Plasma L-arginine Research Articles

The L-Arginine pathway may act as a mediator in the association between impaired one- carbon metabolism and hypertension.

Elevated fasting plasma total homocysteine (tHcy) and the methylenetetrahydrofolate reductase C677T polymorphism (rs1801133) have been associated with hypertension. Whether the L-Arginine pathway is involved, is unclear. We aimed to investigate whether the association between tHcy, the rs1801133 polymorphism and hypertension involves the L-Arginine pathway. THcy, plasma folate and cobalamin, erythrocyte glutathionine reductase activation coefficient, rs1801133 genotype, plasma L-Arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were determined in a cross-sectional study of 788 adults (aged 18 to 75), randomly selected from 2 town population registers. Participants participated in a medical checkup and provided a fasting blood sample. Associations between tHcy, rs1801133 genotype and L-Arginine pathway metabolites were assessed by multiple linear regression analysis and whether the tHcy and rs1801133 genotype are associated with hypertension via the L-Arginine pathway was investigated using mediation analysis. tHcy was positively associated with ADMA (B=0.003; SE=0.001; P<0.001) and SDMA (B=0.007; SE=0.002; P<0.001) and negatively associated with the L-Arginine/ADMA (B=-1.140; SE=0.451; P<0.05) and ADMA/SDMA (B=-0.006; SE=0.003; P<0.05) ratios. The MTHFR 677 CT vs CC genotype was negatively associated with ADMA (B=-0.013; SE=0.007; P<0.05) and with SDMA (B=-0.029; SE=0.013; P<0.05) in participants under 50 years. Each standard deviation increase (37.6) in the L-Arginine/ADMA ratio was associated with reduced hypertension risk (OR [95%CI], 0.6 [0.5, 0.8]). Mediation analysis showed that tHcy and ADMA were mediators in the association between the rs1801133 TT vs CC genotypes and hypertension. Our results support the L-Arginine pathway as a mediator in the association of impaired One-Carbon metabolism and hypertension.

A combination of generated hydrogen sulfide and nitric oxide activity has a potentiated protectant effect against cisplatin induced nephrotoxicity

AimHydrogen sulfide and nitricoxide possess cytoprotective activity and in vivo, they are generated from exogenous sodium hydrosulfide and L-arginine respectively. Cisplatin is a major chemotherapeutic agent used to treat cancer and has a high incidence of nephrotoxicity as a side effect. The study aim was to explore the effects of NaHS and L-arginine or their combination on cisplatin induced nephrotoxicity in rats. MethodsWistar Kyoto rats were given a single intraperitoneal dose of cisplatin (5 mg/kg) followed either by NaHS (56 μmol/kg, i. p.), L-arginine (1.25 g/L in drinking water) or their combination daily for 28-days. Post-mortem plasma, urine and kidney samples were collected for biochemical assays and histopathological analysis. ResultsCisplatin decreased body weights and increased urinary output, while plasma creatinine and urea levels were elevated, but sodium and potassium concentrations were diminished. The renal function parameters, blood urea nitrogen and creatinine clearance, were raised and decreased respectively. Regarding markers of reactive oxygen species, plasma total superoxide dismutase was reduced, whereas malondiadehyde was augmented.Cisplatin also diminished plasma and urinary H2S as well as plasma NO, while NaHS and L-arginine counteracted this activity on both redox-active molecules. Cisplatin cotreatment with NaHS, and/or L-arginine exhibited a reversal of all other measured parameters. ConclusionIn current study, NaHS and L-arginine as monotherapy protected the rats from cisplatin-induced nephrotoxicity but the combination of both worked more effectively suggesting the augmented anti-inflammatory and antioxidative potential of test treatments when administered together.

