Oral Administration Of L-arginine Research Articles

Effect of L-Arginine on the Dynamics of Cardio-specific Enzymes in the Blood in Rabbit with Simulated Atherosclerosis during Short-term Adaptation to High Altitudes

In order to clarify the effect of L-arginine on the course of experimental atherosclerosis in rabbits, we examined the following indicators of cardiac-specific enzymes: high-sensitivity C-reactive protein and troponin I in blood serum. The biological effect of L-arginine, which plays an important role in regulating the functional state of the vascular wall in atherosclerotic lesions, is discussed. It was found that oral administration of L-arginine at a dose of 170 mg/kg body weight once a day for 30 days to animals with experimental atherosclerosis leads to a decrease in the concentration of the studied parameters of cardiac-specific enzymes in the blood.

Regulation of Neuropeptide Y Receptor Gene Expression and Hormone Level in Obese Male Rats Receiving 6-Gingerol and L-Arginine Supplementation.

Obesity and its associated disorders, such as hyperlipidemia, have become a ‎global issue following the consumption of unhealthy, high-fat, and high-‎carbohydrate foods, which burdens the economies and the ‎health systems of human societies worldwide. This study aimed to evaluate ‎the effect of oral consumption of 6-gingerol and L-arginine supplements on obesity factors. Thirty rats in five groups were fed a diet specific to each ‎group for 12 weeks and then treated with the oral administration of L-arginine (200 mg/day) and 6-gingerol (100 mg/day) for 12 weeks. The food and water ‎intake and weight change, were then measured. In addition, plasma glucose, ‎triglyceride, cholesterol, high-density lipoprotein (HDL), very-low-density lipoprotein (VLDL)‎, low-density ‎lipoprotein (LDL), and serum hormone levels, including corticosterone, testosterone, and insulin, were measured, and NPY, Y1, and Y5 receptor gene expression were recorded using real-time PCR. Administration of 6-gingerol and L-arginine decreased food intake, ‎weight gain, glucose levels, insulin levels, and homeostasis model assessment-insulin resistance (HOMA-IR) index compared to ‎the HCD control group. In addition, corticosterone and testosterone levels in the ‎study groups showed a significant decrease (P<0.05) and increase (P<0.01) compared to the control groups, respectively. Triglyceride, total cholesterol, HDL, and VLDL levels in the groups treated with L-arginine and gingerol alone or combined significantly decreased compared to ‎the control group (P<0.01). This study confirms that 6-gingerol and L-arginine supplements prevent ‎HCD-induced hyperlipidemia by controlling hormones and neurotransmitters ‎involved in the general metabolism.‎.

The Effect of L-Arginine Oral Supplementation on the Improvement of Cardiovascular Function and Pulmonary Artery Pressure in Patients with Major and Intermedia β-Thalassemia.

Thalassemia is the most common inherited anemia in worldwide. Heart failure is the most common cause of mortality and morbidity in patients with major and intermedia β-thalassemia. This study aimed to evaluate the effect of oral administration of L-arginine on the improvement of systolic Pulmonary Artery Pressure (PAP) and cardiac function in patients with major and intermedia β-thalassemia. This randomized clinical trial was done on 88 patients with β-thalassemia admitted to Ali Asghar Hospital, Tehran, Iran between 2020 and 2021. Echocardiography was performed for all the patients before the intervention. Afterwards, the patients were randomly divided into two groups of placebo and L-arginine. The patients underwent echocardiography after eight weeks and were compared with respect to the results. The mean blood transfusion interval was 20.21 d in the placebo group and 17.14 d in the L-arginine group (P=0.082). The results revealed no significant difference between the two groups regarding the mean levels of Hemoglobin (Hb) and ferritin, frequency of splenectomy. However, the mean PAP significantly decreased from 32.88 to 26.02 in the L-arginine group (P=0.009), but did not change in the placebo group. Nonetheless, no significant change was observed in the mean Ejection Fraction (EF) before and after L-arginine administration. L-arginine administration prevented the increase of PAP and was effective in preventing cardiovascular disorders including increased systolic PAP in patients with major and intermedia B-thalassemia. However, the results have to be confirmed in further studies with larger sample sizes.

