Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.
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PMID:Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. 134 93

1. We examined regeneration of endothelial cells (ECs), neointima formation, decreased endothelium-dependent relaxation (EDR) and changes in the contents of L-arginine, NG-monomethyl-L-arginine (L-NMMA), asymmetrical NG, NG-dimethylarginine (ADMA) and symmetrical NG,NG-dimethylarginine (SDMA) in the regenerated ECs, 6 weeks after balloon denudation of the rabbit carotid artery. 2. Regeneration of ECs was completed in 6 weeks and a significant neointima formation accompanied by the decreased EDR was observed. 3. L-NMMA and ADMA contents in the regenerated ECs (23.5 +/- 4.3 and 21.2 +/- 2.0 pmol mg-1 DNA, respectively) were significantly (P < 0.05 and P < 0.01) higher than those in the control ECs (8.8 +/- 3.0 and 7.4 +/- 1.9 pmol mg-1 DNA, respectively), whereas L-arginine was significantly (P < 0.005) decreased in the regenerated ECs (31,470 +/- 1,050 pmol mg-1 DNA) as compared to that in the control ECs (47,870 +/- 1,890 pmol mg-1 DNA). SDMA content was below the assay limits. 4. L-NMMA and ADMA, but not SDMA, inhibited the EDR induced by acetylcholine in a concentration-dependent manner. The inhibition with L-NMMA and ADMA was prevented by an addition of L-arginine, but not by D-arginine. 5. These results suggest that the accumulation of endogenous inhibitors for nitric oxide synthesis and decreased L-arginine content are associated with decreased NO production/release from regenerated ECs and neointima formation.
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PMID:Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells. 758 95

Nitric oxide (NO) is a cell-to-cell mediator involved in the regulation of vascular tone and in the mechanisms of host defence. Since uraemic syndrome is characterized by abnormalities in blood pressure and flow and by impairment of white cell function, we studied the regulation of nitric oxide synthase (NOS) activity by uraemic plasma. We used three different cellular types having different levels of NOS activity: tEnd.1 murine endothelial cell line transformed by mT oncogene of polyomavirus had a high NOS activity and expressed endothelial-NOS (eNOS) and inducible-NOS (iNOS) isoforms; human endothelial cells from cord umbilical vein (HUVEC) had low enzymatic activity and expressed only eNOS; finally, J774 murine macrophage line was characterised by iNOS induced after treatment with cytokines. We demonstrated that most (79%) of end-stage uraemic plasma studied inhibited NOS activity in tEnd.1 and in cytokine induced -J774, whereas they were ineffective on HUVEC. Twenty percent of plasma samples (14 of 67) activated NOS activity in tEnd.1 and in J774 cells, but not in HUVEC, suggesting the presence of molecule(s) which influence iNOS. The effect of plasma was not dependent on the type of haemodialysis treatment. A great number of plasmas from patients with moderate renal failure also inhibited NOS activity in tEnd.1, suggesting that the accumulation of molecules affecting NOS was caused by the renal failure rather than the haemodialytic treatment. However, the haemodialysis modified the effect of plasmas on NOS activity. Plasma taken after haemodialysis session showed a reduced inhibitory activity in tEnd.1 and in some cases it enhanced NOS activity. Simultaneously, molecules reducing NOS activity accumulated in the ultrafiltrate. The plasma concentration of NG-NG dimethyl-L-arginine (asymmetrical dimethylarginine, ADMA), an inhibitor of NOS, increased in end-stage uraemic patients and was reduced by haemodialysis. However, the concentrations reached in uraemic plasmas were lower than the ADMA IC50 on tEnd.1 NOS, indicating that this compound contributes with other molecules to the inhibitory effect of uraemic plasma. Haemodialysis reduced also the enhanced effect exerted by some plasmas on NOS in J774. Therefore, the effect of end-stage uraemic plasma on NOS activity derive from the balance between inhibitors and activators.
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PMID:Regulation of nitric oxide synthesis in uraemia. 853 31

Cellular origins of methylarginines are not precisely known but the presence of free methyl and dimethylarginines in the brain were reported. We have investigated the circulating concentrations of asymmetrical dimethylarginine NG,NG-dimethylarginine (ADMA), NG,NG-dimethylarginine (SDMA), nitrate and nitrite levels in drug naive first episode schizophrenic patients and matched control subjects. Three of those patients were treated with neurolepties for 3 months. Plasma ADMA levels increased significantly but nitrate levels were significantly low compared to control subjects. Drug treatment apparently lowered ADMA levels and increased nitrate levels in plasma. Methylation of arginine to methylarginines may have an important role in regulating signal transduction through the nitric oxide system in the brain, and suggest novel therapeutic targets.
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PMID:Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production. 889 50