Changes in the cerebral cortex and thyroid in the simulation of cerebral hypoperfusion and its combination with physical exercise

Cerebral hypoperfusion, as the main mechanism of age-associated diseases, is widespread, which leads to decreased work capacity in the most qualified segment of employees. The study aimed to analyze compensatory and adaptive reactions of the cerebral cortex, thyroid gland, and blood in cerebral hypoperfusion and its combination with short-term physical activity. Chronic cerebral hypoperfusion was modeled by permanent bilateral occlusion of the common carotid arteries. The study included 280 rats, of which 112 were subjected to daily short-term swimming as a model of rehabilitation measures. On days 1, 6, 8, 14, 21, 28, 35, 60, and 90 after surgery, the animals were subjected to the Morris water maze and open field tests. Histological sections of the brain and thyroid gland were examined. The concentrations of the active products of thiobarbituric acid, nitrites, and L-arginine in blood plasma were measured. The results showed that changes in the cerebral cortex and thyroid gland in the cerebral hypoperfusion model were characterized by a general stage: days 18, hypothyroid condition and death of cortical cells, cerebral hemispheres, predominantly neurons; weeks 23, stabilization, transition to the euthyroid condition, accompanied with thyrocyte desquamation, folliculogenesis, perifollicular hemocapillaries fullness, decreased functional activity of neurons, and astrocyte activation; weeks 45, incomplete adaptation, which is characterized by neurons approaching the vessels of the hemocirculatory channel and satellites sinking into the cytoplasm of neurons. Mosaicism of thyroid blood filling was also observed. After 3 months, degenerative changes in the cells of the cerebral cortex of the cerebral hemispheres appear, including a decrease in the numerical density of neurons and immunoreactive cells of glial fibrillar acid protein and a hyperthyroid state with signs of decompensation: plasmorrhagia and desquamation of the thyroid epithelium. Daily 15-min exercise with cerebral hypoperfusion demonstrated a neuroprotective effect, slowed down the progression of hypoxic and neurodegenerative changes, and reduced the concentration of nitrites and malondialdehyde in the blood and the levels of neuronal nitric oxide synthase in immunoreactive neurons.

Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment.

Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with SCD enrolled in the WALK-PHaSST study (clinicaltrials gov. Identifier: NCT00492531). Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin [Hb] SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (fetal Hb%). We investigated metabolic correlates to the degree of intravascular hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma-free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures - including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.

Amyloid beta-correlated plasma metabolite dysregulation in Alzheimer's disease: an untargeted metabolism exploration using high-resolution mass spectrometry toward future clinical diagnosis.

Alzheimer's disease (AD) is a leading cause of dementia, and it has rapidly become an increasingly burdensome and fatal disease in society. Despite medical research advances, accurate recognition of AD remains challenging. Epidemiological evidence suggests that metabolic abnormalities are tied to higher AD risk. This study utilized case-control analyses with plasma samples and identified a panel of 27 metabolites using high-resolution mass spectrometry in both the Alzheimer's disease (AD) and cognitively normal (CN) groups. All identified variables were confirmed using MS/MS with detected fragmented ions and public metabolite databases. To understand the expression of amyloid beta proteins in plasma, ELISA assays were performed for both amyloid beta 42 (Aβ42) and amyloid beta 40 (Aβ40). The levels of plasma metabolites PAGln and L-arginine were found to significantly fluctuate in the peripheral blood of AD patients. In addition, ELISA results showed a significant increase in amyloid beta 42 (Aβ42) in AD patients compared to those who were cognitively normal (CN), while amyloid beta 40 (Aβ40) did not show any significant changes between the groups. Furthermore, positive correlations were observed between Aβ42/Aβ40 and PAGln or L-arginine, suggesting that both metabolites could play a role in the pathology of amyloid beta proteins. Binary regression analysis with these two metabolites resulted in an optimal model of the ROC (AUC = 0.95, p < 0.001) to effectively discriminate between AD and CN. This study highlights the potential of advanced high-resolution mass spectrometry (HRMS) technology for novel plasma metabolite discovery with high stability and sensitivity, thus paving the way for future clinical studies. The results of this study suggest that the combination of PAGln and L-arginine holds significant potential for improving the diagnosis of Alzheimer's disease (AD) in clinical settings. Overall, these findings have important implications for advancing our understanding of AD and developing effective approaches for its future clinical diagnosis.

