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Introduction: Proton pump inhibitors (PPIs) rank among the most frequently prescribed medications to treat acid-related diseases. Mounting concerns surround the potential for serious adverse events, including cardiovascular events, associated with their prolonged use/misuse. Areas covered: This comprehensive review explores cardiovascular adverse events linked to PPI use among high-risk cardiovascular patients. A structured search was conducted on PubMed Expert opinion: Many patients with cardiovascular disease who require antiplatelet treatment will require long-term PPI treatment. Interpreting the published data is not straightforward. First, because there is no plausible mechanistic explanation for PPIs to induce cardiovascular events apart from the potential interaction with the metabolism of thienopyridines. Although several observational studies have shown an increased cardiovascular risk and mortality in patients taking long-term PPIs, most available clinical trials and meta-analyses of available studies do not. However, the absence of firm evidence of this link does not necessarily imply that this association does not exist, and other hypothesis must be explored. Anemia is a common event in patients who take antiplatelet therapy and PPIs, and it is a factor associated with cardiovascular events and death. Anemia in these patients is often attributed to erosive lesions of the small intestine, where PPI may play a key role by modifying the microbiota. [ABSTRACT FROM AUTHOR]

The role of arginine in the development of primary arterial hypertension continues to be clarified up to the present moment. During natural metabolic processes in cells, methylated forms of arginine are produced – symmetric (SDMA) and asymmetric (ADMA) dimethylarginine. ADMA is a nitric oxide synthase inhibitor and is now considered a well-established marker for endothelial dysfunction. SDMA is not a nitric oxide synthase inhibitor, but may indirectly reduce nitric oxide production through competitive interaction with cellular L-arginine.Currently, arginine preparations are practically not used for the treatment of primary arterial hypertension. This was the rationale for the given scientific review. The article summarizes the information available in the literature (2018–2022) on the pathogenetic mechanisms of the relationship between arginine and the development of impaired vascular tone. We used PubMed and RSCI databases for our review. Using keywords, 1784 publications were found over the past 5 years. The final selection criteria were time frame and matching keywords. The review provides data on the increased ADMA concentrations in experimental hypertensive animals and individuals with essential hypertension. The role of arginine metabolites in the genesis of endothelial dysfunction and arterial hypertension and the prospects for the therapeutic use of this compound are discussed.

Scientific relevance. A key anti-ischaemic mechanism of some medicinal products involves their effects on the metabolism of endothelial vasodilators, particularly the synthesis of nitric oxide from arginine and its precursor citrulline.Aim. The study was aimed to determine whether the plasma time course of guanidine derivatives (arginine precursors) is applicable to laboratory control of anti-ischaemic therapy effectiveness using a single oral dose of nicorandil in patients with coronary heart disease as a case study.Materials and methods. The authors used high-performance liquid chromatography to determine metabolites. Blood samples for analysis were obtained from 30 patients with angina pectoris (Grade II–III, Canadian Cardiovascular Society) and 30 healthy donors. All the study participants received a single oral dose of 20 mg nicorandil after 10 h of fasting.Results. At baseline, patients showed significantly higher plasma citrulline levels than donors. However, the elevated levels decreased to the healthy range after nicorandil administration. Plasma arginine levels in patients showed a statistically significant increase following nicorandil administration. Plasma homoarginine levels in patients remained reduced both before and after dosing. Nicorandil did not influence elevated levels of the endogenous nitric oxide synthase inhibitor (asymmetrical dimethylarginine).Conclusions. In addition to the established mechanisms responsible for altering cell metabolism, nicorandil enhances the contribution of citrulline to arginine resynthesis. It is reasonable to include citrulline and arginine, which are involved in the vasodilator response, in model schemes for laboratory control of the effectiveness of anti-ischaemic therapy.

In the present prospective clinical human study, we focused on researching whether or not there is a difference between metabolic syndrome (MS) positive/negative and renal stone disease (SD) positive/negative patients with regard to asymmetrical dimethylarginine (ADMA) serum levels to clarify the possible effect of endothelial cell dysfunction on renal SD. We included 76 patients (17 males and 59 females) who were admitted to the endocrinology and urology outpatient clinic between December 2014 and February 2018. Patients were segregated into 4 groups; group 1; MS (-) SD (-), group 2; MS (-) SD (+), group 3; MS (+) SD (-) and group 4; MS (+) SD (+). Patients' age, sex, medical history, and anthropometric measurements were recorded. Endothelial dysfunction was assessed with serum ADMA levels. The mean age was 40.1 ± 11.4 years (range: 18-59). There was a statistically significant difference between groups for mean homocysteine, uric acid and BMI values. However, there was no statistically significant difference between groups for mean CRP, age and creatinine values. The mean ADMA value was 152 ± 77 (range: 51-445). There was no statistically significant difference between groups for the mean ADMA values. These results showed that studies must focus on MS components separately from each other and sex distribution between patients must be homogeneous or different sexes must be examined separately. In addition, stone compositions of patients enrolled in the study must be known to arrive at more trustworthy and worthwhile results. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) represents a world-wide public health problem. Inflammation, endothelial dysfunction (ED) and vascular calcifications are clinical features of CKD patients that increase cardiovascular (CV) mortality. CKD-related CV disease pathogenic mechanisms are not only associated with traditional factors such as arterial hypertension and dyslipidemia, but also with ED, oxidative stress and low-grade inflammation. The typical comorbidities of CKD contribute to reduce the performance and the levels of the physical activity in nephropathic patients compared to healthy subjects. Currently, the effective role of physical activity on ED is still debated, but the available few literature data suggest its positive contribution. Another possible adjuvant treatment of ED in CKD patients is represented by natural bioactive compounds (NBCs). Among these, minor polar compounds of extra virgin olive oil (hydroxytyrosol, tyrosol and oleocanthal), polyphenols, and vitamin D seem to exert a beneficial role on ED in CKD patients. The objective of the review is to evaluate the effectiveness of physical exercise protocols and/or NBCs on ED in CKD patients.

Erectile Dysfunction (ED) is one of the main complaints of aging male. A reduced production of Nitric Oxide (NO) may be involved in ED pathogenesis. NO is synthesized from l -Arginine, and asymmetrical dimethylarginine inhibits all NO synthases. DDAH1 and DDAH2 are genes that encode enzymes responsible for metabolizing ADMA. We aimed to assess whether: 1) ADMA and nitrite levels associated with ED risk and with symptoms intensity; and whether 2) DDAH1 and DDAH2 gene polymorphisms associate with changes in biochemical data, and with ED risk and symptoms intensity. In this study were included 98 healthy controls and 130 ED patients. ADMA levels were measured by ELISA and nitrite levels by Chemiluminescence. DDAH1 and DDAH2 polymorphisms were assessed by Taqman assays. We found that ED had increased nitrite levels and lower ADMA levels than Control group (P < 0.05). We found a significant correlation of ADMA with Nitrite levels only in ED (B = -0.57, P < 0.001). Genotypes and haplotypes of DDAH1 were associated with ADMA levels in ED (P < 0.05), while haplotypes of DDAH2 were associated with levels of nitrite in ED (P < 0.05). Erectile dysfunction patients show an association between DDAH1 and DDAH2 polymorphisms with ADMA levels, which in turn are negatively correlated with nitrite levels. This is not evident on healthy controls. • ADMA and nitrite plasma levels are negatively associated when ED is present. • There is no association between ADMA and nitrite in healthy controls. • Nitrite levels correlate negatively with Erectile function. • DDAH1 and DDAH2 polymorphisms were associated with changes in ADMA and Nitrite levels. • DDAH1 and DDAH2 polymorphisms were not associated with changes in erectile function, nor ED risk. [ABSTRACT FROM AUTHOR]

