Symmetric Dimethylarginine Levels Research Articles

Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest-Results from the Prospective, Observational COMMUNICATE Trial.

(1) Background: In patients with shock, the L-arginine nitric oxide pathway is activated, causing an elevation of nitric oxide, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels. Whether these metabolites provide prognostic information in patients after out-of-hospital cardiac arrest (OHCA) remains unclear. (2) Methods: We prospectively included OHCA patients, recorded clinical parameters and measured plasma ADMA, SDMA and Arginine levels by liquid chromatography tandem mass spectrometry (LC-MS). The primary endpoint was 90-day mortality. (3) Results: Of 263 patients, 130 (49.4%) died within 90 days after OHCA. Compared to survivors, non-survivors had significantly higher levels of ADMA and lower Arginine and Arginine/ADMA ratios in univariable regression analyses. Arginine levels and Arginine/ADMA ratio were significantly associated with 90-day mortality (OR 0.51 (95%CI 0.34 to 0.76), p < 0.01 and OR 0.40 (95%CI 0.26 to 0.61), p < 0.001, respectively). These associations remained significant in several multivariable models. Arginine/ADMA ratio had the highest predictive value with an area under the curve (AUC) of 0.67 for 90-day mortality. Results for secondary outcomes were similar with significant associations with in-hospital mortality and neurological outcome. (4) Conclusion: Arginine and Arginine/ADMA ratio were independently associated with 90-day mortality and other adverse outcomes in patients after OHCA. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated.

Abstract 13682: Single Nucleotide Polymorphisms in the Ddah1 Gene Are Associated With Delayed Cerebral Ischemia in Patients With Subarachnoid Hemorrhage

Introduction: Delayed cerebral ischemia (DCI) is a major cause of lethality and poor long-term neurological outcome in patients with subarachnoid hemorrhage (SAH). Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are regulators of vascular NO synthesis from L-arginine. We previously reported that elevated concentrations of both, ADMA and SDMA at ICU admission are associated with the incidence of DCI during follow-up. Dimethylarginines (DMAs) are synthesized by PRMT enzymes; ADMA is metabolized by DDAH1 and DDAH2, whilst SDMA is metabolized by AGXT2. Hypothesis: We hypothesized that common genetic variants in genes encoding the core enzymes of DMA metabolism may predispose individuals for the development of DCI after SAH. Methods: We measured L-arginine, ADMA and SDMA in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at ICU admission and followed them for clinical status and neurological outcome until 30 days post-discharge. Single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes were analyzed by PCR, and genotypes were related to biomarker levels and outcome. The primary outcome was the incidence of DCI, which was defined as the appearance of new infarctions on cranial computed tomography or magnetic resonance imaging. Results: 18 out of 51 SAH patients developed DCI. DCI patients did not significantly differ from those without DCI in clinical scores. However, patients who developed DCI had higher plasma ADMA and SDMA levels and higher SDMA levels in CSF at admission. DDAH1 gene variation was associated with plasma ADMA (p=0.02), whilst AGXT2 gene variation was associated with plasma SDMA (p=0.02). There was a strong association of all three DDAH1 SNPs that we analyzed with DCI, with carriers of the minor allele of DDAH1 rs233112 having a significantly increased relative risk of developing DCI (RR=2.61 (1.25-5.43), p=0.002). Conclusions: Sequence variation in the DDAH1 gene is associated with the incidence of DCI in SAH patients, suggesting that SNPs in the DDAH1 gene, which regulates plasma ADMA concentration, significantly influences the risk of cerebral ischemia after subarachnoid hemorrhage.