The inducible human cationic amino acid transporter hCAT-2B was expressed in Xenopus laevis oocytes, and this system was used to test the effect of several NO synthase (NOS) inhibitors and/or L-arginine analogues on L-arginine transport by this y+ carrier. L-NG-Methyl-L-arginine (L-NMA), asymmetrical L-NG, NG-dimethyl-L-arginine (L-ADMA), L-N5-(1-iminoethyl)-ornithine (L-NIO), L-NG-nitro-L-arginine (L-NNA), and L-NG-nitro-L-arginine methyl ester (L-NAME) all inhibited the inducible NOS II extracted from RAW 264.7 macrophages induced with bacterial lipopolysaccharide. L-NMA, L-ADMA, and L-NIO also competed with L-arginine for transport by hCAT-2B, whereas L-NNA and L-NAME did not. The two L-arginine analogues, symmetrical NG, NG-dimethyl-L-arginine (L-SDMA) and alpha-amino-delta-isothioureidovaleric acid (AITV), as well as L-lysine, did not block enzymatic activity of NOS II, but did compete for L-arginine transport mediated by hCAT-2B. L-Lysine and L-SDMA were transported efficiently by hCAT-2B and exchanged against intracellular L-arginine, resulting in an L-arginine depletion of the cells. AITV was a much poorer substrate of hCAT-2B and had only little effect on intracellular L-arginine concentrations. These data indicate that substrate recognition differs markedly between the inducible L-arginine transporter hCAT-2B and the inducible NOS II, with different L-arginine analogues having affinity to only one or both of these proteins.
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PMID:Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. 970 Oct 46

Acute inflammation impairs vascular function. Based on the association between endothelial dysfunction and plasma concentrations of L-arginine and the endogenous nitric oxide synthase inhibitor ADMA (asymmetrical dimethylarginine), we hypothesized that the ratio between L-arginine and ADMA could be affected by experimental inflammation. Plasma concentrations of L-arginine, ADMA and SDMA (symmetrical dimethylarginine) were studied at baseline and 3.5 h after intravenous administration of Escherichia coli endotoxin [LPS (lipopolysaccharide), 20 units/kg of body mass; n =8] or placebo ( n =9) in healthy males. L-Arginine and dimethylarginines were quantified after solid-phase extraction by reversed-phase HPLC. Body temperature, heart rate and leucocyte count increased after LPS administration ( P <0.01 for all). LPS administration decreased plasma concentrations of L-arginine from 66 micromol/l [95% CI (confidence interval): 56, 88] at baseline to 48 micromol/l (CI: 40, 60) after 3.5 h ( P <0.02), but did not affect ADMA and SDMA concentrations. Consequently, the L-arginine/ADMA ratio declined significantly from a median of 159 (CI: 137, 193) to 135 (CI: 103, 146); a decrease of 25 (CI: -68, -13; P <0.02). L-Arginine, ADMA, SDMA and the L-arginine/ADMA ratio remained constant over time in controls. Acute inflammation reduces the L-arginine/ADMA ratio which could contribute to impaired vascular function.
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PMID:Acute Escherichia coli endotoxaemia decreases the plasma l-arginine/asymmetrical dimethylarginine ratio in humans. 1474 Oct 43

This study examined the effects of a new phosphodiesterase type 5 inhibitor, DA-8159, on erectile function associated with hypercholesterolemia. First of all, in order to investigate whether chronic administration of DA-8159 prevents the development of erectile dysfunction associated with hypercholesterolemia, male SD rats were divided into four groups (normal control, hypercholesterolemic control, DA-8159 5 or 20 mg/kg/day). Over a 5-month period, the animals were fed a 2% cholesterol diet and administered DA-8159 orally once a day. After 5 months, the electrostimulation-induced penile erection and the vascular function using acetylcholine-induced vasodilation with endothelium-intact aortic rings were examined. Furthermore, the plasma lipid profiles, endothelin and N(G),N(G)-dimethylarginine (asymmetrical dimethylarginine, ADMA) concentrations were measured. In order to investigate the acute treatment effect of DA-8159 on the erectile function in an established hypercholesterolemic model, additional animals were given a 2% cholesterol diet for 5 months without DA-8159. At the end of 5 months, the rats were divided into three groups (hypercholesterolemic control, DA-8159 0.3 or 1 mg/kg). DA-8159 was administered intravenously 1 min prior to the intracavernous pressure (ICP) measurement. In a chronic treatment study, while the hypercholesterolemic control showed a significantly lower erectile function, vascular reactivity, and increased plasma cholesterol, endothelin and ADMA concentration, the chronic DA-8159 treatment clearly restored the erectile responses by electric stimulation, preserved the potential of thoracic aortic relaxation in a dose-dependent manner, and significantly decreased the plasma endothelin and ADMA concentrations. In an acute treatment study, DA-8159 induced a dose- and frequency-dependent increase in ICP. The ICP/BP ratio and the corresponding AUC values, and the detumescence time were also significantly increased compared to the hypercholesterolemic control. These results suggest that DA-8159 is beneficial for erectile dysfunction in a rat hypercholesterolemic model and provided a rationale for the potential use of DA-8159 for treating erectile dysfunction secondary to hypercholesterolemia.
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PMID:The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction. 1592 Apr 60

