dimethylarginine and Chronic-Disease

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

Topics: Aorta; Arginine; Autonomic Nervous System Diseases; Bone Diseases, Metabolic; Cardio-Renal Syndrome; Cardiovascular Diseases; Chronic Disease; Endothelium, Vascular; Glycation End Products, Advanced; Humans; Inflammation; Myocardial Infarction; Oxidative Stress; Phosphorus; Renal Insufficiency, Chronic; Toxins, Biological; Tunica Intima; Uric Acid; Vascular Stiffness; Vasculitis

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide-dependent vasodilation. In 113 patients with chronic heart failure (CHF) and 26 controls, ADMA level was studied in relation to peripheral blood flow and vasodilator capacity. Further, the effects of allopurinol on concentrations of reactive oxygen species (ROS) and ADMA and peripheral vasodilator capacity were tested in a double-blind design. ADMA level was found to be elevated in CHF patients as compared with controls and increased in parallel with New York Heart Association (NYHA) class and exercise capacity (all P < 0.0001). The level of ADMA predicted resting blood flow (P < 0.05) and postischemic vasodilator capacity (P < 0.001). Sixty eight patients died during the follow-up period. The level of ADMA predicted survival after multivariable adjustment (P = 0.04). Allopurinol reduced uric acid (UA) concentration (P < 0.001) and decreased ROS concentration (allantoin, P < 0.01). Allopurinol lowered ADMA concentration (P = 0.02); postischemic vasodilation as well as endothelium-dependent vasodilation (both P < 0.05) improved. ADMA may be a pathophysiologic factor that is modulated by ROS accumulation and contributes to impaired vascular regulation in CHF.

Topics: Aged; Allopurinol; Arginine; Chronic Disease; Citrulline; Cross-Sectional Studies; Double-Blind Method; Female; Free Radical Scavengers; Heart Failure; Humans; Male; Middle Aged; Reactive Oxygen Species; Uric Acid; Vasodilation

Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure.. 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.. 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 vitamin C (2 g) plus alpha-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.. 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.. 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.

Topics: Adult; alpha-Tocopherol; Arginine; Ascorbic Acid; Cholesterol, LDL; Chronic Disease; Cytokines; Double-Blind Method; Endothelium, Vascular; Female; Forearm; Homocysteine; Humans; Hyperhomocysteinemia; Inflammation; Interleukin-6; Male; Methionine; Oxidative Stress; Time Factors; Vascular Resistance; von Willebrand Factor

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor and a marker of vascular endothelial damage. Angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker (ARB) are reported to reduce the serum ADMA level. Our group administered either ARB or calcium antagonist to patients after cerebral infarction and discussed the ADMA changes observed.. Hypertensives in the chronic stage of cerebral infarction were enrolled. These subjects included patients of atherothrombotic cerebral infarction or lacunar infarction. The patients received candesartan cilexetil (candesartan group) or amlodipine (amlodipine group). The blood pressure and serum ADMA concentration were measured and compared before the treatment commenced and at 1-3 months after the treatment commenced.. Seven subjects received candesartan and six received amlodipine. There was no difference between the groups in the change of blood pressure before and after the drug treatment. The ADMA level (nmol/mL) fell significantly from 0.57±0.10 (before administration) to 0.52±0.09 (after administration) in the candesartan group (P<0.05). The ADMA level did not change between before and after administration in the amlodipine group.. Treatment with candesartan cilexetil reduced the level of ADMA in hypertensive patients in the chronic stage of cerebral infarction. Candesartan cilexetil may be useful in hypertensive patients at the chronic stage of cerebral infarction with expected anti-atherosclerotic effect.

