Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In this study, the plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were determined in relation to plasma nitrate levels (as an index of NO formation) for a group of 80 patients with ESRD. The effects of two treatment methods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and the role of the presence of atherosclerotic disease were evaluated. Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects. Plasma L-arginine and dimethylarginine levels were determined by HPLC, using precolumn derivatization with o-phthaldialdehyde. Plasma nitrate levels were determined by gas chromatography-mass spectrometry. Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group (6.0+/-0.5 versus 1.0+/-0.1 micromol/L; P < 0.05). Plasma nitrate concentrations were significantly lower in HD-treated patients, which suggests that ADMA may inhibit NO synthase. In contrast, plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects. Plasma L-arginine concentrations were not significantly decreased in patients with ESRD. ADMA concentrations were significantly decreased 5 h after HD, compared with baseline values. ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease (7.31+/-0.70 versus 3.95+/-0.52 micromol/L; P < 0.05). This study confirms that ADMA is accumulated in ESRD. PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients. Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD.     

Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia.

BACKGROUND: Asymmetrical dimethylarginine (ADMA) is capable of inhibiting nitric oxide synthase enzymes, whereas symmetrical dimethylarginine (SDMA) competes with arginine transport. The potential role of inflammation in the metabolism of ADMA has been elucidated in an in vitro model using tumour necrosis factor-alpha, resulting in a decreased activity of the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH). The kidney probably plays a crucial role in the metabolism of ADMA by both urinary excretion and degradation by DDAH. We aimed to further elucidate the role of the kidney in a rat model under basal conditions and during endotoxaemia. METHODS: Twenty-five male Wistar rats weighing 275-300 g were used for this study. The combination of arteriovenous concentration differences and kidney blood flow allowed calculation of net organ fluxes. Blood flow was measured using radiolabelled microspheres according to the reference sample method. Concentrations of ADMA, SDMA and arginine were measured by high-performance liquid chromatography. RESULTS: The kidney showed net uptake of both ADMA and SDMA and fractional extraction rates were 35% and 31%, respectively. Endotoxaemia resulted in a lower systemic ADMA concentration (P = 0.01), which was not explained by an increased net renal uptake. Systemic SDMA concentrations increased during endotoxaemia (P = 0.007), which was accompanied by increased creatinine concentrations. CONCLUSIONS: The rat kidney plays a crucial role in the regulation of concentrations of dimethylarginines, as both ADMA and SDMA were eliminated from the systemic circulation in substantial amounts. Furthermore, evidence for the role of endotoxaemia in the metabolism of dimethylarginines was obtained as plasma levels of ADMA were significantly lower in endotoxaemic rats.     

Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men with erectile dysfunction

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) micromol/l ADMA vs. 0.49 (0.36-0.71) micromol/l, p < 0.001. In a multiple logistic regression analysis adjusting for hypertension, hypercholesterolemia, low HDL cholesterol and diabetes or fasting glucose > or =6.1 mmol/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.     

Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans.

BACKGROUND: Recently, the potential importance of dimethylarginines as endogenously produced inhibitors of nitric oxide synthase has become clearer. Interestingly, elevated levels have been reported in patients with vascular disease, but especially in patients suffering end-stage renal disease. Although the kidney obviously seems to play a key role in the elimination of dimethylarginines, clear insight into the renal handling of these compounds is lacking. Thus, our aim was to investigate the renal extraction of dimethylarginines. METHODS: Plasma concentrations of dimethylarginines were determined in both arterial and renal venous blood in 20 fasting patients with normal renal function. Renal extraction was calculated as the arteriovenous concentration difference divided by the arterial concentration times 100%. RESULTS: A significant renal extraction was found for both dimethylarginines. Renal extraction was significantly higher for asymmetrical dimethylarginine (ADMA) when compared with symmetrical dimethylarginine (SDMA) (16.2 vs 10.5% respectively, P=0.001). In addition, arterial SDMA concentration, but not ADMA concentration, significantly correlated with arterial creatinine concentration. CONCLUSIONS: In healthy humans, the kidney contributes to the regulation of plasma levels of dimethylarginines, since both ADMA and SDMA were significantly extracted from the arterial supply. Interestingly, a higher renal extraction of ADMA was found when compared to SDMA extraction, which strongly suggests the presence of an additional catabolic pathway for ADMA in the kidney.     

Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study.

