Arginine: Clinical potential of a semi-essential amino.

Appleton J.

Source

Department chair, National College of Naturopathic Medicine, Portland, OR 97201, USA. [email protected]

Abstract

Arginine, a semi-essential amino acid, is involved in numerous areas of human biochemistry, including ammonia detoxification, hormone secretion, and immune modulation. Arginine is also well known as a precursor to nitric oxide (NO), a key component of endothelial-derived relaxing factor, an endogenous messenger molecule involved in a variety of endothelium-dependent physiological effects in the cardiovascular system. Because ofarginine's NO-stimulating effects, it can be utilized in therapeutic regimens for angina pectoris, congestive heart failure, hypertension, coronary heart disease, preeclampsia, intermittent claudication, and erectile dysfunction. In addition, arginine has been studied in the treatment of HIV/AIDS, athletic performance, burns and trauma, cancer, diabetes and syndrome X, gastrointestinal diseases, male and female infertility, interstitial cystitis, immunomodulation, and senile dementia. Toxicity, dosage considerations, and contraindications are also reviewed.

http://www.ncbi.nlm.nih.gov/pubmed/12495375

Postepy Hig Med Dosw (Online). 2004;58:321-32.

[Arginine--metabolism and functions in the human organism].

[Article in Polish]

Scibior D, Czeczot H.

Source

Katedra i Zakład Biochemii, Akademii Medycznej w Warszawie, Warszawa. [email protected]

Abstract

L-arginine plays important roles in the metabolism of an organism. It is the precursor for the synthesis of proteins and other molecules of great biological importance, including nitric oxide, ornithine, polyamines, agmatine, proline, glutamate, creatine, dimethylarginine, and urea. For young organisms arginine is an essential amino acid for optimal growth and development, and must therefore be provided in the diet. For adults, arginine is a conditionally essential amino acid, especially in such conditions as trauma, burn injury, small-bowel resection, and renal failure. L-arginine administration improves cardiovascular, pulmonary, immune, and digestive functions and protect against the early stages of cancerogenesis.

http://www.ncbi.nlm.nih.gov/pubmed/15459550

Amino Acids. 2004 Jul;26(4):345-51. Epub 2004 Apr 8.

Arginine revisited: minireview article.

Grillo MA, Colombatto S.

Source

Dipartimento di Medicina e Oncologia Sperimentale, Sezione di Biochimica, Università di Torino, Torino, Italy. [email protected]

Abstract

Arginine is a precursor of proteins and employed in urea synthesis. It is also the precursor of many other compounds, such as creatine, nitric oxide, polyamines, agmatine, proline. In this review, its transport and that of other basic amino acids are examined, along with its transformation into nitric oxide, agmatine and proline, and the mutual regulation of the individual pathways.

http://www.ncbi.nlm.nih.gov/pubmed/15290340

Biomed Pharmacother. 2002 Nov;56(9):427-38.

The metabolic basis of arginine nutrition and pharmacotherapy.

Flynn NE, Meininger CJ, Haynes TE, Wu G.

Source

Department of Chemistry and Biochemistry, Angelo State University, San Angelo, TX 76909, USA. [email protected]

Abstract

As an essential precursor for the synthesis of proteins and other molecules with enormous biological importance (including nitric oxide, urea, ornithine, proline, polyamines, glutamate, creatine, agmatine, and dimethylarginines), arginine displays remarkable metabolic and regulatory versatility. Evidence available to date provides a sound reason to classify arginine as an essential amino acid for young mammals (including parenterally fed human infants) and as a conditionally essential amino acid for adults under such conditions as trauma, burn injury, massive small-bowel resection, and renal failure. Arginine administration reverses endothelial dysfunction, enhances wound healing, prevents the early stages of tumorigenesis, and improves cardiovascular, reproductive, pulmonary, renal, digestive, and immune functions. Arginine or its effective precursor citrulline may hold great promise as a nutritional or pharmacotherapeutic treatment for a wide array of human diseases.

http://www.ncbi.nlm.nih.gov/pubmed/12481979

Biomed Pharmacother. 2002 Nov;56(9):439-45.

