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Dragičević M, Košuta I, Kruezi E, Lovrenčić MV, Mrzljak A. Association of Asymmetric Dimethylarginine and Nitric Oxide with Cardiovascular Risk in Patients with End-Stage Liver Disease. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:622. [PMID: 33218157 PMCID: PMC7698953 DOI: 10.3390/medicina56110622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/11/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVES Endothelial dysfunction has been proposed to be an underlying mechanism of the pronounced cardiovascular morbidity in end-stage liver disease (ESLD), but clinical evidence is still limited. In this study, we investigated the association of circulating levels of asymmetric dimethylarginine (ADMA) and nitric oxide (NO) with estimated cardiovascular risk in patients with ESLD awaiting liver transplantation. MATERIALS AND METHODS ADMA and NO levels were measured in the sera of 160 adult ESLD patients. The severity of hepatic dysfunction was assessed by the model for end-stage liver disease (MELD) score. The cardiovascular risk was estimated with the European Society of Cardiology Systematic Coronary Risk Estimation (SCORE) index, which was used to dichotomize patients in the subgroups depicting higher and lower cardiovascular risk. RESULTS Severe hepatic dysfunction (MELD ≥ 18) was present in 38% of the patients, and a higher cardiovascular risk was present in almost half of the patients (N = 74). ADMA and NO both significantly increased with the progression of liver disease and were independently associated with higher cardiovascular risk. Fasting glucose also independently predicted a higher cardiovascular risk, while HDL cholesterol and the absence of concomitant hepatocellular carcinoma were protective factors. CONCLUSIONS These results suggest a remarkable contribution of the deranged arginine/NO pathway to cardiovascular risk in patients with end-stage liver disease.
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Affiliation(s)
- Maro Dragičević
- Department of Cardiology, Merkur University Hospital, 10000 Zagreb, Croatia;
| | - Iva Košuta
- Department of Internal Medicine, University Hospital Centre, 10000 Zagreb, Croatia;
| | - Egon Kruezi
- Department of Gynaecology and Obstetrics, Sisters of Charity University Hospital Centre, 10000 Zagreb, Croatia;
| | - Marijana Vučić Lovrenčić
- Department of Clinical Chemistry and Laboratory Medicie, Merkur University Hospital, 10000 Zagreb, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology, Merkur University Hospital, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Xiong XF, Chen DD, Zhu HJ, Ge WH. Prognostic value of endogenous and exogenous metabolites in liver transplantation. Biomark Med 2020; 14:1165-1181. [PMID: 32969246 DOI: 10.2217/bmm-2020-0073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation has been widely accepted as an effective intervention for end-stage liver diseases and early hepatocellular carcinomas. However, a variety of postoperative complications and adverse reactions have baffled medical staff and patients. Currently, transplantation monitoring relies primarily on nonspecific biochemical tests, whereas diagnosis of multiple complications depends on invasive pathological examination. Therefore, a noninvasive monitoring method with high selectivity and specificity is desperately needed. This review summarized the potential of endogenous small-molecule metabolites as biomarkers for assessing graft function, ischemia-reperfusion injury and liver rejection. Exogenous metabolites, mainly those immunosuppressive agents with high intra- and inter-individual variability, were also discussed for transplantation monitoring.
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Affiliation(s)
- Xiao-Fu Xiong
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China.,College of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Ding-Ding Chen
- College of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Huai-Jun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China.,Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Wei-Hong Ge
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China
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Abstract
The plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is the resultant of many processes at cellular and organ levels. Post-translational methylation of arginine residues of pro teins plays a crucial role in the regulation of their functions, which include processes such as transcription, translation and RNA splicing. Because protein methylation is irreversible, the methylation signal can be turned off only by proteolysis of the entire protein. Consequently, most methylated proteins have high turnover rates. Free ADMA, which is formed during proteolysis, is actively degraded by the intracellular enzyme dimethylarginine dimethylaminohydrolase (DDAH). Some ADMA escapes degradation and leaves the cell via cationic amino acid transporters. These trans porters also mediate uptake of ADMA by neighboring cells or distant organs, thereby facilitating active interorgan transport. Clearance of ADMA from the plasma occurs in small part by urinary excretion, but the bulk of ADMA is degraded by intracellular DDAH, after uptake from the circulation. This review discusses the various processes involved in ADMA metabolism: protein methylation, proteolysis of methylated proteins, metabolism by DDAH, and interorgan transport. In addition, the role of the kidney and the liver in the clearance of ADMA is highlighted.
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Affiliation(s)
- Tom Teerlink
- 1Department of Clinical Chemistry, VU University Medical
Center, Amsterdam, The Netherland
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OKUYUCU A, ŞALIŞ O, ALICI Ö, GÜVENLİ A, TERZİ Y, KELEŞ ME, İLKAYA F, GÖREN İ, ALAÇAM H. The restorative effect of ascorbic acid on liver injury inducedby asymmetric dimethylarginine. Turk J Biol 2016. [DOI: 10.3906/biy-1508-49] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Chertow JH, Alkaitis MS, Nardone G, Ikeda AK, Cunnington AJ, Okebe J, Ebonyi AO, Njie M, Correa S, Jayasooriya S, Casals-Pascual C, Billker O, Conway DJ, Walther M, Ackerman H. Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. PLoS Pathog 2015; 11:e1005119. [PMID: 26407009 PMCID: PMC4583463 DOI: 10.1371/journal.ppat.1005119] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 07/29/2015] [Indexed: 12/04/2022] Open
Abstract
Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis. During a malaria infection, the vascular endothelium becomes more adhesive, permeable, and prone to trigger blood clotting. These changes help the parasite adhere to blood vessels, but endanger the host by obstructing blood flow through small vessels. Endothelial nitric oxide (NO) would normally counteract these pathological changes, but NO signalling is diminished malaria. NO synthesis is inhibited by asymmetric dimethylarginine (ADMA), a methylated derivative of arginine that is released during normal protein turnover. We found the ratio of ADMA to arginine to be elevated in Gambian children with severe malaria, a metabolic disturbance known to inhibit NO synthesis. ADMA was associated with markers of endothelial activation and impaired tissue perfusion. In parallel experiments using mice, the enzyme responsible for metabolizing ADMA, dimethylarginine dimethylaminohydrolase (DDAH), was inactivated after infection with a rodent malaria. Based on these studies, we propose that decreased metabolism of ADMA by DDAH might contribute to the elevated ADMA/arginine ratio observed during an acute episode of malaria. Strategies to preserve or increase DDAH activity might improve NO synthesis and help to prevent the vascular manifestations of severe malaria.
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Affiliation(s)
- Jessica H. Chertow
- Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America
| | - Matthew S. Alkaitis
- Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America
- Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington Oxford, United Kingdom
| | - Glenn Nardone
- Research Technology Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America
| | - Allison K. Ikeda
- Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America
| | | | | | | | | | | | | | | | - Oliver Billker
- Wellcome Trust Sanger Institute, Hinxton Cambridge, United Kingdom
| | - David J. Conway
- MRC Unit, Fajara, The Gambia
- London School of Hygiene and Tropical Medicine, Bloomsbury, London, United Kingdom
| | | | - Hans Ackerman
- Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America
- * E-mail:
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Lluch P, Segarra G, Medina P. Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis. World J Gastroenterol 2015; 21:9466-9475. [PMID: 26327755 PMCID: PMC4548108 DOI: 10.3748/wjg.v21.i32.9466] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 06/05/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.
