Quantification of l-arginine, asymmetric dimethylarginine and symmetric dimethylarginine in human plasma: A step improvement in precision by stable isotope dilution mass spectrometry

Martens‐Lobenhoffer, Jens; Bode‐Böger, Stefanie M.

doi:10.1016/j.jchromb.2012.07.021

Cited by 55 publications

(35 citation statements)

References 20 publications

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“…Separation was started with setting up MRM transitions that were highly specific for each compound. Using transitions 203.15 > 46.11 (collision energy 14) for ADMA and 203.15 > 172.17 (collision energy 12) for SDMA, we saw no crosstalk between signals of both compounds as it was previously reported in literature (Martens-Lobenhoffer et al 2012; Zotti et al 2008). …”

Section: Methodssupporting

confidence: 82%

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

2016

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Alterations in brain nitric oxide (NO)/cGMP synthesis contribute to the pathogenesis of hepatic encephalopathy (HE). An increased asymmetrically dimethylated derivative of l-arginine (ADMA), an endogenous inhibitor of NO synthases, was observed in plasma of HE patients and animal models. It is not clear whether changes in brain ADMA reflect its increased local synthesis therefore affecting NO/cGMP pathway, or are a consequence of its increased peripheral blood content. We measured extracellular concentration of ADMA and symmetrically dimethylated isoform (SDMA) in the prefrontal cortex of control and thioacetamide (TAA)-induced HE rats. A contribution of locally synthesized dimethylarginines (DMAs) in their extracellular level in the brain was studied after direct infusion of the inhibitor of DMAs synthesizing enzymes (PRMTs), S-adenosylhomocysteine (AdoHcy, 2 mM), or the methyl donor, S-adenosylmethionine (AdoMet, 2 mM), via a microdialysis probe. Next, we analyzed whether locally synthesized ADMA attains physiological significance by determination of extracellular cGMP. The expression of PRMT-1 was also examined. Concentration of ADMA and SDMA, detected by positive mode electrospray LC–DMS–MS/MS, was greatly enhanced in TAA rats and was decreased (by 30 %) after AdoHcy and AdoMet infusion. TAA-induced increase (by 40 %) in cGMP was unaffected after AdoHcy administration. The expression of PRMT-1 in TAA rat brain was unaltered. The results suggest that (i) the TAA-induced increase in extracellular DMAs may result from their effective synthesis in the brain, and (ii) the excess of extracellular ADMA does not translate into changes in the extracellular cGMP concentration and implicate a minor role in brain NO/cGMP pathway control.

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Section: Methodssupporting

confidence: 82%

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

2016

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“…Unlike SDMA, ADMA has been reported to be an endogenous inhibitor of nitric oxide synthase, which synthesizes nitric oxide from L-arginine (19). The ratio of arginine:ADMA:SDMA is used to monitor pathophysiological states in a variety of diseases, particularly cardiovascular diseases (20,21). The level of arginine, the precursor of methylated arginine derivatives, including ADMA, was not significantly different between HPAC-ER and HPAC in the present study.…”

Section: Resultsmentioning

confidence: 99%

Comparative metabolomic analysis of HPAC cells following the acquisition of erlotinib resistance

et al. 2017

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Pancreatic cancer is one of the most lethal types of cancer, due to difficulty in early detection and the limited efficacy of available treatments. Erlotinib is used to inhibit the epidermal growth factor receptor for the treatment of pancreatic cancer; however, erlotinib resistance is a major issue and the mechanisms underlying the development of erlotinib resistance remain unclear. To better understand the alterations in tumor metabolism by acquired resistance to erlotinib, an erlotinib-resistant pancreatic cancer cell line (HPAC-ER) was established, followed by a comparison of the metabolic characteristics between these cells and their erlotinib-sensitive parental cells (HPAC). This comparison was accomplished through mass spectrometry-based targeted metabolic profiling. Five metabolite groups (acylcarnitines, amino acids and biogenic amines, glycerophospholipids, sphingolipids and monosaccharides) were semi-quantified and compared statistically. These results revealed significant differences between the two groups of cells. A significant increase in the level of short-chain acylcarnitines and selected lysophosphatidylcholines, and a significant decrease in the level of acyl-alkyl-phosphatidylcholines and one sphingolipid, were observed in the HPAC-ER cells compared with the HPAC cells. The metabolic changes observed in the present study support the theory that there are increased metabolic demands in erlotinib-resistant cancer, reflecting the changes in acetyl-CoA-associated and choline phospholipid metabolism. These findings will aid in elucidating the changes that occur in pancreatic cancer metabolism through the acquired resistance to erlotinib, and in the identification of biomarkers for the early detection of pancreatic cancer.

