arginine-NO Pathway Research Articles

Dysregulated Arginine Metabolism and Cardiopulmonary Dysfunction in Patients with Thalassemia

Pulmonary hypertension (PH) is common in thalassemia and contributes to mortality. Advancing age and a history of splenectomy are major risk factors in this population. The etiology of PH is multifactorial, involving a complex interaction of platelets, the coagulation system, erythrocytes, and endothelial cells along with inflammatory and vascular mediators. The long-term effect of splenectomy, red cell membrane pathology, coagulation abnormalities, low nitric oxide (NO) bioavailability, excess arginase activity, platelet activation, oxidative stress, iron overload, and chronic hemolysis play a role. The process of hemolysis disables the arginine-NO pathway through the simultaneous release of erythrocyte arginase and cell-free hemoglobin. Both NO and its obligate substrate arginine are rapidly consumed. The biological consequences of hemolysis on NO bioavailability ultimately translate into the clinical manifestations of PH. Guidelines for the management of PH in thalassemia have not yet been established; however, clinical trials are ongoing in an effort to guide future therapy.

Dietary supplements and drugs for preeclampsia prophylaxis

Pre-eclampsia (PE) is a major cause of mortality and morbidity during pregnancy. Many different strategies to prevent PE have been investigated in randomized controlled trials, but none have been found to be widely effective and this is not surprising given the complexities in pathogenesis. Low-dose aspirin, diminishing platelet thromboxane synthesis, seems to prevent or delay PE. A meta-analysis of individual patient data from 32,217 women (PARIS collaborative group) asses that low-dose aspirin during pregnancy is associated with moderate reduction in the relative risk of PE (RR 0.90 95%CI 0.84–0.97), of birth before 34 weeks’ gestation (RR 0.90 95%CI 0.83–0.98), and of having a pregnancy with a serious adverse outcome (RR 0.90 95%CI 0.85–0.96). This effect seems to be more significant in women at high risk of developing PE. Regarding diet and nutrients, there does not appear to be any clear benefit for prevention of PE from routine dietary supplementation. There is high quality evidence that vitamin C and vitamin E are not effective for prevention or treatment of PE. Actually a meta-analyses found that supplementation with these antioxidants is associated with a slightly increased risk of gestational hypertension and premature rupture of membranes. Also there is not enough high-quality evidence to show that dietary magnesium or omega-3 fatty acids supplementation during pregnancy is beneficial. Calcium supplementation instead appears to reduce the risk of PE and the rare occurrence of the composite outcome ’death or serious morbidity’ specially in women with a low baseline calcium intake. Some studies assess that preeclamptic women may be deficient in nitric oxide, which mediates vasodilatation and inhibits platelet aggregation. For this reason NO donors, such as isosorbide dinitrate, glyceryl trinitrate and S-Nitroglutathione, were used in some trials as treatment in preeclamptic women. Despite the reduction in blood pressure and in uterine artery pulsatility index, these substances were rarely used in clinical practice because of adverse effects such as headache or preoxynitrite production. Also l -arginine, the substrate for synthesis of nitric oxide, has been investigated as a mean of preventing PE. Even though a dysfunction of the l -arginine-NO pathway that seems to be present in preeclamptic women, l -arginine load appears to be associated with increased nitric oxide (NO) production, hypotension and reduction of PE/eclampsia rate. Also in obese women there is a dysfunction of the l -arginine-NO pathway that causes a decrease of endothelial-dependent vasodilatation. In these women a l -arginine supplement could be helpful. Conclusion Aspirin proven to be of some help provided dose and timing are adequate. Impact on PE is limited, and its use is better in high-risk. Calcium supply could be helpful in population with low dietary intake. l -Arginine supplementation is worth to receive the same attention aspirin had also considering that biological activity seems wider. Actual evidences are more robust than the ones that allows wasting time and money for Vitamins C and E.

NO synthesis from arginine is favored by α-linolenic acid in mice fed a high-fat diet.