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Bekpinar S, Vardagli D, Unlucerci Y, Can A, Uysal M, Gurdol F. Effect of rosiglitazone on asymmetric dimethylarginine metabolism in thioacetamide-induced acute liver injury. ACTA ACUST UNITED AC 2015. [PMID: 26224212 DOI: 10.1016/j.pathophys.2015.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is metabolized in the liver by dimethylarginine dimethylaminohydrolase (DDAH). We aimed to investigate the effect of rosiglitazone, a peroxysome proliferator-activated receptor-gamma (PPAR-γ) agonist, on ADMA metabolism in acute liver injury. Male Sprague Dawley rats were injected thioacetamide (TAA; 500mgkg(-1)) intraperitoneally in order to induce acute liver injury. ADMA, SDMA and arginine levels were determined in plasma by the HPLC. Liver DDAH activity and malondialdehyde (MDA) levels were measured by spectrophotometric procedures. TAA injection caused marked increases in ALT and AST activities. Plasma ADMA levels were increased, while arginine levels and arginine/ADMA ratio were decreased. Liver DDAH activity was significantly diminished and MDA levels were elevated. In another group of animals which were treated with a PPAR-γ agonist (rosiglitazone, 5mgkg(-1)) daily via gastric intubation for a week prior to TAA injection, significant recoveries in DDAH activity and antioxidant status were observed when compared with solely TAA-injected animals. Rosiglitazone pretreatment improved the plasma arginine/ADMA ratio. Our findings indicated that PPAR-γ agonist rosiglitazone beneficially influenced hepatic metabolism of ADMA in TAA-induced acute liver damage.
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Affiliation(s)
- Seldag Bekpinar
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Capa, 34093, Istanbul, Turkey.
| | - Duygu Vardagli
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Yesim Unlucerci
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Ayten Can
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Mujdat Uysal
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Capa, 34093, Istanbul, Turkey
| | - Figen Gurdol
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Capa, 34093, Istanbul, Turkey
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8
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Association of homoarginine and methylarginines with liver dysfunction and mortality in chronic liver disease. Amino Acids 2015; 47:1817-26. [PMID: 25952253 DOI: 10.1007/s00726-015-2000-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/27/2015] [Indexed: 01/18/2023]
Abstract
Previous studies on arginine metabolites reported an association of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) with liver dysfunction and an inverse relation of homoarginine (hArg) with cardiovascular risk. The aim of the present study was to investigate the relationships between hArg, ADMA, SDMA, and the dimethylarginine score (DAS, i.e., ADMA + SDMA) and liver dysfunction and survival in chronic liver disease. In 94 consecutive cirrhotic patients admitted to our outpatient liver clinic, serum levels of hArg, ADMA, and SDMA were measured by HPLC at baseline. Patients were followed with respect to mortality. In the entire study cohort (age 58.5 ± 11.2 years; 31 % females), the serum concentrations were 1.94 ± 0.90 µM for homoarginine, 0.90 ± 0.22 µM for ADMA, and 0.70 (0.60-0.93) µM for SDMA. ADMA correlated with both Child-Pugh and MELD scores, while SDMA, DAS, and hArg correlated with MELD score only. Thirty patients (32 %) died during a median follow-up of 3.5 years. Age- and sex-adjusted Cox proportional hazard ratios (HR) per µM (with 95 % confidence intervals) showed that hArg was associated with decreased mortality [HR 0.59 (0.37-0.96)], whereas mortality was increased in patients with higher ADMA [HR 3.78 (0.98-14.60)], SDMA [HR 6.54 (3.15-13.59)] and DAS [HR 4.13 (2.26-7.56)]. Only SDMA and DAS remained significantly associated with mortality after additional adjustments for either Child-Pugh stage or MELD score. In conclusion, in cirrhotic patients seen in an outpatient liver clinic, hArg as well as the dimethylarginines ADMA and SDMA was related to long-term mortality. In particular, SDMA predicts mortality independently of both Child-Pugh stage and MELD score.
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Ferrigno A, Di Pasqua LG, Berardo C, Richelmi P, Vairetti M. Liver plays a central role in asymmetric dimethylarginine-mediated organ injury. World J Gastroenterol 2015; 21:5131-5137. [PMID: 25954086 PMCID: PMC4419053 DOI: 10.3748/wjg.v21.i17.5131] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/24/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.
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Changes in ADMA/DDAH pathway after hepatic ischemia/reperfusion injury in rats: the role of bile. BIOMED RESEARCH INTERNATIONAL 2014; 2014:627434. [PMID: 25243167 PMCID: PMC4160639 DOI: 10.1155/2014/627434] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/17/2014] [Accepted: 07/17/2014] [Indexed: 12/20/2022]
Abstract
We investigated the effects of hepatic ischemia/reperfusion (I/R) injury on asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor), protein methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH) (involved, resp., in ADMA synthesis and degradation), and the cationic transporter (CAT). Male Wistar rats were subjected to 30 or 60 min hepatic ischemia followed by 60 min reperfusion. ADMA levels in serum and bile were determined. Tissue ADMA, DDAH activity, DDAH-1 and CAT-2 protein, DDAH-1 and PRMT-1 mRNA expression, GSH/GSSG, ROS production, and lipid peroxidation were detected. ADMA was found in bile. I/R increased serum and bile ADMA levels while an intracellular decrease was detected after 60 min ischemia. Decreased DDAH activity, mRNA, and protein expression were observed at the end of reperfusion. No significant difference was observed in GSH/GSSG, ROS, lipid peroxidation, and CAT-2; a decrease in PRMT-1 mRNA expression was found after I/R. Liver is responsible for the biliary excretion of ADMA, as documented here for the first time, and I/R injury is associated with an oxidative stress-independent alteration in DDAH activity. These data are a step forward in the understanding of the pathways that regulate serum, tissue, and biliary levels of ADMA in which DDAH enzyme plays a crucial role.