I. Arginine.

Tapiero H, Mathé G, Couvreur P, Tew KD.

Source

Faculté de pharmacie, université de Paris, CNRS UMR 8612, 5, rue Jean-Baptiste-Clément, 94200 Chatenay-Malabry, France. [email protected]

Abstract

L-Arginine (Arg) is classified as an essential amino acid for birds, carnivores and young mammals and a conditionally essential amino acid for adults. It is converted by arginase to L-ornithine, a precursor of polyamines and urea, which is important in the urea cycle. Arg serves as a precursor for creatine, which plays an essential role in the energy metabolism of muscle, nerve and testis and accounts for Arg catabolism and for the synthesis of agmatine and proteins. Via its ability to increase growth hormone secretion it influences immune function. Depending on nutritional status and developmental stage, normal plasma Arg concentrations in humans and animals range from 95 to 250 micromol/l. Systemic or oral Arg administration has been shown to improve cardiovascular function and reduce myocardial ischemia in coronary artery disease patients. It reduces blood pressure and renal vascular resistance in essential hypertensive patients with normal or insufficient renal function. Although Arg plasma concentrations are not altered in hypercholesterolemic individuals, oral or intravenous Arg administration can reverse endothelial dysfunction in hypercholesterolemic patients and in cigarette smokers. The main importance of Arg is attributed to its role as a precursor for the synthesis of nitric oxide (NO), a free radical molecule that is synthesized in all mammalian cells from L-Arg by NO synthase (NOS). NO appears to be a major form of the endothelium-derived relaxing factor (EDRF). NO and EDRF share similar chemical and pharmacological properties and are derived from the oxidation of a terminal guanidine group of L-Arg. Various mechanisms have been implicated in the defect in vascular relaxation. These include, increased diffusional barrier for NO, L-Arg depletion, altered levels of reactive oxygen, inactivation of NO by superoxide anions (O2-). The independent reactions of O2-, NO and their reaction yielding peroxynitrite are critical in the initiation and maintenance of the atherosclerotic state and contribute to the defect in vasorelaxation. NO also plays a role as a neurotransmitter, mediator of immune response and as signaling molecule. The NO synthesized by iNOS in macrophages contributes to their cytotoxic activity against tumor cells, bacteria and protozoa. Our aim here is to review on some amino acids with high functional priority such as Arg and to define their effective activity in human health and pathologies.

http://www.ncbi.nlm.nih.gov/pubmed/12481980

Int J Sports Med. 2002 Aug;23(6):403-7.

L-arginine reduces exercise-induced increase in plasma lactate and ammonia.

Schaefer A, Piquard F, Geny B, Doutreleau S, Lampert E, Mettauer B, Lonsdorfer J.

Source

Service des Explorations Fonctionnelles Respiratoires et de l'Exercice et EA 3072, Hôpitaux Universitaires et Faculté de Médecine, Strasbourg, France. [email protected]

Abstract

To investigate the effect of L-arginine supplementation (L-ARG) on physiological and metabolic changes during exercise, we determined in a double-blind study the cardiorespiratory (heart rate, oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)) and the metabolic (lactate andammonia) responses to maximal exercise after either an intravenous L-ARG hydrochloride salt or placebo load in 8 healthy subjects. Exercise-induced increases in heart rate, VO(2) and VCO(2) were not significantly different after L-ARG or placebo. By contrast, peak plasma ammonia andlactate were significantly decreased after L-ARG load (60.6 +/- 8.2 vs. 73.1 +/- 9.1 micro mol x l(-1), p < 0.01 and 7.1 +/- 0.7 vs. 8.2 +/- 1.1 mmol x l(-1), p < 0.01, for ammonia and lactate, respectively). Plasma L-citrulline increased significantly during exercise only after L-ARG load, despite a concomitant decrease in plasma L-ARG. Furthermore, a significant inverse relationship was observed between changes in lactate and L-citrulline concentrations after L-ARG load (r = -0.84, p = 0.009). These results demonstrate that intravenous L-ARG reduces significantly exercise-inducedincrease in plasma lactate and ammonia. Taken together, the specific L-citrulline increase and the inverse relationship observed between L-citrulline and plasma lactate after L-ARG might support that L-ARG supplementation enhances the L-arginine-nitric oxide (NO) pathway during exercise.