Abstract 631: Mat2A Inhibitors decrease growth, increase senescence and p53 stability in MTAP-deleted cancer cells

Abstract Deletions in Methylthioadenosine phosphorylase (MTAP) are observed in 15% of all cancers including pancreatic, lung, bladder and GBM cancers (1). MTAP loss results in an accumulation of MTA which partially inhibits Protein Arginine Methyltransferase 5 (PRMT5). MTAP deletions confer enhanced sensitivity to inhibition of Methionine Adenosyltransferase 2A (Mat2A), which is involved in the synthesis of the universal methyl donor and PRMT5 substrate S-Adenosyl Methionine (SAM). In combination with MTA accumulation, Mat2A inhibition depletes SAM levels resulting in further inhibition of PRMT5 activity and a synthetic lethal (SL) relationship in MTAP null cancers. Inhibition of PRMT5 activity as a result increases RNA splicing defects and chromatin dysregulation which impacts tumor cell viability in different models. We developed MAT2A inhibitors for treatment of MTAP-deleted tumors, and in this study sought to determine the mechanism of action of these inhibitors in MTAP null models. These inhibitors were assessed for activity against both MTAP-wt and MTAP-null tumor models using cellular proliferation assays. MTAP-null (KP4, BxPC3, RT112/84, MiaPaCa-2, H647) models were more sensitive to Mat2A inhibition than MTAP-wt (HCT116, NCI-H460) models. Inhibition of Mat2A increased the expression of markers associated with cellular senescence and cell cycle arrest. Cellular SAM levels were diminished in both MTAP-wt and MTAP-null cells and xenografts while selective reduction of Symmetric Dimethyl Arginine (SDMA) levels were observed in MTAP-null models. Cellular response to Mat2A inhibitors is unaltered by RNAi-mediated knockdown of Mat1A. Signaling changes that were observed due to decreased PRMT5 activity included increased stability of p53, which may be due to the inefficient splicing of MDM4 mRNA, and was seen across multiple MTAP-null models but not in MTAP WT. Furthermore, increased protein and mRNA expression of the p53 target gene p21 was also observed in MTAP-null models. In conclusion, Mat2A inhibition effectively decreases SAM and SDMA levels, leading to increased stability of p53 and its targets and resulting in decreased cellular proliferation. Ongoing exploratory studies will further delineate the molecular mechanisms mediated by Mat2A inhibition in MTAP-null cell lines. The genes and metabolites identified from these studies will be validated in Mat2A-dependent and non-dependent MTAP-null cell lines identified from DepMap studies to inform further preclinical and clinical studies. Citation Format: Neil Bhola, Atieh Givmanesh, Marie-Claire Wagle, Candy Garcia, Kedar Vaidya, Leah Cleary, Zhonghua Pei, Mark Lackner, Zineb Mounir. Mat2A Inhibitors decrease growth, increase senescence and p53 stability in MTAP-deleted cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 631.

Abstract 2919: Discovery of PRT811, a potent, selective, and orally bioavailable brain penetrant PRMT5 Inhibitor for the treatment of brain tumors

Abstract Protein arginine methyltransferase 5 (PRMT5) is the major type II PRMT that catalyzes the formation of symmetrical dimethyl arginine (SDMA) on protein substrates and plays important roles in regulating RNA splicing as well as transcription and activity of critical oncogenic signaling pathways. Recent studies have revealed PRMT5 as a potential therapeutic target for various cancers including Central Nervous System (CNS) tumors such as glioblastoma (GBM), the most common and aggressive primary brain tumor in adults. Several PMRT5 inhibitors have entered into the clinic for hematological and solid tumors, but none have been reported to be brain penetrant, a potentially desirable feature of a small molecule designed for treating CNS cancers and brain metastases. PRT811 is a potent, selective, and brain penetrant PRMT5 inhibitor, and exhibits potent in vitro and in vivo activities in preclinical models of brain tumors. PRT811 inhibited the methyltransferase activity of the PRMT5/MEP50 complex with an IC50 of 3.9 nM, but showed minimal inhibition against a panel of 37 human methyltransferases at 10 µM. In a panel of brain cancer cell lines of varied histology, PRT811 reduced SDMA levels and inhibited cell proliferation with IC50 values in the range of 7-40 nM and 29-134 nM, respectively, regardless of expression levels of methylguanine methyltransferase (MGMT), the expression of which is associated with temozolomide (TMZ) resistance. Furthermore, PRT811 demonstrated broad antiproliferative activity in a panel of 87 cell lines consisting of brain, breast, lung, and skin cancers, representing primary and the most common cancer types that metastasize to the brain. Finally, PRT811 effectively inhibited cell growth in a panel of patient derived xenograft models of GBM in ex vivo 3D cultures. PRT811 is a highly permeable molecule with high brain penetrance in rodents, with an efflux ratio &amp;lt;1 and brain/plasma ratio ranging from 2 to 5 in mice. In vivo, oral administration of PRT811 in nude mice bearing U-87 MG human GBM orthotopic xenografts reduced tumor SDMA levels by ~50% but had no effect on SDMA in normal brain cells, as assessed by immunohistochemistry (IHC). Moreover, in a U-87 MG subcutaneous xenograft model in nude rats, once daily oral dosing of PRT811 at 20 and 30 mg/kg resulted in 91% and 100% tumor growth inhibition, respectively. PRT811 and related analogues are being studied across a panel of primary human and murine brain tumors ex vivo, and in vivo in primary orthotopic models of CNS lymphoma, a rare and aggressive subset of non-Hodgkins lymphomas. PRT811 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors, gliomas, and myelofibrosis (NCT04089449). Citation Format: Yang Zhang, Hong Lin, Min Wang, Dimitrios Angelis, Michael Hawkins, Dave Rominger, Tom Emm, Juan Luengo, Bruce Ruggeri, Peggy Scherle, Kris Vaddi. Discovery of PRT811, a potent, selective, and orally bioavailable brain penetrant PRMT5 Inhibitor for the treatment of brain tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2919.