Background. Nitric oxide synthase (NOS) is present in the brain and cerebral arteries and it enables the synthesis of nitric oxide (NO), which plays a critical role in brain perfusion. Asymmetrical dimethylarginine (ADMA) is an endogenous NOS inhibitor. Objectives. The aim of this study was to evaluate serum ADMA levels, which are an indicator of endothelial dysfunction of the renal functions in patients with acute ischemic stroke, and to determine whether there is a possible correlation between ADMA and NO levels and the l-arginine-to-ADMA ratio. Material and methods. Fifty-two patients (22 male and 30 female; mean age: 75.2 ±10.1 years) with a diagnosis of acute ischemic stroke in the first 24 h post-stroke and 48 healthy individuals (controls; 13 male and 35 female; mean age: 60.1 ±7.92 years) were included in this study. The risk factors recorded and evaluated were age and gender of the patients, serum lipid levels, serum ADMA levels, nitrate-to-nitrite ratios, l-arginine, l-arginine-to-ADMA ratios, sedimentation rate, C-reactive protein (CRP), urea and creatinine levels, and glomerular filtration ratio (eGFR). Results. The mean serum ADMA level was 0.48 ±0.23 µM for the patients and 0.36 ±0.18 µM for the controls. The mean NO level was 2.78 ±0.59 µM for the patient group and 4.49 ±2.84 µM for the controls. The ADMA levels for the patient group were significantly higher than for the control group (p = 0.011); the NO levels for the patients were significantly lower than for the controls (p < 0.001). The logistic regression method demonstrated that ADMA and NO levels may be independent risk factors for the patient group, and the receiver operating characteristic (ROC) curve analysis showed that both of these variables were discriminative risk factors. Conclusions. An increased serum level of the NOS inhibitor ADMA was found to be a possible independent risk factor for ischemic stroke. [ABSTRACT FROM AUTHOR]

Aging-related ED is predominantly attributed to neurovascular dysfunction mediated by NO suppression and increased oxidative stress in penis. The alterations of protein arginine methyltransferases 1 (PRMT1)/dimethylarginine dimethylaminohydrolase (DDAH)/asymmetrical dimethylarginine (ADMA)/NO synthase (NOS) pathway regulate NO production in the vascular endothelium. Epigallocatechin-3-gallate (EGCG) is one of the most abundant and antioxidative ingredients isolated from green tea. In the present study, 40 Sprague-Dawley rats were randomly distributed into four groups: one young rat group and three aged rat groups treated with daily gavage feedings of EGCG at doses of 0, 10 mg kg−1 and 100 mg kg−1 for 12 weeks, respectively. Erectile function was assessed by electrical stimulation of the cavernous nerves with intracavernous pressure (ICP) measurement. After euthanasia, penile tissue was investigated using Western blot and ELISA to assess the PRMT1/DDAH/ADMA/NOS metabolism pathway. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. We also evaluated smooth muscle contents. The ratio of maximal ICP and mean systemic arterial pressure (MAP) was markedly higher in EGCG-treated aged rats than in untreated aged rats. We found that DDAH1 and DDAH2 were expressed in cavernosal tissue, and they were downregulated in corpora of aged rats. The administration of EGCG upregulated the expression and activity of DDAH. In contrast, EGCG treatment downregulated the expression of PRMT1 and ADMA content. Moreover, EGCG-treated rats showed an improvement in smooth muscle expression, the ratio of smooth muscle cell/collagen fibril, SOD activity, and MDA levels when compared with untreated aged rats.

Background: The antiatherogenic effect of conjugated linoleic acid (CLA) has been demonstrated in animal models. Although there are plenty of in vitro studies that suggest the profitable properties of CLA, the results in humans remain inconsistent. Objective: In this study, we assessed the impact of CLA supplementation on the levels of atherosclerosis markers – high-sensitivity C-reactive protein (hs-CRP) and asymmetrical dimethylarginine (ADMA). Design: Seventy-four adult female subjects with body mass index ≥25 kg/m2 were enrolled in the double-blind, placebo-controlled nutritional intervention. The study participants were randomly assigned to receive 3 g/day CLA or placebo (sunflower oil) for 12 weeks. In all subjects, we measured hs-CRP and ADMA concentrations by using enzyme-linked immunosorbent assay. Results: No significant differences were found in hs-CRP and ADMA levels before and after nutritional intervention between both groups. The changes in hs-CRP and ADMA concentration values (Δhs-CRP; ΔADMA median [interquartile range]) did not differ between subjects from the placebo (−0.1 [−0.8 to 0.3]; −0.02 [−0.12 to 0.14]) and CLA (0.2 [−0.7 to 0.9]; 0.04 [−0.14 to 0.13]) groups. The incidence of reduction of hs-CRP or ADMA concentration was not different in subjects of the CLA group compared to those of the placebo group (41.9% vs. 50%, relative risk [RR]=0.8387, 95% confidence interval [CI]=0.4887–1.4493, p=0.5232 and 61.3% vs. 56.2%, RR=1.0896, 95% CI=0.7200–1.6589, p=0.6847, respectively). Conclusion: Twelve weeks of CLA supplementation had no effect on selected markers of atherosclerosis in obese and overweight women.

Asymmetric dimethylarginine (ADMA), which is the main endogenous inhibitor of nitric oxide synthase, plays a critical role in the process of endothelial dysfunction. The authors evaluated the association between high plasma ADMA levels in patients with hypertension and the presence of cardiovascular risk factors and the development of type 2 diabetes mellitus (DM) and cardiovascular outcomes, including death. The authors evaluated 191 patients with hypertension who were stratified into two groups according to the median value of basal ADMA: those with high levels of plasma ADMA (>0.55 μmol/L) and low levels of plasma ADMA (≤0.55 μmol/L) who were prospectively evaluated over 5.8 years. High ADMA levels were seen in patients with higher weight, body mass index, waist circumference, triglycerides, uric acid, and high-sensitivity C-reactive protein, and lower levels of high-density lipoprotein cholesterol and in patients with type 2 DM. There was an association between high plasma ADMA levels and the occurrence of cardiovascular death. In a subgroup of patients with hypertension free from metabolic syndrome and DM at baseline, there was an association between high ADMA levels and the development of type 2 DM. This study confirms the association of high plasma ADMA levels and the presence of cardiovascular risk factors in patients with hypertension and suggests a positive predictive value of high plasma ADMA levels for cardiovascular death in patients with hypertension and also for the development of type 2 DM in a subgroup of patients with hypertension free from metabolic abnormalities. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to evaluate the association between high plasma ADMA levels, a biomarker of endothelial dysfunction, with the progression of albuminuria and chronic kidney disease (CKD) in hypertensive patients, with and without type 2 diabetes mellitus.Methods: We successfully contacted 213 of 644 patients who had been evaluated between 2004 and 2005 and for whom basal data were available. After the exclusion of 51 patients, 162 hypertensive patients who were free from albuminuria were stratified into the following 4 groups according to the presence of diabetes and plasma ADMA percentiles: general hypertensive patients with high levels of plasma ADMA (>P4 or ADMA > 0.61 μmol/L), general hypertensive patients with low levels of plasma ADMA (≤P4), diabetic hypertensive patients with high levels of plasma ADMA (>P4), and diabetic hypertensive patients with low levels of plasma ADMA (≤P4).Results: The patients were prospectively evaluated over 5.8 years. High ADMA levels were associated with the progression of albuminuria in hypertensive patients, with and without type 2 diabetes. Major increases in the ADMA value during follow-up were associated with the progression of CKD, and direct correlations between ADMA changes and GFR changes were observed in the whole group and in the subgroup of diabetic patients.Conclusions: We suggest that high plasma ADMA levels might be a biomarker of renal disease progression and might even be an early predictor of albuminuria and its progression to the late stages of renal disease in hypertensive and diabetic hypertensive patients. [ABSTRACT FROM AUTHOR]