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“…Analytical issues rather than differences in studied populations are likely to have contributed to the discrepancies mentioned above. The methods of analysis of ADMA have been reviewed and discussed (see Horowitz and Heresztyn 2007;Tsikas 2008;Martens-Lobenhoffer and Bode-Böger 2012). Some studies which reported circulating ADMA concentrations comparable to those measured by us using GC-MS/MS led to the conclusion that circulating ADMA levels are not considerably different between young diabetics and non-diabetics (Jehlicka et al 2009;Glowinska-Olszewska et al 2010) (Table 7).…”

Section: Amino Acids Of the L-arg/no Pathwaymentioning

confidence: 99%

The l-arginine/NO pathway, homoarginine, and nitrite-dependent renal carbonic anhydrase activity in young people with type 1 diabetes mellitus

et al. 2015

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High circulating levels of asymmetric dimethylarginine (ADMA) and low circulating levels of homoarginine (hArg) are known cardiovascular risk factors in adults. While in adults with type 1 diabetes mellitus (T1DM) circulating ADMA is significantly elevated, in children and adolescents the reported ADMA data are contradictory. In 102 children with T1DM and 95 healthy controls (HC) serving as controls, we investigated the L-arginine (Arg)/nitric oxide (NO) pathway. Children with T1DM were divided into two groups, i.e., in children with newly diagnosed diabetes mellitus [T1DM-ND; n = 10; age, 8.8 (4.4-11.2) years; HbA1c, 13 (8.9-13.9) %] and in those with long-term treatment [T1DM-T; n = 92; age, 12.5 (10.5-15.4) years; HbA1c, 8.0 (7.2-8.6) %]. The age of the HC was 11.3 (8-13.3) years. Amino acids and NO metabolites of the Arg/NO pathway, creatinine and the oxidative stress biomarker malondialdehyde (MDA) were measured by GC-MS or GC-MS/MS. Plasma hArg, ADMA and the hArg/ADMA molar ratio did not differ between the T1DM and HC groups. There was a significant difference between T1DM-T and HC with regard to plasma nitrite [0.53 (0.48-0.61) vs 2.05 (0.86-2.36) µM, P < 0.0001] as well as to urinary nitrite [0.09 (0.06-0.17) vs 0.22 (0.13-0.37) μmol/mmol creatinine, P < 0.0001]. Plasma, but not urinary nitrite, differed between T1DM-ND and HC [0.55 (0.50-0.66) vs 2.05 (0.86-2.36) µM, P < 0.0001]. Plasma MDA did not differ between the groups. The urinary nitrate-to-nitrite molar ratio (UNOXR), a measure of nitrite-dependent renal carbonic anhydrase (CA) activity, was higher in T1DM-T [1173 (738-1481), P < 0.0001] and T1DM-ND [1341 (1117-1615), P = 0.0007] compared to HC [540 (324-962)], but did not differ between T1DM-T and T1DM-ND (P = 0.272). The lower nitrite excretion in the children with T1DM may indicate enhanced renal CA-dependent nitrite reabsorption compared with healthy children. Yet, lower plasma nitrite concentration in the T1DM patients may have also contributed to the higher UNOXR. Patients' age correlated positively with plasma hArg and hArg/ADMA and urinary DMA/ADMA. Plasma ADMA and urinary ADMA, DMA, nitrite and nitrate correlated negatively with age of the T1DM-T children. Significant correlations were found between plasma hArg and plasma Arg (r = 0.468, P < 0.0001), and urinary DMA (r = -0.426, P = 0.0001), ADMA (r = -0.266, P = 0.021) and nitrate (r = -0.234, P = 0.043). Plasma hArg correlated positively with age at diagnosis (r = +0.337, P = 0.002). ADMA, but not hArg, correlated with HbA1c in T1DM-T (r = -0.418, P < 0.0001) and T1DM-ND (r = +0.879, P = 0.0016). The greatest differences between T1DM-T and T1DM-ND were observed for urinary ADMA, DMA/ADMA ratio, nitrite and nitrate. The Arg/NO pathway is altered in T1DM in childhood and adolescence, yet the role and the importance of hArg and ADMA in T1DM remain to be elucidated. In young T1DM patients, oxidative stress (lipid peroxidation) is not elevated.

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Quantification of l-arginine, asymmetric dimethylarginine and symmetric dimethylarginine in human plasma: A step improvement in precision by stable isotope dilution mass spectrometry

Cited by 55 publications

References 20 publications

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

Comparative metabolomic analysis of HPAC cells following the acquisition of erlotinib resistance

The l-arginine/NO pathway, homoarginine, and nitrite-dependent renal carbonic anhydrase activity in young people with type 1 diabetes mellitus

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