L-Arginine is a feasible supplement to heal chronic anal fissure via reducing internal anal sphincter pressure: a randomized clinical trial study.

The hypertonicity of internal anal sphincter resting pressure is one of the main causes of chronic anal fissure. Therefore, the aim of this study was to assess the effect of oral administration of L-arginine on the improvement of the anal fissures by relaxing the internal anal sphincter. Seventy-six chronic anal fissure patients (aged 18-65years) who were referred to Rasoul-e-Akram Hospital, Tehran, Iran from February 2019 to October 2020 participated in this randomized, double-blind, placebo-controlled trial. Participants were allocated into treatment (L-arginine) and placebo groups. They took a 1000mg capsule three times a day for 1 month, and then we followed them at the end of the first and third months after the intervention. Clinical symptoms, anal sphincter resting pressure, and quality of life (QoL) were completed at baseline and the end of the study. The analysis of data showed a significant decrease in bleeding, fissure size, and pain for each group; however, in the L-arginine group was more than the control group at the end of the study (P values < 0.001). Following that, a significant increase in QoL was seen just in patients treated with L-arginine (P value = 0.006). In addition, the comparison of anal pressures at baseline and, between groups at the end of the study showed a significant reduction in sphincter pressure in patients treated with L-arginine (P value < 0.001, = 0.049; respectively). The oral administration of 3000mg L-arginine can heal chronic anal fissures by reducing internal anal sphincter pressure with more negligible side effects. However, we recommend long-term study with more extended follow-up.Clinical trial registry: IRCT20190712044182N1 at Iranian clinical trials, date: 2019-08-27.

Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection

ABSTRACT Nontuberculous mycobacterial pulmonary diseases (NTM-PDs) are emerging as global health threats with issues of antibiotic resistance. Accumulating evidence suggests that the gut–lung axis may provide novel candidates for host-directed therapeutics against various infectious diseases. However, little is known about the gut–lung axis in the context of host protective immunity to identify new therapeutics for NTM-PDs. This study was performed to identify gut microbes and metabolites capable of conferring pulmonary immunity to NTM-PDs. Using metabolomics analysis of sera from NTM-PD patients and mouse models, we showed that the levels of l-arginine were decreased in sera from NTM-PD patients and NTM-infected mice. Oral administration of l-arginine significantly enhanced pulmonary antimicrobial activities with the expansion of IFN-γ-producing effector T cells and a shift to microbicidal (M1) macrophages in the lungs of NTM-PD model mice. Mice that received fecal microbiota transplants from l-arginine-treated mice showed increased protective host defense in the lungs against NTM-PD, whereas l-arginine-induced pulmonary host defense was attenuated in mice treated with antibiotics. Using 16S rRNA sequencing, we further showed that l-arginine administration resulted in enrichment of the gut microbiota composition with Bifidobacterium species. Notably, oral treatment with either Bifidobacterium pseudolongum or inosine enhanced antimicrobial pulmonary immune defense against NTM infection, even with multidrug-resistant clinical NTM strains. Our findings indicate that l-arginine-induced gut microbiota remodeling with enrichment of B. pseudolongum boosts pulmonary immune defense against NTM infection by driving the protective gut–lung axis in vivo.

Dual Strategy with Intracavernosal Implantation of Adipose-derived Stem Cells and Daily Oral L-arginine Optimize Recovery of and Cavernosal Functions after Cavernous Nerve Injury in Rats