Aging-related ED is predominantly attributed to neurovascular dysfunction mediated by NO suppression and increased oxidative stress in penis. The alterations of protein arginine methyltransferases 1 (PRMT1)/dimethylarginine dimethylaminohydrolase (DDAH)/asymmetrical dimethylarginine (ADMA)/NO synthase (NOS) pathway regulate NO production in the vascular endothelium. Epigallocatechin-3-gallate (EGCG) is one of the most abundant and antioxidative ingredients isolated from green tea. In the present study, 40 Sprague-Dawley rats were randomly distributed into four groups: one young rat group and three aged rat groups treated with daily gavage feedings of EGCG at doses of 0, 10 mg kg−1 and 100 mg kg−1 for 12 weeks, respectively. Erectile function was assessed by electrical stimulation of the cavernous nerves with intracavernous pressure (ICP) measurement. After euthanasia, penile tissue was investigated using Western blot and ELISA to assess the PRMT1/DDAH/ADMA/NOS metabolism pathway. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. We also evaluated smooth muscle contents. The ratio of maximal ICP and mean systemic arterial pressure (MAP) was markedly higher in EGCG-treated aged rats than in untreated aged rats. We found that DDAH1 and DDAH2 were expressed in cavernosal tissue, and they were downregulated in corpora of aged rats. The administration of EGCG upregulated the expression and activity of DDAH. In contrast, EGCG treatment downregulated the expression of PRMT1 and ADMA content. Moreover, EGCG-treated rats showed an improvement in smooth muscle expression, the ratio of smooth muscle cell/collagen fibril, SOD activity, and MDA levels when compared with untreated aged rats. [ABSTRACT FROM AUTHOR]

Background Critically ill patients experience metabolic disorders including hypercatabolic state and hyperglycaemia, and these are associated with poor outcome. Hyperglycaemia and asymmetrical dimethylarginine ( ADMA) are reported to have significant influences on endothelial dysfunction. The aim of this study was to examine the relationship between plasma ADMA and related arginine metabolism in patients with critical illness. Materials and methosds Two venous blood samples ( EDTA) (104 patients), on admission and follow-up sample in the last day in intensive care unit (ICU) (died or discharge sample median 7, interquartile range (IQR) 6-8, range 5-15). Plasma ADMA, arginine, homoarginine and SDMA were measured by high-performance liquid chromatography ( HPLC). Result ADMA ( P < 0·01) and SDMA ( P < 0·05) were elevated, and homoarginine was decreased ( P < 0·05) in nonsurvivors and was directly associated with predicted mortality rate ( P < 0·05 and P < 0·001), Sequential Organ Failure Assessment (SOFA) ( P < 0·05, P < 0·001), ICU stay ( P < 0·05, P < 0·001) and mortality ( P < 0·01, P < 0·05). ADMA was directly associated with SDMA ( P < 0·001), albumin ( P < 0·05), ICU stay and mortality ( P < 0·01). SDMA was directly associated with creatinine ( P < 0·001) and Acute physiology and Chronic Health Evaluation II score ( P < 0·001). In the follow-up measurements, there was a significant decrease in SOFA score ( P < 0·01), homoarginine ( P < 0·01), aminotransferase ( P < 0·01), Laboratory Glucose ( P < 0·01) and albumin ( P < 0·01). In contrast, there was an increase in arginine ( P < 0·01), ADMA ( P < 0·01), ADMA: SDMA ratio ( P < 0·01) and the norepinephrine administration ( P < 0·01). Conclusion In the present longitudinal study, ADMA metabolism was altered in patients with critical illness and was associated with disease severity and mortality. [ABSTRACT FROM AUTHOR]

Background: Fluid overload causes excessive systemic vasoconstriction and decreased perfusion of peripheral tissues, leading to abnormalities in cardiopulmonary physiological functions. Prolonged fluid overload caused by inadequate hemodialysis may cause heart dilatation, left ventricular hypertrophy, hypertension, and a decrease in coronary reserves, which later will develop into coronary ischemia, leading to increased morbidity and mortality of cardiovascular disease (CVD). Endothelial dysfunction plays a role in excessive vasoconstriction on fluid overload. Brain natriuretic peptide (BNP) and asymmetric dimethylarginine (ADMA) are used as parameters of fluid overload and endothelial dysfunction, respectively. This study is conducted to describe the relationship between fluid overload with endothelial dysfunction., Method: This study is a cross-sectional study of kidney failure patients who underwent hemodialysis twice weekly for at least three months. BNP and ADMA were used as parameters for fluid overload and taken prior to hemodialysis., Result: From 126 subjects, the proportion with fluid overload (BNP>356 pg/ml) was found to be 64.3% with the median age of subjects being 52 years (47-62). There was 47.6% population with endothelial dysfunction (ADMA>100 ng/ml). Presumptive causes of primary chronic kidney disease (CKD) were hypertension (38.9%), diabetes mellitus (DM) (28.6%), and glomerulonephritis (21.4%). There was no significant association between fluid overload and endothelial dysfunction (PR=1,042, p=0.832 CI 95%=0.714-1.521)., Conclusion: There was no relationship between fluid overload and endothelial dysfunction., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Wijaya et al.)

Esmolol produces early regression of left ventricular hypertrophy and improves coronary artery remodeling, although the impact of short-term treatment with this beta-blocker on remodeling in large arteries has not yet been studied. We hypothesized that even a short (48 h) course of esmolol might alter remodeling of the aorta in the spontaneously hypertensive rat (SHR). Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=8) or esmolol (SHR-E, n=8) (300 μg/kg/min). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=8) served as controls. After 48 h, we studied the structure, volume density of elastic fibers, and passive mechanical properties of the aorta. Determination of asymmetrical dimethylarginine concentrations and total protein carbonyls in the aorta were analyzed. Esmolol significantly attenuated abnormal aortic wall thickness, cross-sectional area, wall-to-lumen ratio, volume density of elastic fibers, and wall stiffness. The protective effect of esmolol could be related to a decrease in asymmetrical dimethylarginine levels after down-regulation by oxidative stress. These findings could play a key role in the selection of antihypertensive therapy in patients with hypertension and aortic remodeling. [ABSTRACT FROM AUTHOR]

Background: The antiatherogenic effect of conjugated linoleic acid (CLA) has been demonstrated in animal models. Although there are plenty of in vitro studies that suggest the profitable properties of CLA, the results in humans remain inconsistent. Objective: In this study, we assessed the impact of CLA supplementation on the levels of atherosclerosis markers - high-sensitivity C-reactive protein (hs-CRP) and asymmetrical dimethylarginine (ADMA). Design: Seventy-four adult female subjects with body mass index ≥25 kg/m² were enrolled in the doubleblind, placebo-controlled nutritional intervention. The study participants were randomly assigned to receive 3 g/day CLA or placebo (sunflower oil) for 12 weeks. In all subjects, we measured hs-CRP and ADMA concentrations by using enzyme-linked immunosorbent assay. Results: No significant differences were found in hs-CRP and ADMA levels before and after nutritional intervention between both groups. The changes in hs-CRP and ADMA concentration values (Dhs-CRP; DADMA median [interquartile range]) did not differ between subjects from the placebo (-0.1 [-0.8 to 0.3]; 0.02 [-0.12 to 0.14]) and CLA (0.2 [-0.7 to 0.9]; 0.04 [-0.14 to 0.13]) groups. The incidence of reduction of hs-CRP or ADMA concentration was not different in subjects of the CLA group compared to those of the placebo group (41.9% vs. 50%, relative risk [RR] = 0.8387, 95% confidence interval [CI] = 0.4887-1.4493, p = 0.5232 and 61.3% vs. 56.2%, RR = 1.0896, 95% CI = 0.7200-1.6589, p = 0.6847, respectively). Conclusion: Twelve weeks of CLA supplementation had no effect on selected markers of atherosclerosis in obese and overweight women. [ABSTRACT FROM AUTHOR]