Alterations in NO availability and signaling play a pivotal role at early stages of the metabolic syndrome (MetSynd). We hypothesized that dietary α-linolenic acid (ALA, 18:3 n-3) favors NO availability by modulating amino acid metabolism, with a specific impact on the arginine-NO pathway. Mice were fed a hyperlipidic diet (285g lipid/kg, 51.1% energy), rich in either saturated fatty acids (SFA, provided by palm oil, PALM group) or ALA (provided by linseed oil, LIN group). We measured whole-body NO synthesis and systemic arginine hydrolysis with a tracer-based method, plasma concentration of related metabolites, and hepatic mRNA level of related enzymes, and the study was completed by a transcriptomic analysis in the liver. As expected with this model, hyperlipidic diets resulted in increased adiposity and glycemia after 5weeks. As compared to PALM mice, LIN mice had a higher plasma nitrite and nitrate concentration, a higher whole-body conversion of arginine into NO vs urea, and a similar plasma concentration of asymmetric dimethylarginine (ADMA), despite a higher expression of the liver dimethylargininase-1. In LIN mice, there was a higher expression of genes involved in PPARα signaling, but a little impact on gene expression related to amino acids and arginine metabolism. This effect cannot be directly ascribed to changes in arginase activity in the liver or ADMA metabolism, nor to direct regulation of the related target genes. In conclusion, dietary ALA favors NO synthesis, which could contribute to rescue NO availability when jeopardized by the nutritional conditions in relation with the initiation of the MetSynd.

Abstract 4712: Targeting the arginine-nitric oxide pathway to arrest development and progression of invasive bladder cancer

Abstract Background: In United States there will be an estimated 74,690 new diagnoses and 15,580 deaths in 2014 due to bladder cancer. Lack of reliable markers of early disease and limited chemotherapy options have resulted in poor patient outcomes. A better approach is to treat patients with early intervention using targeted therapy. Arginine metabolic pathway has been identified to be deregulated in bladder cancer. Arginine is either derived from the microenvironment or synthesized by cells containing arginosuccinate synthase I (ASS1). Arginine undergoes subsequent conversion to nitric oxide (NO), which which can activate numerous intracellular signaling mediators, including guanylate cyclase (GC). We evaluated dual targeting of this metabolic pathway by arginine deprivation (ADI-PEG 20, Polaris Pharmaceuticals, San Diego, CA) and NO chelation (Cobinamide) as a therapy for bladder cancer. Experimental Design: Expression of arginine-NO pathway components in FFPE tissue sections was assessed by IHC and correlated with histopathology, outcomes and progression to identify pathway activation during early and late disease and stratified based on moderate to strong expression (2+, 3+) compared to absent to weak expression (0, 1+). In addition, a panel of bladder cell lines was screened for arginine-NO pathway components by immunoblotting and representative ASS1 negative and positive cells were used to evaluate the effects of arginine deprivation and/or NO chelation in vitro on colony formation and cell viability by clonogenic and MTT assays. Effects of NO production on bladder cancer survival and motility was assessed utilizing siRNA gene silencing and small molecule inhibitors. Effects of arginine deprivation by ADI-PEG 20 treatment in vivo was assessed by a mouse xenograft model. Results: Analysis of human tumors showed that ASS1 loss and increase in NOS occurred early in the course of bladder neoplastic progression. We identified loss of the ASS1 enzyme in bladder cancer cells and compensatory dependence on extracellular arginine, which can be successfully targeted using arginine removal to induce bladder cancer cell death, both in vitro and in vivo. We also identified increased nitric oxide synthase (NOS; the enzyme that catalyzes NO production) and GC activation in invasive bladder cancer cell lines. We characterized the effects of NO production on bladder cancer cell survival, growth and motility. Disruption of the NO pathway through gene silencing and small molecule inhibitors resulted in decreased cell survival, migration and invasion. Conclusions: Thus, dual targeting of this metabolic pathway using arginine chelation by the arginine degrading enzyme ADI-PEG20 and NO scavenging by a novel compound Cobinamide can be a potential mechanism to prevent development and/or progression of early bladder neoplasia. Citation Format: Divya Sahu, Sounak Gupta, Andrew M. Hau, Paul Elson, John Bomalaski, Gerry R. Boss, Donna E. Hansel. Targeting the arginine-nitric oxide pathway to arrest development and progression of invasive bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2015-4712

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Arginine‐rich coconut kernel diet influences nitric oxide synthase activity in alloxandiabetic rats