Phenotypic characteristics of asthma and morbidity are associated with distinct longitudinal changes in L-arginine metabolism

BackgroundThe L-arginine metabolome is dysregulated in asthma, though it is not understood how longitudinal changes in L-arginine metabolism differ among asthma phenotypes and relate to disease outcomes.ObjectivesTo determine the longitudinal...

The effect of microencapsulated watermelon rind (Citrullus lanatus) and beetroot (Beta vulgaris L.) ingestion on ischemia/reperfusion-induced endothelial dysfunction: a randomised clinical trial.

Endothelial dysfunction is commonly associated with a cardiovascular event, such as myocardial infarction. Myocardial infarction is marked by an ischemia/reperfusion (IR) phenomenon associated with endothelial dysfunction, contributing even more to future cardiovascular events. Although the supplementation with L-citrulline and nitrate from watermelon and beetroot have been used to improve vascular function, the effect of microencapsulated watermelon rind (WR) or its co-ingestion with beetroot (WR + B) on endothelial IR injury has not been addressed. Therefore, this study aimed to investigate the effect of a single dose of WR and WR + B on IR-induced macro-and microvascular dysfunction. In a randomized, crossover, placebo-controlled study, 12 volunteers underwent macro (flow-mediated dilation) and microvascular (muscle oxygen saturation) assessment and blood collection (to measure L-citrulline, L-arginine, nitrate and nitrite) before and after 20 min of blood occlusion in WR, WR + B and placebo conditions. Prolonged ischemia induced endothelial dysfunction in the macro but not in the microvasculature. The WR and WR + B supplementation significantly restored FMD after IR injury compared to the placebo (p < 0.05). However, there was no significant difference between WR and WR + B in the macrovascular function (p > 0.05). Plasma L-citrulline, L-arginine, nitrate, and nitrite significantly increased (p > 0.05) after WR and WR + B supplementation compared to the placebo. A single dose of WR and WR + B effectively minimizes IR-induced macrovascular endothelial dysfunction in healthy individuals. Beetroot co-ingestion with watermelon did not provide an additional effect of endothelial dysfunction induced by IR (NCT04781595, March 4, 2021).

&lt;i&gt;Astragalus membranaceus&lt;/i&gt; and &lt;i&gt;Panax notoginseng&lt;/i&gt; saponins improves intestinal l-arginine absorption and protects against intestinal disorder &lt;i&gt;in vivo&lt;/i&gt;

Nutritional supplementation with L-arginine has been shown to promote cell growth and exercise performance, and is helpful to various disorders. Astragalus membranaceus and Panax notoginseng are traditional herbal medicines that display a wide range of beneficial activities. To understand their effects on L-arginine absorption in human intestinal cells, in vitro and in vivo experiments were performed using a standardized mixture of Astragalus membranaceus and Panax notoginseng saponins (APS). Our studies indicated that APS increased the expression of cationic amino acid transporter 1 (CAT1) and L-arginine transport in human Caco-2 cells. In addition, APS benefits TNBS-induced-colitis rats by increasing food intake, body weight, intestinal epithelial integrity, CAT1 gene expression, and blood L-arginine level. APS also reduces intestinal inflammation associated with increased myeloperoxidase activity in colitis rats. Further studies indicated that the plasma L-arginine level significantly increases in human subjects administered APS.

A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice.

Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are increased in cancer-bearing aged hosts. Arginase-I in MDSCs degrades L-arginine, an amino acid required for T cell activation and proliferation. In this study, we compared the therapeutic efficacy of 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and cyclophosphamide (CP) between young and aged colon cancer-bearing mice. Therapy with 5-FU/L-OHP and CP significantly suppressed the in vivo growth of CT26 and MC38 colon carcinomas in syngeneic young mice, whereas this effect was attenuated in aged mice. L-arginine monotherapy showed no effect in aged mice. However, additional therapy with anti-programmed cell death (PD)-1 antibody and L-arginine supplementation boosted the effect of chemoimmunotherapy in aged mice, and some mice were cured. During all combination therapy, tumor-specific cytotoxic T lymphocytes (CTLs) were generated from mice with non-progressing tumor, but not from those with progressing tumor. Plasma L-arginine levels were lower in aged than young mice, and chemotherapy tended to decrease the plasma L-arginine levels in aged mice. Compared to young mice, CT26-bearing aged mice decreased arginase activity, arginase-I expression, and the proportion of monocytic MDSCs in tumor tissues, whereas contrasting results were observed in MC38-bearing aged mice. Importantly, the induction of tumor-specific CTLs was impaired at lower doses of L-arginine in vitro, and the infiltration of CTLs into CT26 tissues after chemoimmunotherapy was promoted by L-arginine administration in vivo. These results indicate that chemoimmunotherapy was less effective in cancer-bearing aged mice, but that L-arginine supplementation can modulate its therapeutic efficacy via its effect on tumor-specific CTLs.

Increased Plasma L-Arginine Levels and L-Arginine/ADMA Ratios after Twelve Weeks of Omega-3 Fatty Acid Supplementation in Amateur Male Endurance Runners.

It is not fully understood how supplementation with omega-3 fatty acids affects the metabolism of amino acids required for the bioavailability/synthesis of NO, i.e., L-arginine (L-arg), asymmetric dimethylarginine (ADMA), their metabolites, and the L-arg/ADMA ratio and their impact on running economy (RE) in runners. Thus, 26 male amateur endurance runners completed a twelve-week study in which they were divided into two supplemented groups: the OMEGA group (n = 14; 2234 mg and 916 mg of eicosapentaenoic and docosahexaenoic acid daily) or the MCT group (n = 12; 4000 mg of medium-chain triglycerides daily). At the same time, all participants followed an endurance training program. Before and after the 12-week intervention, blood was collected from participants at two time points (at rest and immediately post-exercise) to determine EPA and DHA in red blood cells (RBCs) and plasma levels of L-arg, ADMA, and their metabolites. RBC EPA and DHA significantly increased in the OMEGA group (p &lt; 0.001), which was related to the resting increase in L-arg (p = 0.001) and in the L-arg/ADMA ratio (p = 0.005) with no changes in the MCT group. No differences were found in post-exercise amino acid levels. A total of 12 weeks of omega-3 fatty acid supplementation at a dose of 2234 mg of EPA and 916 mg of DHA daily increased levels of L-arg and the L-arg/ADMA ratio, which indirectly indicates increased bioavailability/NO synthesis. However, these changes were not associated with improved RE in male amateur endurance runners.

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach.

Rheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA. Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points. Twenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other. One-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.

251 (PB-075) Poster - Plasma L-arginine metabolic profiling in breast cancer patients reflects differences in cellular gene expression and metabolic activities according to subtype – A translational study in human breast cancer

Background: L-arginine is a semi-essential amino acid; its availability for protein synthesis is limiting for cell proliferation. It is also a substrate for nitric oxide synthases (nNOS, iNOS, eNOS) and arginases (ARG) 1 and 2. The effects of L-arginine on cell proliferation and disease progression in breast cancer have remained controversial. We studied whether breast cancer subtypes show different levels of L-arginine and its metabolites, and if this relates to NOS and ARG isoform expression and tumor cell proliferation.

Plasma L-Arginine Predicts Clinical Response to Immune Checkpoint Inhibitors

Baseline plasma L-Arginine (ARG) levels can predict response to immune checkpoint inhibitors (ICI).

Current Evidence of Watermelon (Citrullus lanatus) Ingestion on Vascular Health: A Food Science and Technology Perspective.