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Strobel J, Müller F, Zolk O, Endreß B, König J, Fromm MF, Maas R. Transport of asymmetric dimethylarginine (ADMA) by cationic amino acid transporter 2 (CAT2), organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1). Amino Acids 2013; 45:989-1002. [PMID: 23864433 DOI: 10.1007/s00726-013-1556-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 07/01/2013] [Indexed: 01/11/2023]
Abstract
Asymmetric dimethylarginine (ADMA), inhibiting the nitric oxide (NO) synthesis from L-arginine, is a known cardiovascular risk factor. Our aim was to investigate if ADMA and/or L-arginine are substrates of the human cationic amino acid transporters 2A (CAT2A, SLC7A2A) and 2B (CAT2B, SLC7A2B), the organic cation transporter 2 (OCT2, SLC22A2), and the multidrug and toxin extrusion protein 1 (MATE1, SLC47A1). We systematically investigated the kinetics of ADMA and L-arginine transport in human embryonic kidney (HEK293) cells stably overexpressing CAT2A, CAT2B, OCT2, or MATE1. Vector-only transfected HEK293 cells served as controls. Compared to vector control cells, uptake of ADMA and L-arginine was significantly higher (p < 0.05) in cells expressing CAT2B and OCT2 at almost all investigated concentrations, while cells expressing CAT2A only showed a significant uptake at concentrations above 300 μM. Uptake of MATE1 overexpressing cells was significantly (p < 0.05) higher at pH 7.8 and 8.2 than controls. Apparent V max values (nmol mg protein(-1) min(-1)) for cellular uptake of ADMA and L-arginine were ≈11.8 ± 1.2 and 19.5 ± 0.7 for CAT2A, ≈14.3 ± 1.0 and 15.3 ± 0.4 for CAT2B, and 6.3 ± 0.3 and >50 for OCT2, respectively. Apparent K m values (μmol/l) for cellular uptake of ADMA and L-arginine were ≈3,033 ± 675 and 3,510 ± 419 for CAT2A, ≈4,021 ± 532 and 952 ± 92 for CAT2B, and 967 ± 143 and >10,000 for OCT2, respectively. ADMA and L-arginine are substrates of human CAT2A, CAT2B, OCT2 and MATE1. Transport kinetics of CAT2A, CAT2B, and OCT2 indicate a low affinity, high capacity transport, which may be relevant for renal and hepatic elimination of ADMA or L-arginine.
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Affiliation(s)
- Joachim Strobel
- Emil Fischer Center, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstraße 17, 91054, Erlangen, Germany
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Brenner T, Fleming TH, Spranz D, Schemmer P, Bruckner T, Uhle F, Martin EO, Weigand MA, Hofer S. Reactive metabolites and AGE-RAGE-mediated inflammation in patients following liver transplantation. Mediators Inflamm 2013; 2013:501430. [PMID: 23766560 PMCID: PMC3677670 DOI: 10.1155/2013/501430] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 04/29/2013] [Indexed: 02/07/2023] Open
Abstract
Recent investigations have indicated that reactive metabolites and AGE-RAGE-mediated inflammation might play an important role in the pathogenesis of ischemia-reperfusion injury in liver transplantation. In this observational clinical study, 150 patients were enrolled following liver transplantation from deceased donors. The occurrence of short-term complications within 10 days of transplantation was documented. Blood samples were collected prior to transplantation, immediately after transplantation, and at consecutive time points, for a total of seven days after transplantation. Plasma levels of methylglyoxal were determined using HPLC, whereas plasma levels of L-arginine, asymmetric dimethylarginine, advanced glycation endproducts-carboxylmethyllysine, soluble receptor for advanced glycation endproducts, and total antioxidant capacity were measured by ELISA. Patients following liver transplantation were shown to suffer from increased RAGE-associated inflammation with an AGE load mainly dependent upon reactive carbonyl species-derived AGEs. In contrast, carboxylmethyllysine-derived AGEs were of a minor importance. As assessed by the ratio of L-arginine/asymmetric dimethylarginine, the bioavailability of nitric oxide was shown to be reduced in hepatic IRI, especially in those patients suffering from perfusion disorders following liver transplantation. For the early identification of patients at high risk of perfusion disorders, the implementation of asymmetric dimethylarginine measurements in routine diagnostics following liver transplantation from deceased donors should be taken into consideration.
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Affiliation(s)
- Thorsten Brenner
- Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
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Develi-Is S, Bekpinar S, Kalaz EB, Evran B, Unlucerci Y, Gulluoglu M, Uysal M. The protection by heme oxygenase-1 induction against thioacetamide-induced liver toxicity is associated with changes in arginine and asymmetric dimethylarginine. Cell Biochem Funct 2012; 31:122-8. [PMID: 22886620 DOI: 10.1002/cbf.2866] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2012] [Revised: 07/09/2012] [Accepted: 07/13/2012] [Indexed: 12/13/2022]
Abstract
This study was designed to investigate the role of HO-1 induction in prevention of thioacetamide (TAA)-induced oxidative stress, inflammation and liver damage. The changes in hepatic dimethylarginine dimethylaminohydrolase (DDAH) activity as well as plasma arginine and asymmetric dimethylarginine (ADMA) levels were also measured to evaluate nitric oxide (NO) bioavailability. Rats were divided into four groups as control, hemin, TAA and hemin + TAA groups. Hemin (50 mg kg(-1) , i.p.) was injected to rats 18 h before TAA treatment to induce HO-1 enzyme expression. Rats were given TAA (300 mg kg(-1) , i.p.) and killed 24 h after treatment. Although TAA treatment produced severe hepatic injury, upregulation of HO-1 ameliorated TAA-induced liver damage up to some extent as evidence by decreased serum alanine transaminase, aspartate transaminase and arginase activities and histopathological findings. Induction of HO-1 stimulated antioxidant system and decreased lipid peroxidation in TAA-treated rats. Myeloperoxidase activity and inducible NO synthase protein expression were decreased, whereas DDAH activity was increased by hemin injection in TAA-treated rats. Induction of HO-1 was associated with increased arginine levels and decreased ADMA levels, being the main determinants of NO production, in plasma of TAA-treated rats. In conclusion, our results indicate that HO-1 induction alleviated increased oxidative stress and inflammatory reactions together with deterioration in NO production in TAA-induced liver damage in rats.
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Affiliation(s)
- Seval Develi-Is
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Davids M, Richir MC, Visser M, Ellger B, van den Berghe G, van Leeuwen PAM, Teerlink T. Role of dimethylarginine dimethylaminohydrolase activity in regulation of tissue and plasma concentrations of asymmetric dimethylarginine in an animal model of prolonged critical illness. Metabolism 2012; 61:482-90. [PMID: 22000584 DOI: 10.1016/j.metabol.2011.08.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 08/16/2011] [Accepted: 08/18/2011] [Indexed: 12/26/2022]
Abstract
High plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are associated with adverse outcome in critically ill patients. Asymmetric dimethylarginine is released within cells during proteolysis of methylated proteins and is either degraded by dimethylarginine dimethylaminohydrolase (DDAH) or exported to the circulation via cationic amino acid transporters. We aimed to establish the role of DDAH activity in the regulation of tissue and plasma concentrations of ADMA. In 33 critically ill rabbits, we measured DDAH activity in kidney, liver, heart, and skeletal muscle and related these values to concentrations of ADMA in these tissues and in the circulation. Both DDAH activity and ADMA concentration were highest in kidney and lowest in skeletal muscle, with intermediate values for liver and heart. Whereas ADMA content was significantly correlated between tissues (r = 0.40-0.78), DDAH activity was not. Significant inverse associations between DDAH activity and ADMA content were only observed in heart and liver. Plasma ADMA was significantly associated with ADMA in the liver (r = 0.41), but not in the other tissues. In a multivariable regression model, DDAH activities in muscle, kidney, and liver, but not in heart, were negatively associated with plasma ADMA concentration, together explaining approximately 50% of its variation. In critical illness, plasma ADMA poorly reflects intracellular ADMA. Furthermore, tissue DDAH activity is a stronger predictor of plasma ADMA than of intracellular ADMA, indicating that, compared with DDAH activity, generation of ADMA and cationic amino acid transporter-mediated exchange may be more important regulators of intracellular ADMA.