Serum symmetric dimethylarginine levels in a half-breed German shepherd dog with renal cystadenocarcinoma and nodular dermatofibrosis

This report describes the diagnosis, clinical signs, and laboratory and histopathological findings of a canine renal cystadenocarcinoma and nodular dermatofibrosis. A 10-year-old entire female half-breed German Shepherd Dog x Rottweiler was brought to a veterinary clinic with hematuria and was non-responsive to the treatment with ciprofloxacin and prednisone. Erythrogram showed a normocytic normochromic anemia. Serum biochemical analysis revealed mildly elevated aspartate aminotransferase activity and high level of symmetric dimethylarginine. Data acquired during physical examination, abdominal sonography and X-ray evaluation allowed for the presumptive diagnosis of renal cystadenocarcinoma and nodular dermatofibrosis, which was confirmed by kidney histopathology. Symmetric dimethylarginine serum level is useful with evaluating and staging of the chronic kidney disease in dogs affected by renal cystadenocarcinoma and nodular dermatofibrosis.

Arginine derivatives in atrial fibrillation progression phenotypes

Arginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography–tandem mass spectrometry in patients with atrial fibrillation (AF) (n = 241) with a focus on heart rhythm at blood withdrawal, AF progression phenotypes, and successful sinus rhythm (SR) restoration (n = 22). AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and persistent AF with/without LVA. While arginine, ADMA, and hArg were within reference limits for healthy controls, SDMA was higher in the AF cohort (0.57 ± 0.12 vs. 0.53 μmol/L (97.5th percentile in reference cohort)). SR restoration in AF patients resulted in normalization of SDMA concentrations (0.465 ± 0.082 vs. 0.570 ± 0.134 μmol/L at baseline, p < 0.001). Patients with AF at the time of blood sampling had significantly lower hArg (1.65 ± 0.51 vs. 1.85 ± 0.60 μmol/L, p = 0.006) and higher ADMA concentrations (0.526 ± 0.08 vs. 0.477 ± 0.08 μmol/L, p < 0.001) compared with AF patients in SR. hArg concentrations were lower in patients with advanced AF progression phenotypes (persistent AF with LVA (p = 0.046)) independent of heart rhythm at blood sampling. Summarizing, arginine metabolism imbalance is associated with AF in general and AF progression and may contribute to associated risk.Key messages• Heart rhythm at blood withdrawal affects ADMA and hArg level in AF patients.• SDMA is higher in AF patients.• SDMA levels normalize after sinus rhythm restoration.• hArg levels decrease in advanced AF progression phenotypes.