Coconut kernel protein (CKP) has been reported to contain significant amounts of L-arginine. Its potential effect on glucose homeostasis, possibly through the nitric oxide synthase (NO) pathway, was therefore investigated in alloxan-induced diabetic rats. Diabetes was induced by a single intraperitoneal dose of alloxan (150 mg kg⁻¹ body weight). Experimental rats were grouped as follows: Group I, normal control; Group II, diabetic control; Group III, diabetic + CKP; Group IV, diabetic + L-arginine; Group V, diabetic + L-arginine + L-N(G)-Nitroarginine methyl ester (L-NAME). Purified CKP isolated from dried coconut kernel and L-arginine was administered to rats along with a semi-synthetic diet for 45 days. L-NAME (0.5 mg kg⁻¹ body weight) was given to Group V animals. After the experimental period, serum glucose, insulin, activities of liver nitric oxide synthase and arginase, liver glycogen levels and histopathology of the pancreas were evaluated. Serum glucose, insulin and antioxidant enzyme activities and liver glycogen levels were found to be restored to basal levels in CKP-fed rats. Decreased arginase and increased nitric oxide synthase (NOS) activities were found in CKP- and arginine-fed rats. L-NAME treatment showed a partial effect on these parameters. Histopathology revealed that CKP and L-arginine feeding reduced the diabetes-related pancreatic damage in treated rats compared to the diabetic control. The results observed in this study indicate that the potential antidiabetic activity of CKP may be through an arginine-NO pathway leading to pancreatic beta cell regeneration.

Pulmonary hypertension in thalassemia

Pulmonary hypertension (PH) is common in thalassemia and contributes to mortality. Advancing age and a history of splenectomy are major risk factors in this population. The etiology of PH is multifactorial, involving a complex interaction of platelets, the coagulation system, erythrocytes, and endothelial cells along with inflammatory and vascular mediators. The long-term effect of splenectomy, red cell membrane pathology, coagulation abnormalities, low nitric oxide (NO) bioavailability, excess arginase activity, platelet activation, oxidative stress, iron overload, and chronic hemolysis play a role. The process of hemolysis disables the arginine-NO pathway through the simultaneous release of erythrocyte arginase and cell-free hemoglobin. Both NO and its obligate substrate arginine are rapidly consumed. The biological consequences of hemolysis on NO bioavailability ultimately translate into the clinical manifestations of PH. Guidelines for the management of PH in thalassemia have not yet been established; however, clinical trials are ongoing in an effort to guide future therapy.

Changes of <I>L</I>-arginine-NO pathway in platelets of microvascular angina patients and reversing effects of intravenous <I>L</I>-arginine infusion on <I>L</I>-Arg-NO transport

Changes of <I>L</I>-arginine-NO pathway in platelets of microvascular angina patients and reversing effects of intravenous <I>L</I>-arginine infusion on <I>L</I>-Arg-NO transport

Arginine metabolism in a small animal model of sepsis and after hemihepatectomy

Asymmetric dimethylarginine (ADMA) is an inhibitor of the arginine–NO pathway. ADMA accumulates when degradation in the liver by dimethylarginine dimethylaminohydrolase is impaired. In theory, plasma citrulline, formed when arginine is converted by NO synthase, and when ADMA is metabolized, would be lowered and ornithine, formed by the degradation of arginine in the urea cycle, would be potentially elevated when ADMA accumulates as in sepsis and in liver failure [1].

Nitric oxide and vascular insulin resistance

Obesity and type-II diabetes are growing major health issues worldwide. They are the leading risk factors for vascular insulin resistance, which plays an important role in the pathogenesis of cardiovascular disease, the leading cause of death in developed nations. Recent studies have shown that reduced synthesis of nitric oxide (NO; a major vasodilator) from L-arginine in endothelial cells is a major factor contributing to the impaired action of insulin in the vasculature of obese and diabetic subjects. The decreased NO generation results from a deficiency of (6R)-5,6,7,8-tetrahydrobiopterin [BH4; an essential cofactor for NO synthase (NOS)], as well as increased generation of glucosamine (an inhibitor of the pentose cycle for the production of NADPH, another cofactor for NOS) from glucose and L-glutamine. Accordingly, endothelial dysfunction can be prevented by (1) enhancement of BH4 synthesis through supplementation of its precursor (sepiapterin) via the salvage pathway; (2) transfer of the gene for GTP cyclohydrolase-I (the first and key regulatory enzyme for de novo synthesis of BH4); or (3) dietary supplementation of L-arginine (which stimulates GTP cyclohydrolase-I expression and inhibits hexosamine production). Modulation of the arginine-NO pathway by BH4 and arginine is beneficial for ameliorating vascular insulin resistance in obesity and diabetes.