Nutritional factors such as magnesium, folic acid, vitamins B12 and B6, L-arginine, and polyunsaturated fatty acids (PUFAs) appear to be significantly beneficial for patients with coronary artery disease (CAD), and in the prevention and arresting the progression of HF and cardiac arrhythmias. Additionally, ingestion of adequate amounts of protein and maintaining normal concentrations of plasma albumin seem to be essential for these patients. These nutrients closely interact with the metabolism of L-arginine-nitric oxide (NO) system, essential fatty acids, and eicosanoids such that beneficial products such as NO, prostaglandin E1, prostacyclin, prostaglandin I3, lipoxins, resolvins, and protectins are generated and synthesis of proinflammatory cytokines is suppressed that results in platelet anti-aggregation, vasodilation, angiogenesis, and prevention of CAD, cardiac arrhythmias, and stabilization of HF. This implies that individuals at high risk for CAD, cardiac arrhythmias, and HF and those who have these diseases need to be screened for plasma levels of magnesium, folic acid, vitamins B12 and B6, L-arginine, NO, various PUFAs, lipoxin A4, resolvins, protectins, asymmetrical dimethylarginine (an endogenous inhibitor of NO), albumin, and various eicosanoids and cytokines and correct their abnormalities to restore normal physiology. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to investigate the distribution of plasma asymmetrical dimethylarginine (ADMA) and homocysteine levels in Chinese patient with acute cerebral infarction (ACI) and their correlations with various risk factors. Methods In total, 178 patients within the first 72 hours of ACI were assigned to 5 groups according to the Trial of Org 10172 in Acute Stroke Treatment classification and further divided into primary group and recurrent group; 52 healthy controls were also recruited in this study. Blood samples were collected for detecting plasma concentrations of ADMA and homocysteine and other biochemical parameters. Results Plasma concentrations of ADMA and homocysteine were significantly higher in patients with ACI compared with healthy control ( P < .05) and varied among the different subsets of patients. Both the levels were significantly different between the primary group and recurrent group. Age, systolic pressure, blood glucose, total cholesterol, body mass index, ADMA, and homocysteine were significant risk factors for ACI in Chinese population. Correlation analysis showed that plasma ADMA level was positively correlated with the plasma level of homocysteine in patients with ACI, and each of them was positively correlated with age, systolic pressure, diastolic pressure, and total cholesterol, whereas homocysteine level was also found to be positively correlated with smoking. Conclusions The current results indicated that ADMA and homocysteine were important contributors to the development of ACI among Chinese population, and plasma concentrations of ADMA and homocysteine were positively correlated with one another and other risk factors. Our study also suggested close-response relationships of plasma concentrations of ADMA and homocysteine to recurrent ACI. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effect of a six-month lifestyle intervention on ghrelin and asymmetrical dimethylarginine (ADMA) in obese Mexican adolescents. A total of 65 obese Mexican adolescents aged 10-16 years completed a six-month lifestyle intervention. Anthropometric and biochemical parameters were assessed at baseline and at six months. Twenty normal-weight adolescents were also evaluated at baseline. Insulin resistance (IR) was determined by the homeostasis model assessment of IR (HOMA-IR). Ghrelin and ADMA were determined by enzyme-linked immunosorbent assay. Obese adolescents presented significantly higher triglycerides, cholesterol, glucose, insulin, HOMA-IR, and ADMA levels, while ghrelin was significantly lower. The lifestyle intervention led to a significant improvement in HOMA-IR, ghrelin, and ADMA in the whole studied obese subjects. ADMA and ghrelin levels were associated with BMI and IR components. According to the value of HOMA-IR, the obese subjects were divided into subjects with or without IR, no difference in ghrelin and ADMA was observed in these two subgroups. After intervention, the obese with IR showed increased ghrelin and decreased ADMA, while the obese without IR only showed improvement in ghrelin. The multiple linear regression analysis revealed that the changes of systolic blood pressure were the only predictor for the changes of ghrelin in the obese with IR. Our study demonstrated the increase of ADMA and the decrease of ghrelin in obese adolescents. Lifestyle intervention improved insulin resistance, decreased ADMA, and increased ghrelin in obese subjects with IR although no significant weight loss was observed. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the level of asymmetrical dimethylarginine (ADMA) levels before gonadotrophine treatment and on the day of oocytes retrieval in order to determine whether ADMA can be used as a predictive marker for implantation success in in vitro fertilization (IVF) cycles. Forty-four unexplained infertile patients were included in the study. Controlled ovarian hyperstimulation was performed using the recombinant follicle-stimulating hormone (FSH) with the standard long protocol for all patients. ADMA and E2 were measured at the beginning of the ovulation induction and on oocyte retrieval day. The primary outcome was the difference in ADMA levels in implantation positive and implantation negative women. At the beginning of the ovulation induction, the mean ADMA levels were 1553 μmol/L and 1.464 μmol/L in the implantation positive and negative groups, respectively. There was no statistically significant difference between groups ( p: 0.90). On the day of oocyte retrieval, the mean ADMA levels were 1173 μmol/L and 1170 μmol/L in the implantation positive and negative groups, respectively. There was no statistically significant difference between groups ( p: 0.97). In conclusion, ADMA levels before gonadotrophine treatment and the day of oocytes retrieval cannot be used as a predictive marker for implantation success in IVF cycles. [ABSTRACT FROM AUTHOR]

Within the paraventricular nucleus (PVN), there is a balance between the excitatory and inhibitory neurotransmitters that regulate blood pressure; in hypertension, the balance shifts to enhanced excitation. Nitric oxide (NO) is an atypical neurotransmitter that elicits inhibitory effects on cardiovascular function. We hypothesized that reduced PVN NO led to elevations in blood pressure during both the onset and sustained phases of hypertension due to decreased NO synthase (NOS) and increased asymmetrical dimethylarginine (ADMA; an endogenous NOS inhibitor) and symmetric dimethylarginine (SDMA). Elevated blood pressure, in response to PVN bilateral microinjections of a NO inhibitor, nitro-L-arginine methyl ester, was blunted in renal wrapped rats during the onset of hypertension (day 7) and sustained renal wrap hypertension (day 28) compared with sham-operated rats. Adenoviruses (Ad) encoding endothelial NOS (eNOS) or LacZ microinjected into the PVN [1 ≤ 109 plaque-forming units, bilateral (200 nl/site)] reduced mean arterial pressure compared with control (Day 7, Ad LacZ wrap: 144 ± 7 mmHg and Ad eNOS wrap: 117 ± 5 mmHg, P ≤ 0.05) throughout the study (Day 28, Ad LacZ wrap: 123 ± 1 mmHg and Ad eNOS wrap: 108 ± 4 mmHg, P ≤ 0.05). Western blot analyses of PVN NOS revealed significantly lower PVN neuronal NOS during the onset of hypertension but not in sustained hypertension. Reduced SDMA was found in the PVN during the onset of hypertension; however, no change in ADMA was observed. In conclusion, functional indexes of NO activity indicated an overall downregulation of NO in renal wrap hypertension, but the mechanism by which this occurs likely differs throughout the development of hypertension. [ABSTRACT FROM AUTHOR]