http://www.ncbi.nlm.nih.gov/pubmed/12215958

J Nutr. 2008 Aug;138(8):1421-5.

Dietary arginine supplementation during early pregnancy enhances embryonic survival in rats.

Zeng X, Wang F, Fan X, Yang W, Zhou B, Li P, Yin Y, Wu G, Wang J.

Source

State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China 100094.

Abstract

Four experiments were conducted with 120 pregnant Sprague-Dawley rats to determine effects of dietary arginine supplementation on embryonicsurvival. Rats were fed a nonpurified diet supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) throughoutpregnancy (Expt. 1), between d 1 and 7 of gestation and then the nonpurified diet until parturition (Expt. 2), between d 1 and 7 of gestation for determining the number of surviving embryos on d 7 (Expt. 3), or between d 1 and 4 of pregnancy for blood sampling on d 5 after overnight food deprivation (Expt. 4). Litter size increased (P < 0.01) in response to arginine supplementation throughout pregnancy (14.5 +/- 0.62 vs. 11.3 +/- 0.61) or during the first 7 d of pregnancy (14.7 +/- 0.33 vs. 11.3 +/- 0.37). The number of surviving embryos was greater (P < 0.01) when arginine was supplemented between d 1 and 7 of pregnancy (14.7 +/- 0.39 vs. 11.4 +/- 0.66). Concentrations of nitric-oxide metabolites, arginine, proline, glutamine, and ornithine were higher (P < 0.05), but urea levels were lower (P < 0.05) in the serum of arginine-supplemented rats compared with the control group. The arginine treatment increased (P < 0.05) protein levels for inducible and constitutive nitric-oxide synthase at implantation sites by 35-37%. These results indicate that dietary arginine supplementation enhances embryonic survival, therefore increasing litter size by 30% at term birth. This novel finding has important implications for preventing early pregnancy loss and enhancing reproductive performance in mammals.

http://www.ncbi.nlm.nih.gov/pubmed/18641185

Mini Rev Med Chem. 2004 Oct;4(8):823-32.

Cellular and physiological effects of arginine.

Tong BC, Barbul A.

Source

Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Abstract

Arginine is a semi-essential amino acid that is required during periods of maximal growth, severe stress, and injury. Arginine is a substrate for protein synthesis but also modulates cellular biochemical functions via conversion to a number of biologically active compounds. Arginine is utilized by a vast variety of metabolic pathways that produce a variety of biologically active compounds such as nitric oxide, creatine phosphate, agmatine, polyamines, ornithine, and citrulline. Arginine supply is primarily regulated by two enzyme systems: arginase (part of the urea cycle) and nitric oxide synthase.Arginine has many effects in the body that include modulation of immune function, wound healing, hormone secretion, vascular tone, insulin sensitivity, and endothelial function. Arginine mediates its effects via nitric oxide independent and dependent pathways. Nitric oxide modulates manycellular functions that include vascular tone, expression of adhesion molecules, leukocyte adhesion, and platelet aggregation. Arginine modulates the development of atherosclerotic cardiovascular disease, improves immune function in healthy and ill patients, stimulates wound healing in healthy and ill patients, and modulates carcinogenesis and tumor growth. Thus, arginine is a biologically active dietary compound with numerous physiologic and pharmacological activities.

http://www.ncbi.nlm.nih.gov/pubmed/15544543

Curr Opin Clin Nutr Metab Care. 2000 Jan;3(1):59-66.