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Affiliation(s)
- Mariska Davids
- Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, PO Box 7057, 1007MB Amsterdam, The Netherlands
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Yang YY, Lee TY, Huang YT, Chan CC, Yeh YC, Lee FY, Lee SD, Lin HC. Asymmetric dimethylarginine (ADMA) determines the improvement of hepatic endothelial dysfunction by vitamin E in cirrhotic rats. Liver Int 2012; 32:48-57. [PMID: 22098317 DOI: 10.1111/j.1478-3231.2011.02651.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Accepted: 08/25/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatic endothelial dysfunction (HED), which is caused by decreased hepatic nitric oxide (NO) bioavailability and increased lipid peroxidation, contributes to portal hypertension, which is a characteristic of cirrhosis. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is involved in cirrhosis-related HED and portal hypertension. AIMS We evaluated the effect of vitamin E treatment on the lipid peroxidation, HED and portal hypertension in cirrhotic rats. METHODS The common bile duct ligation (BDL)-induced cirrhotic rats were treated orally either with vehicle or with vitamin E for 1 month immediately after BDL. Systemic and portal haemodynamics, the magnitude of the increase in portal pressure induced by volume expansion, HED, oxidative stress, levels of ADMA, various proteins and mRNAs were then measured. RESULTS In the vitamin E-treated BDL rats, a decrease in portal pressure was associated with an attenuation of the increased portal pressure induced by volume expansion. In isolated and perfused BDL rat livers, the vitamin E treatment significantly inhibited the (paradoxical) vasoconstriction response to methoxamine and acetylcholine (HED), and this was abolished by the presence of NOS. Vitamin E decreased ADMA synthesizing enzyme PRMT1 expression and the level of thiobarbituric acid-reactive substances (TBARS) in the liver, while increasing the levels of hepatic ADMA metabolizing enzyme DDAH2, eNOS, phosphor-eNOS, ADMA level and superoxide dismutase activity. CONCLUSIONS The administration of vitamin E suppressed hepatic ADMA and oxidative stress in the cirrhotic liver circulation, and therefore increases NO bioavailability, which improved HED and portal hypertension.
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Affiliation(s)
- Ying-Ying Yang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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16
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Richir MC, Bouwman RH, Teerlink T, Siroen MPC, de Vries TPGM, van Leeuwen PAM. The prominent role of the liver in the elimination of asymmetric dimethylarginine (ADMA) and the consequences of impaired hepatic function. JPEN J Parenter Enteral Nutr 2009; 32:613-21. [PMID: 18974239 DOI: 10.1177/0148607108321702] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), the enzyme which converts the amino acid arginine into nitric oxide (NO). ADMA has been identified as an important risk factor for cardiovascular diseases. Besides the role of ADMA in cardiovascular diseases, it also seems to be an important determinant in the development of critical illness, (multiple) organ failure, and the hepatorenal syndrome. ADMA is eliminated from the body by urinary excretion, but it is mainly metabolized by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes that convert ADMA into citrulline and dimethylamine. DDAH is highly expressed in the liver, which makes the liver a key organ in the regulation of the plasma ADMA concentration. The prominent role of the liver in the elimination of ADMA and the consequences of impaired hepatic function on ADMA levels will be discussed in this article.
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Affiliation(s)
- Milan C Richir
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
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Siroen MPC, Wiest R, Richir MC, Teerlink T, Rauwerda JA, Drescher FT, Zorger N, Leeuwen PAMV. Transjugular intrahepatic portosystemic shunt-placement increases arginine/asymmetric dimethylarginine ratio in cirrhotic patients. World J Gastroenterol 2008; 14:7214-9. [PMID: 19084936 PMCID: PMC2776879 DOI: 10.3748/wjg.14.7214] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the change of dimethylarginine plasma levels in cirrhotic patients receiving transjugular intrahepatic portosystemic shunt (TIPS).
METHODS: To determine arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and nitric oxide (NO) plasma levels, blood samples were collected from the superior cava, hepatic, and portal vein just before, directly after, and 3 mo after TIPS-placement.
RESULTS: A significant increase in the arginine/ADMA ratio after TIPS placement was shown. Moreover, TIPS placement enhanced renal function and thereby decreased systemic SDMA levels. In patients with renal dysfunction before TIPS placement, both the arginine/ADMA ratio and creatinine clearance rate increased significantly, while this was not the case in patients with normal renal function before TIPS placement. Hepatic function did not change significantly after TIPS placement and no significant decline in ADMA plasma levels was measured.
CONCLUSION: The increase of the arginine/ADMA ratio after TIPS placement suggests an increase in intracellular NO bioavailability. In addition, this study suggests that TIPS placement does not alter dimethylarginine dimethylaminohydrolase (DDAH) activity and confirms the major role of the liver as an ADMA clearing organ.
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18
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Effect of acute variations of insulin and glucose on plasma concentrations of asymmetric dimethylarginine in young people with Type 1 diabetes. Clin Sci (Lond) 2008; 115:361-9. [DOI: 10.1042/cs20080079] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
ADMA (asymmetric dimethylarginine), an endogenous inhibitor of nitric oxide synthase, is considered a major risk factor for cardiovascular disease and progression of renal disease. In the present study we aim to investigate the effect of acute variations in plasma glucose and insulin on plasma ADMA levels in young people with T1D (Type 1 diabetes). Fifteen young patients (ten males) with T1D, median age 18.3 (13.2–24.4) years, HbA1c (glycated haemoglobin) 9% (6.4–13.6%), underwent an overnight (18:00–08:00 hours) variable insulin infusion for euglycaemia, followed by a hyperinsulinaemic–euglycaemic clamp (08:00–12:00 hours). Blood samples were collected every 15 min for determination of ADMA, SDMA (symmetric dimethylarginine), valine, phenylalanine, arginine, creatinine and glucose. Insulin levels were assessed every 30 min. During the overnight period, glucose levels increased following the evening meal. In response to the protein intake there was a significant increase in ADMA, arginine, valine, phenylalanine and creatinine. For the remaining part of the night, glucose levels progressively decreased reaching 5 mmol/l by 04:00 hours. ADMA and SDMA did not change significantly. During the hyperinsulinaemic clamp, a significant fall in ADMA was observed, from 0.468±0.056 to 0.364±0.050 μmol/l (P<0.001). A significant fall was also found in SDMA, valine, phenylalanine, arginine and the ADMA/SDMA ratio (all P<0.001), but not in creatinine levels. No correlation was found between insulin sensitivity and ADMA. We conclude that acute changes in glycaemia do not significantly affect plasma ADMA levels whereas infusion of insulin significantly reduces ADMA, suggesting an important role for insulin in the regulation of this cardiovascular risk factor.