ABSTRACT Introduction Radical prostatectomy for prostate cancer has a significant potential role in inducing cavernous nerve injury (CNI). Increasing hypoxia and fibrosis induces destructive changes within cavernous vasculature. Adipose-derived stem cells (ADSCs) can maintain self-renewal and enhanced multi-differentiation potential through the release of a variety of paracrine factors and extracellular vesicles, allowing to repair damaged tissues. Considerable attention has increasingly been paid to their application in tissue engineering and regeneration. In addition, ADSCs can be obtained with a minimally invasive procedure and easily expanded in vitro with low immunogenicity. Nitric oxide (NO) is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases (NOS). Orally administered L-arginine enhances the erectile response presumably by stimulating NO production by the corporal tissues increasing cGMP production. Objective To evaluate the efficacy and tolerability of ADSCs and daily oral L-arginine alone or combination in treating rats with bilateral CNI (BCNI)-induced ED. Methods Adult Sprague-Dawley rats (n = 35) were divided into five groups: 1) control; 2) BCNI (4-wk); 3) BCNI+ADSCs (1 × 106 cells by intracavernosal injection); 4) BCNI+ L-arginine (4wk,10 mg/kg/day, oral); and 5) combination treatment with ADSCs and L-arginine in BCNI. Rats in the ADSCs treatment groups were subjected to intracavernosal injection after BCNI. In vivo erectile response was measured by CN stimulation. The relaxant and contractile responses were also detected on in vitro preparations of corpus cavernosum (CC) strips. The expression and localization of neuronal (nNOS), endothelial NOS (eNOS) as well as hypoxia (hypoxia-inducible factor-1α, HIF-1α), fibrosis [transforming growth factor-beta 1 (TGF- β1)]and apoptosis (Bax and Bcl-2) markers were determined using Western blotting and immunohistochemistry. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Results Rats with CNI had the lowest ICP/MAP ratio at 63% and total ICP at 55% for 7.5 V (P &amp;lt; .001 vs controls) as well as in vitro electrical field stimulation-induced relaxant response at 10% (P &amp;lt; .05 vs controls) and endothelium-dependent acetylcholine-caused relaxation at 56% (P &amp;lt; .001 vs controls). The combined treatment showed more significantly improved erectile and relaxant responses more effectively than ADSCs or L-arginine treatment alone. Increased in the expressions of nNOS, HIF-1α, Bax, and Bcl-2 in the BCNI group were restored by all treatment regiments. eNOS and TGF- β1 protein expressions were similar among groups. Mono-treatment partially improved decreased smooth muscle mass while combined therapy completely recovered. Conclusions The intracavernous injection of ADSCs and oral administration of L-arginine, and, importantly, their combination could effectively protect against hypoxia-induced neurotoxicity, via their increasing endothelial cell function and smooth muscle content, anti-inflammatory, anti-apoptotic, anti-fibrotic properties in addition to reversing erectile function in the BCNI rat model. HIF-1α overexpression by the inhibition of the apoptotic pathway with the Bcl-2 family may have protective effects on the survival of cavernosal neurons. Disclosure No

Effectiveness of acute L-arginine supplementation on physical performance in strength training: a systematic review and meta-analysis

Background: The oral administration of L-arginine has been related to improved physical performance due to a likely reduction in muscle fatigue, resulting from the vasodilator effect of nitric oxide on skeletal muscle. However, there is no precise and quantitative analysis of the information in the literature. The main objective of this study was to assess the effectiveness of L-arginine supplementation on physical performance in strength training with a systematic review and meta-analysis. We hypothesized that L-arginine supplementation would improve performance capacity and the effects involved in strength training. Methods: The study period was from 2010 to 2020. The inclusion process established articles with well-designed human experiments that included only L-arginine supplementation (without any additional compounds) testing the effects of L-arginine supplementation on sports performance related to strength training; identical experimental conditions in placebo or control group; and publications in the last ten years (until December 31, 2020). Three studies were included that compared L-arginine supplementation with placebo in anaerobic performance tests. Test analysis supplementation with other supplements was removed and there was no gender, age, and ethnicity level. Results: There was no significant heterogeneity (p&gt;0.05) in the analysis of the three selected articles and the effects of L-arginine supplementation in muscular endurance; performance had a mean of 0.26 (95% CI = -0.129; 0.649; p = 0.190), peak torque with a mean of -0.002 (95% CI = -0.531; 0.527; p = 0. 99) of the third series of exercises and, furthermore, when comparing the integrated effect (resistance rate with the peak torque) there was no difference with a mean of 0.168 (95% CI = -0.145; 0.481; p = 0.292). Conclusions: Acute L-arginine supplementation provides no ergogenic effect on strength training performance.