Doença renal crônica em cães e gatos – estudo retrospectivo e revisão de literatura

Chronic kidney disease (CKD) is defined as the structural and/or functional impairment of one or both kidneys of 3 or more months duration, and resulting in irreversible loss of renal functions. The International Renal Interest Society (IRIS) classifies CKD into 4 stages according to levels of serum creatinine and symmetric dimethylarginine (SDMA), Urinary protein/creatinine ratio and systemic arterial pressure are subcriteria used in stating the disease. We reviewed the records of 50 dogs and 67 cats diagnosed with CKD. The staging criteria was recorded in 39.5% of the dogs (n = 32), and 60.5% of the cats (n = 49). Stage 1 CKD was diagnosed in 10 dogs (12.4%), while stage 2, 3, and 4 were diagnosed in respectively 4 (4.9%), 7 (8.7%), and 11 (13.6%) of the dogs. In cats, Stage 1 CKD was diagnosed in 8 (9.8%), and stages 2, 3, and 4 were diagnosed in respectively 18 (22.2%), 13 (16%), and 10 (12,4%) of the cats.

Increased Serum Levels of Asymmetric Dimethylarginine and Symmetric Dimethylarginine and Decreased Levels of Arginine in Sudanese Patients with Essential Hypertension

Introduction: Essential hypertension (EH) is a disease caused by various environmental and genetic factors. Nitric oxide (NO) is important for the functional integrity of the endothelium. It is produced in endothelial cells by endothelial NO synthase (eNOS) that mediates the conversion of the amino acid arginine into NO and citrulline. Asymmetric dimethylarginine (ADMA) acts as an inhibitor of eNOS. In contrast, symmetric dimethylarginine (SDMA) has no direct effect on eNOS but plays an important role competing with arginine for transport across the amino acid transporter. ADMA and SDMA have been found to play a central role in the development of cardiovascular diseases. Serum ADMA levels may serve as a future diagnostic marker and a target of therapy in hypertensive patients in the Sudanese population. This study aimed to investigate the relation between serum arginine, ADMA, and SDMA levels with EH in the Sudanese population. Methods: Patients (n = 260) with established hypertension and controls (n = 144) with normal blood pressure were included in this case-control study. Serum blood samples were analyzed for arginine, ADMA, and SDMA, using high-performance liquid chromatography-tandem mass spectrometry. Other laboratory data were measured using routine methods. Mann-Whitney’s U test and χ² tests were used for continuous and categorical data, respectively. A multivariate logistic regression analysis was conducted to investigate the independent effect of multiple variables on the development of hypertension. Results: Serum arginine levels were significantly lower in the patient group than in the control group (p < 0.001). ADMA and SDMA levels were significantly higher in the patient group than the control group (p < 0.001, p = 0.001, respectively). Multivariate logistic regression analysis showed that only older age, being a male, and arginine levels are independent factors controlling the development of hypertension (p < 0.001, p < 0.001, and p = 0.046, respectively). ADMA and SDMA levels were not independent factors for the development of hypertension. Conclusions: This study demonstrated increased serum levels of ADMA and SDMA and decreased arginine levels in Sudanese patients with EH. Lowering serum ADMA levels or increasing the arginine levels might be a novel therapeutic target in these individuals.

Nitric oxide, asymmetric dimethylarginine, symmetric dimethylarginine and L-arginine levels in psychotic exacerbation of schizophrenia and bipolar disorder manic episode.

Objectives:To examine the changes in nitric oxide (NO), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-arginine levels in schizophrenia during acute psychotic exacerbation and in bipolar disorder during mania and to compare those changes to healthy controls.Methods:Thirty schizophrenia patients with acute psychotic exacerbation and 30 bipolar disorder patients with mania, who attended the Psychiatry Department, Erenköy Hospital for Mental and Nervous Diseases, Istanbul, Turkey, in 2010. Thirty healthy controls were included. The diagnosis was made using the Structured Clinical Interview for Axis I Disorders (SCID-I) interviews. Patients’ demographic data were recorded, and NO, SDMA, L-arginine, and ADMA levels were studied.Results:Nitric oxide levels in schizophrenia patients were significantly lower than the control group. Nitric oxide levels in the bipolar group were lower than the control group but the difference was not statistically significant. The levels of SDMA, ADMA, and L-arginine were found to be significantly higher in schizophrenia and bipolar disorder patients than the control group. The disease duration was slightly negatively correlated with NO levels in bipolar patients. In schizophrenia patients, the disease severity was slightly positively correlated with NO levels.Conclusion:Significant changes in NO, SDMA, ADMA, and L-arginine levels in schizophrenia and bipolar disorder patients suggest that NO and inhibitors of NO might be implicated in the neurobiology of schizophrenia and bipolar disorder.

