Role Of Symmetric Dimethylarginine Research Articles

Small animal Review

Summary: In this month's Small Animal Review, we summarise three recently published papers from other veterinary journals. The papers focus on feline morbillivirus, a congenital case of canine porphyria and the role of symmetric dimethylarginine in defining renal disease.

Scientific Prize Papers

Objective Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD). Methods In 238 patients with symptomatic PAD and an ABI of Results The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality ( P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI ( r = −0.236, N = 216, P r = −0.209, N = 208, P = .002, respectively). Conclusions The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes

The guanidines asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, and its counterpart symmetric dimethylarginine (SDMA), considered inert, are accumulated in chronic kidney disease (CKD). The present study evaluates their effect on monocyte function, since previous data demonstrated leukocyte activation by other guanidino compounds. The effect of ADMA and SDMA on reactive oxygen species (ROS) production in human whole blood at baseline and after N-formyl-methionine-leucine-phenylalanine (fMLP) stimulation was evaluated. By using the fluorescent probe Fluo3-AM, the role of changes in monocytic cytoplasmic calcium ([Ca2+]i) was studied. Thapsigargin, and removal followed by addition of extracellular Ca2+ (Ca2+(ex)), was used to investigate the contribution of store-operated Ca2+-channels (SOCs). SKF96365 was used as a selective inhibitor of the SOCs. A pharmacologic intervention with captopril, known to affect Ca2+ influx, was tested. SDMA enhanced ROS production in fMLP-stimulated monocytes using heparinized blood, and this effect was abolished in EDTA-anticoagulated blood. In the presence of SDMA, an increased Ca2+ entry from the extracellular milieu resulted in an elevated amplitude of the peak [Ca2+]i change triggered by fMLP. None of these effects were seen with ADMA. Depletion of the intracellular stores with thapsigargin in the absence of Ca2+(ex), followed by re-addition of Ca2+(ex) triggered a significantly larger Ca2+ entry after SDMA treatment versus saline. This effect was prevented with SKF96365, as was the SDMA-enhanced oxidative burst after fMLP. Pre-incubation with captopril also reduced the increased ROS production seen with SDMA. SDMA, a uraemic retention solute considered inert, stimulates ROS production of monocytes by acting on Ca2+ entry via SOCs. This pro-inflammatory effect may trigger vascular pathology and may be involved in altering the prevalence of cardiovascular disease in CKD.

HPLC–Tandem Mass Spectrometric Method for Rapid Quantification of Dimethylarginines in Human Plasma

Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are derived from posttranslational methylation of arginine residues in proteins and after proteolytic release. Whereas protein methylation appears to be important in RNA binding and protein sorting, ADMA evolved as a competitive inhibitor of nitric oxide synthase at the arginine-binding site (1)(2). At a constant arginine supply, increased ADMA concentrations decrease NO formation and impair vascular homeostasis by multiple mechanisms (3). Consequently, arginine supplementation improves small-vessel function (4). Inactivation of ADMA occurs via dimethylarginine dimethylaminohydrolase, and it has been hypothesized that this enzyme might be inhibited by homocysteine. The role of SDMA is less clear; it probably is an inhibitor of arginine transport across the cell membrane (5). From the clinical perspective, ADMA has been established as a possible risk factor for the development of endothelial dysfunction and cardiovascular disease (6). Its plasma concentrations also predict the probability of restenosis after stent implantation. The possible contribution of high-resistance placental circulation, endothelial dysfunction, and increased ADMA concentrations to the development of preeclampsia has been investigated (7). Recently, a significant decrease in circulating ADMA was reported during hormone replacement therapy in postmenopausal women (8). Plasma concentrations of ADMA are also influenced by insulin sensitizers such as rosiglitazone, indicating a possible link of NOS activity to the metabolic syndrome (9). Thus, there is considerable demand for specific, sensitive, and rapid methods for ADMA determination in biological fluids. Previously, several methods for ADMA and SDMA determination have been described, including gas chromatography–tandem mass spectrometry (MS/MS) (10), liquid chromatography …