GC–MS assay for hepatic DDAH activity in diabetic and non-diabetic rats by measuring dimethylamine (DMA) formed from asymmetric dimethylarginine (ADMA): Evaluation of the importance of S-nitrosothiols as inhibitors of DDAH activity in vitro and in vivo in humans

Chobanyan, Kristine; Thum, Thomas; Suchy, Maria-Theresia; Zhu, Bijun; Mitschke, Anja; Gutzki, Frank‐Mathias; Beckmann, Bibiana; Stichtenoth, Dirk O.; Tsikas, Dimitrios

doi:10.1016/j.jchromb.2007.08.002

Cited by 26 publications

(15 citation statements)

References 27 publications

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“…In the catalytic reaction, the SH group of a certain cysteine moiety in the active-site of DDAH is involved, as has been demonstrated by using the SH-blocking substance HgCl 2 . We confirmed this in rat liver homogenate [65] and found, moreover, that SNACET and other RCysSNO may also inhibit DDAH activity, most likely by reversibly nitrosating the SH group of the CysSH residue in the active site of DDAH. The order of inhibition was determined to be S -nitroso-homocysteine > SNACET > CysSNO > GSNO.…”

Section: The Pharmacology Of Snacet and Nacetsupporting

confidence: 70%

“…The order of inhibition was determined to be S -nitroso-homocysteine > SNACET > CysSNO > GSNO. However, the inhibitory potency (IC 50 about 500 µM) of SNACET and the other RCysSNO is negligible from a pharmacological perspective [65] . Indeed, the in vivo study in two healthy subjects showed that oral administration of S 15 NACET (1 µmol/kg bodyweight) resulted in contemporary elevation of urinary [ 15 N]nitrate and [ 15 N]nitrite excretion, yet without inhibiting endogenous DMA formation when measured as urinary excretion of DMA [65] .…”

Section: The Pharmacology Of Snacet and Nacetmentioning

confidence: 99%

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S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview

Tsikas

Schwedhelm

Surdacki

et al. 2018

Journal of Pharmaceutical Analysis

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S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation (NO+) and a thiolate (RS−), the base of the corresponding acids RSH. The smallest S-nitrosothiol is HSNO and derives from hydrogen sulfide (HSH, H2S). The most common physiological S-nitrosothiols are derived from the amino acid L-cysteine (CysSH). Thus, the simplest S-nitrosothiol is S-nitroso-L-cysteine (CysSNO). CysSNO is a spontaneous potent donor of nitric oxide (NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate (cGMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation. Like NO, CysSNO is a short-lived species and occurs physiologically at concentrations around 1 nM in human blood. CysSNO can be formed from CysSH and higher oxides of NO including nitrous acid (HONO) and its anhydride (N2O3). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NO+ group is reversibly transferred to another thiolate. By this way numerous RSNO can be formed such as the low-molecular-mass S-nitroso-N-acetyl-L-cysteine (SNAC) and S-nitroso-glutathione (GSNO), and the high-molecular-mass S-nitrosol-L-cysteine hemoglobin (HbCysSNO) present in erythrocytes and S-nitrosol-L-cysteine albumin (AlbCysSNO) present in plasma at concentrations of the order of 200 nM. All above mentioned RSNO exert NO-related biological activity, but they must be administered intravenously. This important drawback can be overcome by lipophilic charge-free RSNO. Thus, we prepared the ethyl ester of SNAC, the S-nitroso-N-acetyl-L-cysteine ethyl ester (SNACET), from synthetic N-acetyl-L-cysteine ethyl ester (NACET). Both NACET and SNACET have improved pharmacological features over N-acetyl-L-cysteine (NAC) and S-nitroso-N-acetyl-L-cysteine (SNAC), respectively, including higher oral bioavailability. SNACET exerts NO-related activities which can be utilized in the urogenital tract and in the cardiovascular system. NACET, with high oral bioavailability, is a strong antioxidant and abundant precursor of GSH, unlike its free acid N-acetyl-L-cysteine (NAC). Here, we review the chemical and pharmacological properties of SNACET and NACET as well as their analytical chemistry. We also report new results from the ingestion of S-[15N]nitroso-N-acetyl-L-cysteine ethyl ester (S15NACET) demonstrating the favorable pharmacological profile of SNACET.

