine glutamate; the free base amino acid is also sometimes used, although it is more problematic to use in a capsule or tablet because it is very hygroscopic.

  • Well absorbed orally, with time to peak serum concentration approximately 2 hours.
  • Best taken away from meals, in divided doses, throughout day.
  • Intravenously administered for pituitary function test.

Dosage Range

Adult

  • Dietary:   Optimal levels of intake have not been established.
  • Supplemental/Maintenance:   1.5 to 6.0 grams per day, usually 2 to 3 g/day; best in divided doses because absorption of doses greater than 3 g is usually poor. Arginine can be synthesized endogenously, and supplementation is usually not necessary for most individuals.
  • Pharmacological/Therapeutic:   Researchers and practitioners of nutritional therapeutics have used a wide range of dosages, from 2 to 30 g daily, with 6 g daily being representative for most conditions. For example, 6 to 15 g daily has been used in CHF treatment. Long-term use is usually not advisable.

Pediatric (<18 Years)

  • Dietary:   Optimal levels of intake have not been established.
  • Supplemental/Maintenance:   Usually not administered as a nutritional supplement to children.
  • Pharmacological/Therapeutic:   Usually not administered therapeutically to children, except possibly in relation to burns, injuries, or surgery; in such cases, dosage levels would be proportional to typical adult doses by weight.

Laboratory Values

Research laboratory methods for measuring NOS activity are available, but they are not used clinically to any significant degree. Serum and urine amino acid profiles are available, but not likely to be clinically relevant to the status of arginine-derived NO production capability, because more factors are involved than simply the amount of arginine present in tissues and body fluids. Therefore, effects of arginine supplementation are best judged clinically. Various measures of circulatory and endothelial function are most likely to show changes if supplemental arginine enhances NOS activity, as well as blood pressure, erectile function, and exercise tolerance.

safety profile

Overview

Dosage levels of 1 to 6 g per day generally are well tolerated by healthy adults. Adverse effects are estimated to occur in 1% to 10% of patients administered arginine, with more severe reactions associated with intravenous (IV) administration.

Nutrient Adverse Effects

General Adverse Effects

Minor gastrointestinal (GI) distress is occasionally associated with supplemental intake; headache also may occur. Excessive doses of arginine (>40 g/day) may cause diarrhea, most likely as a result of poor absorption at higher dosage levels. Rapid IV infusion may produce flushing.

Despite numerous studies demonstrating the immune-enhancing activity of arginine, including research with breast cancer, some researchers have suggested that high doses of arginine can increase the growth of cancer cells in humans. 1-4Clinicians with experience in integrative oncology have observed that amino acids, particularly arginine, can have opposite effects at different stages in the disease process, for tissues at different sites, and for different individuals. Further research into such aspects of nutritional therapeutics within cancer prevention and treatment are warranted to delineate such patterns and determine their implications in developing therapeutic strategies. However, pending such studies, the influence of arginine on growth of cancers can generally be qualified as unpredictable.

Adverse Effects Among Specific Populations

Individuals with a history of gastritis, reflux esophagitis, or peptic ulcer disease may experience exacerbations with arginine administration, possibly from stimulation of gastrin. However, the evidence for such concern is mixed.

Hyperphosphatemia can be induced by arginine in patients with severe hepatic disease and kidney problems. The maximum safe dosage levels for arginine administration in individuals with compromised hepatic function have not been established.

Pregnancy and Nursing

Data on long-term safety for arginine administration in pregnant or lactating women are lacking, and maximum safe dosage levels have not been established.

Infants and Children

Data on long-term safety for arginine administration in infants and children are lacking, and maximum safe dosage levels have not been established.

Contraindications

Administration ofL-arginine after acute myocardial infarction (MI) may lead to worsened clinical outcomes or death, particularly in older patients with diffuse atherosclerosis, and should be avoided except under the direct supervision of a physician trained and experienced in such interventions. 5 As a possible explanation for these results, it has been hypothesized thatL-arginine may only help to alleviate vascular stiffness in patients with preexistingL-arginine deficiency. Continued research is warranted to clarify the role ofL-arginine in cardiovascular health.