BACKGROUND: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase and a proposed cardiovascular risk factor, is elevated in chronic kidney disease (CKD). Pharmacological strategies that lower plasma concentration of ADMA may be expected to increase nitric oxide (NO.) bioavailability and potentially limit atherosclerosis. We hypothesized that the antioxidant alpha-tocopherol (vitamin E) reduces ADMA levels in CKD. METHODS: An open-label pilot interventional study using 800 IU of vitamin E was undertaken in eight stable out-patients with non-diabetic CKD (creatinine clearance <30 ml/min/1.73 m(2)) and six healthy controls, with the objective of measuring plasma ADMA levels at baseline and after 8 weeks of treatment. Plasma ADMA, symmetric dimethylarginine (SDMA) and alpha-tocopherol concentrations were determined at study entry and exit using high-performance liquid chromatography, while plasma total F2-isoprostanes, an index of oxidative stress, were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: ADMA and SDMA concentrations were significantly higher in the plasma of patients compared with that of controls (P 相似文献   

Inhibition of eNOS phosphorylation mediates endothelial dysfunction in renal failure: new effect of asymmetric dimethylarginine

Patients with chronic kidney disease have elevated circulating asymmetric dimethylarginine (ADMA). Recent studies have suggested that ADMA impairs endothelial nitric oxide synthase (eNOS) by effects other than competition with the substrate L-arginine. Here, we sought to identify the molecular mechanism by which increased ADMA causes endothelial dysfunction in a chronic kidney disease model. In wild-type mice with remnant kidney disease, blood urea nitrogen, serum creatinine, and ADMA were increased by 2.5-, 2-, and 1.2-fold, respectively, without any change in blood pressure. Nephrectomy reduced endothelium-dependent relaxation and eNOS phosphorylation at Ser1177 in isolated aortic rings. In transgenic mice overexpressing dimethylarginine dimethylaminohydrolase-1, the enzyme that metabolizes ADMA, circulating ADMA was not increased by nephrectomy and was decreased to half that of wild-type mice. These mice did not exhibit the nephrectomy-induced inhibition of both endothelium-dependent relaxation and eNOS phosphorylation. In cultured human endothelial cells, agonist-induced eNOS phosphorylation and nitric oxide production were decreased by ADMA at concentrations less than that of L-arginine in the media. Thus, elevated circulating ADMA may be a cause, not an epiphenomenon, of endothelial dysfunction in chronic kidney disease. This effect may be attributable to inhibition of eNOS phosphorylation.     

Asymmetric dimethylarginine (ADMA) is a novel emerging risk factor for cardiovascular disease and the development of renal injury in chronic kidney disease

Endothelial dysfunction due to the reduced bioavailability of nitric oxide (NO) is involved in the course of atherosclerotic cardiovascular disease as well as chronic kidney disease (CKD). NO is synthesized from L-arginine via the action of NO synthase, which is blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA). ADMA is a naturally occurring amino acid found in plasma and various types of tissues. The plasma level of ADMA is reported to be associated with cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia, and CKD, and is a strong predictor for cardiovascular disease and the progression of CKD. In this review, we discuss the biology of ADMA, the molecular mechanisms of the elevation of ADMA levels in CKD, and the pathological role of ADMA in patients with CKD.     

Methylated arginine derivatives in children and adolescents with chronic kidney disease

Asymmetric dimethylarginine (ADMA), a methylated L: -arginine (Arg) derivative is associated with endothelial dysfunction, vasoconstriction, and hypertension in animals and humans. We examined the relationship between these derivatives, estimated glomerular filtration rate (eGFR), and awake (AW) and asleep (AS) blood pressure (BP) load in children and adolescents (n = 28) with stage 2-3 chronic kidney disease (CKD) and in matched intra-familial controls (n = 10). Plasma L: -Arg, ADMA, and symmetric dimethylarginine (SDMA) levels were measured by high-performance liquid chromatography-tandem mass spectrometry. Subjects wore a 24-hr ambulatory BP monitor with BP load >95th percentile. ADMA, SDMA/ADMA ratio and SDMA were 38-200% higher in CKD patients while L: -Arg/ADMA and L: -Arg/SDMA ratios and the L: -Arg level were 11-64% lower. The eGFR explained 42-60% of L: -Arg/SDMA, SDMA/ADMA, and SDMA variability (n = 38). Using linear regression, SDMA and SDMA/ADMA separately explained 15-38% of AW and AS systolic (S) BP and diastolic (D) BP load variability (p < 0.001-0.022). Using multivariate stepwise regression with eGFR held constant, SDMA/ADMA was a significant independent variable for AW DBP load (p = 0.03). In conclusion, BP load and a disproportionate elevation of SDMA are seen in children and adolescents with stage 2-3 (mild-moderate) CKD. SDMA is a strong marker for reduced eGFR and serves as a moderate but significant indicator of 24-hr BP load variability.     

Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease

Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine. Whereas the major route of asymmetric dimethylarginine elimination is the hydrolytic degradation by dimethylarginine dimethylaminohydrolase, SDMA is eliminated by renal excretion. SDMA does not directly inhibit NOS but is a competitor of arginine transport. This study showed for the first time that measurement of SDMA can be a marker of estimated GFR and extent of coronary artery disease (CAD). In 97 patients with CAD, SDMA was a marker of estimated GFR. On multiple regression analysis of the CAD parameter stenosis score, SDMA was the only parameter retained. In addition, endothelial cells from the third passage were cultured in medium that contained 70 micromol/L arginine and was incubated for 24 h in the presence of various concentration of SDMA (0, 2, 5, 10, and 100 micromol/L). The levels of nitrate and nitrite in conditioned media, the protein expression of NOS, and the content of reactive oxygen species in endothelial cells were determined. SDMA inhibited dose dependently the NO synthesis in intact endothelial cells, whereas it had no effect on protein expression of NOS. This effect was associated with an increase in reactive oxygen species. Co-incubation with L-arginine but not D-arginine reversed the effect of SDMA on NOS pathway. Our data suggest that SDMA reduced the endothelial NO synthesis, probably by limiting L-arginine supply to NOS. It is concluded that SDMA might be a useful parameter for detecting patients in very early stages of chronic kidney disease and for determining their risk for developing cardiovascular disease.     

Assessment of the relationship between asymmetric dimethylarginine and severity of erectile dysfunction and coronary artery disease

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.     

Asymmetrical dimethylarginine plasma concentrations are related to basal nitric oxide release but not endothelium-dependent vasodilation of resistance arteries in peritoneal dialysis patients

Vascular dysfunction in chronic renal failure may be linked to reduced nitric oxide (NO) bioactivity and increased circulating concentrations of the endogenous NO synthase inhibitor asymmetrical dimethyl L-arginine (ADMA). The association between ADMA and basal endothelial NO release and endothelium-dependent vasodilation in resistance arteries of chronic renal failure patients is unknown. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerine, and the endothelium-dependent vasoconstrictor N(G)-monomethyl-L-arginine (L-NMMA) were assessed in 37 peritoneal dialysis patients. L-arginine and ADMA plasma concentrations were measured by HPLC. ADMA (mean +/- SEM: 0.68 +/- 0.02 micromol/L) was associated with basal forearm blood flow (r = -0.33; P < 0.05) and L-NMMA induced vasoconstriction (r = -0.55; P < 0.0005), but not with dilator effects of acetylcholine or nitroglycerine. L-arginine (68 +/- 3 micromol/L) tended to correlate with acetylcholine-induced vasodilation (r = 0.32; P = 0.05) but was not associated with other parameters. ADMA is related to basal but not to acetylcholine-stimulated NO bioactivity in patients on peritoneal dialysis. Impaired endothelium-dependent vasodilation found in chronic renal failure is not explained by elevated circulating NO synthase inhibitors in renal failure.     

Intravenous N-acetylcysteine during hemodialysis reduces asymmetric dimethylarginine level in end-stage renal disease patients