Topics: Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Arginine; Benzimidazoles; Biomarkers; Biphenyl Compounds; Cerebral Infarction; Chronic Disease; Female; Humans; Hypertension; Male; Tetrazoles

Previous studies on arginine metabolites reported an association of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) with liver dysfunction and an inverse relation of homoarginine (hArg) with cardiovascular risk. The aim of the present study was to investigate the relationships between hArg, ADMA, SDMA, and the dimethylarginine score (DAS, i.e., ADMA + SDMA) and liver dysfunction and survival in chronic liver disease. In 94 consecutive cirrhotic patients admitted to our outpatient liver clinic, serum levels of hArg, ADMA, and SDMA were measured by HPLC at baseline. Patients were followed with respect to mortality. In the entire study cohort (age 58.5 ± 11.2 years; 31 % females), the serum concentrations were 1.94 ± 0.90 µM for homoarginine, 0.90 ± 0.22 µM for ADMA, and 0.70 (0.60-0.93) µM for SDMA. ADMA correlated with both Child-Pugh and MELD scores, while SDMA, DAS, and hArg correlated with MELD score only. Thirty patients (32 %) died during a median follow-up of 3.5 years. Age- and sex-adjusted Cox proportional hazard ratios (HR) per µM (with 95 % confidence intervals) showed that hArg was associated with decreased mortality [HR 0.59 (0.37-0.96)], whereas mortality was increased in patients with higher ADMA [HR 3.78 (0.98-14.60)], SDMA [HR 6.54 (3.15-13.59)] and DAS [HR 4.13 (2.26-7.56)]. Only SDMA and DAS remained significantly associated with mortality after additional adjustments for either Child-Pugh stage or MELD score. In conclusion, in cirrhotic patients seen in an outpatient liver clinic, hArg as well as the dimethylarginines ADMA and SDMA was related to long-term mortality. In particular, SDMA predicts mortality independently of both Child-Pugh stage and MELD score.

Topics: Adult; Aged; Arginine; Chronic Disease; Disease-Free Survival; Female; Follow-Up Studies; Homoarginine; Humans; Liver Cirrhosis; Male; Middle Aged; Retrospective Studies; Survival Rate

To investigate the protective effects of oxymatrine on chronic heart failure induced by isoproterenol (ISO) and to observe its effects on ADMA metabolism pathway in ISO-induced chronic heart failure in rats.. Male Sprague-Dawley rats were given oxymatrine (100,50 mg kg-1) orally for 14 days. Heart failure was induced in rats by subcutaneous injection of isoproterenol (5 mg kg-1 d-1 ) at the 8th day for 1 week. Serum parameters, haemodynamic parameters, Heart weight, and histopathological variables were analysed. Expression of protein levels were measured by Western blot.. Oxymatrine (100,50 mg kg-1) significantly attenuated serum content of cTn I, improved left ventricle systolic and diastolic function and left ventricular remodeling, reduced the ISO-induced myocardial pathological changes compared with ISO group. In addition, oxymatrine (100,50 mg kg-1) significantly reduced serum level of ADMA (P <0. 01), normalize the reduced dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression (P <0. 01) , but had no effect on the isoproterenol-induced upregulated protein arginine methyltransferases 1 expression.. Oxymatrine could ameliorate the experimental ventricular remodeling in ISO-induced chronic heart failure in rats and the mechanism involved in reducing serum content of ADMA and increased DDAH2 expression.

Topics: Alkaloids; Amidohydrolases; Animals; Arginine; Chronic Disease; Gene Expression Regulation, Enzymologic; Heart Failure; Hemodynamics; Isoproterenol; Male; Organ Size; Quinolizines; Rats; Rats, Sprague-Dawley; Troponin I