Avoidance of arginine supplementation by individuals with active or past herpes simplex virus (HSV) infections has often been asserted based on the theory that elevated arginine levels might stimulate viral replication or provoke an outbreak, especially in the context of low lysine levels. Although supported by broad anecdotal reports and older in vitro data, 6 evidence from clinical trials is lacking to confirm elevated susceptibility and validate this contraindication. Nevertheless, caution is warranted. If herpetic reactivations consistently occur shortly after initiating arginine administration or otherwise increasing intake, clinical anecdotes have suggested that a therapeutic trial of coadministration with equal amounts ofL-lysine may be useful. Currently, no clinical evidence indicates whether or notL-lysine coadministration may interfere withL-arginine's bioavailability, based on the known competition between the two amino acids for intestinal absorption.

Arginine administration is generally contraindicated in individuals with hepatic or renal failure, except when clinically appropriate and then only under direct medical supervision. 7

Individuals with a known history of hypersensitivity to arginine generally need to avoid supplemental intake.

Precautions and Warnings

Arginine administration, at usual dosage levels, is generally considered safe in individuals with stable type 2 diabetes mellitus. However, regular monitoring of blood glucose levels is appropriate in diabetic individuals supplementing with arginine because of possible effects on insulin and glucagon. 6

interactions review

Strategic Considerations

Despite positive findings from a range of disparate studies, scientific research on the therapeutic use of arginine has not matured; evidence of interactions involving arginine, based on well-designed clinical trials and documented case reports, is uneven and often absent. In many cases, well-known pharmacological principles enable us to predict many probable patterns of interaction, but the body of evidence articulating mechanisms, actions, and efficacy has not yet produced a consistent set of clinically applicable knowledge and related practices. Medical conditions and pharmaceutical agents that deplete or impair arginine status inherently influence relationships between NO and arginase and their interdependent levels and functions and consequently affect cardiac, muscular, and respiratory tissues and processes of growth, inflammation, and expansion/contraction. Interactions involving arginine are primarily characterized by their beneficial effect in supporting the therapeutic strategy and reducing drug adverse effects; such action inherently invokes the occasional bimodal interaction that carries potential for adverse or supportive character largely dependent on communication, observation, and responsive clinical management. Thus, for example, drugs that reduce arginase activity would theoretically increase arginine's availability to be converted to NO. Further research into this apparent bimodal activity of NO, and arginine, is warranted because some aspects of current knowledge suggest that excess NO levels might be involved in chronic inflammatory disorders. Any resulting evidence of peroxynitrate/nitrite formation from NO in situations of increased oxidative stress in the context of inadequate antioxidant reserves would suggest that clinicians give further attention to antioxidant reserves when administering arginine.

In some respects, arginine has already established a role for itself within the inpatient clinical setting, more so than in conventional outpatient care. Within critical care guidelines, arginine hydrochloride is considered a fourth-line treatment for uncompensated metabolic alkalosis after sodium chloride, potassium chloride, and ammonium chloride supplementation has been optimized. The immunomodulatory actions of arginine in nourishing hospitalized patients represent an area of continued research and significant potential benefit. Research on immunonutrition using arginine as part of parenteral formulas in combination with other nutrients has focused on mucosal barrier function, cellular defense, and local or systemic inflammation; results have been promising but mixed.

Within nutritional pharmacology and integrative therapeutic strategies, arginine is primarily used as a component of multifactorial interventions to promote detoxification (especially excretion of ammonia), stimulate immune function and modulate inflammation, aid wound healing, enhance healthy function of cardiac and vascular tissue, and promote secretion of several hormones, including glucagon, insulin, and GH. Thus, the emerging concept of immunonutrition as a proactive component of an integrative therapeutic strategy represents a convergence of conventional practice and nutritive therapies, with further research inevitable.

nutrient-drug interactions
Angiotensin-Converting Enzyme (ACE) Inhibitors
Potassium-Sparing Diuretics
Cyclosporine

Effect and Mechanism of Action

L-Arginine is the substrate for nitric oxide (NO) synthesis. A diminished role of the NO/cyclic guanosine monophosphate (cGMP)–mediated vasodilator mechanism, particularly NO blockade, may be responsible for cyclosporine-induced vascular dysfunction. Nitric oxide can decrease cyclosporine nephrotoxicity; it can also have both effector (cytotoxic) and regulatory roles in immune function.L-Arginine is also the substrate for both nitric oxide synthase (NOS), which produces NO, and a component in the experimental NOS inhibitor, N-nitro-L-arginine-methyl ester (L-NAME); both substances have been shown to modify acute cyclosporin A (CsA)–induced intrarenal vasoconstriction.