Effectiveness of acute L-arginine supplementation on physical performance in strength training: a systematic review and meta-analysis

Background: The oral administration of L-arginine has been related to improved physical performance due to a likely reduction in muscle fatigue, resulting from the vasodilator effect of nitric oxide on skeletal muscle. However, there is no precise and quantitative analysis of the information in the literature. The main objective of this study was to assess the effectiveness of L-arginine supplementation on physical performance in strength training with a systematic review and meta-analysis. We hypothesized that L-arginine supplementation would improve performance capacity and the effects involved in strength training. Methods: The study period was from 2010 to 2020. The inclusion process established articles with well-designed human experiments that included only L-arginine supplementation (without any additional compounds) testing the effects of L-arginine supplementation on sports performance related to strength training; identical experimental conditions in placebo or control group; and publications in the last ten years (until December 31, 2020). Three studies were included that compared L-arginine supplementation with placebo in anaerobic performance tests. Test analysis supplementation with other supplements was removed and there was no gender, age, and ethnicity level. Results: There was no significant heterogeneity (p&gt;0.05) in the analysis of the three selected articles and the effects of L-arginine supplementation in muscular endurance; performance had a mean of 0.26 (95% CI = -0.129; 0.649; p = 0.190), peak torque with a mean of -0.002 (95% CI = -0.531; 0.527; p = 0. 99) of the third series of exercises and, furthermore, when comparing the integrated effect (resistance rate with the peak torque) there was no difference with a mean of 0.168 (95% CI = -0.145; 0.481; p = 0.292). Conclusions: Acute L-arginine supplementation provides no ergogenic effect on strength training performance.

Highly Enhanced Antitumor Immunity by a Three-Barreled Strategy of the l-Arginine-Promoted Nanovaccine and Gene-Mediated PD-L1 Blockade.

Weak T cell responses and immune checkpoints within tumors could be two key factors for limiting antitumor efficacy in the field of cancer immunotherapy. Thus, the combined strategy of tumor vaccines and immune checkpoint blockade has been widely studied and expected to boost antitumor immune responses. Herein, we first developed a two-barreled strategy to combine the nanovaccine with a gene-mediated PD-L1 blockade. On the one hand, polyethyleneimine (PEI) worked as a vaccine carrier to codeliver the antigen ovalbumin (OVA) and the adjuvant unmethylated cytosine-phosphate-guanine (CpG) to formulate the PEI/OVA/CpG nanovaccine through electrostatic binding, which realized both dendritic cell activation and antigen cross-presentation enhancement. On the other hand, the PD-L1 silence gene was loaded by PEI to form PEI/pshPD-L1 complexes, which were further in situ shielded by aldehyde-modified polyethylene glycol (OHC-PEG-CHO) via pH-responsive Schiff base bonds. The formed pshPD-L1@NPs could decrease PD-L1 expression on the tumor cells. However, such a combined two-barreled strategy improved feebly for tumor inhibition in comparison with monotherapy, exhibiting the antagonistic effect, which might be due to the limited T cell response enhancement in the tumor microenvironment. To solve this problem, we have further developed a three-barreled strategy to combine oral administration of l-arginine, which worked as an amplifier to induce robust T cell response enhancement, without causing the upregulation of other negative immune regulators. Superior antitumor behavior and tumor rechallenge protection were realized by the three-barreled strategy in B16F10-OVA (B16-OVA)-bearing mice. The unique three-barreled strategy we developed might offer a novel clinical therapeutic treatment.

Antiatherogenic Effect of L-Arginine in Streptozotocin-Induced Diabetic Rats

L-Arginine is one of the essential amino acids elaborated in numerous areas of human physiology which produce nitric oxide (NO). Current study was designed to examine the antiatherogenic and anti-diabetic activities of L-arginine in experimental diabetic rats’ model. Fifty rats were divided into; Control group, L-Arginine group, Diabetic group, Treated group and Prophylactic group. Fasting blood samples were collected from all groups for determination of fasting blood glucose, insulin, insulin resistance, atherogenic index (AI), cardiac risk ratio (CRR), atherogenic coefficient(AC), intercellular adhesion molecule-1 (I-CAM-1), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO). The result showed that oral administration of L-arginine induced significant decrease in the plasma level of I-CAM-1, TNF-α, AC, AI,CRR, glucose, and insulin resistance while induced significant increase in NO, and insulin levels in the treated group . In conclusion, L-arginine may be a novel nutrient, which improves the endothelial function and protects against the development of atherosclerosis in diabetic rats.