Objective: Changes in NO synthesis have been shown in studies regarding NO function in mood disorders, schizophrenia, autism, obsessive compulsive disorder and Alzheimer's disease. The aim of this study was to compare plasma NO and simultaneous plasma ADMA levels of bipolar patients in acute mania with healthy controls. Methods: A group of 30 patients experiencing a manic episode and diagnosed as having bipolar disorder according to the DSM-IV TR criteria were included in the study. The healthy control group consisted of the same number of age and sex-matched individuals with a similar smoking status. The SCID-I, Hamilton Depression Scale, Young Mania Scale, and Montgomery Asberg Assessment Scale were used to evaluate clinical condition and to exclude any concurrent mental disorders in both groups. Two tubes of blood were collected from all participants to examine plasma NO and ADMA levels. Results: Plasma NO levels of patients were found to be significantly lower, whereas the ADMA levels were significantly higher than the control group. Conclusions: The results of this study can contribute to a better understanding of the role of inflammatory processes in acute mania in relation to NO and ADMA, which are suspected to be involved in the pathogenesis of various neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

In healthy, mostly normotensive blacks, 19 salt-sensitive (SS) and 18 salt-resistant (SR), we tested the hypothesis that, in SS subjects, dietary NaCl loading induces its initial pressor effect by inducing a normal increase of cardiac output, while failing to induce a normal pressor-offsetting vasodilatation, consequent to its inhibition by asymmetrical dimethylarginine that is abnormally increased by NaCl. In SS and SR subjects, dietary NaCl loading, 250 from 30 mmol/d, over a 7-day period, induced similar, immediate increases in external Na(+) balance (by day 2, ≈360 mmol), plasma volume (+11%), and cardiac output (+8%). In SR subjects, from day 1, transient decreases occurred in both systemic vascular resistance (nadir: -13%, day 2) and mean arterial pressure (nadir: -5%, day 2). In SS subjects, systemic vascular resistance did not change over days 1 to 3, whereas mean arterial pressure increased progressively after day 1, ultimately by 10 mm Hg. Failure of systemic vascular resistance to normally decrease, while cardiac output normally increased, accounted for salt's initial pressor effect in the SS subjects. In SS subjects, baseline plasma levels of asymmetrical dimethylarginine (0.76 μmol/L) and symmetrical dimethylarginine (0.60 μmol/L), which does not affect vasodilatation, approximated those in SR subjects. In SS but not SR subjects, NaCl loading induced increases in asymmetrical dimethylarginine on both days 2 (+38%, median) and 7 (+14%, median). Symmetrical dimethylarginine changed in neither group. For all of the subjects combined, changes in asymmetrical dimethylarginine on day 2 predicted changes in systemic vascular resistance (R=0.751; P<0.001) and mean arterial pressure (R=0.527; P=0.006) on day 2 and similarly on day 7. These observations support the hypothesis tested. [ABSTRACT FROM AUTHOR]

Aim: Endothelial damage and dysfunction are held responsible for the etiopathogenesis of Behçet's disease (BD). In the present study, we aimed to investigate the relationship of BD with nitric oxide (NO), asymmetrical dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA) and L-arginine levels, which are known to play a role in the pathogenesis of vasculitis. Materials and methods: Sixty patients enrolled in the study were allocated to groups as follows: active/inactive patient groups; the patient group with active/inactive vessel involvement, and mucocutaneous patient group without vessel involvement. Results: NO, SDMA, ADMA levels of the active patients and SDMA and ADMA levels of the inactive patients were found to be significantly higher than those of the healthy controls. SMDA and ADMA levels in the group with active vessel involvement; NO, SDMA, ADMA, and L-arginine levels in the group with inactive vessel involvement; and, NO, SDMA, and ADMA levels of the mucocutaneous group were significantly higher than those of the healthy controls. However we detected no statistically significant difference among the patient groups. Conclusion: These criteria cannot be utilized in evaluating the activity of the disease and in predicting vessel involvement. [ABSTRACT FROM AUTHOR]

BackgroundNitric oxide synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) is synthesized by the methylation of arginine as part of the methionine/homocysteine cycle. However, the mechanisms regulating ADMA synthesis in hypertension are unclear.MethodsWe investigated the role of ADMA and antioxidants in endothelial dysfunction during methionine-induced homocysteinemia in hypertensives. Thirty-nine hypertensives and forty-nine normotensive controls underwent methionine loading (100 mg methionine/kg BW), after being randomized to receive vitamin C (2 g) and E (800 IU) or placebo. Endothelium-dependent dilation (EDD) was evaluated by plethysmography (baseline and 4-h post-methionine loading (4-h PML)).ResultsHypertensives had higher homocysteine at baseline (P < 0.001) and 4-h PML (P < 0.05), whereas methionine increased homocysteine in all groups. EDD was decreased in both vitamins and placebo groups in controls (P < 0.01 for both) and vitamins- and placebo-treated hypertensives (P < 0.05 and P < 0.01, respectively). In controls, ADMA was increased in both vitamin- and placebo groups (P < 0.01 for both) at 4-h PML. Hypertensives had higher ADMA at baseline (P < 0.01 vs. normotensive) and remained unchanged at 4-h PML (P = NS in placebo and vitamins treated).ConclusionsADMA is elevated in hypertensives but remains unchanged after methionine loading, suggesting that ADMA plays an important role in endothelial dysfunction in hypertensives, but it is not responsible for homocysteine-induced endothelial dysfunction in these patients.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.65 [ABSTRACT FROM AUTHOR]

Background Renal failure is a frequent complication of juxtarenal abdominal aortic aneurysm (JAA)-repair. During this operation, suprarenal aortic-clamping is followed by infrarenal aortic-clamping (below renal arteries) to restore renal flow, while performing the distal anastomosis. We hypothesized that infrarenal aortic-clamping, despite restoring renal perfusion provokes additional renal damage. Materials and methods We studied three groups of rats. After 45 min of suprarenal aortic-clamping, group 1 had renal reperfusion for 90 min without aortic-clamps (n = 7). In group 2, 45 min of suprarenal aortic-clamping with a distal clamp on the aortic-bifurcation was followed by 20 min of infrarenal aortic-clamping. Renal reperfusion was continued for 70 min without aortic-clamps (i.e. 90 min of renal reperfusion; n = 8). The sham-group had no clamps (n = 7). We measured renal haemodynamics, functional parameters and tissue damage. Results On suprarenal aortic-clamp removal, renal artery flow, cortical flow and arterial pressures were higher in group 2 than in group 1. We detected increased tubular brush border damage, luminal lipocalin-2 and 30-60% higher renal protein nitrosylation in group 2 when compared to group 1 (P < 0∙05). Group 2 showed more release of asymmetrical dimethylarginine (ADMA) from the kidneys in the renal vein, therefore indicating diminished clearing capacity (P < 0∙001). Arginine / ADMA-ratio, which defines the bio-availability of nitric oxide, tended to be lower in group 2 and correlated with renal flow. Furthermore, there were no significant differences found in creatinine levels and renal leucocyte accumulation between group 1 and 2. Conclusions Additional infrarenal aortic-clamping leads to increased renal damage and oxidative stress, despite adequate perfusion of kidneys after suprarenal aortic-clamping. This study indicates that the clamping sequence used in JAA-repair causes more than simple renal I / R-injury. [ABSTRACT FROM AUTHOR]

The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, has been linked to endothelial dysfunction. We investigated the relation between plasma ADMA concentration and severity of erectile dysfunction (ED) and coronary artery disease (CAD). We measured plasma levels of ADMA in 92 male patients. Patients were divided into three groups: group 1 ( n = 41), patients with ED and without CAD; group 2 ( n = 29), patients with stable CAD; group 3 ( n = 22), control group (patients without CAD or ED). Erectile function was evaluated by the erectile function domain of the international index of erectile function (IIEF-EFD) a validated 15-item self-administered questionnaire. Erectile function is specifically addressed by six questions that form the so-called erectile function domain of the questionnaire. Each question is scored 0-5. ED is defined as any value <26. Patients with CAD who have stable angina pectoris were selected after coronary angiography. ADMA was analyzed by ELISA method. Group 1 had significantly higher concentrations of plasma ADMA than groups 2 and 3 (respectively, 0.75 ± 0.40 vs. 0.50 ± 0.30, P = 0.013; 0.75 ± 0.40 vs. 0.50 ± 0.25, P = 0.021). There was negative correlation between ADMA and IIEF-EFD score in all groups ( n = 92) ( r = −0.322, P = 0.002). In a multiple logistic regression analysis adjusting for age, hyperlipidemia, ADMA remained independent predictor for severe ED. Odds ratio for plasma ADMA was 14.151 (1.101-181.940; P = 0.042). First of all, this study provides that ADMA concentrations are significantly higher in patients who have ED when compared to patients with CAD and controls. Second, there was a negative correlation between ADMA and severity of ED. Elevating levels of circulating ADMA is an independent risk factor for severe of ED, and ADMA may be a link between CAD and ED. [ABSTRACT FROM AUTHOR]