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Section: The Pharmacology Of Snacet and Nacetsupporting

confidence: 70%

Section: The Pharmacology Of Snacet and Nacetmentioning

confidence: 99%

S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview

Tsikas

Schwedhelm

Surdacki

et al. 2018

Journal of Pharmaceutical Analysis

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“…ADMA is predominantly removed by catabolism via the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which catalyses one molecule of ADMA into one molecule of L-citrulline and one molecule of dimethylamin (30). DDAH activity in diabetic rats was found to be higher than in non-diabetic rats (31). Both the synthesis and degradation of ADMA appear to be highly regulated with dysregulation leading to increased levels, which may contribute to endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Diyabetik nöropatili hastalarında serum asimetrik dimetilarjinin ve nitrik oksit düzeyleri

...

2012

npa

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Re cei ved/Ge liş ta ri hi: 21.07.2011 Ac cep ted/Ka bul ta ri hi: 16.12.2011 © Arc hi ves of Neu ropsy chi atry, pub lis hed by Ga le nos Pub lis hing / © Nö rop si ki yat ri Ar şi vi Der gi si, Ga le nos Ya yı ne vi ta ra f›n dan ba s›l m›fl t›r. ABS TRACTObjective: Asymmetric dimethylarginine (ADMA) is a novel marker of endothelial dysfunction. ADMA is an endothelial nitric oxide synthase inhibitor. Due to scarcity of studies on the role of ADMA in pathogenesis of diabetic neuropathy, it remains to be determined whether blood ADMA and nitric oxide (NO) levels are associated with diabetic neuropathy. In this case control study, we aimed to evaluate the relationship between serum NO and ADMA levels among diabetic neuropathy cases Methods: 48 patients with diabetic neuropathy and 34 healthy subjects were included in the study. All type 2 diabetic patients underwent electrophysiological and neurological examination. NO levels were determined using the Griess method. Serum ADMA levels were determined by using the ELISA method. Results: The serum ADMA levels in diabetic neuropathy patients were found to be statistically significantly lower than those of the control group (p=0.005). However, a statistically significant increase was observed in serum NO levels in patients with diabetic neuropathy compared with those in the control group (p = 0.009). A negative correlation was found between NO levels and ADMA levels (p=0.041, r=-0.23). Discussion: Changes in NO and ADMA levels in the blood of diabetic neuropathy patients may indicate oxidative stress and endothelial dysfunction in the pathogenesis of diabetic neuropathy. (Arc hi ves of Neu ropsy chi atry 2012; 49: 183-187)

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“…ADMA is an endogenous inhibitor of nitric oxide synthase isozymes (8), a cardiovascular risk marker (6), and a molecule with additional still unrevealed physiological functions. DDAH is expressed in many tissues and is the main enzyme responsible for the metabolism of ADMA to dimethylamine and L-citrulline (2). By using proteosomal and protease inhibitors in combination with clinically proven analytical methodology, Davids et al (4) convincingly demonstrated that erythrocytic proteins contain considerable amounts of ADMA.…”

mentioning

confidence: 99%

“…B: dimethylamine concentration measured in plasma and erythrocytes upon incubation at 37°C of externally added [2,3,3,4,4,5,5-2 H7]-ADMA (Eurisotop, Saarbrücken, Germany) at a final concentration of 1 mM with respect to the blood volume in EDTA blood donated by a healthy volunteer with informed consent. Dimethylamine was measured by GC-MS as described elsewhere (2). Data are shown as the means from two independent analyses each.…”

mentioning

confidence: 99%

Letter to the editor: “Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine”

Großkopf

Böhmer

Tsikas

2012

American Journal of Physiology-Heart and Circulatory Physiology

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GC–MS assay for hepatic DDAH activity in diabetic and non-diabetic rats by measuring dimethylamine (DMA) formed from asymmetric dimethylarginine (ADMA): Evaluation of the importance of S-nitrosothiols as inhibitors of DDAH activity in vitro and in vivo in humans

Cited by 26 publications

References 27 publications

S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview

S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview

Diyabetik nöropatili hastalarında serum asimetrik dimetilarjinin ve nitrik oksit düzeyleri

Letter to the editor: “Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine”

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