The Role of Arginine–Nitric Oxide Pathway in Patients with Alzheimer Disease

There is a reciprocal regulation of arginase and nitric oxide synthase in L-arginine-metabolizing pathways. There are various evidences of the role of nitric oxide in several neuropsychiatric disorders including Alzheimer's disease. However, there is no study that has investigated the role of arginase as an important part of the arginine regulatory system affecting nitric oxide synthase activity in Alzheimer's disease. This study aims to investigate arginase, manganese (a cofactor of arginase), and total nitrite levels (a metabolite of NO) and their relationship to the arginine-NO pathway in patients with Alzheimer's disease. Arginase activities, Mn, and total nitrite levels were measured in plasma from 47 patients with Alzheimer's disease and 43 healthy control subjects. Plasma arginase activities and manganese were found to be significantly lower and total nitrite level higher in patients with Alzheimer's disease compared with controls. Our results suggest that the arginine-NO pathway is involved in the pathogenesis of Alzheimer's disease.

Regulatory role for amino acids in mammary gland growth and milk synthesis

The health and growth of mammalian neonates critically depend on the yield and composition of their mothers' milk. However, impaired lactogenesis occurs in both women in response to stress and hormonal imbalance and in primiparous sows which exhibit low voluntary feed intake and underdevelopment of mammary tissues. Because of ethical concerns over lactation research with women and children, swine is often used as an animal model to study mammary gland development and the underlying regulatory mechanisms. Available evidence from work with lactating sows shows that amino acids are not only building blocks for protein but are also key regulators of metabolic pathways critical to milk production. Particularly, arginine is the common substrate for the generation of nitric oxide (NO; a major vasodilator and angiogenic factor) and polyamines (key regulators of protein synthesis). Thus, modulation of the arginine-NO pathway may provide a new strategy to enhance the growth (including vascular growth) of mammary tissue and its uptake of nutrients, therefore improving lactation performance in mammals. In support of this proposition, supplementing 0.83% L: -arginine (as 1% L: -arginine-HCl) or 50 mg/day diethylenetriamine-NO adduct (NO donor) to diets of lactating primiparous sows increased milk production and the growth of suckling piglets. Future studies with animal models (e.g., pigs, sheep, cows, and rats) are necessary to elucidate the underlying mechanisms at molecular, cellular, tissue, and whole-body levels.

Dietary supplementation with cholesterol and docosahexaenoic acid increases the activity of the arginine-nitric oxide pathway in tissues of young pigs

Nitric oxide (NO), synthesized from l-arginine by tetrahydrobiopterin (BH4)-dependent NO synthase (NOS), is critical for neurological and muscular development and function. This study was designed to test the hypothesis that cholesterol and docosahexaenoic acid (DHA) may modulate the arginine-NO pathway in tissues of the young pig. Sixteen newborn pigs were nursed by sows for 24 h and then assigned to one of four treatment groups, representing supplementation with 0.0%, 0.2% cholesterol, 0.2% DHA, or cholesterol plus DHA to the basal milk-formula. All piglets were euthanized at 49 days of age. Brain, liver and gastrocnemius muscle were analyzed for BH4, NADPH and arginine, GTP cyclohydrolase-I (GTP-CH) and NOS activities, and NOS protein isoforms. Hepatic NOS activity was below the detection limit in all pigs. DHA supplementation ( P < 0.01) increased GTP-CH activities, as well as BH4 and NADPH concentrations in brain, liver, and muscle by 24–46%, while enhancing ( P < 0.05) NOS activities by 45–48% in brain and muscle. Dietary cholesterol supplementation increased ( P < 0.05) NOS and GTP-CH activities by 17–26% in brain but had no effect in liver or muscle. The enhanced NOS activity in the brain or muscle of cholesterol- or DHA-supplemented piglets was attributable to the combined effects of increased eNOS and nNOS activation (changes in phosphorylation levels) and total iNOS protein. Additionally, DHA and cholesterol enhanced ( P < 0.05) arginine concentrations in brain (35–42%), but not in liver or muscle. These tissue-specific effects of cholesterol and DHA on NO synthesis may play an important role in postnatal growth and development.

Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease

Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increased hemolysis and oxidative stress, contributes to the pathogenesis of pulmonary hypertension (PH) in sickle cell disease (SCD). We hypothesized that altered glutathione and glutamine metabolism play a role in this process. Total glutathione (and its precursors) and glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than in healthy volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r = -0.62, P < .001), plasma arginase concentration (r = -0.45, P = .002), and plasma-free hemoglobin level (r = -0.41, P = .01), linking erythrocyte glutamine depletion to dysregulation of the arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD.

Pulmonary Hypertension in Thalassemia: Association with Hemolysis, Arginine Metabolism Dysregulation, and a Hypercoagulable State

Pulmonary Hypertension in Thalassemia: Association with Hemolysis, Arginine Metabolism Dysregulation, and a Hypercoagulable State

The arginine‐NO pathway modulates lipolysis in adipose tissues of obese human subjects

Previous studies involving high extracellular concentrations of various NO donors (20 μM to 2 mM) showed that they strongly inhibited lipolysis in adipose tissue. However, the physiological significance of these findings remains obscure. On the basis of our recent report that dietary supplementation with L-arginine (the physiological nitrogenous precursor of NO) reduced fat mass in Zucker diabetic fatty rats, the present study was conducted to test the hypothesis that the arginine-NO pathway modulates lipolysis in adipose tissues of obese human subjects. Subcutaneous and omental fat tissues (~100 mg) were obtained from 8 adult women with BMI between 30 and 40 kg/m2, minced into small fragments, and incubated at 37 oC for 3 h in 1 ml of Krebs bicarbonate buffer (pH 7.4) containing 5 mM glucose, 4% BSA, and one of the following: 0, 0.5, 1, 5, 10, 25, 50, 100, or 500 μM sodium nitroprusside (SNP; an NO donor); 0, 0.5 or 2 mM L-arginine; or 5 μM 8-bromo cGMP (a mediator of NO effect). At the end of the incubation, the medium was analyzed for glycerol as an indicator of lipolysis. SNP at 0 to 5 μM dose-dependently increased (P < 0.05) lipolysis by up to 50–54% in both subcutaneous and omental fat tissues, whereas SNP at 25 to 500 μM dose-dependently decreased (P < 0.05) lipolysis by up to 90% in the tissues. L-Arginine at 0.5 and 2 mM increased (P < 0.05) lipolysis by ~ 24% and 50%, respectively, in both fat tissues, whereas 5 μM 8-bromo cGMP stimulated their lipolysis by 47–55%. Our results indicate that physiologic levels of NO increase, while excess levels inhibit, lipolysis in human adipose tissue. The dose-dependent lipolytic effects of NO clarify the discrepancies in the literature regarding a role for NO in fat metabolism. Supported by GRECC-BVAMC, NIH, and Texas A&M.

The lung in the balance: arginine, methylated arginines, and nitric oxide

the lung is a major source of nitric oxide (NO), be it from nitric oxide synthase (NOS) III in the endothelium of the vast pulmonary circulation, NOS II in the epithelium of the large surface area of the airways, or NOS I in the nonadrenergic noncholinergic nerves ([6][1]). NO produced in the lung

Effect of psychological stress on the L-arginine-nitric oxide pathway and semen quality