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Becker T, Mevius I, de Vries DK, Schaapherder AFM, zu Vilsendorf AM, Klempnauer J, Frölich JC, Tsikas D. The L-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications. Nitric Oxide 2008; 20:61-7. [PMID: 18948222 DOI: 10.1016/j.niox.2008.10.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2008] [Revised: 08/08/2008] [Accepted: 10/03/2008] [Indexed: 12/21/2022]
Abstract
The L-arginine/nitric oxide (L-Arg/NO) pathway is altered in liver and kidney diseases. However, the status of the L-Arg/NO pathway during and after orthotopic transplantation is insufficiently investigated and findings are uncertain because of analytical shortcomings. Also, most human studies have focused on individual members of the L-Arg/NO pathway such as nitrate or asymmetric dimethylarginine (ADMA). In the present article we report on a pilot study investigating extensively the status of the L-Arg/NO pathway before and during orthotopic liver transplantation (OLT). By using fully validated, highly sensitive and specific GC-MS and GC-MS/MS methods nitrite, nitrate, ADMA and its hydrolysis product dimethylamine (DMA), L-arginine and L-ornithine were measured in blood and urine. Our study gives strong evidence of the exceptional importance of hepatic dimethylarginine dimethylaminohydrolase (DDAH) activity for the elimination of systemic ADMA. In end-stage liver disease the synthesis of NO and ADMA as well as the DDAH activity are elevated. However, increase in DDAH activity is insufficient to efficiently eliminate overproduced ADMA. The transplanted liver graft is capable of clearing ADMA in a rapid and sufficient manner. In contrast to studies from other groups, our study shows that in OLT as well as in living donor kidney transplantation, the second study reported here, reperfusion of the graft does not cause drastic alterations to the L-Arg/NO pathway with regard to NO synthesis. In the OLT study the concentration of circulating L-arginine fell temporally dramatically, while L-ornithine levels increased diametrically, most likely due to elevation of arginase activity. However, the relatively long-lasting decrease in plasmatic L-arginine in OLT seems not to have affected NO synthesis after reperfusion. Our OLT study suggests that liver reperfusion is associated with greatly elevated activity of proteolytic and hydrolytic enzymes including DDAH and arginase. Suppression of proteolytic and hydrolytic activity in transplantation could be a useful measure to improve outcome and remains to be investigated in further studies on larger patient collectives. The importance of analytical chemistry in this area of research is also discussed in this article.
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Affiliation(s)
- Thomas Becker
- Department of Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
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20
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Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 2007; 293:H3227-45. [PMID: 17933965 DOI: 10.1152/ajpheart.00998.2007] [Citation(s) in RCA: 251] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Asymmetric (N(G),N(G))-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH +/- mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1 but increases the expression of DDAH-2. This rapidly evolving evidence of isoform-specific distribution and regulation of DDAH expression in the kidney and blood vessels provides potential mechanisms for nephron site-specific regulation of NO production. In this review, the recent advances in the regulation and function of DDAH enzymes, their roles in the regulation of NO generation, and their possible contribution to endothelial dysfunction in patients with cardiovascular and kidney diseases are discussed.
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Affiliation(s)
- Fredrik Palm
- Division of Nephrology and Hypertension, Georgetown University, 3800 Reservoir Road N.W., Washington, DC 20007, USA
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21
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Chobanyan K, Thum T, Suchy MT, Zhu B, Mitschke A, Gutzki FM, Beckmann B, Stichtenoth DO, Tsikas D. 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. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 858:32-41. [PMID: 17825631 DOI: 10.1016/j.jchromb.2007.08.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2007] [Revised: 07/30/2007] [Accepted: 08/02/2007] [Indexed: 11/21/2022]
Abstract
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, is hydrolyzed to dimethylamine (DMA) and L-citrulline by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). In the present article we report on a GC-MS assay for DDAH activity in rat liver homogenate in phosphate buffered saline. The method is based on the quantitative determination of ADMA-derived DMA by GC-MS as the pentafluorobenzamide derivative. Quantification was performed by selected-ion monitoring of the protonated molecules at m/z 240 for DMA and m/z 246 for the internal standard (CD3)2NH in the positive-ion chemical ionization mode. The assay was applied to determine the enzyme kinetics in rat liver, the hepatic DDAH activity in streptozotocin-induced (50 mg/kg) diabetes in rats, and to evaluate the importance of S-nitrosothiols as DDAH inhibitors. The KM and Vmax values were determined to be 60 microM ADMA and 12.5 pmol DMA/minmg liver corresponding to 166 pmol DMA/minmg protein. Typical DDAH activity values measured in rat liver homogenate were 8.7 pmol DMA/minmg liver at added ADMA concentration of 100 microM. DDAH activity was found to be 1.7-fold elevated in diabetic as compared to non-diabetic rats (P=0.01). The SH-specific agents HgCl2, S-nitrosocysteine ethyl ester (SNACET), a synthetic lipophilic S-nitrosothiol, S-nitrosoglutathione (GSNO), S-nitrosocysteine (CysNO) and S-nitrosohomocysteine (HcysNO) were found to inhibit DDAH activity in rat liver homogenate. The IC50 values for HcysNO, SNACET, CysNO and GSNO were estimated to be 300, 500, 700 and 1000 microM, respectively. Oral administration of 15N-labelled SNACET to two healthy volunteers (1 micromol/kg) resulted in elevated urinary excretion of 15N-labelled nitrite and nitrate, but did not reduce creatinine-corrected excretion of DMA in the urine. Our results suggest that inhibition of DDAH activity on the basis of reversible nitros(yl)ation or irreversible N-thiosulfoximidation of the sulfhydryl group of the cysteine moiety involved in the catalytic process is most likely not a rationale design of DDAH inhibitors. A major advantage of the present GC-MS assay over other assays is that DDAH activity is assessed by measuring the formation of the specific enzymatic product DMA but not the formation of unlabelled or (radio)labelled L-citrulline or the decay of the substrate ADMA. The GC-MS assay reported here should be suitable to probe for DDAH activity in various disease models.
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Affiliation(s)
- Kristine Chobanyan
- Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
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22
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Mookerjee RP, Vairappan B, Jalan R. The puzzle of endothelial nitric oxide synthase dysfunction in portal hypertension: The missing piece? Hepatology 2007; 46:943-946. [PMID: 17879360 DOI: 10.1002/hep.21905] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Rajeshwar P Mookerjee
- Institute of Hepatology, Department of Medicine, University College London, London, United Kingdom
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23
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Wilcken DEL, Sim AS, Wang J, Wang XL. Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of L-arginine on its metabolism. Mol Genet Metab 2007; 91:309-17; discussion 308. [PMID: 17560156 DOI: 10.1016/j.ymgme.2007.04.017] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2007] [Revised: 04/30/2007] [Accepted: 04/30/2007] [Indexed: 12/12/2022]
Abstract
Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase (NOS), has been identified as a new and emerging contributor to, or marker for, cardiovascular risk. The ADMA-mediated regulation of nitric oxide (NO) production is determined by the quantitative bioavailability of intracellular and extracellular ADMA. Dimethylarginine dimethylaminohydrolase (DDAH), which is ubiquitously expressed in tissues, especially liver and kidney, converts the majority of the ADMA to citrulline. In this review, we discuss a new regulatory mechanism for the metabolism of ADMA in which L-arginine acts as a competitive inhibitor of DDAH activity. This novel regulatory pathway is consistent with ADMA contributing to cardiovascular risk when levels are increased but not when levels are within the normal range. The pathway then has a physiological role in the regulation of NO production by preventing overproduction of NO. The regulatory role of L-arginine on ADMA may explain the unexpected outcomes in some L-arginine supplementation studies. This paper also reviews associations between the metabolism of ADMA and insulin resistance, smoking and homocysteine which are all associated with an increased risk of vascular disease.