Black Africans have a higher incidence of cardiovascular disease than white Europeans. We explored potential mechanisms of this excess risk by assessing endothelium function, inflammatory status (C-reactive protein), oxidative stress (isoprostane-F2alpha), and plasma asymmetrical dimethyl arginine (ADMA; an endogenous competitive inhibitor of NO synthase) in each ethnic group. Thirty healthy black Africans and 28 well-matched white European male subjects were studied (mean age+/-SE: 32.2+/-0.9 and 29.2+/-1.2 years, respectively; P=0.07). High-resolution ultrasound was used to assess vascular function in the brachial artery by measuring flow mediated dilatation ([percentage of change]; endothelium-dependent function) and glyceryltrinitrate dilatation ([percentage of change]; endothelium-independent function). Blood pressure, fasting lipids, glucose, and estimated glomerular filtration rate levels were similar in both groups. There was no difference in C-reactive protein (black Africans: 0.8+/-0.1 mg/L; white Europeans: 0.6+/-0.1 mg/L; P=0.22), isoprostane-F2alpha (black Africans: 42.9+/-1.5 pg/mL; white Europeans: 39.2+/-1.5 pg/mL; P=0.23), and leptin (black Africans: 64.1+/-10.2 ng/mL; white Europeans: 47.8+/-9.8 ng/mL; P=0.37) levels between the 2 ethnic groups. However, compared with white Europeans, plasma ADMA levels were significantly higher in black Africans (0.34+/-0.02 micromol/L and 0.25+/-0.03 micromol/L; P=0.03). There was no difference in the percentage of glyceryltrinitrate dilatation (P=0.7), but the percentage of flow-mediated dilatation was significantly lower in black Africans (black Africans: 5.2+/-0.3; white Europeans: 6.3+/-0.4; P=0.02). In a stepwise multiple regression model, ADMA level was the only independent determinant of flow-mediated dilatation (P=0.02). In turn, race was the only independent determinant of ADMA levels (P=0.03). Our findings indicate that circulating ADMA levels are significantly higher in healthy black African males than in white European males. This may contribute to the lower NO bioavailability and higher incidence of cardiovascular disease seen in black Africans.
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PMID:Asymmetric dimethylarginine and reduced nitric oxide bioavailability in young Black African men. 1726 43

The present study is based on the assumption that changes in an ADMA-DDAH-NOS (ADMA-asymmetrical dimethylarginine; DDAH-dimethyl-arginine dimethylaminohydrolase; NOS-nitric oxide synthase) system could be employed as indirect markers for recombinant human erythropoietin (rHuEPO) administration in doping control. We assessed a predictive value of four proposed new markers for rHuEPO abuse. Preliminary data showed that concentrations of ADMA, symmetrical dimethylarginine (SDMA), citrulline and arginine in human urine were increased after administration of a single intravenous erythropoietin injection (2000 U day(-1), Epocrine, St-Petersburg, Russia). The study of variations of ADMA, SDMA, arginine and citrulline levels before and after rHuEPO administration was performed with two healthy male volunteers. Urine samples were collected before rHuEPO administration and urinary concentrations of ADMA and SDMA were determined at 10.0-40 microg mL(-1) and of arginine and citrulline at 0.5-10 microg mL(-1). A single dose injection of rHuEPO caused an increase in ADMA, SDMA, arginine and citrulline concentrations up to 40-270 microg mL(-1), 40-240 microg mL(-1), 10-60 microg mL(-1) and 12-140 microg mL(-1), respectively. These preliminary results indicated that an indirect approach could be used as a pre-screening of urine samples in order to decrease the number of samples with a low probability of rHuEPO abuse and, thus, save costs and human workload.
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PMID:Possible indirect detection of rHuEPO administration in human urine by high-performance liquid chromatography tandem mass spectrometry. 1870

Metabolic syndrome (MetS) denotes a clustering of risk factors that may affect nitric oxide (NO) bioavailability and predispose to cardiovascular diseases, which are delayed by exercise training. However, no previous study has examined how MetS affects markers of NO formation, and whether exercise training increases NO formation in MetS patients. Here, we tested these two hypotheses. We studied 48 sedentary individuals: 20 healthy controls and 28 MetS patients. Eighteen MetS patients were subjected to a 3-month exercise training (E+group), while the remaining 10 MetS patients remained sedentary (E-group). The plasma concentrations of nitrite, cGMP, and ADMA (asymmetrical dimethylarginine; an endogenous nitric oxide synthase inhibitor), and the whole blood nitrite concentrations were determined at baseline and after exercise training using an ozone-based chemiluminescence assay, and commercial enzyme immunoassays. Thiobarbituric acid reactive species (TBA-RS) were measured in the plasma to assess oxidative stress using a fluorometric method. We found that, compared with healthy subjects, patients with MetS have lower concentrations of markers of NO formation, including whole blood nitrite, plasma nitrite, and plasma cGMP, and increased oxidative stress (all P<0.05). Exercise training increased the concentrations of whole blood nitrite and cGMP, and decreased both oxidative stress and the circulating concentrations of ADMA (both P<0.05). These findings show clinical evidence for lower endogenous NO formation in patients with MetS, and for improvements in NO formation associated with exercise training in MetS patients.
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PMID:Enhanced concentrations of relevant markers of nitric oxide formation after exercise training in patients with metabolic syndrome. 1879 38


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