Soluble Fiber and Omega-3 Fatty Acids Reduce Levels of Advanced Glycation End Products and Uremic Toxins in Senior Dogs by Modulating the Gut Microbiome

Aging is associated with changes in the gut microbiome composition and levels of circulating metabolites. This study evaluates the effect of increased soluble fiber and omega-3 fatty acids on the gut microbial composition and levels of circulating and fecal metabolites in senior dogs, older than 7 years. Thirty six dogs between 8 and 13 years of age were maintained on a control food (control 1) containing 0.5% soluble fiber and 0.4 % omega-3 fatty acids, dry matter basis (DM). After 30 days, dogs were divided into two groups of 18 dogs. One of the groups received a test food containing increased soluble fiber (2.7%) and omega 3 fatty acids (0.92%) for 30 days while the other group received a control food (Control 2), containing 1.8% soluble fiber and 0.43% omega-3 fatty acids. After a washout period on the control 1 food for 30 days, a cross-over was performed to feed the test or the control 2 food for 30 days. Samples from feces and blood were collected after each 30 days period to analyze changes in gut microbial composition and metabolites. The consumption of the test food led to increased proportions of the bacterial genera Phascolarcobacteria, Faecalibacterium and Ruminococcus, and families Christensenellaceae and Ruminococcaceae. Dogs had lower abundance of Megamonas, Salmonella, Fusobacterium and Enterobacteriaceae after eating the test food. Pets had higher levels of glycerol and fatty acids and lower levels of pyrraline and mucin amino acids in feces. The test food reduced circulating levels of pyrraline, symmetric dimethylarginine and phenolic uremic toxins, including the microbial, 4-ethylphenyl sulfate, which as linked to brain damage. Christensenellaceae abundance was strongly associated with the observed health benefits. The study shows omega-3 fatty acids and soluble fiber enhance health in senior dogs by modulating the gut microbiome and metabolites associated with in aging.

Endothelial dysfunction and glycocalyx shedding in heart failure: insights from patients receiving cardiac resynchronisation therapy.

To determine (a) whether chronic heart failure with reduced ejection fraction (HFrEF) is associated with increased glycocalyx shedding; (b) whether glycocalyx shedding in HFrEF with left ventricular dyssynchrony is related to inflammation, endothelial dysfunction and/or redox stress and is ameliorated by cardiac resynchronisation therapy. Glycocalyx shedding has been reported to be increased in heart failure and is a marker of increased mortality. Its role in dyssynchronous systolic heart failure and the effects of cardiac resynchronisation therapy (CRT) are largely unknown. Twenty-six patients with dyssynchronous HFrEF were evaluated before and 6months after CRT insertion. Echocardiographic septal to posterior wall delay (SPWD) assessed intra-ventricular mechanical dyssynchrony, and quality of life, integrity of nitric oxide (NO) signalling, inflammatory and redox-related biomarkers were measured. Glycocalyx shedding was quantitated via plasma levels of the glycocalyx component, syndecan-1. Syndecan-1 levels pre-CRT were inversely correlated with LVEF (r = - 0.45, p = 0.02) and directly with SPWD (r = 0.44, p = 0.02), QOL (r = 0.39, p = 0.04), plasma NT-proBNP (r = 0.43, p = 0.02), and the inflammatory marker, symmetric dimethylarginine (SDMA) (r = 0.54, p = 0.003). On multivariate analysis, syndecan-1 levels were predicted by SPWD and SDMA (β = 0.42, p = 0.009 and β = 0.54, p = 0.001, respectively). No significant correlation was found between syndecan-1 levels and other markers of endothelial dysfunction/inflammatory activation. Following CRT there was no significant change in syndecan-1 levels. In patients with dyssynchronous HFrEF, markers of glycocalyx shedding are associated withthe magnitude of mechanical dyssynchrony and elevation of SDMA levels and inversely with LVEF. However, CRT does not reverse this process.