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Affiliation(s)
- David E L Wilcken
- Department of Cardiovascular Medicine, The University of New South Wales and the Prince of Wales Hospital, Sydney, Australia.
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24
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Teerlink T. HPLC analysis of ADMA and other methylated l-arginine analogs in biological fluids. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 851:21-9. [PMID: 16931194 DOI: 10.1016/j.jchromb.2006.07.024] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2006] [Revised: 07/11/2006] [Accepted: 07/14/2006] [Indexed: 02/07/2023]
Abstract
Post-translational methylation of arginine residues in proteins leads to generation of N(G)-monomethylarginine (MMA) and both symmetric and asymmetric dimethylarginine (SDMA and ADMA), that are released into the cytosol upon proteolysis. Both MMA and ADMA are inhibitors of nitric oxide synthase and especially elevated levels of ADMA are associated with endothelial dysfunction and cardiovascular disease. Plasma concentrations of ADMA and SDMA are very low, typically between 0.3 and 0.8 microM, making their quantification by HPLC an analytical challenge. Sample preparation usually involves a cleanup step by solid-phase extraction on cation-exchange columns followed by derivatization of amino acids into fluorescent adducts. Because ADMA and SDMA concentrations in healthy subjects show a very narrow distribution, with a between-subject variability of 13% for ADMA and 19% for SDMA, very low imprecision is an essential assay feature. Procedures for sample cleanup, derivatization, and chromatographic separation of arginine and its methylated analogs are the main topics of this review. In addition, important aspects of method validation, pre-analytical factors, and reference values are discussed.
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Affiliation(s)
- Tom Teerlink
- Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
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25
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Mookerjee RP, Dalton RN, Davies NA, Hodges SJ, Turner C, Williams R, Jalan R. Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure. Liver Transpl 2007; 13:400-5. [PMID: 17318866 DOI: 10.1002/lt.21053] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Acute liver failure (ALF) is characterized by rapid progressive organ failure and poor outcome. The pathophysiology of multiorgan dysfunction in ALF remains unclear but increased systemic inflammatory response is believed to be an important determining factor. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, results from proteolysis and the liver is a major site for its metabolism. ADMA has been shown to independently predict outcome in multiorgan failure associated with severe liver dysfunction. In this study, we tested the hypothesis that proinflammatory cytokine driven responses are important in modulating ADMA levels in patients with acetaminophen-induced ALF. Blood samples were collected from 10 ALF patients (grade IV encephalopathy) from admission until the time of transplantation or death, and assayed for cytokines and ADMA. A total of 8 patients required treatment for raised intracranial pressure and all patients were managed with standard of care, including full mechanical ventilation and veno-venous hemofiltration. ADMA levels were markedly higher in ALF patients compared to age-matched controls (P < 0.001) and correlated with the levels of proinflammatory cytokines. In pretransplantation patients undergoing hepatic venous catheterization, we demonstrated no significant uptake of ADMA across the failing liver. However, following liver transplantation, ADMA levels reduced acutely. A timed study of ADMA levels during transplantation demonstrated a slight increase during the anhepatic phase but a marked and sustained reduction in ADMA following liver reperfusion. In conclusion, our data show a significant correlation between ADMA levels and proinflammatory cytokines, supporting a hypothesis that proinflammatory cytokines may regulate ADMA metabolism in ALF.
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Affiliation(s)
- Rajeshwar P Mookerjee
- Liver Failure Group, Institute of Hepatology, Division of Medicine, University College London, London, UK
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Verhoeven MO, Hemelaar M, Teerlink T, Kenemans P, van der Mooren MJ. Effects of intranasal versus oral hormone therapy on asymmetric dimethylarginine in healthy postmenopausal women: a randomized study. Atherosclerosis 2006; 195:181-8. [PMID: 17084844 DOI: 10.1016/j.atherosclerosis.2006.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2006] [Revised: 08/30/2006] [Accepted: 09/27/2006] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Oral estrogens reduce asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, and an independent risk factor for cardiovascular disease. This study was conducted to compare the effect on ADMA between intranasal and oral 17beta-estradiol (E2) combined with norethisterone (acetate) (NET(A)) administration in postmenopausal women. METHODS In a two-center, randomized, double-blind, comparative study 90 healthy postmenopausal women (age 56.6+/-4.7 years) received daily continuous combined intranasal E2/NET 175 microg/275 microg (n=47) or oral E2/NETA 1 mg/0.5 mg (n=43) for one year. At baseline, week 12 and 52, plasma concentrations of ADMA, arginine and symmetric dimethylarginine (SDMA) were measured by high-performance liquid chromatography. RESULTS Oral E2/NETA reduced ADMA concentrations (-7.4%; 95% confidence interval (CI) -10.4 to -4.4%), while intranasal E2/NET had no effect (-0.8%; 95% CI -3.7 to 2.1%) after 52 weeks. In both groups, arginine was transiently decreased compared to baseline at week 12 (intranasal: -6.1%; 95% CI -9.1 to -3.0%; oral: -6.5%; 95% CI -10.9 to -2.1%). Only oral E2/NETA reduced SDMA concentrations. CONCLUSIONS Oral administration of E2/NETA reduced ADMA and SDMA concentrations, whereas intranasal administration did not. Both treatments transiently reduced arginine. The decrease in ADMA by oral estrogens could be a key phenomenon in the modulation of nitric oxide synthesis by postmenopausal hormone therapy.