The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure.

Nitric oxide (NO) is a well-known vasodilator produced by the vascular endothelium via the enzyme endothelial nitric oxide synthase (eNOS). The inadequate production of NO has been linked to elevated blood pressure (BP) in both human and animal studies, and might be due to substrate inaccessibility. This review aimed to investigate whether oral administration of the amino acids l-arginine (Arg) and l-citrulline (Cit), which are potential substrates for eNOS, could effectively reduce BP by increasing NO production. Both Arg and Cit are effective at increasing plasma Arg. Cit is approximately twice as potent, which is most likely due to a lower first-pass metabolism. The current data suggest that oral Arg supplementation can lower BP by 5.39/2.66 mmHg, which is an effect that is comparable with diet changes and exercise implementation. The antihypertensive properties of Cit are more questionable, but are likely in the range of 4.1/2.08 to 7.54/3.77 mmHg. The exact mechanism by which Cit and Arg exert their effect is not fully understood, as normal plasma Arg concentration greatly exceeds the Michaelis constant (Km) of eNOS. Thus, elevated plasma Arg concentrations would not be expected to increase endogenous NO production significantly, but have nonetheless been observed in other studies. This phenomenon is known as the “l-arginine paradox”.

Safety and efficacy of l-arginine produced by fermentation with Corynebacteriumglutamicum KCCM 80182 for all animal species.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on l‐arginine produced by fermentation with a genetically modified strain of Corynebacterium glutamicum KCCM 80182 when used as a nutritional additive in feed and water for drinking for all animal species categories. Viable cells of the production strain and its recombinant DNA were not detected in the additive. The product l‐arginine, manufactured by fermentation with C. glutamicum, KCCM 80182, does not give rise to any safety concern with regard to the production strain. l‐Arginine produced using C. glutamicum KCCM 80182 is considered safe for the target species. The FEEDAP Panel has concerns regarding the safety of the simultaneous oral administration of l‐arginine via water for drinking and feed. l‐Arginine produced using C. glutamicum KCCM 80182 is safe for the consumer and for the environment. The additive is not hazardous by inhalation, is not a skin sensitiser, but is corrosive to skin and eyes. The product under assessment is considered an efficacious source of the amino acid l‐arginine for all animal species. For l‐arginine to be as efficacious in ruminants as in non‐ruminant species, it requires protection against microbial degradation in the rumen.

Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

Robust GLP-1 secretion by basic L-amino acids does not require the GPRC6A receptor.

The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids that are hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1 (GLP-1) secretion is unclear. Therefore, to discover whether the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands (L-arginine and L-ornithine) and assessed GLP-1 levels in circulation. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion at the 30- and 60-minute time points in the KO mice was attenuated and did not reach statistical significance. In summary, these data confirm that L-arginine is a potent GLP-1 secretagogue and show that the main effect occurs independently of GPRC6A. In addition, this is the first study to show that also L-ornithine powerfully elicits GLP-1 release in vivo.

Oral L-arginine administration improves anthropometric and biochemical indices associated with cardiovascular diseases in obese patients: A randomized, single blind placebo controlled clinical trial

Background: Recently, the potential of L-arginine supplementation as a novel and effective strategy for weight loss and improving biochemical parameters in obese patients has been under consideration. Objectives: To evaluate the influence of 8-week oral L-arginine supplementation on body mass index (BMI), waist circumference (WC), triceps skinfold (TS), subscapular skinfold (SS), systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma fasting blood sugar (FBS), glycated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and malondialdehyde (MDA) in patients with BMI values > 29.9 or visceral obesity (WC > 102 cm in men or > 88 cm in women). Patients and Methods: Ninety obese patients were included in a single-blind randomized controlled trial. Patients were randomized to receive either L-arginine (3 or 6 g thrice daily) or placebo for 8 weeks. Anthropometric and biochemical indices, dietary intake, and blood pressure values were measured at the baseline and after the 8-week intervention. Results: Significant decreases in anthropometric parameters, blood pressure (SBP, DBP), FBS, HbA1c, LDL, MDA (P < 0.001), TG (P = 0.02), and TC (P = 0.002) and a significant increase in HDL (P < 0.001) were observed in the intervention group, compared to the control group. In the control group, no significant differences were found between the baseline and end-of-intervention measurements. Conclusions: In conclusion, oral L-Arginine supplementation appears to improve anthropometric parameters, blood pressure values, and some blood biochemical indices associated with cardiovascular disease prevention.

