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]

---

A detailed in vivo protocol was used to induce acute pancreatitis with Arginine HCl.

1. **Animals:** Male ICR mice, 4 weeks old and weighing 25-30 grams, were used. They were housed under controlled temperature (25-30°C) with a 12-hour light/dark cycle and free access to food and water. They were acclimated for one week before the experiment. [5]
2. **Drug Preparation:** Arginine HCl solution was prepared by dissolving L-arginine powder in 0.9% normal saline. The pH of the solution was adjusted to 7 using 5 N HCl. [5]
3. **Dosing Regimen for AP Induction:** Mice received two intraperitoneal (i.p.) injections of Arginine HCl at a total dose of 450 mg/100 g body weight. The two injections were given one hour apart. [5]
4. **Experimental Timeline:** After Arginine HCl administration, mice were observed for 72 hours. At the end of this period, they were sacrificed by an overdose of sodium thiopental (50 mg/kg, i.p.). Pancreatic tissue and blood samples were collected for subsequent analyses. [5]

Absorption
L-arginine is absorbed from the small intestine into intestinal cells. Absorption is highly efficient, occurring through active transport mechanisms.

---

Metabolism/Metabolites
Partial metabolism of L-arginine occurs within intestinal cells. L-arginine not metabolized within intestinal cells enters the portal circulation and is then transported to the liver, where some amino acids are metabolized again.

Oral LD50 in rats 12 g/kg: Behavior: altered sleep duration (including righting reflex); Behavior: ataxia; Lung, pleural or respiratory: dyspnea. Journal of Pharmaceutical Sciences, 62(49), 1973 [PMID:4734197]
Intraperitoneal LD50 in rats 3793 mg/kg: Behavior: coma; Lung, pleural or respiratory: dyspnea. Archives of Biochemistry and Biophysics, 58(253), 1955 [PMID:13259702]
Intravenous LD50 in children 3900 mg/kg/30 months: Brain and meninges: other degenerative changes; Heart: 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 an L-α-amino acid. Arginine hydrochloride is the hydrochloride form of arginine, an essential amino acid for adolescents. Arginine is a complex amino acid, often found at the active sites of proteins and enzymes due to its amine side chain. Arginine may help prevent or treat heart and circulatory system diseases, combat fatigue, and stimulate the immune system. It also promotes the production of nitric oxide, thereby relaxing blood vessels and treating angina and other cardiovascular diseases. Arginine is also an important intermediate in the urea cycle and the detoxification of nitrogenous waste. (NCI04) An essential amino acid whose physiologically active form is L-arginine. Mechanism of Action Many of the activities of L-arginine supplementation, including its potential anti-atherosclerotic effects, may be related to its role as a precursor to nitric oxide (NO). Nitric oxide (NO) is produced by all tissues throughout the body and plays a vital role in the cardiovascular, immune, and nervous systems. NO is produced from L-arginine by NO synthase (NOS), and its action is primarily mediated by 3,5'-cyclic guanosine monophosphate (cGMP). NO activates guanylate cyclase, which catalyzes the synthesis of cGMP from guanosine triphosphate (GTP). cGMP is then converted to guanylate nucleotides by cGMP phosphodiesterase. NOS is a heme-containing enzyme, with a partial sequence similar to cytochrome P-450 reductase. NOS exists in multiple isoenzymes, two of which are constitutive NOS, and one is induced by immune stimulation. The constitutive NOS present in vascular endothelial cells is called eNOS, and the constitutive NOS present in the brain, spinal cord, and peripheral nervous system is called nNOS. The NOS form induced by immune or inflammatory stimulation is called iNOS. iNOS can be constitutively expressed in some tissues (e.g., lung epithelial cells). All nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O₂) as cosubstrates, with cofactors including FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin, and heme. Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin levels. eNOS and nNOS synthesize NO in response to elevated calcium ion concentrations or, in some cases, under non-calcium-dependent stimuli such as shear stress. In vitro studies of NOS show that the enzyme's Km value for L-arginine is in the micromolar range. The concentrations of L-arginine in endothelial cells, other cells, and plasma are in the millimolar range. This implies that, under physiological conditions, NOS is saturated with its substrate, L-arginine. In other words, L-arginine is not expected to be the rate-limiting step of this enzyme, and oral supplementation with this amino acid may lead to L-arginine concentrations exceeding physiological levels, but this appears to have no effect on NO production. The reaction appears to have reached its maximal level. However, in vivo studies suggest that, in certain conditions, such as hypercholesterolemia, L-arginine supplementation can enhance endothelium-dependent vasodilation and NO production. Pharmacodynamic studies have shown that L-arginine can improve immune responses to bacteria, viruses, and tumor cells; promote wound healing and liver regeneration; promote the release of growth hormone; and is considered essential 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.

---

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