Research

Arginine has many beneficial effects on the kidneys and may be beneficial in many forms of renal disease, including hypertension and ureteral obstructive nephropathy. A series of studies using a rat model indicate that oral administration ofL-arginine can prevent chronic cyclosporine nephrotoxicity through effects on NO metabolites and cGMP.14-16Initially, Andoh et al.14found that “chronic CsA nephrotoxicity can be aggravated by NO blockade and ameliorated by NO enhancement.” Later, Lee et al.16conducted in vitro experiments using tissue isolated from the thoracic aorta of normal rats and those acutely treated with CsA to investigate vascular relaxation response to acetylcholine and tissue levels of NO metabolites and cGMP. They found that acute treatment with CsA in vitro greatly attenuated the vasorelaxation response to acetylcholine and that such response was completely restored byL-arginine. The vascular accumulation of NO metabolites in response to acetylcholine was decreased significantly by CsA, but coadministration ofL-arginine prevented this effect. While CsA decreased cGMP accumulation in response to acetylcholine (and sodium nitroprusside), acetylcholine-stimulated cGMP generation was restored, although not completely, byL-arginine, but it did not affect sodium nitroprusside–stimulated cGMP generation. After chronic CsA treatment in the whole animal, the vasorelaxation response to acetylcholine was decreased significantly, along with tissue levels of NO metabolites; administration ofL-arginine preserved this effect. The authors concluded: “CsA causes anL-arginine-sensitive vascular dysfunction which is associated with impaired generation of NO and cGMP.”16Other research with animals indicates that arginine may inhibit tumor growth by activating macrophage cytotoxic effects.17

Zhang et al.18conducted a randomized, double-blind clinical trial involving 11 young renal allograft recipients, age 11 to 22 years, with chronic renal transplant dysfunction treated with CsA. The subjects were randomly assigned to a 6-week treatment period with placebo, followed by two subsequent 6-week periods withL-arginine supplementation (0.1 g/kg/day) or 6-week treatment withL-arginine, followed by two subsequent 6-week periods with placebo. At the end of each treatment period, 24-hour blood pressure readings were taken, and glomerular filtration rate (GFR), renal perfusion function (RPF; PAH clearance), and urinary excretion of protein, albumin, nitrate, cGMP, and urea were evaluated. These researchers found that subjects receiving arginine did not demonstrate significant changes in GFR, RPF, proteinuria/albuminuria, mean systolic/diastolic blood pressure, compared with placebo. These researchers concluded that arginine administration “did not improve renal function and did not decrease proteinuria in CsA-treated renal allograft recipients with chronic transplant dysfunction possibly because of inhibition of NO-cGMP forming mechanism.”18Given the negative results of this small clinical trial, with the suggestive preclinical data, clinicians might consider the question of how a trial might be designed with a stronger opportunity for a positive outcome. Higher doses, longer term, starting arginine vs. placebo concurrent with CsA, or other design variants might enable investigators to determine if CsA nephropathy can be prevented, if correction is not obtainable. Arginine may also increase oxidative stress by forming peroxynitrite radicals (NO reacting with superoxide radicals), so some measure of oxidative stress and correction with either dietary or supplemental antioxidants may be needed to demonstrate benefit.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The body of research on arginine can reasonably be interpreted as supporting the general hypothesis that arginine may provide a salutary effect to renal function, particularly in individuals whose kidneys are in a compromised state. However, the mixed character and preliminary state of the available research data suggest that sufficient evidence is lacking to support coadministration ofL-arginine as likely to offer significant definite benefit to patients undergoing cyclosporine therapy. Well-designed clinical trials comparing different dosage levels of arginine and pretreatment versus coadministration are warranted to further determine arginine's ability to mitigate adverse effects of CsA therapy and elucidate therapeutic protocols for effective integrative therapeutics.

Sildenafil and Related Phosphodiesterase-5 Inhibitors
Theophylline/Aminophylline
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Estrogen-Progestin Combinations
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Hormone Replacement Therapy, Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications
Nitrates
Pentoxifylline
nutrient-nutrient interactions
Lysine
Omega-3 Fatty Acids (Fish Oils)
Ornithine
Parenteral and Enteral Nutrition Formulations Containing Antioxidants, Fatty Acids, and Other Nutrients
herb-nutrient interactions
Yohimbe
Citations and Reference Literature
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