Abstract: Objectives and methods: Methylarginines like asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are formed by post-translation methylation of arginine residues in proteins. ADMA inhibits nitric-oxide synthase and predicts clinical outcomes in various diseases including end stage renal disease (ESRD). SDMA competes with l-arginine for cell entry and is associated with organ failure in patients with severe illness. We investigated the inter-relationships between methylargines, l-arginine and other risk factors and tested the prediction power of methylargines for mortality in a prospective cohort study including 288 ESRD patients. Results: ADMA and SDMA exceeded the upper limit of the corresponding normal range in almost all cases (98% and 100%, respectively) and were inter-related (r =0.30, P <0.001) but only ADMA was associated with l-arginine. SDMA, was inversely related with haemoglobin (r =−0.23, P <0.001) and this association was independent of other risk factors. During the follow-up, 140 patients died. In unadjusted analysis, ADMA was strongly related to death [hazard ratio (HR) (1μmol/L): 2.07, 95% CI: 1.31–3.26] while plasma SDMA and l-arginine were largely unrelated to survival. In a multiple Cox regression model adjusting for potential confounders, ADMA maintained an independent relationship with death [HR: 1.92, 95% CI: 1.16–3.16]. Conclusions: Methylarginines ADMA and SDMA are inter-related. ADMA is associated with l-arginine while SDMA correlates inversely with haemoglobin. ADMA but not SDMA is a death predictor in ESRD. Given the exceedingly high risk for death of this population, establishing whether or not ADMA is causally implicated in the high death risk of ESRD is a research priority. [Copyright &y& Elsevier]

Asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is recently defined as a novel atherogenic factor. Communication via gap junction (GJIC) is involved in the regulation of a variety of endothelial activities, such as cell differentiation and senescence. The aim of this study is to explore the effects of ADMA on connexin43 (Cx43) mediated endothelial GJIC. Lysophosphatidylcholine (LPC) caused the downregulation of Cx43 expression and GJIC dysfunction in cultured human umbilical vein endothelial cells (HUVECs), which were significantly ameliorated by decreasing ADMA accumulation. Furthermore, we found that ADMA (10 µmol·L-1, 24 h) markedly downregulated Cx43 expression and damaged GJIC function in HUVECs. ADMA also increased production of intracellular reactive oxygen species (ROS) and induced phosphorylation of p38 MAPK. Furthermore, the inhibitory effect of ADMA on Cx43-mediated GJIC could be attenuated by NADPH oxidase inhibitor diphenyleneiodonium and apocynin as well as p38 MAPK inhibitor SB203580, respectively. In conclusion, our present results suggest that ADMA inhibits endothelial GJIC function via downregulating Cx43 expression, which suggesting a novel mechanism linking between elevated ADMA level and progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

Endogenous NO synthase inhibitors (end-NOSIs) have been associated with cardiovascular risk factors and atherosclerosis. In addition, end-NOSIs may directly cause hypertension through hemodynamic effects. We aimed to examine the association between end-NOSI asymmetrical dimethylarginine (ADMA) and N-guanidino-monomethyl-arginine (NMMA), subclinical atherosclerosis, and arterial hemodynamics. We studied 922 adults participating in a population-based study (PREVENCION Study) and examined the correlation between end-NOSI/L-arginine and arterial hemodynamics, carotid-femoral pulse wave velocity, and carotid intima-media thickness using linear regression. ADMA, NMMA, and L-arginine were found to be differentially associated with various classic cardiovascular risk factors. ADMA and NMMA (but not L-arginine) were significant predictors of carotid intima-media thickness, even after adjustment for cardiovascular risk factors, C-reactive protein, and renal function. In contrast, ADMA and NMMA did not predict carotid-femoral pulse wave velocity, blood pressure, or hemodynamic abnormalities. Higher L-arginine independently predicted systolic hypertension, higher central pulse pressure, incident wave amplitude, central augmented pressure, and lower total arterial compliance but not systemic vascular resistance or cardiac output. We conclude that ADMA and NMMA are differentially associated with cardiovascular risk factors, but both end-NOSIs are independent predictors of carotid atherosclerosis. In contrast, they are not associated with large artery stiffness, hypertension, or hemodynamic abnormalities. Our findings are consistent with a role for asymmetrical arginine methylation in atherosclerosis but not in large artery stiffening, hypertension, or long-term hemodynamic regulation. L-arginine is independently associated with abnormal pulsatile (but not resistive) arterial hemodynamic indices, which may reflect abnormal L-arginine transport, leading to decreased intracellular bioavailability for NO synthesis. [ABSTRACT FROM AUTHOR]

Background: Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase and may alter NO production during pathological conditions. Concerning Alzheimer’s disease (AD), there are reports on altered cerebral NO metabolism, but only few studies on ADMA concentrations in plasma and cerebrospinal fluid (CSF). Methods: We assessed plasma ADMA in 80 AD patients and 80 age- and gender-matched controls and CSF ADMA in a subgroup of 53 AD patients and 20 controls. Results: ADMA plasma concentrations were increased, while CSF ADMA concentrations were decreased in AD patients. There was a significant association between decreasing CSF ADMA levels and the severity of cognitive impairment. Conclusion: Elevated ADMA in plasma might be a contributing factor for AD through alterations of NO metabolism, for example decreased cerebral microperfusion, while decreased levels of CSF ADMA might lead to a cerebral increase of NO, peroxynitrite production and oxidative protein damage. Our study reveals different mechanisms of plasma and CSF ADMA regulation, both potentially contributing to AD pathology. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Methionine is an essential amino acid and methyl donor for most transmethylation reactions in mammals. The product of transmethylation reactions is homocysteine, which is associated with enhanced risk for CVD. The aim of this study was to analyse metabolic and vascular functional consequences of a methionine-enriched diet in rats. The dose of methionine was chosen to reflect the range of over-nutrition in man. We quantified plasma levels of homocysteine, asymmetrical dimethylarginine and adenosine, determined methionine and its metabolites in tissues and blood plasma and assessed relaxation of mesenteric arteries toward acetylcholine and sodium nitroprusside. A methionine-enriched diet for 4 weeks elevated homocysteine levels in plasma 2-fold and in spleen by 70??%. The level of S-adenosylhomocysteine was increased in liver only, while methionine and S-adenosylmethionine were unchanged in all organs studied. Plasma adenosine and asymmetrical dimethylarginine levels were unchanged, as were vessel relaxations. A 2-fold elevation of plasma homocysteine, which is assigned a risk indicator for cardiovascular events, did not impair mesenteric artery vasodilatation during 4 weeks of a methionine-rich diet. Furthermore, asymmetrical dimethylarginine and adenosine, which have been shown to be changed in more severe degrees of hyperhomocysteinaemia, remained unaltered. [ABSTRACT FROM PUBLISHER]

