Microbial Metabolite; Endogenous Metabolite

Alpha-amino acids include arginine. Among the twenty most prevalent naturally occurring amino acids is the L-form. In terms of molecular genetics, the triplets CGU, CGC, CGA, CGG, AGA, and AGG are nucleotide bases or codons that code for arginine during protein synthesis. These bases are found in the structure of messenger ribonucleic acid (mRNA). Arginine is categorized as either a conditionally essential or semi-essential amino acid in mammals based on the developmental stage and overall health of the individual. In individuals with severe sepsis, L-arginine was linked to a lower cardiac index but no change in stroke index. In 40% of the L-arginine group and 24% of the placebo group, shock subsided in less than 72 hours. After receiving chronic simvastatin therapy (2 mg/kg subcutaneously daily for 14 days), L-arginine (450 mg/kg over 15 min) boosts absolute brain eNOS upregulation and amplifies and maintains hyperemia (38%) in the brain. Blood flow in mice with SV-129.

L-arginine can be utilized in animal modeling to build animal pancreatitis models. L-Arginine is a NO-producing substrate of endothelial nitric oxide synthase (eNOS) and can be metabolized into nitric oxide (NO), polyamines or L-proline to stimulate inflammation. L-Arginine can also selectively destroy pancreatic acinar cells, resulting in acute necrotizing pancreatitis. When male rats were given single i.p. injection of 500 mg of L-arginine/100 g body weight, the pancreatic acinar cells were destroyed selectively, without any morphological change of Langerhans' islets. As early as 24 hours after the injection, loss of basophilia, zymogen degranulation, and vacuolar and necrotic changes of the acinar cells were noted. After 3 days, fibroblastic activity and atrophy of pancreatic lobuli were evident. Early electron microscopic findings were changes of the endoplasmic reticulum, such as partial dilatation or vacuolation of the cisternae, usually with loss of ribosomes attached to the membrane. The effect of arginine excess may be ascribed to imbalance of amino acids and subsequent to decrease of protein synthesis in the acinar cells. In the course of this study, fat necrosis with marked infiltration of leucocytes was observed in adipose tissues in peripancreatic, epididymal, omental and retroperitoneal areas. This change correlated closely with the marked necrosis of the pancreas. An increase in the level of lipase in the blood was also demonstrated.[4]

Nitric oxide, a product of nitric oxide synthase activity, relaxes vascular smooth muscle and elevates brain blood flow. We evaluated the importance of eNOS to cerebral blood flow augmentation after L-arginine infusion and increases in flow after eNOS upregulation in SV-129 mice. Blood flow was measured by laser-Doppler flowmetry before and after L-arginine infusion (450 mg/kg during a 15-minute period) or measured by 14C-iodoamphetamine indicator fractionation or 14C-iodoantipyrine tissue equilibration techniques. rCBF increased by 26% (laser Doppler flowmetry) after L-arginine infusion but did not change in mutant mice deficient in eNOS expression. After eNOS upregulation by chronic simvastatin treatment (2 mg/kg subcutaneously, daily for 14 days), L-arginine amplified and sustained the hyperemia (38%) and increased absolute brain blood flow from 86 +/- 7 to 119 +/- 10 mL/100 g per minute. Furthermore, pretreatment with simvastatin enhanced blood flow within ischemic brain tissue after middle cerebral artery occlusion. Together, these findings suggest that eNOS activity is critical for blood flow augmentation during acute L-arginine infusion, and chronic eNOS upregulation combined with L-arginine administration provides a novel strategy to elevate cerebral blood flow in the normal and ischemic brain.[3]

Absorption
Absorbed from the lumen of the small intestine into the enterocytes. Absorption is efficient and occurs by an active transport mechanism.

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Metabolism / Metabolites
Some metabolism of L-arginine takes place in the enterocytes. L-arginine not metabolized in the enterocytes enters the portal circulation from whence it is transported to the liver, where again some portion of the amino acid is metabolized.

rat LD50 oral 12 gm/kg BEHAVIORAL: ALTERED SLEEP TIME (INCLUDING CHANGE IN RIGHTING REFLEX); BEHAVIORAL: ATAXIA; LUNGS, THORAX, OR RESPIRATION: DYSPNEA Journal of Pharmaceutical Sciences., 62(49), 1973 [PMID:4734197]
rat LD50 intraperitoneal 3793 mg/kg BEHAVIORAL: COMA; LUNGS, THORAX, OR RESPIRATION: DYSPNEA Archives of Biochemistry and Biophysics., 58(253), 1955 [PMID:13259702]
child LDLo intravenous 3900 mg/kg/30M BRAIN AND COVERINGS: OTHER DEGENERATIVE CHANGES; CARDIAC: OTHER CHANGES Journal of Toxicology, Clinical Toxicology., 35(621), 1997 [PMID:9365430]

[1]. Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med. 2004 Jan;32(1):1-12.