AIM: Cardiovascular disease is the main cause of mortality in chronic kidney disease patients. Moreover, uremic patients are in a pro-oxidant state and show an increase in asymmetric dimethylarginine (ADMA) levels due to inhibition of the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Asymmetric dimethylarginine per se seems responsible for a 52% increase in the risk of death and for a 34% increase in the risk of cardiovascular events in dialysis patients. N-acetylcysteine (NAC) is a thiol molecule that has direct and indirect antioxidant effects which decrease reactive oxidant species and increase the bioavailability of the DDAH enzyme. The aim of the current study was to determine the effect of intravenous NAC on plasma ADMA level when administered during hemodialysis in end-stage renal disease (ESRD) patients. MATERIALS AND METHODS: 40 patients with ESRD were randomized to receive a 4-hour intravenous infusion of NAC or placebo during a 4-hour hemodialysis session. There were 3 diabetic patients (15%) in the treatment group and 6 patients in the control group. Plasma ADMA levels were measured before and immediately after hemodialysis. Hemodynamic parameters, including pulse pressure, were also measured. The paired t-test was used to compare the difference of ADMA levels before and after hemodialysis in each group, while the independent t-test was used to compare the difference of ADMA levels between the groups. RESULTS: Compared with the pre-dialysis condition, there was a decrease of ADMA level in the control group (1.1253 +/- 0.1797 microM to 0.8676 +/- 0.1449 microM) (p < 0.001), and in the NAC group (1.1522 +/- 0.1737 microM to 0.7844 +/- 0.1586 microM) (p < 0.001). Compared with hemodialysis alone, NAC had a greater lowering effect on the ADMA level (21.3 vs. 31.9%, p < 0.05). CONCLUSION: N-acetylcysteine (NAC) administered intravenously during hemodialysis reduced asymmetric dimethylarginine (ADMA) levels more significantly than hemodialysis alone.     

危重病危险因子非对称性二甲基精氨酸体内表达的临床意义

非对称性二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶抑制剂，与内皮功能不全密切相关，尤其在急性心血管事件、脏器功能衰竭等危重病疾患者体内中表达水平较高，目前被认为是一个新的急危重疾病的危险因子，正受到人们广泛关注。现就体内ADMA表达水平对预测急性心血管事件和危重病发生、发展及转归的临床意义作一综述。     

Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure

Abstract. N^GN^Gdimethyl-L-arginine (asymmetric dimethyl-L-arginineADMA) and N^GN^G dimethyl-L-arginine (symmetric dimethyl-L-arginine;SDMA) are naturally occurring analogues of L-arginine, the substratefor nitric oxide (NO) synthesis. ADMA is a potent inhibitorof NO synthesis, and accumulates in the plasma of patients withrenal failure. However the precise concentration of ADMA andSDMA in renal patients is still controversial. This study wasperformed to measure plasma ADMA and SDMA concentrations bytwo different HPLC techniques in nine healthy controls and 10uraemic subjects, and to investigate the effects of haemodialysis.In controls, the mean (±SEM) plasma concentrations ofADMA and SDMA were 0.36±0.09 and 0.39±0.05 µmol/lrespectively, yielding an ADMA/SDMA ratio of 1.2± 0.17.In uraemic patients, the plasma concentrations of ADMA and SDMAwere 0.9±0.08 µmol/l (P<0.001 compared to controls)and 3.4±0.3 µmol/l (P<0.001 compared to controls)with an ADMA/SDMA ratio of 0.27±0.015 (P<0.001). Inthe course of one 4 h haemodialysis session, ADMA concentrationsdecreased from 0.99±0.13 to 0.77±0.3 µmol/land SDMA concentrations from 3.38±0.44 to 2.27±0.21µmol/l. The plasma ADMA/creatinine ratio tended to increasefrom 1.26±0.20 x 10^–3 to 2.01±0.41 x 10^–3It is concluded that there is a modest (3-fold) but definiteincrease in plasma ADMA concentration in uraemic patients comparedto controls. SDMA accumulates to a greater degree (8-fold increase)and more closely parallels creatinine concentration than ADMA.The change in the ADMA/SDMA ratio is not accounted for by greaterrenal or dialysis clearance of ADMA, and, even though alternativeexplanations are not excluded, greater metabolism of ADMA thanSDMA is the most likely explanation. Although small in magnitude,the increase in ADMA concentration might be biologically significant.     

Low dialysance of asymmetric dimethylarginine (ADMA)--in vivo and in vitro evidence of significant protein binding

BACKGROUND: Increased blood levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predict cardiovascular mortality in patients with end-stage renal disease. Despite its low molecular weight, available information on the impact of hemodialysis (HD) on ADMA plasma levels is controversial. METHODS: We assessed plasma concentrations, dialyzer clearance and total amount of ADMA removed in 30 patients with end-stage renal disease during regular HD. In addition, plasma ADMA levels were assessed in 10 patients with acute renal failure treated with extended HD. RESULTS: Regular HD decreased plasma creatinine (from 774 +/- 42 to 312 +/- 17 micromol/l) and urea (from 24.5 +/- 1.5 to 8.4 +/- 0.5 mmol/l) concentrations significantly (both p < 0.001), whereas plasma ADMA remained unchanged (4.35 +/- 0.19 vs. 4.76 +/- 0.24 micromol/l). ADMA clearance was 92 +/- 6 ml/min, and the total amount removed in the spent dialysate was 37 +/- 4 micromol. The clearances of creatinine (161 +/- 3 ml/min) and of urea (173 +/- 3 ml/min) were significantly higher. Furthermore, even during extended HD, plasma ADMA concentrations did not decrease significantly (1.73 +/- 0.22 vs. 1.63 +/- 0.18 micromol/l). CONCLUSION: In conclusion, dialysance of ADMA is markedly lower than expected from its molecular weight because of significant protein binding of the substance. Since markedly increased ADMA blood concentrations have been linked to cardiovascular complications due to atherosclerosis in patients with ESRD, new strategies should be evaluated to remove this putative uremic toxin.     