Asymmetric (ADMA) and Symmetric (SDMA) Dimethylarginines in Chronic Kidney Disease: A Clinical Approach

Asymmetric dimethylarginine (ADMA) and its enantiomer, Symmetric dimethylarginine (SDMA), are naturally occurring amino acids that were first isolated and characterized in human urine in 1970. ADMA is the most potent endogenous inhibitor of nitric oxide synthase (NOS), with higher levels in patients with end-stage renal disease (ESRD). ADMA has shown to be a significant predictor of cardiovascular outcome and mortality among dialysis patients. On the other hand, although initially SDMA was thought to be an innocuous molecule, we now know that it is an outstanding marker of renal function both in human and in animal models, with ESRD patients on dialysis showing the highest SDMA levels. Today, we know that ADMA and SDMA are not only uremic toxins but also independent risk markers for mortality and cardiovascular disease (CVD). In this review, we summarize the role of both ADMA and SDMA in chronic kidney disease along with other cardiovascular risk factors.

Assessment of potential cardiovascular risk in trichloroethylene exposure by serum methylated arginine levels

ABSTRACT Trichloroethylene (TCE) is a widely used solvent in industrial applications and has toxic effects on various systems. Methylated arginine amino acids (eg asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA)) cause the development of cardiovascular disease by inhibiting NO synthesis, which is considered to be heart-protector. The aim of this study is to determine the risk of cardiovascular diseases in TCE exposure by methylated arginine biomarkers. About 98 controls and 100 TCE-exposed male subjects were included in the study. Trichloroacetic acid (urinary metabolite of TCE), arginine, homoarginine, citrulline ADMA, SDMA, and N-monomethyl L-arginine (L-NMMA) levels were found significantly higher than control group (p < 0.001). The strongest correlation was found between ADMA and Trichloroacetic acid (TCA) level (r = 0.453, p < 0.01). Long-term TCE exposure, may be an important risk factor for cardiovascular diseases by increasing methylated arginine levels.

Total methylated arginine load as a risk parameter in subjects with masked hypertension

ABSTRACTAsymmetric dimethylarginine, symmetric dimethylarginine, and L-monomethylarginine are originated from the subsequent proteolytic catalysis of methylated arginine residues on different proteins and inhibit the endogenous nitric oxide generation. The changes in total methylarginine load (Asymmetric dimethylarginine plus symmetric dimethylarginine plus L-monomethylarginine) may contribute to hypertension. The aim of this study was to determine serum methylarginine concentrations in patients with masked hypertension and determine the association between these biomarkers and blood pressure measurements. Control group, masked hypertension and hypertension groups consisted of 40 subjects (11 males, 28 females, mean age 48.6 ± 13.1), 28 subjects (14 males, 14 females, mean age 50.9 ± 11.0) and 36 subjects (15 males, 21 females, mean age 54.4 ± 12.3 years), respectively (P= 0.149). Serum total methylarginine load was significantly higher in hypertension group (0.63 ± 0.23) compared to masked hypertension (0.49 ± 0.16) and control groups (0.38 ± 0.13) (P= 0.008 and P< 0.001). While there was no statistically significant difference between healthy control groups [0.147 (0.03–0.29)] and masked hypertension patients [0.144 (0.05–0.42)] for serum symmetric dimethylarginine levels (P= 0.970), it was markedly elevated in hypertension group [0.25 (0.07–0.54)] compared to masked hypertension group [0.14 (0.05–0.42)] (P= 0.001). Serum total methylarginine load was positively correlated with night-time SBP (r = 0.214, P= 0.029). Serum methylarginine levels might be a useful marker for determining the courses of clinical hypertension.