It has been reported that mental stress causes abnormality of spermiogram parameters. We investigated the effect of psychological stress on the L-arginine-nitric oxide (NO) pathway. Semen samples were collected from 29 healthy fourth semester medical students just before (stress) and 3 months after (non-stress) the final examinations. Psychological stress was measured by the State Anxiety Inventory questionnaire. After standard semen analysis, arginase activity and NO concentration were measured spectrophotometrically in the seminal plasma. Measurements were made in duplicate. During the stress period, sperm concentration (41.28 +/- 3.70 vs 77.62 +/- 7.13 x 10(6)/mL), rapid progressive motility of spermatozoa (8.79 +/- 1.66 vs 20.86 +/- 1.63%) and seminal plasma arginase activity (0.12 +/- 0.01 vs 0.22 +/- 0.01 U/mL) were significantly lower than in the non-stress situation, whereas seminal plasma NO (17.28 +/- 0.56 vs 10.02 +/- 0.49 micromol/L) was higher compared to the non-stress period (P < 0.001 for all). During stress there was a negative correlation between NO concentration and sperm concentration, the percentage of rapid progressive motility and arginase activity (r = -0.622, P < 0.01; r = -0.425, P < 0.05 and r = -0.445, P < 0.05, respectively). These results indicate that psychological stress causes an increase of NO level and a decrease of arginase activity in the L-arginine-NO pathway. Furthermore, poor sperm quality may be due to excessive production of NO under psychological stress. In the light of these results, we suggest that the arginine-NO pathway, together with arginase and NO synthase, are involved in semen quality under stress conditions.

Effectiveness of scaling and root planing versus modified Widman flap on nitric oxide synthase and arginase activity in patients with chronic periodontitis

Nitric oxide (NO) is synthesized from the conversion of L-arginine to L-citrulline by NO synthase (NOS). Arginase, which is an arginine-depleting enzyme, can compete with NOS for the common substrate L-arginine and thus inhibit NO production. In the present study, we aimed to examine the correlation between the arginase and NOS activity in patients with chronic periodontitis and to compare the effects of scaling and root planing and modified Widman flap procedures on enzyme activity. The study included 13 patients diagnosed with chronic periodontitis. Using a split-mouth design, the defects showing>or=7 mm of attachment loss were treated either with scaling and root planing or with modified Widman flap. Gingival biopsies from both sites were obtained at baseline and 2 months after periodontal treatment. Immunohistochemical staining was performed for evaluating NOS expression and specific arginase activity was determined spectrophotometrically. Although inflamed periodontal tissues demonstrated a strong inducible NOS (iNOS) expression at baseline, immunostaining decreased after periodontal treatment. iNOS expression intensity and the number of inflammatory cells showing iNOS expression were found to be higher in the scaling and root planing group compared to the modified Widman flap group. The specific activity of arginase was measured as 0.18+/-0.07 IU/mg protein in the modified Widman flap group and 0.25+/-0.11 IU/mg protein in the scaling and root planing group at baseline. After periodontal therapy, the enzyme level was increased to 0.68+/-0.14 IU/mg protein in the modified Widman flap and to 1.10+/-0.23 IU/mg protein in the scaling and root planing group. This study was the first report of evaluating the involvement of the arginine-NO pathway in chronic periodontitis and this might be considered to be of value in understanding the periodontal disease mechanisms.

Gut and liver handling of asymmetric and symmetric dimethylarginine in the rat under basal conditions and during endotoxemia.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase enzymes, whereas symmetric dimethylarginine (SDMA) competes with arginine transport. Although both dimethylarginines may be important regulators of the arginine-NO pathway, their metabolism is largely unknown. In previous studies, evidence was found for the liver in the metabolism of dimethylarginines. We aimed to investigate dimethylarginine handling of the gut and the liver in detail under basal conditions and during endotoxemia. Twenty-one male Wistar rats were used for this study. Endotoxemia was induced by lipopolysaccharide (LPS) infusion (8 mg/kg). Blood flow was measured using radiolabeled microspheres according to the reference sample method. Concentration of dimethylarginines were measured by high-performance liquid chromatography. The combination of arteriovenous concentration difference and organ blood flow allowed calculation of net organ fluxes and fractional extraction (FE) rates. Arterial plasma concentration of ADMA was lower in LPS rats, in contrast to a higher SDMA concentration. For the gut, net release of ADMA was found, which was higher in LPS rats. In contrast, for the gut, net uptake of SDMA was found, which was lower in LPS rats. For the liver, a high net uptake of ADMA was found in both groups, while FE was significantly increased in LPS rats. Hepatic handling of SDMA was negligible. The liver plays an important role in eliminating ADMA from the circulation and endotoxemia stimulates this capacity. In contrast to the liver, the gut releases ADMA. Endotoxemia results in a reduced systemic ADMA concentration.