Endothelial Functions Improve with Decrease in Asymmetric Dimethylarginine (ADMA) Levels after Renal Transplantation

Yılmaz, Mahmut İlker; Sağlam, Mutlu; Çağlar, Kayser; Çakır, Erdinç; Özgürtaş, Taner; Sönmez, Alper; Eyıleten, Tayfun; Yenicesu, Müjdat; Açıkel, Cengizhan; Oğuz, Yusuf; Özcan, Ömer; Bozlar, Uğur; Erbil, Kemal; Aslan, İsmail; Vural, Abdülgaffar

doi:10.1097/01.tp.0000183750.22675.be

Cited by 69 publications

(62 citation statements)

References 36 publications

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“…ADMA, an endogenous inhibitor of NOS, is synthesized by the action of protein arginine methyl transferase on arginine residues of nuclear proteins. ADMA is released following proteolysis, and most of the freely circulating ADMA is metabolized by dimethylarginine dimethylaminohydrolase, which occurs mostly in the liver (29) but can also occur in other organs such as the kidney (46). Data from this model study have previously been described and shown to have renal dysfunction and changes in vascular dynamics as part of the developing multiple organ dysfunction syndrome (50).…”

Section: Discussionmentioning

confidence: 92%

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Sharma

Have

Ytrebø

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N ϭ 8) or hepatic devascularization ALF (N ϭ 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased Ͼ85% of the basal level at t ϭ 6 h (P Ͻ 0.001), whereas citrulline and ornithine progressively increased in ALF (P Ͻ 0.001 and P Ͻ 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P Ͻ 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P Ͻ 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.arginine; asymmetric dimethylarginine; arginase ACUTE LIVER FAILURE (ALF) is characterized by sudden and severe liver dysfunction with rapid progression to coagulopathy, encephalopathy, and multiorgan failure. Without liver transplantation, mortality from ALF is about 50% (4). A hallmark of ALF is the presentation of systemic hypotension and a hyperdynamic circulation (39). This is associated with increased guanylate cyclase (GC) activation by nitric oxide (NO) (33), which converts guanidine triphosphate to cyclic guanidine monophosphate and is thought to cause the vasodilatation seen in ALF (34). Previously, we have reported the characteristics of the same devascularized porcine liver model of ALF, which was shown to have a hyperdynamic circulation as evidenced by a high cardiac output and low mean arterial pressure and systemic vascular resistance (50). However, in this hyperacute model of ALF, no significant changes in the metabolites of NO were observed. Indeed, the kinetics of NO in this model and whether it is involved in the initiation of the vasodilation of ALF remain unknown.L-Arginine has several important biological functions (2, 3, 5), one of which is to be the nitrogen-donating substrate for endothelial NO synthase (eNOS) to produce NO and citrulline in stoichiometric quantities (...

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Section: Discussionmentioning

confidence: 92%

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Sharma

Have

Ytrebø

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…As expected, blood urea nitrogen decreased signifi cantly after kidney transplantation. On the other hand, no signifi cant In general, plasma levels of some biomarkers indicating uremia or infl ammation decrease in patients with endstage renal disease (ESRD) after kidney transplantation ( 26,27 ). However, it is not known whether CYP3A activity recovers with improvement in renal function after kidney transplantation.…”