Arginine nutrition in development, health and disease.

Wu G, Meininger CJ, Knabe DA, Bazer FW, Rhoads JM.

Faculty of Nutrition and Department of Animal Science, Texas A&M University, College Station 77843-2471, USA. [email protected]

Abstract

As a precursor of nitric oxide, polyamines and other molecules with enormous biologic importance, L-arginine plays versatile key roles in nutrition and metabolism. Arginine is an essential amino acid in the fetus and neonate, and is conditionally an essential nutrient for adults, particularly in certain disease conditions. L-Arginine administration is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, and in facilitating wound healing. The effect of L-arginine in treating many common health problems is unique among amino acids, and offers great promise for improved health and well-being in the future.

http://www.ncbi.nlm.nih.gov/pubmed/10642085

J Nutr. 2004 Oct;134(10 Suppl):2880S-2887S; discussion 2895S.

Arginine and endothelial and vascular health.

Gornik HL, Creager MA.

Source

Vascular Medicine Section, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.

Abstract

The vascular endothelium is a crucial regulator of vascular function and homeostasis. Nitric oxide (NO) is an important paracrine substance released by the endothelium to regulate vasomotor tone. Risk factors for atherosclerosis, as well as atherosclerosis per se, are associated with endothelialdysfunction and decreased bioavailablilty of NO. Indeed, endothelial dysfunction is integral to the pathogenesis of atherosclerosis and other cardiovascular diseases. Moreover, endothelial dysfunction relates to an increased risk of adverse cardiovascular outcomes. L-Arginine is an essential amino acid required by the constitutive enzyme, endothelial NO oxide synthase (eNOS), to produce NO. Administration of L-arginine improvesendothelial function in animal models and in humans with hypercholesterolemia and with atherosclerosis. Clinical trials to date support potential clinical applications of L-arginine in the treatment of coronary artery disease and peripheral arterial disease, as well as in the prevention of in-stent restenosis. The mechanism of benefit of L-arginine on endothelial function is unclear, because intracellular concentrations of L-arginine far exceed that required by eNOS. One potential explanation of this "arginine paradox" is that L-arginine restores endothelial function in atherosclerotic patients, in whom there are elevated levels of asymmetric dimethylarginine, an endogenous inhibitor of eNOS. Given the promising findings of early studies of L-arginine as a potential therapy for cardiovascular disorders, large-scale clinical trials are warranted.

http://www.ncbi.nlm.nih.gov/pubmed/15465805

Nitric Oxide. 2004 Aug;11(1):1-8.

Hypercholesterolemia impairs basal nitric oxide synthase turnover rate: a study investigating the conversion of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate by gas chromatography--mass spectrometry.

Böger RH, Tsikas D, Bode-Böger SM, Phivthong-Ngam L, Schwedhelm E, Frölich JC.

Source

Institute of Clinical Pharmacology, Medical School, Hannover, Germany; Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Germany. [email protected]

Abstract

Endothelial function is impaired in hypercholesterolemia and atherosclerosis, which is probably due to reduced biological activity of endothelium-derived nitric oxide (NO). NO is synthesized in functionally intact endothelium by oxidation of the terminal guanidino nitrogen atom(s) of the amino acid precursor, L-arginine. We applied stable isotope dilution techniques and gas chromatographic-mass spectrometric approaches to investigate metabolism of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate in hypercholesterolemic rabbits and controls. After 4 weeks on control or 1% cholesterol-enriched diet, rabbits received 267 +/- 6 micromol of L-[guanidino-(15)N(2)]-arginine/kg of body weight via gastric cannulation. (15)N-isotope content of L-arginine in plasma and in platelet lysates increased 2h later in both groups, and almost returned to baseline until 24h. (15)N-isotope content of plasma nitrite and nitrate also increased in both groups at 2h, and had almost returned to natural content 24h later. (15)N-isotope content of urinary nitrate was significantly increased in control animals in urines collected from 0 to 12, 12 to 24, and had returned to baseline in the urine sample collected from 24 to 48 h. In the cholesterol group only a slight, insignificant elevation of (15)N-isotope content was observed for urinary nitrate. The extent of conversion of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate was strongly and inversely correlated to plasma concentration of the endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which was elevated in cholesterol-fed rabbits (R=0.77; p < 0.05). Our data show that baseline NO synthase turnover rate is reduced in rabbits during early hypercholesterolemia. Our study gives evidence that the mechanism of the impaired conversion of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate most likely involves inhibition of NO synthase by ADMA, which is present in elevated concentrations in hypercholesterolemia.

