Endogenous Metabolite; Microbial Metabolite; eNOS

l -精氨酸（Arg）是鸟类、食肉动物和幼龄哺乳动物的必需氨基酸，也是成年动物的有条件必需氨基酸。它被精氨酸酶转化为l -鸟氨酸，这是多胺和尿素的前体，在尿素循环中很重要。精氨酸是肌酸的前体，而肌酸在肌肉、神经和睾丸的能量代谢中起着至关重要的作用，并负责精氨酸的分解代谢以及精氨酸和蛋白质的合成。通过其增加生长激素分泌的能力，它影响免疫功能。根据营养状况和发育阶段的不同，人类和动物的正常血浆精氨酸浓度在95至250微摩尔/升之间。全身或口服精氨酸已被证明可以改善冠心病患者的心血管功能并减少心肌缺血。降低肾功能正常或肾功能不全的原发性高血压患者的血压和肾血管阻力。虽然精氨酸血浆浓度在高胆固醇血症患者中没有改变，但口服或静脉注射精氨酸可以逆转高胆固醇血症患者和吸烟者的内皮功能障碍。精氨酸的重要性主要归因于其作为一氧化氮（NO）合成的前体的作用，一氧化氮是一种自由基分子，在所有哺乳动物细胞中由l -精氨酸通过NO合成酶（NOS）合成。一氧化氮似乎是内皮源性松弛因子（EDRF）的主要形式。NO和EDRF具有相似的化学和药理学性质，都是由l -精氨酸的末端胍基氧化而来。血管松弛缺陷涉及多种机制。这些包括：NO扩散屏障增加，L-Arg耗竭，活性氧水平改变，超氧阴离子（O2-）使NO失活。O2-、NO的独立反应及其生成过氧亚硝酸盐的反应在动脉粥样硬化状态的启动和维持中起着至关重要的作用，并有助于血管松弛的缺陷。一氧化氮还作为神经递质、免疫反应介质和信号分子发挥作用。巨噬细胞中由iNOS合成的NO参与了巨噬细胞对肿瘤细胞、细菌和原生动物的细胞毒活性。我们的目的是回顾一些具有高功能优先权的氨基酸，如精氨酸，并确定它们在人类健康和病理中的有效活性。[1]

L-精氨酸可用于动物建模，建立动物胰腺炎模型。L -精氨酸是内皮型一氧化氮合酶（eNOS）产生NO的底物，可代谢为一氧化氮（NO）、多胺或l -脯氨酸，刺激炎症。l -精氨酸还能选择性地破坏胰腺腺泡细胞，导致急性坏死性胰腺炎。

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雄性大鼠单次腹腔注射l -精氨酸500 mg /100 g体重时，胰腺腺泡细胞被选择性破坏，朗格汉斯胰岛未见形态学改变。早在注射后24小时，嗜碱性细胞丧失，酶原脱颗粒，腺泡细胞空泡和坏死改变。3天后，成纤维细胞活性明显，胰腺小叶萎缩明显。早期电镜发现内质网改变，如池池部分扩张或空泡化，通常伴有附着在膜上的核糖体的丢失。精氨酸过量的影响可能归因于氨基酸的不平衡和随后的腺泡细胞中蛋白质合成的减少。在本研究过程中，胰腺周围、附睾、大网膜和腹膜后区域的脂肪组织均可见脂肪坏死伴明显白细胞浸润。这种变化与胰腺的明显坏死密切相关。血液中的脂肪酶水平也有所增加。[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, Distribution and Excretion
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.
PRODUCT OF OXIDATIVE DEAMINATION OR TRANSAMINATION OF L-ARGININE IS ALPHA-KETO-GAMMA-GUANIDOVALERIC ACID; PRODUCT OF DECARBOXYLATION IS AGMATINE. PATHWAYS & PRODUCTS OF METABOLISM: ARGININE YIELDS ORNITHINE + UREA; ARGININE YIELDS CITRULLINE + NH3; ARGININE + GLYCINE YIELDS GUANIDOACETIC ACID + ORNITHINE /FROM TABLE/
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.

Toxicity Summary
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.

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

[2]. 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.

[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.

Therapeutic Uses
EXPTL USE: IN MICE, L-ARGININE-HCL HAD AN INHIBITORY EFFECT ON MURINE SARCOMA VIRUS-MOLONEY & C3H BREAST ADENOCARCINOMA TUMOR SYSTEMS.
EXPTL USE: EXPTL DIETS GIVEN 10 DAYS AFTER WALKER 256 CARCINOSARCOMA CELLS INOCULATED INTO RATS, RESULTED IN LOWER TUMOR WEIGHTS.
EXPTL USE: L-ARGININE-HCL INCR IN VITRO MOTILITY IN SPECIMENS OF HUMAN SEMEN EXHIBITING SUBNORMAL MOTILITY. EFFECT WAS DOSE DEPENDENT.
EXPTL USE: ARGININE (1% IN DIET) GIVEN TO RATS INCR THYMIC SIZE & PREVENTED THYMIC INVOLUTION WHICH OCCURS WITH INJURY. ARGININE PROMOTED WOUND HEALING IN RATS.
For more Therapeutic Uses (Complete) data for (L)-ARGININE (6 total), please visit the HSDB record page.

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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.

C6H14N4O2

174.2010

174.111

C, 41.37; H, 8.10; N, 32.16; O, 18.37

74-79-3

DL-Arginine;7200-25-1;L-Arginine (L-glutamate);4320-30-3;L-Arginine butanoate;80407-72-3; 74-79-3; 2485-55-4 (caprate); 4320-30-3 (glutamate); 1119-34-2 (HCl)

6322

White to off-white solid powder

1.5±0.1 g/cm3

367.6±52.0 °C at 760 mmHg

222 °C (dec.)(lit.)

176.1±30.7 °C

0.0±1.8 mmHg at 25°C

1.601

-1.79

125.22

4

4

5

12

176

1

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

ODKSFYDXXFIFQN-BYPYZUCNSA-N

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

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

L-arginine; arginine; 74-79-3; L-(+)-Arginine; (S)-2-Amino-5-guanidinopentanoic acid; L-Arg; H-Arg-OH; L(+)-Arginine;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

H2O : ~50 mg/mL (~287.03 mM)

配方 1 中的溶解度: 100 mg/mL (574.05 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。