Asymmetric dimethylarginine and critical illness

Brinkmann, Saskia J. H.; Boer, Myrte C. de; Buijs, Nikki; Leeuwen, Paul A. M. van

doi:10.1097/mco.0000000000000020

Cited by 23 publications

(28 citation statements)

References 39 publications

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“…The plasma concentration of these methylarginines in renal transplant patients correlates inversely with the renal expression of alanine-glyoxylate aminotransferase 2 (26). ADMA is substantially raised in hyperthyroidism (27) and critical illness (28), that is, two conditions characterized by high sympathetic activity (29,30) and enhanced protein degradation (31,32), suggesting that reduced sympathetic activity after renal denervation may attenuate the release of these compounds from methylated proteins. Whether the sympathetic system regulates methylarginines by interfering with the synthesis or the degradation of these compounds remains to be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric and Symmetric Dimethylarginine and Sympathetic Nerve Traffic after Renal Denervation in Patients with Resistant Hypertension

Seravalle

Trevano

Spaziani³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives The plasma concentration of the endogenous inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) associates with sympathetic activity in patients with CKD, but the driver of this association is unknown.Design, setting, participants, & measurements In this longitudinal study (follow-up: 2 weeks-6 months), repeated measurements over time of muscle sympathetic nerve activity corrected (MSNAC), plasma levels of ADMA and symmetric dimethylarginine (SDMA), and BP and heart rate were performed in 14 patients with drug-resistant hypertension who underwent bilateral renal denervation (enrolled in 2013 and followed-up until February 2014). Stability of ADMA, SDMA, BP, and MSNAC over time (6 months) was assessed in two historical control groups of patients maintained on stable antihypertensive treatment.Results Time-integrated changes in MSNAC after renal denervation ranged from -40.6% to 10% (average, -15.1%), and these changes were strongly associated with the corresponding changes in plasma ADMA (r= 0.62, P=0.02) and SDMA (r=0.72, P=0.004). Changes in MSNAC went along with simultaneous changes in standardized systolic (r=0.65, P=0.01) and diastolic BP (r=0.61, P=0.02). In the historical control groups, no change in ADMA, SDMA, BP, and MSNAC levels was recorded during a 6-month follow-up. ConclusionsIn patients with resistant hypertension, changes in sympathetic activity after renal denervation associate with simultaneous changes in plasma levels of the two major endogenous methylarginines, ADMA and SDMA. These observations are compatible with the hypothesis that the sympathetic nervous system exerts an important role in modulating circulating levels of ADMA and SDMA in this condition.

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Section: Discussionmentioning

confidence: 99%

Asymmetric and Symmetric Dimethylarginine and Sympathetic Nerve Traffic after Renal Denervation in Patients with Resistant Hypertension

Seravalle

Trevano

Spaziani³

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…Among the guanidine compounds listed as uremic toxins [2], ADMA and SDMA and have been increasingly recognized as putative toxic non-proteinogenic amino acids in a wide range of human diseases over the past decades [3,4,5,6,7,8,9,10,11]. …”

Section: Introductionmentioning

confidence: 99%

Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA)

Tain

Hsu

2017

Toxins

202

195

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Asymmetric and symmetric dimethylarginine (ADMA and SDMA, respectively) are toxic, non-proteinogenic amino acids formed by post-translational modification and are uremic toxins that inhibit nitric oxide (NO) production and play multifunctional roles in many human diseases. Both ADMA and SDMA have emerged as strong predictors of cardiovascular events and death in a range of illnesses. Major progress has been made in research on ADMA-lowering therapies in animal studies; however, further studies are required to fill the translational gap between animal models and clinical trials in order to treat human diseases related to elevated ADMA/SDMA levels. Here, we review the reported impacts of ADMA and SDMA on human health and disease, focusing on the synthesis and metabolism of ADMA and SDMA; the pathophysiological roles of these dimethylarginines; clinical conditions and animal models associated with elevated ADMA and SDMA levels; and potential therapies against ADMA and SDMA. There is currently no specific pharmacological therapy for lowering the levels and counteracting the deleterious effects of ADMA and SDMA. A better understanding of the mechanisms underlying the impact of ADMA and SDMA on a wide range of human diseases is essential to the development of specific therapies against diseases related to ADMA and SDMA.

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“…[12][13][14][15] ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to dimethylamine and citrulline. 16 Two isoforms of DDAH exist which have differing distributions throughout the body.…”

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confidence: 99%

Dimethylarginine Dimethylaminohydrolase 2 Regulates Nitric Oxide Synthesis and Hemodynamics and Determines Outcome in Polymicrobial Sepsis

Lambden

Kelly

Ahmetaj‐Shala

et al. 2015

ATVB

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Objective— Nitric oxide is a key to numerous physiological and pathophysiological processes. Nitric oxide production is regulated endogenously by 2 methylarginines, asymmetric dimethylarginine (ADMA) and monomethyl- l -arginine. The enzyme that specifically metabolizes asymmetric dimethylarginine and monomethyl- l -arginine is dimethylarginine dimethylaminohydrolase (DDAH). The first isoform dimethylarginine dimethylaminohydrolase 1 has previously been shown to be an important regulator of methylarginines in both health and disease. This study explores for the first time the role of endogenous dimethylarginine dimethylaminohydrolase 2 in regulating cardiovascular physiology and also determines the functional impact of dimethylarginine dimethylaminohydrolase 2 deletion on outcome and immune function in sepsis. Approach and Results— Mice, globally deficient in Ddah2, were compared with their wild-type littermates to determine the physiological role of Ddah2 using in vivo and ex vivo assessments of vascular function. We show that global knockout of Ddah2 results in elevated blood pressure during periods of activity (mean [SEM], 118.5 [1.3] versus 112.7 [1.1] mm Hg; P =0.025) and changes in vascular responsiveness mediated by changes in methylarginine concentration, mean myocardial tissue asymmetric dimethylarginine (SEM) was 0.89 (0.06) versus 0.67 (0.05) μmol/L ( P =0.02) and systemic nitric oxide concentrations. In a model of severe polymicrobial sepsis, Ddah2 knockout affects outcome (120-hour survival was 12% in Ddah2 knockouts versus 53% in wild-type animals; P <0.001). Monocyte-specific deletion of Ddah2 results in a similar pattern of increased severity to that seen in globally deficient animals. Conclusions— Ddah2 has a regulatory role both in normal physiology and in determining outcome of severe polymicrobial sepsis. Elucidation of this role identifies a mechanism for the observed relationship between Ddah2 polymorphisms, cardiovascular disease, and outcome in sepsis.

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Asymmetric dimethylarginine and critical illness

Abstract: Elevated ADMA levels occur in critically ill patients, which is detrimental for morbidity and mortality. The arginine : ADMA ratio should be restored to maintain nitric oxide production and therewith improve the clinical outcome of the patient.

Cited by 23 publications

References 39 publications

Asymmetric and Symmetric Dimethylarginine and Sympathetic Nerve Traffic after Renal Denervation in Patients with Resistant Hypertension

Asymmetric and Symmetric Dimethylarginine and Sympathetic Nerve Traffic after Renal Denervation in Patients with Resistant Hypertension

Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA)

Dimethylarginine Dimethylaminohydrolase 2 Regulates Nitric Oxide Synthesis and Hemodynamics and Determines Outcome in Polymicrobial Sepsis

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