The amino acid L-arginine is crucial for nitric oxide (NO) synthesis, an important molecule regulating vascular tone. Considering that vascular dysfunction precedes cardiovascular disease, supplementation with precursors of NO synthesis (e.g., L-arginine) is warranted. However, supplementation of L-citrulline is recommended instead of L-arginine since most L-arginine is catabolized during its course to the endothelium. Given that L-citrulline, found mainly in watermelon, can be converted to L-arginine, watermelon supplementation seems to be effective in increasing plasma L-arginine and improving vascular function. Nonetheless, there are divergent findings when investigating the effect of watermelon supplementation on vascular function, which may be explained by the L-citrulline dose in watermelon products. In some instances, offering a sufficient amount of L-citrulline can be impaired by the greater volume (>700 mL) of watermelon needed to reach a proper dose of L-citrulline. Thus, food technology can be applied to reduce the watermelon volume and make supplementation more convenient. Therefore, this narrative review aims to discuss the current evidence showing the effects of watermelon ingestion on vascular health parameters, exploring the critical relevance of food technology for acceptable L-citrulline content in these products. Watermelon-derived L-citrulline appears as a supplementation that can improve vascular function, including arterial stiffness and blood pressure. Applying food technologies to concentrate bioactive compounds in a reduced volume is warranted so that its ingestion can be more convenient, improving the adherence of those who want to ingest watermelon products daily.

Effect of microencapsulated watermelon (Citrullus lanatus) intake on plasma amino acids and glycemic response in healthy adults

Watermelon is an l-citrulline-rich fruit that has been used as a supplement to increase l-arginine in plasma, which in turn plays a critical role in the synthesis of nitric oxide, a molecule that regulates vascular tone. Watermelon rind, similar to its pulp, presents a high l-citrulline content, yet a lower concentration of sugar, which would be more convenient for individuals who need to refrain from excessive sugar ingestion (i.e., diabetics and obese individuals). Further, ingestion of watermelon rind can be a sustainable alternative to increase plasma l-arginine, given that rind of fruits is commonly discarded. Therefore, we evaluated the effect of ingestion of a product derived from watermelon rind and pulp (microencapsulation in spray drier) on plasma amino acids (l-citrulline, l-arginine and l-ornithine), glucose, and insulin. Eleven participants (28.36 ± 5.70 years) were enrolled in a single blind, cross-over and randomized study. They ingested microencapsulated watermelon rind and pulp (containing 4 g of l-citrulline) plasma amino acids, glucose, and insulin were evaluated before and 30, 60, 90 and 120 min after ingestion. It was observed that both microencapsulated watermelon rind and pulp increased l-citrulline through 120 min and microencapsulated watermelon rind significantly increased l-arginine at 30 min. In addition, microencapsulated watermelon rind and pulp similarly increased plasma glucose and insulin levels. In conclusion, these findings suggest that both microencapsulated watermelon rind and pulp are effective to increase plasma l-citrulline and microencapsulated watermelon rind effectively increases plasma l-arginine. In addition, rind and pulp promote similar changes on plasma glucose and insulin.

Oral administration of l-citrulline alters the vascular delivery of substances to rat skeletal muscles

Vascular endothelial function deteriorates with age and disease, and the production of vasodilator factors like nitric oxide (NO) decreases. The free amino acid l-citrulline increases vasodilation and blood flow through increased NO production. We examined the effects of oral l-citrulline administration on vascular delivery of substances to skeletal muscles. In Experiment 1, following oral l-citrulline administration and subsequent intravenous Evans blue dye (EBD) administration to rats, EBD levels delivered to skeletal muscles were measured after 60 min. In Experiment 2, plasma concentrations of amino acids and NOx, an indicator of vasodilation, were measured over time after oral l-citrulline administration. In Experiment 3, we measured EBD levels in skeletal muscles of streptozotocin-induced type 1 diabetic rats following l-citrulline administration. In these experiments, EBD levels in the soleus muscle were higher in the l-citrulline group than in the control group (19.9 ± 0.7 vs. 22.5 ± 1.9 μg/g tissue, p < 0.05). Plasma l-arginine, l-citrulline, and NOx levels were increased within 30 min after l-citrulline administration. EBD levels in the soleus and gastrocnemius muscles were higher in diabetic rats with l-citrulline administration (18.7 ± 2.2 vs. 25.0 ± 4.3 μg/g tissue, p < 0.05 and 8.0 ± 0.5 vs. 9.2 ± 0.8 μg/g tissue, p = 0.05, respectively). These data suggest that oral l-citrulline administration may increase the level of substances delivered to skeletal muscles by increasing the NO production in both normal and vascular endothelial dysfunction models.