Dimethylarginines are inhibitors of NO synthesis and are involved in the pathogenesis of vascular diseases. In this study, we ask the question if asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels change during fatal and reversible acute rejection, and contribute to the pathogenesis of chronic vasculopathy.. The Dark Agouti to Lewis rat strain combination was used to investigate fatal acute rejection. Fischer 344 kidneys were transplanted to Lewis rats to study reversible acute rejection episode and the process of chronic rejection. Isograft recipients and untreated Lewis rats were used as controls. l-arginine derivatives were determined by HPLC, and ADMA-metabolizing enzymes were studied by quantitative RT-PCR and western blotting.. Renal transplantation transiently increased dimethylarginine levels independent of acute rejection. ADMA plasma levels did not importantly differ between recipients undergoing fatal or reversible acute rejection, whereas SDMA was even lower in recipients of Fisher 344 grafts. In comparison to isograft recipients, ADMA and SDMA levels were slightly elevated during reversible, but not during the process of chronic rejection. Increased dimethylarginine levels, however, did not block NO synthesis. Interestingly, protein methylation, but not ADMA degradation, was increased in allografts.. Our data do not support the concept that renal allografts are protected from fatal rejection by dimethylarginines. Dimethylarginines may play a role in triggering chronic rejection, but a contribution to vascular remodelling itself is improbable. In contrast, differential arginine methylation of yet unknown proteins by PRMT1 may be involved in the pathogenesis of acute and chronic rejection.

Topics: Acute Disease; Animals; Arginine; Blotting, Western; Chronic Disease; Graft Rejection; Immunoenzyme Techniques; Kidney Diseases; Kidney Transplantation; Male; Nitrates; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Protein-Arginine N-Methyltransferases; Rats; Rats, Inbred Strains; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transplantation, Homologous

Topics: Arginine; Chronic Disease; Humans; Liver Cirrhosis; Liver Failure, Acute; Severity of Illness Index

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). It was recently reported that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of chronic kidney disease (CKD). ADMA is a strong predictor of the progression of CKD as well. However, a role for the ADMA-DDAH in the pathogenesis of CKD remains to be elucidated. This study investigated the effects of DDAH-elicited ADMA lowering on renal function and pathology in a rat remnant kidney model. Four weeks after five-sixths subtotal nephrectomy (Nx), the rats were given tail-vein injections of recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ) or orally administered 20 mg/kg per d hydralazine (Hyz), which served as a BP control model. In comparison with Adv-LZ or Hyz administration, Adv-DDAH decreased plasma levels of ADMA and inhibited the deterioration of renal dysfunction. Plasma levels of ADMA were associated with decreased number of peritubular capillaries, increased tubulointerstitial fibrosis, and proteinuria levels in Nx rats. These changes were progressed in Adv-LZ-or Hyz-treated Nx rats, which were ameliorated by DDAH overexpression. In addition, semiquantitative reverse transcriptase-PCR and immunohistochemistry for TGF-beta revealed that Adv-DDAH inhibited upregulation of TGF-beta expression in Nx rats. These data suggest that ADMA may be involved in peritubular capillary loss and tubulointerstitial fibrosis, thereby contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.

Topics: Amidohydrolases; Animals; Arginine; Capillaries; Chronic Disease; Disease Models, Animal; Disease Progression; Fibrosis; Gene Expression Regulation, Enzymologic; Genetic Therapy; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

The aim of this study was to investigate the possible relationship among dimethylarginines (asymmetric, ADMA; symmetric, SDMA) and homocysteine (Hcy) levels in subjects affected by chronic, mild to intermediate, hyperhomocysteinemia. ADMA and SDMA were assayed by an optimised HPLC method in 75 patients (Hcy = 20.8 micromol/L, 17.1-30.2; median and percentile range) and, for comparison, in 85 healthy subjects (Hcy = 8.0 micromol/L, 7.0-9.1). In controls, the cut-off values were set at 0.61 micromol/L for ADMA and 0.56 or 0.48 micromol/L for male and female SDMA, respectively. In patients, ADMA and SDMA levels were increased (p < 0.001) with respect to controls, but no correlation with Hcy was observed. Hyperhomocysteinemic subjects showed a different behaviour in respect to ADMA and SDMA levels and this allowed their stratification in 3 subgroups characterized by ADMA and SDMA in the normal range, only SDMA, or both ADMA and SDMA over the cut-off values. A lack of correlation with Hcy was again observed, thus minimizing the direct role of Hcy on ADMA and SDMA metabolism and suggesting the need for further studies on this issue.

Topics: Adult; Arginine; Chronic Disease; Female; Homocysteine; Humans; Kidney Diseases; Male; Middle Aged; Predictive Value of Tests