Section: Resultsmentioning

confidence: 99%

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Suzuki

Sato

Kawasaki

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org Phenotyping of cytochrome CYP3A seems to be of special importance because enzymes belonging to this family, particularly CYP3A4, are involved in the metabolism of more than 50% of currently prescribed drugs. However, the selection of an appropriate CYP3A phenotyping substrate and metric is still a matter of discussion, although some CYP3A test substrates, including midazolam, erythromycin, alprazolam, and nifedipine have been proposed ( 15 ). However, administration of these drugs poses challenges in specifi c patient populations such as pediatric and elderly patients, transplant recipients, and cancer patients, in whom administration of probe drugs may have a negative impact on patient safety. Identifi cation of an appropriate endogenous CYP3A substrate and corresponding metrics would be a promising alternative, allowing simple and possibly broader application of the phenotyping approach. Oxidation of the endogenous compound cortisol to 6 ␤ -hydroxycortisol has been shown to be a CYP3A-dependent pathway in humans. Consequently, a urinary 6 ␤ -hydroxycortisol-to-cortisol ratio has been proposed as a suitable phenotyping marker for the assessment of CYP3A activity ( 16,17 ). However, the sensitivity of the method to detect small changes in enzyme activity is low because of pronounced background variation ( 17 ). Another compound, 4 ␤ -hydroxycholesterol, which is identifi ed as one of the major oxysterols in humans, was reported to be formed solely by CYP3A4 ( 18 ). Markedly elevated concentrations of 4 ␤ -hydroxycholesterol were found in patients treated with CYP3A4 inducers ( 19-23 ), and decreased concentrations in patients treated with CYP3A4 inhibitors ( 22-24 ). Furthermore, a relationship between blood 4 ␤ -hydroxycholesterol concentration and the number of active CYP3A5*1 alleles has been demonstrated, suggesting that 4 ␤ -hydroxycholesterol is formed not only by CYP3A4 but also by CYP3A5 ( 25 ). Accordingly, 4 ␤ -hydro xycholesterol has been proposed to be a potential endogenous biomarker of CYP3A activity. Impaired renal function alters the clearance of many drugs mainly by decreasing their renal elimination. However, several studies in rats ( 1-6 ) and in patients ( 7-9 ) have shown that renal failure also decreases the metabolic clearance of drugs, particularly those metabolized by cytochrome P450 (CYP). The underlying causes of altered CYP functional expression observed in kidney disease remain unclear, but several studies indicate that uremic toxins ( 10-13 ) and infl ammation ( 14 ) may play a role via transcriptional or translational modifi cations of CYP enzymes.

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“…In our study, 81% of patients experienced an improvement in central arterial pressure waveform after HD, and a reduction in ADMA level was present in 87% of patients. It was recently shown that renal transplantation also reduces ADMA levels and improves endothelial function and that these parameters correlate [25]. …”

Section: Discussionmentioning

confidence: 99%

Improvement in Central Arterial Pressure Waveform during Hemodialysis Is Related to a Reduction in Asymmetric Dimethylarginine (ADMA) Levels

Soveri

Lind²,

Wíkström³

et al. 2007

Nephron Clin Pract

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Background: Cardiovascular mortality is high in hemodialysis (HD) patients. Early arterial pressure wave reflections, reflecting arterial stiffness and the endogenous nitric oxide synthesis inhibitor asymmetric dimethylarginine (ADMA) levels predict mortality in HD patients. Therefore, we aimed to study changes in ADMA levels and central arterial pressure waveform during HD. Methods: Thirty-two chronic HD patients were studied before and after a HD session. In a subset of 22 patients without arrhythmias, pulse wave analysis was performed on radial artery (SphygmoCor). Augmentation index (AIx), defined as difference between the second and first systolic peak divided by central pulse pressure, was used as a measure of arterial stiffness. ADMA was measured in plasma with the ELISA technique. Homocysteine was measured in plasma using the EIA technique. Results: HD reduced both AIx (19%; p = 0.003) and ADMA levels (17%; p < 0.001). The magnitudes of changes in AIx and ADMA during HD were correlated (r = 0.44; p = 0.045). Mean arterial pressure change was not significant. HD reduced homocysteine levels, but homocysteine was not related to ADMA or AIx. Conclusion: The reduction in ADMA level seen after HD was associated with improvement in the central arterial pressure waveform, suggesting involvement of nitric oxide in the regulation of arterial stiffness in HD patients.

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Endothelial Functions Improve with Decrease in Asymmetric Dimethylarginine (ADMA) Levels after Renal Transplantation

Abstract: The results indicate that ADMA is associated with FMD in CKD both before and after kidney transplantation. Endothelial functions improve at the very beginning of the posttransplantation period with accompanying reduction in ADMA and hsCRP levels.

Cited by 69 publications

References 36 publications

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Improvement in Central Arterial Pressure Waveform during Hemodialysis Is Related to a Reduction in Asymmetric Dimethylarginine (ADMA) Levels

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