Effects of sex and estrous cycle on the brain and plasma arginine metabolic profile in rats.

L-arginine is a versatile amino acid with a number of bioactive metabolites. Increasing evidence implicates altered arginine metabolism in the aging and neurodegenerative processes. The present study, for the first time, determined the effects of sex and estrous cycle on the brain and blood (plasma) arginine metabolic profile in naïve rats. Female rats displayed significantly lower levels of L-arginine in the frontal cortex and three sub-regions of the hippocampus when compared to male rats. Moreover, female rats had significantly higher levels of L-arginine and γ-aminobutyric acid, but lower levels of L-ornithine, agmatine and putrescine, in plasma relative to male rats. The observed sex difference in brain L-arginine appeared to be independent of the enzymes involved in its metabolism, de novo synthesis and blood-to-brain transport (cationic acid transporter 1 protein expression at least), as well as circulating L-arginine. While the estrous cycle did not affect L-arginine and its metabolites in the brain, there were estrous cycle phase-dependent changes in plasma L-arginine. These findings demonstrate the sex difference in brain L-arginine in the estrous cycle-independent manner. Since peripheral blood has been increasingly used to identify biomarkers of brain pathology, the influences of sex and estrous cycle on blood arginine metabolic profile need attention when experimental research involves female rodents.

Cardiovascular Risk and Endothelial Dysfunction in Primary Sjogren Syndrome Is Related to the Disease Activity.

The aim of our study was to evaluate if endothelial-dysfunction (ED) occurs in patients with primary Sjogren syndrome (pSS) and whether it is associated with the disease characteristics and activity. A total of 46 patients with pSS and 30 controls, without known cardiovascular disease, were enrolled in this study. A flow-mediated-dilation (FMD) of the brachial artery, plasma concentrations of the nitric oxide (NO) metabolic pathway (ADMA, L-arginine, SDMA, cGMP), and markers of endothelial inflammatory function (PAI-1, sE-selectin) and angiogenesis (angiostatin, VEGF) were analyzed. The FMD was significantly lower in pSS patients (7.56 ± 3.08 vs. 10.91 ± 1.02%, p = 0.043) and positively correlated with the Ro/SS-A-antibodies (r = 0.34, p = 0.03), pulmonary involvement (r = 0.52, p = 0.001) and inversely with ADMA (r = −0.35, p = 0.04). Plasma ADMA, L-arginine and angiostatin levels were significantly higher in pSS patients (0.39 ± 0.08 vs. 0.36 ± 0.06 µmol/L, p = 0.05; 29.07 ± 6.7 vs. 25.4 ± 5.23 µmol/L, p = 0.01; 152.25 ± 60.99 vs. 120.07 ± 38.7 pg/mL, p = 0.0, respectively). ADMA was associated with ESSDAI (r = 0.33, p = 0.02), SCORE (r = 0.57, p = 0.00003) and focus score (r = 0.38, p = 0.04). In the multiple regression analysis, the ESSDAI was significantly and independently associated with plasma ADMA levels (β = 0.24, p = 0.04). Moreover, plasma cGMP concentrations were negatively correlated with the disease duration (r = −0.31, p = 0.03). Endothelial function is impaired in patients with pSS and associated with the measures of disease activity, which supports the key-role of inflammation in developing and maintaining accelerated atherosclerosis.