Telmisartan, in addition to blocking angiotensin (Ang) II type 1 receptor (AT(1)R), activates peroxisome proliferator activated receptor gamma (PPARgamma) signaling that interferes with nitric oxide (NO) system. Because aging of endothelial cells (ECs) is hallmarked by a reduction in NO synthesis, we hypothesized that telmisartan increases NO formation by regulated asymmetrical dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-system through blocking AT(1)R and activating PPARgamma signaling. To test this hypothesis, ECs were cultured with telmisartan, eprosartan, Ang II, and GW9662 (PPARgamma antagonist) until the twelfth passage. During the process of aging, PPARgamma protein expression decreased significantly, whereas the expression of AT(1)R increased. Telmisartan reversed these effects and dose-dependently decreased reactive oxygen species and 8-iso-prostaglandin (PG) F(2alpha) formation. This effect was associated with an upregulated activity and protein expression of DDAH, accompanied by a decrease in ADMA concentration, an increase in NO metabolites, and delayed senescence. Blockade of PPARgamma signaling by GW9662 or PPARgamma small-interference RNA prevented the effect of telmisartan on ADMA-DDAH-NO system. Coincubation with Ang II did not affect the effect of telmisartan-delayed senescence, whereas Ang II itself accelerated endothelial aging. Moreover, AT(1)R blocker eprosartan that did not influence PPARgamma protein expression had no effect on ADMA system and senescence. We have demonstrated that telmisartan mainly by activating PPARgamma signaling can alter the catabolism and release of ADMA as an important cardiovascular risk factor. We therefore propose that telmisartan translationally and posttranslationally upregulated DDAH expression via activation of PPARgamma signaling, causing ADMA to diminish and increase NO synthesis sufficient to delay senescence. [ABSTRACT FROM AUTHOR]

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as a putative biomarker in cardiovascular and renal disease. Elevated plasma levels of ADMA are the consequence of increased synthesis, reduced renal clearance or reduced enzymatic degradation. Based upon the metabolic fate the highest plasma concentrations of ADMA have been reported in patients with renal failure in whom this molecule accumulates. However, the range of published ADMA levels in patients with chronic renal failure as well as in patients with end-stage renal failure undergoing maintenance hemodialysis, peritoneal dialysis or kidney transplant recipients is widely scattered and overlaps with the levels reported in healthy individuals. This wide distribution can in part be explained by different bioanalytical techniques and the lack of standardization of such assays. This review summarizes available literature on ADMA in patients with kidney disease and stresses the urgent need for a consensus regarding reference values for different analytical methods in order to appreciate the prognostic significance of elevated ADMA levels. At present, one cannot advocate this molecule for risk assessment or individual patient prognosis in the clinical work-up of patients with renal impairment. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Cardiovascular diseases (CVD) are still the most frequent cause of death in Western Europe. Pathophysiological experiments revealed in the last years that the vascular endothelium, as well as a result of the synthesis of nitric oxide (NO), is a crucial regulator of vascular function and homeostasis. The vascular endothelium plays a key role in cardiovascular physiology and pathophysiology, largely via NO-dependent processes. l-Arginine is the substrate for the endothelial NO synthase (eNOS) to generate NO. Endothelial dysfunction is caused by various cardiovascular risk factors. In most studies, acute and chronic administration of l-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. Therefore, numerous studies have been conducted to elucidate whether dietary l-arginine supplementation can augment NO production in humans and thereby improve endothelium-dependent vasodilatation. The most likely mechanism that explains the occurrence of endothelial dysfunction and the effect of l-arginine is that application of l-arginine antagonizes asymmetric dimethylarginine (ADMA), the endogenous NO synthase (NOS) inhibitor. This could solve the l-arginine paradox namely that l-arginine improves NO-mediated vascular function in vivo, although its baseline plasma concentration is about 25- to 30-fold higher than the Michaelis-Menten constant K m of the isolated, purified eNOS in vitro. Recent findings suggest that large, prospective, randomized clinical trials might be needed to identify those patients who are the most likely to benefit from l-arginine. Testing patients for ADMA and l-arginine plasma levels for calculating the l-arginine/ADMA ratio might be an adequate strategy. [Copyright &y& Elsevier]

Black Africans have a higher incidence of cardiovascular disease than white Europeans. We explored potential mechanisms of this excess risk by assessing endothelium function, inflammatory status (C-reactive protein), oxidative stress (isoprostane-F2alpha), and plasma asymmetrical dimethyl arginine (ADMA; an endogenous competitive inhibitor of NO synthase) in each ethnic group. Thirty healthy black Africans and 28 well-matched white European male subjects were studied (mean age+/-SE: 32.2+/-0.9 and 29.2+/-1.2 years, respectively; P=0.07). High-resolution ultrasound was used to assess vascular function in the brachial artery by measuring flow mediated dilatation ([percentage of change]; endothelium-dependent function) and glyceryltrinitrate dilatation ([percentage of change]; endothelium-independent function). Blood pressure, fasting lipids, glucose, and estimated glomerular filtration rate levels were similar in both groups. There was no difference in C-reactive protein (black Africans: 0.8+/-0.1 mg/L; white Europeans: 0.6+/-0.1 mg/L; P=0.22), isoprostane-F2alpha (black Africans: 42.9+/-1.5 pg/mL; white Europeans: 39.2+/-1.5 pg/mL; P=0.23), and leptin (black Africans: 64.1+/-10.2 ng/mL; white Europeans: 47.8+/-9.8 ng/mL; P=0.37) levels between the 2 ethnic groups. However, compared with white Europeans, plasma ADMA levels were significantly higher in black Africans (0.34+/-0.02 micromol/L and 0.25+/-0.03 micromol/L; P=0.03). There was no difference in the percentage of glyceryltrinitrate dilatation (P=0.7), but the percentage of flow-mediated dilatation was significantly lower in black Africans (black Africans: 5.2+/-0.3; white Europeans: 6.3+/-0.4; P=0.02). In a stepwise multiple regression model, ADMA level was the only independent determinant of flow-mediated dilatation (P=0.02). In turn, race was the only independent determinant of ADMA levels (P=0.03). Our findings indicate that circulating ADMA levels are significantly higher in healthy black African males than in white European males. This may contribute to the lower NO bioavailability and higher incidence of cardiovascular disease seen in black Africans. [ABSTRACT FROM AUTHOR]

Abstract: This report describes an approach for the study of the biology of methylarginine proteins based on the generation of immunological reagents capable of recognizing the methylarginine status of cellular proteins. Two forms of an immunizing peptide were prepared based upon an amino acid sequence motif found most prevalently among verified dimethylarginine-containing proteins. One form of the peptide was constructed with 7 arginine residues alternating with 8 glycine residues. None of the arginines used in the synthesis were methylated. The alternative form of the peptide was synthesized with the identical repeating GRG sequence, but with asymmetrical dimethylarginine at each arginine residue. A methylarginine-specific antiserum was generated using the latter peptide. ELISA and western blotting of glycine arginine-rich peptides, each synthesized with or without asymmetric dimethylarginine, demonstrate the methyl specificity of the antiserum. The methylarginine-specific antibody co-localizes with the highly methylated native nucleolin protein conspicuously concentrated in the nucleolus. The methylarginine-specific antiserum recognizes a GRG peptide and bacterially expressed RBP16 only after incubation of the peptide or RBP16 with recombinant protein arginine methyltransferase 1, or cell extracts, respectively. Proteins isolated from cells in different developmental states exhibit different patterns of reactivity observed by western blots. Finally, the methylarginine-specific reagent interacts specifically with the methylarginine of cellular hnRNPA1 and human fragile X mental retardation protein expressed in cultured PC12 cells. An immunological reagent capable of detecting the methylarginine status of cellular methylproteins will facilitate the cellular and molecular analysis of protein arginine methylation in a wide variety of research and biomedical applications. [Copyright &y& Elsevier]

