Urinary excretion of NG-dimethylarginines in multiple sclerosis patients: preliminary observations

doi:10.1016/0022-510X(94)00277-U

Journal of the Neurological Sciences

Volume 129, Issue 2, April 1995, Pages 186-191

https://doi.org/10.1016/0022-510X(94)00277-U Get rights and content

Abstract

The concentrations of N^G,N′^G-dimethylarginine [Me₂(sym)Arg] and N^G,N^G-dimethylarginine [Me₂(asym)Arg] were determined in the urine samples from multiple sclerosis (MS) and control subjects, using a highly sensitive HPLC post-column o-phthaldialdehyde derivatization method. The presence of approximately equal amounts of both dimethylarginine isomers, of Arg concentration nearly half of Me₂Arg, and of the undetectable amount of N^G-monomethylarginine were the characteristic urinary excretion pattern in all human samples studied. The urinary excretion of Me₂(asym)Arg and Me₂(sym)Arg from MS (n = 9) and control (n = 7) were analyzed: the mean values from the samples were approximately 20% (for all MS) and 33% (for chronic-progressive MS) lower than those from the control for both dimethylarginine-derivatives when compared to the respective compounds. Although there were contrasting trends between controls and MS patients in the relationship of urinary N^G-dimethylarginines and myelin basic protein like material (MBPLM), the correlations were not significant. Differences in the ratios of the concentrations of the two dimethyl derivatives, $Me_{2} (sym)Arg Me_{2} (asym)Arg$ , were not significantly different between MS and control groups. These findings warrant further investigation of possible links between urinary excretion of N^G-dimethylarginine and MBPLM in MS. The possible significance of myelin metabolism in relation to urinary N^G-dimethylarginines in MS is discussed.