POS0383 EFFECTS OF TOFACITINIB THERAPY ON ARGININE AND METHIONINE METABOLITES IN ASSOCIATION WITH VASCULAR PATHOPHYSIOLOGY IN RHEUMATOID ARTHRITIS: A METABOLOMIC APPROACH

Background:Rheumatoid arthritis (RA) has been associated with increased cardiovascular (CV) risk and metabolic changes.Objectives:We wished to determine how the Janus kinase (JAK) inhibitor tofacitinib influences vascular pathophysiology and metabolites of the arginine and methionine-homocysteine pathways.Methods:Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib and evaluated at baseline and after 6 and 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (aCCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels.Results:Twenty-six patients completed the study. Tofacitinib treatment maintained FMD and PWV. Ten mg bid tofacitinib significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. Tofacitinib transiently increased L-citrulline and L-NMMA and decreased homocysteine levels after 12 months. Based on L-citrulline, L-ornithine, ADMA and SDMA levels, L-arginine remained highly available for endothelial NO production. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with aCCP. Regarding vascular pathophysiology, only PWV and methionine correlated with each other after 12 months.Conclusion:Tofacitinib suppressed systemic inflammation in RA yielding stabilization of vascular function. It may exert CV protective effects in RA, at least in part, by shifting L-arginine metabolism to high arginine availability and decreasing homocysteine levels.Acknowledgements:This research was supported by the European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program ’(Z.S.); by the European Union grant GINOP-2.3.2-15-2016-00015 (Z.S.) and by the WI188341 investigator-initiated research (IIR) grant obtained from Pfizer US (Z.S.).Disclosure of Interests:Boglárka Soós: None declared, Attila Hamar: None declared, Anita Pusztai: None declared, Monika Czókolyová: None declared, Edit Végh: None declared, Szilvia Szamosi Speakers bureau: Roche, Zsófia Pethö: None declared, Katalin Gulyás: None declared, György Kerekes: None declared, Éva Szekanecz: None declared, Sándor Szántó Speakers bureau: Abbvie, MSD, Novartis, Consultant of: Abbvie, Novartis, Gabriella Szücs Speakers bureau: Actelion, Roche, Sager, Boehringer, Consultant of: Boehringer, Actelion, Sager, Uwe Christians: None declared, Jelena Klawitter: None declared, Tamas Seres: None declared, Zoltán Szekanecz Speakers bureau: Pfizer, Abbvie, Roche, Lilly, Novartis, Boehringer, Consultant of: Pfizer, Abbvie, Novartis, Grant/research support from: Pfizer

L-arginine supplementation to mitigate cardiovascular effects of walking outside in the context of traffic-related air pollution in participants with elevated blood pressure: A randomized, double-blind, placebo-controlled trial.

Exposure to traffic-related air pollution (TRAP) increases blood pressure (BP) and cardiovascular morbidity and mortality. We aimed to evaluate the potential efficacy of L-arginine supplementation in mitigating the adverse cardiovascular effects of adults with elevated BP walking outside under TRAP using a randomized, double-blind and placebo-controlled trial. 118 adults with elevated BP were recruited and were randomly assigned to either the placebo group or the intervention group with 9g/day L-arginine supplementation for 2weeks. On the 14th day, paired participants from the two groups walked along a traffic road for 2h. Resting BP, L-arginine-nitric oxide metabolites and inflammatory biomarkers were measured before, during and after the 2h exposure scenario, and ambulatory BP and Holter were measured during the 2h outdoor walk. Participants in the intervention group had significantly elevated plasma L-arginine levels compared to the placebo group after supplementation. The two groups had similar exposures to traffic-related air pollutants. However, participants in the intervention group showed significant reductions of 5.3mmHg (95% CI: -9.9, -0.7) in resting systolic BP (SBP), 4.3mmHg (95% CI: -7.2, -1.3) in resting diastolic BP (DBP) and 4.6mmHg (95% CI: -7.9, -1.3) in resting mean arterial pressure (MAP) at 30min after the 2h outdoor walk compared with the placebo group. There were also significant decreases in ambulatory SBP, DBP and MAP (7.5-9.9mmHg, 5.3-7.6mmHg and 4.7-7.9mmHg, respectively) during the walk in the intervention group compared with the placebo group. There were no substantial changes in ST-segment level, L-arginine-NO metabolites and inflammatory biomarkers, and no significant associations were found between specific traffic-related air pollutants and cardiovascular health indicators. Specifically, our study shows that oral L-arginine supplementation was safe and well-tolerated, and could improve BP levels in adults with elevated BP during outside walk under TRAP.