To identify a possible role for nitric oxide (NO) in acute hypoxic tolerance (HT) we measured hypoxic survival time (HST), effect of hypoxic conditioning (HC), and survival following hypoxic conditioning while blocking or mimicking the action of nitric oxide synthase (NOS). To inhibit NOS, CD-1 mice were given supplemental endogenous NOS inhibitor asymmetrical dimethylarginine (ADMA) or a synthetic NOS inhibitor Nω-nitro-L-arginine (L-NNA), both of which nonselectively inhibit three of the isoforms of NOS [inducible (iNOS), neuronal (nNOS), and endothelial NOS (eNOS)]. ADMA (10 mg/kg ip) or saline vehicle was given 5 mm before HST testing. L-NNA was given orally at 1 g/l in drinking water with tap water as the control for 48 h before testing. Both ADMA and L-NNA significantly increased HST and augmented the HC effect on HST. Neither the nNOS selective inhibitor 7-nitroindazole (7-NI) nor the iNOS selective inhibitor N-{[3-(amino- methyl)phenyl]methyl}-enthanimidamide (1400W) had a statistically significant effect on HST or HT. The NO donor, 3-morpholinosydnoeimine, when given alone did not significantly decrease HT, but it did mitigate the increased HT effect of L-NNA. These data confirm that acute hypoxic conditioning increases HT and that NOS inhibition by endogenous (ADMA) and a synthetic NOS inhibitor (L-NNA) further increases HT, whereas iNOS and nNOS inhibition does not, suggesting that it is the inhibition of eNOS that mediates enhancement of HT. [ABSTRACT FROM AUTHOR]

Aims Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients. Methods ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 ± 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD). Results ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55–0.70) µmol/l and 0.62 (0.50–0.79) µmol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48–0.63) µmol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42–0.80) µmol/l and 0.64 (0.50–0.96) µmol/l] compared with normoalbuminuric subjects [0.44 (0.37–0.53) µmol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA1c or plasma lipids. Conclusions Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation. [ABSTRACT FROM AUTHOR]

Background: Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure. Objective: We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA. Design: In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitaminC(2 g) plus α-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading. Results: Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r=-0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction. Conclusions: Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli. [ABSTRACT FROM AUTHOR]

Abstract: Background: Infants born term have substantially elevated plasma concentrations of the endogenous nitric oxide synthase antagonist asymmetrical dimethylarginine (ADMA) that normalize with growth. The plasma levels of ADMA in preterm newborns are unknown. Subjects and methods: Plasma concentrations of ADMA, symmetrical dimethylarginine (SDMA) and l-arginine were analyzed from venous umbilical cord blood samples of 19 preterm and 21 term infants by high performance liquid chromatography. Results: Male preterm newborns (n =11) had higher ADMA (median [95% confidence interval (CI)]: 1.90 [1.73–2.10] μmol/l) than females born preterm (n =8; 1.57 [1.24–1.69] μmol/l; p <0.005). In term born males (n =10) and females (n =11) ADMA was significantly lower than in preterm male infants (all p <0.005), and without sex differences. SDMA and l-arginine concentrations were comparable between all groups. ADMA correlated inversely with body weight in male preterm newborns (r =−0.67; p <0.03). Conclusion: Male neonates delivered preterm have significantly higher umbilical cord venous plasma concentrations of ADMA compared to female neonates and infants born term. The sex difference and the time course of elevated ADMA may play a role in development and warrant further investigation. [Copyright &y& Elsevier]

Abstract: Recent studies suggested that endothelium is a main source of reactive oxygen species (ROS) and the major source was via NADPH oxidase pathway. Various stimuli including lysophosphatidylcholine (LPC), a major component of oxidized low-density lipoprotein (ox-LDL), can enhance the activity of NADPH oxidase and lead to a marked ROS generation. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthase (NOS) inhibitor, which is synthesized by protein arginine methyltransferase I (PRMT I) and degraded by dimethylarginine dimethylaminohydrolase (DDAH) in endothelial cells. Much evidence showed that ADMA was closely related to endothelial dysfunction. Our previous study showed that LPC elevated ADMA level in endothelial cells via increasing oxidative stress, but the precise cellular mechanism is not defined yet. The present study was to explore the mechanism of NADPH oxidase in LPC-induced elevation of ADMA. In LPC-treated endothelial cells, the ROS production, cell viability, ADMA and NO levels, the activity of DDAH and expression of PRMT I were detected. Treatment with LPC (10 μg/ml) for 24 h markedly increased intracellular ROS production, the expression of PRMT I, level of ADMA, decreased the concentration of NO and the activity of DDAH. These effects were attenuated by diphenyliodonium, the NADPH oxidase inhibitor. In summary, the present results suggested that LPC-induced elevation of ADMA was due to reduction of DDAH activity and the up-regulation of PRMT expression by stimulation of ROS production via NADPH oxidase pathway. [Copyright &y& Elsevier]

Abstract: Background: Coronary artery disease (CAD) and erectile dysfunction (ED) of vascular origin are closely related and share common risk factors. The endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) has recently been identified as an independent risk marker for cardiovascular disease and it was the purpose of the present study to investigate the role ADMA in ED with and without underlying CAD. Methods and results: We determined plasma ADMA levels in 132 men with ED. Patients were divided into a group of 56 men with underlying CAD (ED-CAD) and a group of 76 men without clinical evidence for underlying CAD (ED-No-CAD). Diagnosis of ED was based on the International Index of Erectile Function Score (IIEF-5). Plasma ADMA concentrations in the ED-CAD group were elevated as compared to the ED-No-CAD group, median (IQR): 0.76 (0.65–0.91) μmol/l ADMA vs. 0.49 (0.36–0.71) μmol/l, p <0.001. In a multiple logistic regression analysis adjusting for hypertension, hypercholesterolemia, low HDL cholesterol and diabetes or fasting glucose ≥6.1mmol/l, ADMA remained a strong and independent predictor for presence of CAD. Odds ratios for second and third tertiles as compared to lowest tertile of plasma ADMA were 3.3 (95%CI, 1.1–10.3; p =0.041) and 8.7 (95%CI, 2.8–27.2; p <0.001), respectively. Conclusion: As elevation of ADMA has been found to be associated with many risk factors for both CAD and ED, our data provide further strong evidence for the close interrelation of CAD and ED. Determination of ADMA may help to identify underlying cardiovascular disease in men with ED. [Copyright &y& Elsevier]

Abstract: In mammals and yeasts, arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), has been implicated in regulation of diverse processes such as protein–protein interaction, protein localization, signal transduction, RNA processing, and transcription. A large number of PRMT substrates are RNA binding proteins. In trypanosomes, gene regulation is controlled primarily at the levels of RNA processing, stability, and translation, and likely involves numerous RNA binding proteins. Thus, arginine methylation may be especially important in controlling gene expression in this evolutionarily ancient group of organisms. To begin to understand the role of arginine methylation in trypanosomes, we identified and characterized a type I PRMT from Trypanosoma brucei, termed TbPRMT1. TbPRMT1 displays 51% amino acid identity to human PRMT1. It possesses an S-adenosylmethionine binding site and double E and THW loops, common and absolute features associated with other PRMTs. Recombinant TbPRMT1 methylates both an artificial RG-rich peptide and the T. brucei mitochondrial RNA binding protein, TBRGG1, and it exhibits differences in substrate specificity compared to rat PRMT1. TbPRMT1 is constitutively expressed during the T. brucei life cycle. Disruption of TbPRMT1 gene expression by RNA interference did not result in a significant growth defect in procyclic form T. brucei. Finally, we observe a dramatic decrease in the cellular level of asymmetric dimethylarginine upon TbPRMT1 knock down, indicating that TbPRMT1 is the predominant type I PRMT in T. brucei. The strong conservation of PRMT1 homologs between protozoa and humans highlights the importance of arginine methylation as a regulatory mechanism in eukaryotes. [Copyright &y& Elsevier]

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