Increased Aqueous Humor Symmetric Dimethylarginine Level in Patients with Primary Open Angle Glaucoma

ABSTRACTPurpose: To evaluate the asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and L-arginine (L-Arg) levels both in plasma and aqueous humor of primary open angle glaucoma (POAG) patients and matched controls.Patients and Methods: 25 primary open angle glaucoma patients and 42 control cases with senile cataract were included in the study. Plasma and aqueous humor ADMA, SDMA and L-Arg levels of the participants were measured by using liquid chromatography-tandem mass spectrometry.Results: A significant increase in aqueous humor SDMA level was detected in POAG patients compared with controls (p = 0.0115). No significant difference was detected in plasma and aqueous humor ADMA, L-Arg levels.Conclusion: The aqueous humor levels of SDMA are found to be associated with POAG. The result of this current study supports the role of nitric oxide pathway in glaucoma.

Arginine, symmetric and asymmetric dimethylarginine levels in the molsidomine treatment of experimental ischemia-reperfusion retinopathy

Arginine, symmetric and asymmetric dimethylarginine levels in the molsidomine treatment of experimental ischemia-reperfusion retinopathy

Serum Levels of Asymmetric and Symmetric Dimethylarginine in Women with Vitamin D Deficiency and History of Pregnancy Loss - A Pilot Study.

SummaryBackgroundVitamin D deficiency has been reported to be associated with pregnancy loss. Asymmetric dimethyl-L-arginine (ADMA) and symmetric dimethyl-L-arginine (SDMA) are arginine analogues that have direct and indirect effects on nitric oxide (NO) synthesis and endothelial dysfunction. This study aimed to evaluate ADMA and SDMA levels among women with history of pregnancy loss compared to women without history of pregnancy loss and all participants were suffering from vitamin D deficiency.MethodsTo investigate the relationship between vitamin D deficiency and ADMA and SDMA, both groups of women were experiencing vitamin D deficiency. All women enrolled in this study had a vitamin D level below 75 nmol/L and were not pregnant. ADMA and SDMA levels were investigated in 28 women without a history of pregnancy loss and 19 women with a history of pregnancy loss.ResultsNo statistically significant differences were found in ADMA and SDMA levels among the two groups. The correlation analysis showed that vitamin D deficiency was not significantly inversely correlated with ADMA and SDMA in women without a history of pregnancy loss, but was significantly correlated with SDMA in women with a history of pregnancy loss.ConclusionsVitamin D deficiency, in women with or without a history of failed clinical pregnancies, has no effect on the circulating levels of ADMA and SDMA. Further studies are needed to investigate any possible link between these parameters.

Dairy milk, regardless of fat content, protects against postprandial hyperglycemia-mediated impairments in vascular endothelial function in adults with prediabetes by limiting oxidative stress responses that reduce nitric oxide bioavailability

Postprandial hyperglycemia (PPH) transiently impairs vascular endothelial function (VEF) in an oxidative-stress-dependent manner by decreasing nitric oxide (NO•) bioavailability. Dairy milk, regardless of fat content, attenuates PPH, but whether this improves VEF by limiting oxidative stress responses that otherwise decrease NO• bioavailability is not known. We hypothesized that nonfat and full-fat dairy milk would similarly improve VEF by attenuating PPH-induced oxidative stress that otherwise decreases NO• biosynthesis and bioavailability. A randomized, crossover trial was conducted in adults with prediabetes (n=22) who ingested glucose (75 g) dissolved in 473 ml of water (GLU), or glucose with an equal volume of nonfat dairy milk (NFM) or full-fat dairy milk (FFM). Prior to and at 30-min intervals for 180 min postprandially, we assessed brachial artery flow-mediated dilation (FMD) and measured circulating biomarkers of glycemic control, oxidative stress and NO• homeostasis. AUC0–180 min for FMD and NO• metabolites was lowest in GLU but relatively greater in NFM and FFM. Compared with GLU, AUCs for glucose, malondialdehyde, F2-isoprostanes and endothelin-1 were similarly lower in dairy trials. Milk-mediated vasoprotection was accompanied by greater levels of plasma arginine and lower levels of asymmetric dimethylarginine and symmetric dimethylarginine. Postprandial insulin, lipids and tetrahydrobiopterin redox status did not differ among trials. Thus, dairy milk, regardless of its fat content, attenuates PPH-mediated impairments in VEF by limiting oxidative stress. This improves NO• bioavailability to the vascular endothelium by increasing arginine availability and limiting competitive inhibition on NO• biosynthesis by asymmetric dimethylarginine.