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Affiliation(s)
- Marieke O Verhoeven
- Project Aging Women and the Institute for Cardiovascular Research-Vrije Universiteit, Department of Obstetrics & Gynecology, VU University Medical Center, Amsterdam, The Netherlands
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27
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Tsikas D, Thum T, Becker T, Pham VV, Chobanyan K, Mitschke A, Beckmann B, Gutzki FM, Bauersachs J, Stichtenoth DO. Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography-mass spectrometry as pentafluorobenzamide derivative: evaluation of the relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 851:229-39. [PMID: 17011246 DOI: 10.1016/j.jchromb.2006.09.015] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2006] [Revised: 09/01/2006] [Accepted: 09/08/2006] [Indexed: 12/21/2022]
Abstract
Dimethylamine [DMA, (CH(3))(2)NH)] is abundantly present in human urine. Main sources of urinary DMA have been reported to include trimethylamine N-oxide, a common food component, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis. ADMA is excreted in the urine in part unmetabolized and in part after hydrolysis to DMA by dimethylarginine dimethylaminohydrolase (DDAH). Here we describe a GC-MS method for the accurate and rapid quantification of DMA in human urine. The method involves use of (CD(3))(2)NH as internal standard, simultaneous derivatization with pentafluorobenzoyl chloride and extraction in toluene, and selected-ion monitoring of m/z 239 for DMA and m/z 245 for (CD(3))(2)NH in the electron ionization mode. GC-MS analysis of urine samples from 10 healthy volunteers revealed a DMA concentration of 264+/-173 microM equivalent to 10.1+/-1.64 micromol/mmol creatinine. GC-tandem MS analysis of the same urine samples revealed an ADMA concentration of 27.3+/-15.3 microM corresponding to 1.35+/-1.2 micromol/mmol creatinine. In these volunteers, a positive correlation (R=0.83919, P=0.0024) was found between urinary DMA and ADMA, with the DMA/ADMA molar ratio being 10.8+/-6.2. Elevated excretion rates of DMA (52.9+/-18.5 micromol/mmol creatinine) and ADMA (3.85+/-1.65 micromol/mmol creatinine) were found by the method in 49 patients suffering from coronary artery disease, with the DMA/ADMA molar ratio also being elevated (16.8+/-12.8). In 12 patients suffering from end-stage liver disease, excretion rates of DMA (47.8+/-19.7 micromol/mmol creatinine) and ADMA (5.6+/-1.5 micromol/mmol creatinine) were found to be elevated, with the DMA/ADMA molar ratio (9.17+/-4.2) being insignificantly lower (P=0.46). Between urinary DMA and ADMA there was a positive correlation (R=0.6655, P<0.0001) in coronary artery disease, but no correlation (R=0.27339) was found in end-stage liver disease.
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Affiliation(s)
- Dimitrios Tsikas
- Institut für Klinische Pharmakologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
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Abstract
The plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is the resultant of many processes at cellular and organ levels. Post-translational methylation of arginine residues of proteins plays a crucial role in the regulation of their functions, which include processes such as transcription, translation and RNA splicing. Because protein methylation is irreversible, the methylation signal can be turned off only by proteolysis of the entire protein. Consequently, most methylated proteins have high turnover rates. Free ADMA, which is formed during proteolysis, is actively degraded by the intracellular enzyme dimethylarginine dimethylaminohydrolase (DDAH). Some ADMA escapes degradation and leaves the cell via cationic amino acid transporters. These transporters also mediate uptake of ADMA by neighboring cells or distant organs, thereby facilitating active interorgan transport. Clearance of ADMA from the plasma occurs in small part by urinary excretion, but the bulk of ADMA is degraded by intracellular DDAH, after uptake from the circulation. This review discusses the various processes involved in ADMA metabolism: protein methylation, proteolysis of methylated proteins, metabolism by DDAH, and interorgan transport. In addition, the role of the kidney and the liver in the clearance of ADMA is highlighted.
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Affiliation(s)
- Tom Teerlink
- Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
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Bulau P, Zakrzewicz D, Kitowska K, Leiper J, Gunther A, Grimminger F, Eickelberg O. Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. Am J Physiol Lung Cell Mol Physiol 2006; 292:L18-24. [PMID: 16891395 DOI: 10.1152/ajplung.00076.2006] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Protein arginine methylation is catalyzed by a family of enzymes called protein arginine methyltransferases (PRMTs). Three forms of methylarginine have been identified in eukaryotes: monomethylarginine (l-NMMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), all characterized by methylation of one or both guanidine nitrogen atoms of arginine. l-NMMA and ADMA, but not SDMA, are competitive inhibitors of all nitric oxide synthase isoforms. SDMA is eliminated almost entirely by renal excretion, whereas l-NMMA and ADMA are further metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To explore the interplay between methylarginine synthesis and degradation in vivo, we determined PRMT expression and DDAH activity in mouse lung, heart, liver, and kidney homogenates. In addition, we employed HPLC-based quantification of protein-incorporated and free methylarginine, combined with immunoblotting for the assessment of tissue-specific patterns of arginine methylation. The salient findings of the present investigation can be summarized as follows: 1) pulmonary expression of type I PRMTs was correlated with enhanced protein arginine methylation; 2) pulmonary ADMA degradation was undertaken by DDAH1; 3) bronchoalveolar lavage fluid and serum exhibited almost identical ADMA/SDMA ratios, and 4) kidney and liver provide complementary routes for clearance and metabolic conversion of circulating ADMA. Together, these observations suggest that methylarginine metabolism by the pulmonary system significantly contributes to circulating ADMA and SDMA levels.
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Affiliation(s)
- Patrick Bulau
- Lung Center, University of Giessen School of Medicine, Aulweg 123, D-35329 Giessen, Germany.
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30
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Siroen MPC, Teerlink T, Nijveldt RJ, Prins HA, Richir MC, van Leeuwen PAM. The Clinical Significance of Asymmetric Dimethylarginine. Annu Rev Nutr 2006; 26:203-28. [PMID: 16848705 DOI: 10.1146/annurev.nutr.26.061505.111320] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.
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Affiliation(s)
- Michiel P C Siroen
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.
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31
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Verhoeven MO, Hemelaar M, van der Mooren MJ, Kenemans P, Teerlink T. Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo-controlled study. J Intern Med 2006; 259:199-208. [PMID: 16420549 DOI: 10.1111/j.1365-2796.2005.01602.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To compare the effects of oral and transdermal hormone therapy (HT) on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in postmenopausal women. DESIGN In a multicentre, placebo-controlled, double-blind study, 152 hysterectomized healthy women were randomized to receive daily transdermal 17beta-oestradiol (tE2, n = 33), or oral micronized 17beta-oestradiol either unopposed (oE2, n = 37), or continuous combined with gestodene (oE2 + G, n = 33), or placebo (n = 49) for 13, 28-day treatment cycles. Plasma concentrations of ADMA, arginine and symmetric dimethylarginine (SDMA) were measured at baseline and in treatment cycles 4 and 13 with a high-performance liquid chromatography method. RESULTS After 13 cycles all active treatment groups showed a significant reduction in ADMA compared with placebo: tE2, -4.0% (95% CI: -7.5 to -0.6%); oE2, -7.7% (95% CI: -10.9 to -4.4%) and oE2 + G, -7.5% (95% CI: -10.8 to -4.3%). ancova showed a significantly larger reduction in the oral groups compared with the transdermal group (tE2 vs. oE2 and tE2 vs. oE2 + G, both P < 0.01). Oral, but not transdermal treatment, significantly reduced arginine compared with placebo. All active treatments reduced SDMA; however, this was only statistically significant in the oE2 group. CONCLUSION Reduction of ADMA was more pronounced after oral than after tE2 administration. Adding gestodene to oral 17beta-oestradiol did not alter the reduction of ADMA. The clinical implications of these findings remain uncertain; however, the decrease of ADMA by 17beta-oestradiol could be a key phenomenon in the modulation of nitric oxide synthesis by postmenopausal HT.