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Elevated cerebrospinal fluid (CSF) concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), are assumed to be related to delayed vasospasm after subarachnoid haemorrhage (SAH). However, data on CSF concentrations of l-arginine, ADMA and its structural isomer symmetric dimethylarginine (SDMA) are very sparse in humans. We here present a new hydrophilic interaction chromatography–tandem mass spectrometry (HILIC–MS–MS) method for the precise determination of these substances in CSF. The method requires only minimal sample preparation and features isotope labeled internal standards. First data of patients with SAH showed that on the day of admission CSF concentration values of l-arginine and ADMA were not significantly different from controls, but increased markedly during the course of the hospital stay. The decrease of the l-arginine to ADMA ratio points to a progressive impairment of the NO production rate in the brain after SAH which is confirmed by a simultaneous decrease in nitrate and nitrite concentrations in CSF.
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Experimental autoimmune (or allergic) encephalomyelitis (EAE), an animal model useful for the study of human multiple sclerosis, can be induced by immunization with different components of the myelin complex. In this review, the different EAE models are discussed with particular emphasis on their clinical characteristics, inflammatory mediators, as well as contributions and limitations of each variant related to the study of the progression and recuperation course phases of the disease.
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An increasing number of reports in the literature indicate that endogenously produced inhibitors of nitric oxide synthase (NOS), particularly asymmetric dimethylarginine (ADMA) regulate nitric oxide generation in numerous disease states. Two dimethylarginine dimethylaminohydrolase (DDAH) enzymes metabolise ADMA. We and others have postulated that activity of DDAH is a key determinant of ADMA levels in vivo. This review summarises recent advances in the regulation and function of DDAH enzymes and its role in the regulation of nitric oxide generation.
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Citation Excerpt :
Although the stereoisomer NG,N′G-dimethylarginine (SDMA) has not this biological activity like ADMA, it can interrupt the transportation of ARG and other cationic amino acids [9]. For these reasons, the quantification of these intermediates in the nitric oxide pathway in human plasma, urine and tissue is very important in clinical study [10–21]. Many methods for the separation and determination of l-arginine and dimethylarginines in biological samples have been developed.
A simple, sensitive and fast method using reversed-phase high-performance liquid chromatography (HPLC)–mass spectrometry (MS) coupling with an atmospheric pressure chemical ionization (APCI) interface was developed for simultaneous separation and determination of l-arginine (ARG), N^G,N^G-dimethylarginine (ADMA) and N^G,N′^G-dimethylarginine (SDMA) in human urine. This method involved the use of the [M+H]⁺ ions of ARG, ADMA and SDMA at m/z 175, 203 and 203 in the selective ion monitoring (SIM) mode. Satisfactory separation was achieved on a $2.0 mm ×150$ mm Shimadzu VP-ODS column by using the mobile phase consisting of water (95%), acetonitrile (5%) and trifluoroacetic acid (TFA, 0.4%). l-Homoarginine was used as the internal standard for the assay. With an isocratic HPLC, the total LC–APCI–MS analysis time was less than 5 min, making the method the fastest and most specific method reported to date. The limits of quantification (LOQ) were found to be 0.2 μmol l⁻¹ for ARG, ADMA and SDMA. The inter-assay precision and accuracy were in the range of 2.1–6.8 and −4.4–5.4%, respectively. The intra-assay precision and accuracy were in the order of 1.6–4.1 and −1.8–3.2%, respectively. The recoveries were between 98.2 and 103.2%. With the help of the proposed method, the levels of ARG, ADMA and SDMA in human urine were determined.
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The activity and expression of nitric oxide synthase (NOS) isoforms and protein nitrotyrosine (NT) residues were investigated in whole encephalic mass (WEM) homogenates during the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. EAE stages (0–III) were daily defined by clinical evaluation, and in the end of each stage, WEMs were removed for analysis of NOS activity, protein NT residues and mRNA for the different NOS isoforms. In the presence of NADPH, WEMs from EAE-III rats showed lower Ca²⁺-dependent NOS activity than those from control group. These differences disappeared in the presence of exogenous calmodulin, flavin adenine dinucleotide (FAD), tetrahydrobiopterin (BH₄) and NADPH. Of all the cofactors, just the omission of FAD caused comparable decrease of Ca²⁺-dependent NOS activity from both groups. Ca²⁺-independent NOS activity from EAE-III animals was insensitive to the omission of any of the cofactors, while in control animals this activity was significantly inhibited by the omission of either FAD or BH₄. Increased levels of both iNOS mRNA and protein NT expression were observed in animals with EAE, which also showed lower levels of a thermolabile NOS inhibitor in WEM homogenates and sera than controls. In conclusion, during late EAE stages, constitutive Ca²⁺-dependent NOS activity decreases concomitantly with iNOS upregulation, which could be responsible for the high protein NT levels. The differential dependence of iNOS activity on cofactors and the absence of an endogenous thermolabile NOS inhibitor in animals with EAE could reflect additional control mechanisms of NOS activity in this model of multiple sclerosis.
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We investigated the possible role of endogenous methylarginine derivatives, such as N^G-monomethyl-L-arginine (L-NMMA), asymmetrical N^G, N^G-dimethyl-L-arginine (ADMA) and symmetrical N^G, N^′G-dimethyl-L-arginine (SDMA), for regulating nitric oxide synthase in the rabbit lower urinary tract.
Strips of detrusor, trigone and proximal urethra were processed for the determination of endogenous methylarginines and L-arginine by automated high performance liquid chromatography. We also compared nitric oxide synthase activity and nitric oxide mediated functional responses to electrical field stimulation in the 3 regions. Nitric oxide synthase activity was measured by determining the conversion of [³H] L-arginine to [³H] L-citrulline.
L-NMMA, ADMA and SDMA were detectable by high performance liquid chromatography in the detrusor, trigone and proximal urethra. Electrical field stimulation induced nitric oxide mediated prominent relaxation in the trigone and proximal urethra, while no relaxation response was observed in the detrusor. Exogenously applied 1 to 100 μM. L-NMMA and 1 to 100 μM. ADMA but not 100 μM. SDMA dependently inhibited Ca²⁺ dependent nitric oxide synthase activity in all regions, and electrical field stimulation induced relaxation in the trigone and proximal urethra. Inhibition with L-NMMA and ADMA was blocked in the presence of 3 mM. L-arginine but not by 3 mM. D-arginine.
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Research articleUrinary excretion of NG-dimethylarginines in multiple sclerosis patients: preliminary observations

Abstract

Metabolism

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Neurosci. Methods

Clin. Immunol. Allergy

Biochem. Med.

Regulation of myelin basic protein (arginine) methyltransferase by thyroid hormone in myelinogenic cultures of cells disassociated from embryonic mouse brain

J. Neurochem.

Specific enzymatic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin

Science

Proteinases in inflammatory demyelinating disease

Localization of methylated arginine in the A1 protein from myelin

Molecular biology of myelin proteins from the CNS

J. Neurochem.

Research article
Urinary excretion of N^G-dimethylarginines in multiple sclerosis patients: preliminary observations