dimethylarginine and Acute-Disease

Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown.. We studied Tanzanian children ages 4-8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured.. ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde-pendent-ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria.. In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children.

Topics: Acute Disease; Arginase; Arginine; Case-Control Studies; Child; Child, Preschool; Female; Hemoglobins; Humans; Malaria, Falciparum; Male; Nitric Oxide

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

Asymmetric dimethylarginine (ADMA) has been identified as a marker of endothelial dysfunction and an independent risk factor for cardiovascular events in uremic subjects. This study evaluated ADMA plasma levels in kidney transplant recipients. ADMA levels were serially measured during the first year posttransplantation in 41 recipients treated with cyclosporine regimen (CY), sirolimus (SIR), or low-dose cyclosporine plus everolimus (E). Homocysteine, C reactive protein (CRP), nitric oxide (NO), and standard routine laboratory analyses were determined serially. ADMA significantly increased at 6 months posttransplantation, but was significantly lower among patients on SIR or E. NO was only slightly reduced in patients with increased ADMA levels. Interestingly, ADMA was significantly increased during the first 4 days posttransplantation in patients who experienced acute rejection during the first 6 months after transplantation. The same group of patients demonstrated higher levels of CRP and systolic blood pressure before transplantation. Our results demonstrated that ADMA was increased in patients on CY at 6 months. When increased soon after transplantation ADMA may be associated with episodes of acute rejection in kidney transplant recipients. The presence of elevated systolic blood pressure, as well as CRP and ADMA levels, suggested a role for endothelial dysfunction in the development of acute rejection episodes among deceased donor kidney transplant recipients.

Topics: Acute Disease; Adult; Arginine; Biomarkers; Blood Pressure; C-Reactive Protein; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Homocysteine; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged

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 N(omega)-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 i.p.) or saline vehicle was given 5 min 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-(aminomethyl)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.

Topics: Acute Disease; Animals; Arginine; Endothelium, Vascular; Enzyme Inhibitors; Hypoxia; Imines; Indazoles; Male; Mice; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Time Factors

Endothelial dysfunction is reflected by an impaired nitric oxide (NO)-mediated vasodilatation. Insulin resistance may be linked to endothelial dysfunction by several mechanisms, including disturbances in signaling pathways common to both insulin action and NO production. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may contribute to endothelial dysfunction, and elevated ADMA levels have been associated with both insulin levels and the degree of insulin resistance. The direct link between insulin and ADMA, however, has not yet been established. In the present study, we aimed to investigate the effects of acute hyperinsulinemia on circulating ADMA and L-arginine levels and on forearm blood flow (FBF). Male volunteers, aged 21 to 24 years, with borderline hypertension were included in the study. The participants underwent a 90-minute hyperinsulinemic isoglycemic glucose clamp with insulin levels at the postprandial levels (n=20) or a saline infusion (control) (n=9). Fasting blood samples were drawn at baseline and after 90 minutes. Insulin infusion was accompanied by a reduction in ADMA (0.78 to 0.68 micromol/L, P<.01), which was significantly different (P=.001) from the increase seen in the saline control group (0.69 to 0.79 micromol/L, P<.05). The same profile was obtained for L-arginine with a significantly more pronounced decrease (P<.001) in the insulin clamp group (74 to 61 micromol/L, P<.001) than in the saline control group (59 to 57 micromol/L, P=.95). The FBF level and nitrate/nitrite (NOx) levels were not affected by any of the clamp procedures. Short-term administration of insulin was accompanied by a decrease in both ADMA and L-arginine levels, with no change in FBF, in our population of young men with borderline hypertension. The possible influence of insulin on ADMA levels in a chronic state of insulin resistance can, however, not be deduced from the present investigation.

Topics: Acute Disease; Adult; Arginine; Humans; Hyperinsulinism; Insulin; Male; Plethysmography

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been shown to be involved in the pathogenesis of atherosclerosis. The present study was initiated to investigate the role of ADMA as a risk marker of acute cerebrovascular disease (CVD). We examined 363 CVD patients and 48 controls. The ADMA concentration (mean+/-S.D., mumol/L) in controls was 0.50 +/- 0.06. Compared to controls, increased concentrations of ADMA were observed in cardio-embolic infarction (0.55 +/- 0.08; p < 0.001; n = 71), and TIA (0.54 +/-0 .05; p < 0.001; n = 31), but not in non-cardio-embolic infarction (0.51 +/- 0.07; p = 0.56; n = 239) and haemorrhagic stroke (0.51 +/- 0.11; p = 0.77; n = 22). In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group (odds ratio for highest versus lowest quartile 13.1; 95% CI: 2.9-58.6; p trend 0.001) A decreased arginine/ADMA ratio was significantly associated with CVD in the entire study population (p < 0.01). Our results indicate that ADMA is a weak independent marker for acute stroke and a strong marker for TIA and that relative arginine deficiency, measured as the l-arginine/ADMA ratio, is present in acute CVD.

Topics: Acute Disease; Aged; Arginine; Biomarkers; Cerebral Hemorrhage; Cerebral Infarction; Enzyme Inhibitors; Female; Glycated Hemoglobin; Humans; Ischemic Attack, Transient; Male; Multivariate Analysis; Nitric Oxide Synthase; Odds Ratio; Risk Factors; Stroke