Left ventricular hypertrophy,cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients

BACKGROUND: The endogenous inhibitor of nitric oxide (NO), asymmetric dimethylarginine (ADMA), is a strong predictor of adverse cardiovascular outcomes in patients with end-stage renal disease (ESRD). METHODS: Since arterial and cardiac remodeling is associated with altered endothelial microcirculatory responses to forearm ischemia (a NO-dependent response), interference of ADMA with the NO system may be important for the pathogenesis of left ventricular hypertrophy (LVH) in these patients. This study sought to identify the relationship between plasma ADMA and LV geometry and function in a cohort of 198 hemodialysis patients. RESULTS: Plasma ADMA was significantly higher (P = 0.008) in patients with LVH (median 3.00 micromol/L, inter-quartile range 1.73 to 3.97 micromol/L) than in those without this alteration (1.88 micromol/L, 1.15 to 3.56 micromol/L) and was significantly related to left ventricular (LV) mass (r = 0.26, P < 0.001). Interestingly, ADMA was much higher (P < 0.001) in patients with concentric LVH (3.60 micromol/L, 2.90 to 4.33 micromol/L) than in patients with eccentric LVH (2.17 micromol/L, 1.47 to 3.24 micromol/L) or normal LV mass (1.76 micromol/L, 1.13 to 2.65 micromol/L). Furthermore, plasma ADMA was higher (P = 0.02) in patients with systolic dysfunction (3.52 micromol/L, 2.08 to 5.87 micromol/L) than in those with normal LV function (2.58 micromol/L, 1.53 to 3.84 micromol/L) and inversely related to ejection fraction (EF; r = -0.25, P < 0.001). The link between ADMA and LV mass and EF was confirmed by multivariate analysis (ADMA vs. LVMI, beta = 0.17, P = 0.006; ADMA vs. EF, beta = -0.24, P < 0.001). CONCLUSIONS: Overall, this study indicates that raised plasma concentration of ADMA is associated to concentric LVH and LV dysfunction. Intervention studies are needed to see whether the link between ADMA and concentric LVH remodeling and LV dysfunction is a causal one.     

The transplanted liver graft is capable of clearing asymmetric dimethylarginine.

Asymmetric dimethylarginine (ADMA) has been recognized as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. Its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is highly expressed in the liver. Considering the liver as a crucial organ in the clearing of ADMA, we hypothesized increased ADMA levels during hepatic failure and, consequently, a decline of ADMA concentrations after successful liver transplantation. The aim of the present study was to investigate the role of the liver in the metabolism of ADMA in patients undergoing liver transplantation. In this prospective study, we investigated the course of ADMA concentrations in 42 patients undergoing liver transplantation and results showed that preoperative ADMA concentrations were higher in patients with acute (1.26 micromol/L, P < .001) and in patients with chronic (.69 micromol/L, P < .001) hepatic failure compared with healthy volunteers (.41 micromol/L). In addition, ADMA concentrations decreased from the preoperative day to the first postoperative day in both the acute (Delta(ADMA): -.63 micromol/L, P = .005) and the chronic hepatic failure group (Delta(ADMA): -0.15 micromol/L, P < .001). Furthermore, in patients who experienced acute rejection, ADMA concentrations were higher during the whole first postoperative month compared with nonrejectors (P = .012). Moreover, in 11 of 13 rejectors (85%) a clear increase in ADMA concentration preceded the onset of the first episode of rejection, which was confirmed by liver biopsy. In conclusion, our results indicate that the transplanted liver graft is quickly capable of clearing ADMA, suggesting preservation of DDAH. In addition, increased ADMA concentrations in the posttransplantation period reflect serious dysfunction of the liver graft during acute rejection.     