[2]. I. Arginine. Biomed Pharmacother. 2002 Nov;56(9):439-45.

[3]. Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J Cereb Blood Flow Metab. 2000 Apr;20(4):709-17.

[4]. Effects of injecting excess arginine on rat pancreas. J Nutr. 1984 Mar;114(3):467-71.

[5]. Effects of curcumin on oxidative stress, inflammation and apoptosis in L-arginine induced acute pancreatitis in mice. Heliyon. 2019 Aug 27;5(8):e02222.

Arginine hydrochloride is a L-alpha-amino acid.
Arginine Hydrochloride is the hydrochloride salt form of arginine, an essential amino acid in juvenile humans. Arginine is a complex amino acid, often found at active sites in proteins and enzymes due to its amine-containing side chain. Arginine may prevent or treat heart and circulatory diseases, combat fatigue, and stimulate the immune system. It also boosts production of nitric oxide, relaxing blood vessels, and treating angina and other cardiovascular problems. Arginine is also an important intermediate in the urea cycle and in detoxification of nitrogenous wastes. (NCI04)
An essential amino acid that is physiologically active in the L-form.

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Mechanism of Action
Many of supplemental L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3,'5' -cyclic guanylate or cyclic GMP. NO activates the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. Cyclic GMP is converted to guanylic acid via the enzyme cyclic GMP phosphodiesterase. NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The form of NOS induced by immunological or inflammatory stimuli is known as iNOS. iNOS may be expressed constitutively in select tissues such as lung epithelium. All the nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O2) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin. eNOS and nNOS synthesize NO in response to an increased concentration of calcium ions or in some cases in response to calcium-independent stimuli, such as shear stress. In vitro studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate. In other words, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid^would make any difference with regard to NO production. The reaction would appear to have reached its maximum level. However, in vivo studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, supplemental L-arginine could enhance endothelial-dependent vasodilation and NO production.

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Pharmacodynamics
Studies have shown that is has improved immune responses to bacteria, viruses and tumor cells; promotes wound healing and regeneration of the liver; causes the release of growth hormones; considered crucial for optimal muscle growth and tissue repair.

C6H15CLN4O2

210.66

210.088

C, 34.21; H, 7.18; Cl, 16.83; N, 26.60; O, 15.19

1119-34-2

DL-Arginine;7200-25-1;L-Arginine-15N2 hydrochloride;204633-92-1;L-Arginine-15N4 hydrochloride;204633-95-4;L-Arginine-d7 hydrochloride;204244-77-9;L-Arginine-13C6 hydrochloride;201740-91-2;L-Arginine-13C6,15N4 hydrochloride;202468-25-5;L-Arginine butanoate;80407-72-3;L-Arginine-1-13C hydrochloride;2483735-41-5;L-Arginine-13C6,15N4,d7 hydrochloride;2483829-29-2;L-Arginine-1,2-13C2 hydrochloride;201740-75-2;L-Arginine-13C hydrochloride;94740-43-9;L-Arginine-15N4,d7 hydrochloride

66250

White to off-white solid powder

1.42

409.1ºC at 760 mmHg

226-230 °C(lit.)

201.2ºC

1.354

5

4

5

13

176

1

C(C[C@@H](C(=O)O)N)CN=C(N)N.Cl

KWTQSFXGGICVPE-WCCKRBBISA-N

InChI=1S/C6H14N4O2.ClH/c7-4(5(11)12)2-1-3-10-6(8)9;/h4H,1-3,7H2,(H,11,12)(H4,8,9,10);1H/t4-;/m0./s1

(2S)-2-amino-5-(diaminomethylideneamino)pentanoic acid;hydrochloride

NSC-203450; NSC203450; L-Arginine hydrochloride; 1119-34-2; Arginine Hydrochloride; L-ARGININE HCL; L-Arginine monohydrochloride; Arginine HCl; H-Arg-OH.HCl; R-Gene;NSC 203450; Arginine HCl; Detoxargin; Levargin; Arginine Hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~474.70 mM)
DMSO :< 1 mg/mL

Solubility in Formulation 1: 100 mg/mL (474.70 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)