Renal function and blood pressure in 11 year old children born extremely preterm or small for gestational age.

BackgroundPreterm birth and low birth weight are associated with reduced nephron numbers and increased risk of hypertension and kidney disease in later life.AimsWe tested the hypothesis that extremely preterm birth and intrauterine growth restriction is associated with decreased renal function in mid childhood.MethodsAt 11 years of age the following measures were obtained in a regional cohort of children born extremely premature (EP, i.e. < 28 weeks gestational age—GA) or with extremely low birth weight (ELBW, i.e. BW < 1000 grams) and in matched controls born at term with appropriate BW (AGA): Height, weight, abdominal circumference, triceps and subscapular skin fold thicknesses, blood pressure, plasma levels of creatinine, cystatin C and symmetric dimethyl arginine (SDMA). Small for gestational age (SGA) was defined as a BW < 10th percentile for GA. Glomerular filtration rate (GFR) was estimated according to the equations by Schwartz, Zappitelli and Gao.ResultsFifty-seven of 61 eligible EP/ELBW children, 20 (35%) born SGA, and 54 controls, were assessed. Estimated GFR decreased while plasma SDMA increased from the children born AGA at term through those born preterm AGA to preterm SGA. Systolic BP was correlated to fat mass indices (p<0.03), but not to renal function (p>0.2) and did not differ between the groups.ConclusionsChildren born EP/ELBW, particularly those born SGA, had impaired renal function at age 11 years as judged from estimated GFRs and plasma levels of SDMA. Since reduced renal function is associated with an increased risk of later disease, these children should be followed in order to minimize additional risk factors.

The impact of sitagliptin, inhibitor of dipeptidyl peptidase-4 (DPP-4), on the ADMA-DDAH-NO pathway in ischemic and reperfused rat livers.

A correlation between the level of asymmetric dimethylarginine (ADMA) - the inhibitor of the nitric oxide (NO) synthesis - and the liver function and survival after a liver transplantation has been reported. The aim of this study was to evaluate the effect of sitagliptin -the inhibitor of dipeptidyl peptidase-4 (DPP-4) - on the NO-ADMA-dimethylarginine dimethylaminohydrolase (DDAH) pathway in rat livers subjected to ischemia/reperfusion (IR). The rats received sitagliptin (5 mg/kg, per os - p.o.) (groups: S - livers not subjected to IR procedure, and SIR - livers subjected to IR procedure) or a saline solution (groups: C - livers not subjected to IR procedure, and CIR - livers subjected to IR procedure) for 14 days; following this, livers in the SIR and CIR groups were subjected to ischemia (60 min) and reperfusion (24 h). Aminotransferases were measured before the surgery; additionally, the arginine (ARG), ADMA and symmetric dimethylarginine (SDMA) levels were estimated just before ischemia and during reperfusion (at 0.5, 4 and 24 h). After IR, citrulline, the DDAH activity, mRNA for type 1 DDAH (DDAH1), and arginine methyltransferase type 1 (PRMT1) were determined. The increase in the initial level of ARG/ADMA0 (A/A) ratio in group S compared to group C verged on statistical significance. At 0.5 and 4 h of reperfusion, the highest concentration of ADMA was found in group CIR. At those time points, the ARG level and the A/A ratio were decreased in groups CIR and SIR as compared to groups C and S, respectively. The alanine transaminase (ALT) activity was lower in the sitagliptin-treated group than in the non-treated one. The DDAH and citrulline levels were reduced in group CIR as compared to group C, but were greater in group SIR as compared to group S. The PRMT1 mRNA expression was higher in groups CIR and SIR, compared to groups C and S, respectively. The increased A/A ratio suggests a protective effect of sitagliptin on livers not subjected to IR. Changes in the DDAH activity and the PRMT1 mRNA expression also imply the protective activity of sitagliptin during IR.