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Affiliation(s)
- M O Verhoeven
- Department of Obstetrics and Gynaecology, Project Ageing Women and Institute for Cardiovascular Research-Vrije Universiteit, Amsterdam, Netherlands
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32
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Abstract
There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction.
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Affiliation(s)
- Rainer H Böger
- Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
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Carello KA, Whitesall SE, Lloyd MC, Billecke SS, D'Alecy LG. Asymmetrical dimethylarginine plasma clearance persists after acute total nephrectomy in rats. Am J Physiol Heart Circ Physiol 2005; 290:H209-16. [PMID: 16113067 DOI: 10.1152/ajpheart.00208.2005] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Elevated plasma concentrations of symmetrical dimethylarginine (SDMA) and asymmetrical dimethylarginine (ADMA) are repeatedly associated with kidney failure. Both ADMA and SDMA can be excreted in urine. We tested whether renal excretion is necessary for acute, short-term maintenance of plasma ADMA and SDMA. Sprague-Dawley rats underwent sham operation, bilateral nephrectomy (NPX), ureteral ligation, or ureteral section under isoflurane anesthesia. Tail-snip blood samples (250 microl) were taken before and at 6- or 12-h intervals for 72 h after operation. Plasma clearance was assessed in intact and NPX rats. High-performance liquid chromatography determined SDMA and ADMA concentrations. Sodium, potassium, creatinine, blood urea nitrogen (BUN), and body weight were also measured. Forty-eight hours after NPX, SDMA increased 25 times (0.23 +/- 0.03 to 5.68 +/- 0.30 microM), whereas ADMA decreased (1.17 +/- 0.08 to 0.73 +/- 0.08 microM) by 38%. Creatinine and BUN increased, paralleling SDMA. Sham-operated animals showed no significant changes. Increased SDMA confirms continuous systemic production of SDMA and its obligatory renal excretion, much like creatinine. In contrast, decreased plasma ADMA suggests that acute total NPX either reduced systemic ADMA formation and/or systemic hydrolysis of ADMA increased 48-h post-NPX. However, plasma clearance of ADMA appeared unchanged 48 h after NPX. We conclude that renal excretory function is needed for SDMA elimination but not needed for acute, short-term ADMA elimination in that systemic hydrolysis is fully capable of clearing plasma ADMA.
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Affiliation(s)
- Katari A Carello
- Dept. of Molecular and Integrative Physiology, Univ. of Michigan Medical School, Ann Arbor, MI 48109-0622, USA
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Siroen MPC, van Leeuwen PAM, Nijveldt RJ, Teerlink T, Wouters PJ, Van den Berghe G. Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: A possible explanation of reduced morbidity and mortality?*. Crit Care Med 2005; 33:504-10. [PMID: 15753739 DOI: 10.1097/01.ccm.0000155784.59297.50] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Asymmetric dimethylarginine, which inhibits production of nitric oxide, has been shown to be a strong and independent predictor of mortality in critically ill patients with clinical evidence of organ dysfunction. Interestingly, intensive insulin therapy in critically ill patients improved morbidity and mortality, but the exact mechanisms by which these beneficial effects are brought about remain unknown. Therefore, we aimed to investigate whether modulation of asymmetric dimethylarginine concentrations by intensive insulin therapy is involved in these effects. DESIGN A prospective, randomized, controlled trial. SETTING A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. PATIENTS From a study of 1,548 critically ill patients who were randomized to receive either conventional or intensive insulin therapy, we included 79 patients who were admitted to the intensive care unit after complicated pulmonary and esophageal surgery and required prolonged (>/=7 days) intensive care. INTERVENTIONS Determination of asymmetric dimethylarginine concentrations. MEASUREMENTS AND MAIN RESULTS Asymmetric dimethylarginine concentrations were determined with high-performance liquid chromatography on the day of admission, on day 2, on day 7, and on the last day at the intensive care unit. Although the asymmetric dimethylarginine levels did not change between day 0 and day 2 in patients receiving intensive insulin treatment, there was a significant increase during this period in the conventionally treated patients (p = .043). Interestingly, the mean daily insulin dose was inversely associated with the asymmetric dimethylarginine concentration on the last day (r = -.23, p = .042), and the asymmetric dimethylarginine concentration on the last day at the intensive care unit was significantly lower in the intensive insulin treatment group (p = .048). Furthermore, asymmetric dimethylarginine was positively associated with duration of intensive care unit stay, duration of ventilatory support, duration of inotropic and vasopressor treatment, number of red cell transfusions, duration of antibiotic treatment, presence of critical illness polyneuropathy, mean Acute Physiology and Chronic Health Evaluation II score, and cumulative Therapeutic Intervention Scoring System-28 score. In addition, asymmetric dimethylarginine levels in patients who died were significantly higher compared with survivors, and changes in the course of asymmetric dimethylarginine plasma concentrations were predictive for adverse intensive care unit outcome. CONCLUSIONS Modulation of asymmetric dimethylarginine concentration by insulin at least partly explains the beneficial effects found in critically ill patients receiving intensive insulin therapy.
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Affiliation(s)
- Michiel P C Siroen
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
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Siroen MPC, van der Sijp JRM, Teerlink T, van Schaik C, Nijveldt RJ, van Leeuwen PAM. The human liver clears both asymmetric and symmetric dimethylarginine. Hepatology 2005; 41:559-65. [PMID: 15726655 DOI: 10.1002/hep.20579] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) inhibit production of nitric oxide. The concentration of both dimethylarginines is regulated by urinary excretion, although ADMA, but not SDMA, is also subject to degradation by dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver but also present in the kidney. The exact roles of the human liver and kidney in the metabolism of dimethylarginines are currently unknown. Therefore, we aimed to investigate renal and hepatic handling of ADMA and SDMA in detail in 24 patients undergoing hepatic surgery. To calculate net organ fluxes and fractional extraction (FE) rates, blood was collected from an arterial line, the portal vein, hepatic vein, and renal vein, and blood flow of the hepatic artery, portal vein, and renal vein was determined using Doppler ultrasound techniques. Results showed a significant net uptake (median [IQR]) of ADMA in both the liver (9.6 nmol/min [5.6-13.2]) and the kidney (12.1 nmol/min [1.3-17.1]). SDMA uptake was present not only in the kidney (12.7 nmol/min [3.5-25.4]), but also in the liver (7.7 nmol/min [2.8-16.4]). FE rates of ADMA for the liver and kidney were 5.0% (3.5%-7.4%) and 8.4% (1.3%-13.9%), respectively. For SDMA, hepatic and renal FE rates were 3.4% (2.1%-7.5%) and 12.5% (3.6%-16.2%), respectively. In conclusion, this study gives a detailed description of the hepatic and renal elimination of dimethylarginines and shows that the clearing of SDMA is not only confined to the kidney, but the human liver also takes up substantial amounts of SDMA from the portal and systemic circulation.
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Affiliation(s)
- Michiel P C Siroen
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
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