Oral L-Arginine Administration Improves Anthropometric and Biochemical Indices Associated With Cardiovascular Diseases in Obese Patients: A Randomized, Single Blind Placebo Controlled Clinical Trial.

Background:Recently, the potential of L-arginine supplementation as a novel and effective strategy for weight loss and improving biochemical parameters in obese patients has been under consideration.Objectives:To evaluate the influence of 8-week oral L-arginine supplementation on body mass index (BMI), waist circumference (WC), triceps skinfold (TS), subscapular skinfold (SS), systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma fasting blood sugar (FBS), glycated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and malondialdehyde (MDA) in patients with BMI values > 29.9 or visceral obesity (WC > 102 cm in men or > 88 cm in women).Patients and Methods:Ninety obese patients were included in a single-blind randomized controlled trial. Patients were randomized to receive either L-arginine (3 or 6 g thrice daily) or placebo for 8 weeks. Anthropometric and biochemical indices, dietary intake, and blood pressure values were measured at the baseline and after the 8-week intervention.Results:Significant decreases in anthropometric parameters, blood pressure (SBP, DBP), FBS, HbA1c, LDL, MDA (P < 0.001), TG (P = 0.02), and TC (P = 0.002) and a significant increase in HDL (P < 0.001) were observed in the intervention group, compared to the control group. In the control group, no significant differences were found between the baseline and end-of-intervention measurements.Conclusions:In conclusion, oral L-Arginine supplementation appears to improve anthropometric parameters, blood pressure values, and some blood biochemical indices associated with cardiovascular disease prevention.

Safety of long-term dietary supplementation with L-arginine in rats.

This study was conducted with rats to determine the safety of long-term dietary supplementation with L-arginine. Beginning at 6 weeks of age, male and female rats were fed a casein-based semi-purified diet containing 0.61 % L-arginine and received drinking water containing L-arginine-HCl (0, 1.8, or 3.6 g L-arginine/kg body-weight/day; n = 10/group). These supplemental doses of L-arginine were equivalent to 0, 286, and 573 mg L-arginine/kg body-weight/day, respectively, in humans. After a 13-week supplementation period, blood samples were obtained from rats for biochemical analyses. Supplementation with L-arginine increased plasma concentrations of arginine, ornithine, proline, homoarginine, urea, and nitric oxide metabolites without affecting those for lysine, histidine, or methylarginines, while reducing plasma concentrations of ammonia, glutamine, free fatty acids, and triglycerides. L-Arginine supplementation enhanced protein gain and reduced white-fat deposition in the body. Based on general appearance, feeding behavior, and physiological parameters, all animals showed good health during the entire experimental period; Plasma concentrations of all measured hormones (except leptin) did not differ between control and arginine-supplemented rats. L-Arginine supplementation reduced plasma levels of leptin. Additionally, L-arginine supplementation increased L-arginine:glycine amidinotransferase activity in kidneys but not in the liver or small intestine, suggesting tissue-specific regulation of enzyme expression by L-arginine. Collectively, these results indicate that dietary supplementation with L-arginine (e.g., 3.6 g/kg body-weight/day) is safe in rats for at least 91 days. This dose is equivalent to 40 g L-arginine/kg body-weight/day for a 70-kg person. Our findings help guide clinical studies to determine the safety of long-term oral administration of L-arginine to humans.

Safety of long-term dietary supplementation with L-arginine in pigs.