Asymmetric dimethylarginine may be a missing link between cardiovascular disease and chronic kidney disease

Decreased nitric oxide (NO) production and/or impaired NO bioavailability may occur in patients with chronic kidney disease (CKD), and could contribute to the elevation of blood pressure, cardiovascular disease (CVD) and the progression of renal injury in these patients. However, the underlying molecular mechanisms for reduced NO action in patients with CKD remains to be elucidated. Asymmetric dimethylarginine (ADMA) is a naturally occurring L-arginine analogue found in plasma and various types of tissues, acting as an endogenous NO synthase inhibitor in vivo. Further, plasma level of ADMA is elevated in patients with CKD and found to be a strong biomarker or predictor for future cardiovascular events. In addition, plasma level of ADMA could predict the progression of renal injury in these patients as well. These findings suggest that elevation of ADMA may be a missing link between CVD and CKD. In this review, we discuss the molecular mechanisms for the elevation of ADMA and its pathophysiological role for CVD in high-risk patients, especially focusing on patients with CKD.     

Symmetric dimethylarginine (SDMA) as endogenous marker of renal function--a meta-analysis.

BACKGROUND: Dosing of most drugs must be adapted in renal insufficiency, making accurate assessment of renal function essential in clinical medicine. Furthermore, even modest impairment of renal function has been recognized as a cardiovascular risk factor. The purpose of this analysis was to identify the role of symmetric dimethylarginine (SDMA), the structural isomer of the cardiovascular risk marker asymmetric dimethylarginine, as an endogenous marker of renal function. METHODS: Comprehensive searches of Medline and the Cochrane Library from 1970 to February 2006 were performed to identify studies that evaluated the correlation between SDMA and renal function. The search was augmented by scanning references of identified articles and reviews. The correlation coefficients (R) were recorded from each study for the values of 1/SDMA and clearance estimates and for SDMA and creatinine levels. The summary correlation coefficients with 95% confidence intervals (CIs) were pooled using the random-effects method. RESULTS: In 18 studies involving 2136 patients systemic SDMA concentrations correlated highly with inulin clearance [R = 0.85 (CI 0.76-0.91, P < 0.0001)], as well as with various clearance estimates combined [R = 0.77 (CI 0.65-0.85, P < 0.0001)] and serum creatinine [R = 0.75 (CI 0.46-089, P < 0.0001)]. CONCLUSIONS: SDMA exhibits some properties of a reliable marker of renal function. Future studies have to clarify whether SDMA is indeed suited to improve diagnosis and eventually optimize care of patients.     

Human recombinant erythropoietin augments serum asymmetric dimethylarginine concentrations but does not compromise nitric oxide generation in mice.

BACKGROUND: Patients with advanced chronic renal disease (CRD) suffer from excessive morbidity and mortality due to complications of accelerated atherosclerosis. Recombinant human erythropoietin (EPO), which is routinely used to treat the anaemia present in approximately 90% of dialysis-dependent patients with end-stage renal disease, may induce vascular dysfunction by reducing nitric oxide (NO) availability. Pathophysiologic concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), are found in patients with CRD and correlate with vascular disease and cardiovascular mortality. The aim of the current study was to investigate the effect of EPO on ADMA concentrations and NO generation in vitro and in vivo. Furthermore, we wanted to study the effect of EPO on the expression of the enzymes that regulate ADMA metabolism and NO generation. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to therapeutic concentrations of EPO. The expression and metabolic activity of dimethylarginine dimethylaminohydrolase II (DDAH II), the enzyme that degrades ADMA, was evaluated. Following subcutaneous administration of EPO to Balb/c mice for 10 weeks, serum ADMA concentrations were determined. Systolic blood pressure was measured noninvasively. Urinary nitrite and nitrate (NOx) concentrations were assessed by Griess assay. Protein expression of DDAH and NOS in livers and kidneys was measured by western blotting. RESULTS: EPO suppressed ADMA elaboration by HUVECs. Systolic blood pressure and serum concentrations of ADMA were significantly elevated in EPO-treated mice. The protein expression of DDAH I in the kidney and liver was upregulated while hepatic expression of DDAH II was decreased and renal DDAH II expression remained unchanged by EPO administration. However, EPO augmented urinary NOx concentrations as well as the expression of NOS 1 and NOS 2 in the kidney. CONCLUSION: In spite of elevating serum ADMA concentrations, EPO does not appear to compromise overall NO generation in Balb/c mice.