http://www.ncbi.nlm.nih.gov/pubmed/15350551

Curr Opin Nephrol Hypertens. 1998 Jan;7(1):63-70.

Cardiovascular effects of L-arginine.

Maxwell AJ, Cooke JP.

Source

Section of Vascular Medicine, Stanford University, California, USA.

Abstract

Most of the known cardiovascular effects of L-arginine are exerted via its conversion to nitric oxide by nitric oxide synthase. Accumulating evidence indicates that supplemental administration of L-arginine is sufficient to restore endothelium-derived nitric oxide production in many disorders in whichendothelium-derived nitric oxide production is altered. L-arginine may enhance nitric oxide production by competing as a substrate with an endogenous antagonist for nitric oxide synthase. In other cases, L-arginine may act by competing with molecular oxygen as a substrate so as to reduce the production of superoxide anion. It is likely that other mechanisms exist by which the nitric oxide synthase pathway can be perturbed.Regardless of the mechanism, a wide array of cardiovascular disorders characterized by endothelial dysfunction are reversible by L-arginine.

http://www.ncbi.nlm.nih.gov/pubmed/9442365

Transplantation. 2006 Jul 15;82(1):108-12.

L-arginine improves endothelial and myocardial function after brain death.

Szabó G, Soós P, Heger U, Mandera S, Buhmann V, Bährle S, Kohl B, Hagl S.

Source

Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. [email protected]

Abstract

BACKGROUND:

Recently, we showed that brain death (BD) leads to a severe impairment of endothelial function.

METHODS:

To test the hypothesis, that nitric oxide supply improves endothelial function, we infused L-arginine (40 mg/kg) in 6 dogs after BD induction (subdural balloon). Six vehicle-treated BD animals served as controls. Coronary blood flow (CBF), preload recruitable stroke work (PRSW), and plasma L-arginine and nitrite/nitrate levels were measured before and 6 hr after BD induction. In addition, endothelium-dependent vasodilatation after intracoronary application of acetylcholine (ACH) and endothelium-independent vasodilation after sodium nitroprusside (SNP) were assessed.

RESULTS:

Six hours after BD, CBF decreased significantly in the control group (38.2+/-3.5 vs. 26.8+/-3.1 ml/min, P<0.05), whereas the decrease was less pronounced in the L-arginine group (41.8+/-6.9 vs. 36.0+/-1.2 ml/min, P<0.05 vs. control). Before BD, ACH led to a similar vasodilative response in both groups (81+/-6 vs. 75+/-7%). After BD, a paradox vasoconstriction occurred after ACH in the control group, while the vasodilative response did not change in the L-Arginine group (36+/-6 vs. 69+/-7%, P<0.05). The response to SNP did not differ between the groups and over the time. After BD PRSW decreased in both groups, however, it was still significantly higher in the L-arginine group (56+/-7 vs. 71+/-7 kerg, P<0.05). L-arginine (711+/-144 vs. 234+/-54 microM P<0.05) and nitrite/nitrate (39+/-3 vs. 27+/-3 microM P<0.05) levels were significantly higher in the L-arginine group.

CONCLUSION:

L-arginine treatment prevents endothelial dysfunction and improves myocardial performance after BD via enhancement of endogenous nitric oxide synthesis.

http://www.ncbi.nlm.nih.gov/pubmed/16861949