This study was conducted with a swine model to determine the safety of long-term dietary supplementation with L-arginine-HCl or L-arginine free base. Beginning at 30 days of age, pigs were fed a corn- and soybean meal-based diet (31.5 g/kg body weight/day) supplemented with 0, 1.21, 1.81 or 2.42 % L-arginine-HCl (Experiment 1) or with 0, 1, 1.5 or 2 % L-arginine (Experiment 2). The supplemental doses of 0, 1, 1.5, and 2 % L-arginine provided pigs with 0, 315, 473, and 630 mg L-arginine/kg body weight/day, respectively, which were equivalent to 0, 286, 430, and 573 mg L-arginine/kg body weight/day, respectively, in humans. At 121 days of age (91 days after initiation of supplementation), blood samples were obtained from the jugular vein of pigs at 1 and 4 h after feeding for hematological and clinical chemistry tests. Dietary supplementation with L-arginine increased plasma concentrations of arginine, ornithine, proline, albumin and reticulocytes, while reducing plasma concentrations of ammonia, free fatty acids, triglyceride, cholesterol, and neutrophils. L-Arginine supplementation enhanced protein gain and reduced white-fat deposition in the body. Other variables in standard hematology and clinical chemistry tests, serum concentrations of insulin, growth hormone and insulin-like growth factor-I did not differ among all the groups of pigs. These results indicate that dietary supplementation with L-arginine (up to 630 mg/kg body weight/day) is safe in pigs for at least 91 days. Our findings help guide clinical studies to determine the safety of long-term oral administration of L-arginine to humans.

Nitric oxide concentrations in gas emanating from the tails of obese rats

This study was undertaken to investigate the effects of oral L-arginine administration and exercising training on the NO concentration emanating from rat tail and NOx in plasma. Obese (fa/fa) Zucker rats (n = 22) were divided into four groups: (1) oral L-arginine administration (A) (n = 6), (2) exercise training (E), (3) exercise training + L-arginine administration (E + A) (n = 5), and (4) non-exercise training + non-L-arginine administration (N) (n = 6). The control (+/+) Zucker rats (n = 22) were also divided into the same four groups. The body weight of the E + A and the A groups was significantly lower than that of the N group. The NO concentration emitted from the tail was higher in the L-arginine (E + A and A) groups than in the non-L-arginine (E and N) groups in both obese and control rats. Exercise training did not affect the skin gas NO concentration in either obese or control rats. Plasma NOx concentrations in four obese rats were significantly higher than those observed in control rats. Exercise training did not influence the level of plasma NOx in obese or control rats. In conclusion, this study confirmed that L-arginine administration increases the skin gas NO concentration and obesity increases the plasma NOx level. The plasma NOx concentrations were not affected by L-arginine administration or exercise training in obese or control rats.

Is High Oral Dose L-arginine Intake Effective in Leukoaraiosis? Preliminary Data, Study Protocol and Expert&amp;#8217;s Opinion

Leukoraraiosis is worldwide considered as a part of the normal aging process, although it is strongly associated with dementia and other disabilities. The pathogenesis of leukoaraiosis still has not been thoroughly acknowledged, even though chronic ischemia with consequent arteriolosclerosis probably due to endothelial dysfunction has been suggested. Treatment focuses on prevention of lesion formation and progression by aggressive control of risk factors, which should begin at an early age and continue on regular basis. Aim of our protocol is to evaluate the effect of long-term oral administration of high-dose L-arginine (6 g/day at least for 24 months) on white matter lesions and neurological and cognitive functions. Patients affected by mild to moderate leukoaraiosis will be enrolled in the study. After a complete neurovascular assessment (i.e. accurate blood test examinations, Echocardiography, Doppler ultrasound of the neck and peripheral arteries), they will undergo MRI, specific neuropsychological tests and gait analysis. Patients will be evaluated at baseline, at 6, 12, 18 and 24 month-follow up. Statistical Analysis will be performed using the software R. A significant level of P<0.05 will be set for all the tests. PRELIMINARY DATA: Two of the 4 patients currently enrolled in the study presented a mild improvement in cognitive function. Because of its high prevalence in over-65-year-old subjects, we hypothesized that treatment with 6 gr of Larginine, as supplementary dietary option, could be helpful in patients affected by leukoaraiosis to improve the cognitive and gait impairment often observed in these subjects (as demonstrated by the LADIS study).