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We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride NO which, in the presence of thiols (RSH), are further converted to S-nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., UR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of UR. We determined UR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined UR values in healthy young men who ingested isosorbide dinitrate (ISDN), pentaerythrityl tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of UR in two animal models, i.e., the LEW.1AR1-iddm rat, an animal model of human T1DM, and the APOE*3-Leiden.CETP mice, a model of human dyslipidemia. Mean UR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of UR were of the order of 50% in young and elderly healthy subjects. UR values were lower in black compared to white boys (314 vs. 483, P = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean UR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30 mg) decreased stronger UR compared to PETN (3 × 80 mg) after 1 day (P = 0.046) and after 5 days (P = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO (0.1 mmol/kg/d), UR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1-iddm rats, mean UR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3-Leiden.CETP mice (151).

Elevated circulating concentrations of total L-homocysteine (thCys) and free asymmetric dimethylarginine (ADMA) are long-established cardiovascular risk factors. Low circulating L-homoarginine (hArg) concentrations were recently found to be associated with increased cardiovascular morbidity and mortality. The biochemical pathways of these amino acids overlap and share the same cofactor S-adenosylmethionine (SAM). In the present study, we investigated potential associations between hArg, L-arginine (Arg), ADMA and thCys in plasma of patients suffering from rheumatoid arthritis (RA), coronary artery disease (CAD) or peripheral artery occlusive disease (PAOD). In RA, we did not find any correlation between ADMA or hArg and thCys at baseline (n = 100) and after (n = 83) combined add-on supplementation of omega-3 fatty acids, vitamin E, vitamin A, copper, and selenium, or placebo (soy oil). ADMA correlated with Arg at baseline (r = 0.446, P < 0.001) and after treatment (r = 0.246, P = 0.03). hArg did not correlate with ADMA, but correlated with Arg before (r = 0.240, P = 0.02) and after treatment (r = 0.233, P = 0.03). These results suggest that hArg, ADMA and Arg are biochemically familiar with each other, but unrelated to hCys in RA. In PAOD and CAD, ADMA and thCys did not correlate.

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Objectives: The present study evaluated the effects of a combined nutritional supplement, containing omega-3 fatty acids (ω-3 FA) and different antioxidative micronutrients on nutrient status and disease activity in patients with rheumatoid arthritis (RA). Methods: The study was conducted as a double-blind, randomised placebo-controlled trial. A hundred patients with defined RA were allocated to the verum or placebo group. During a period of twelve weeks they were given three capsules of their specific study supplementation every day. The daily dosage of ω-3 FA was 1.35 g (thereof 900 mg eicosapentaenoic acid, EPA), 90 mg vitamin E, 600 μg vitamin A, 3 mg copper, and 75 μg selenium, or soy oil (placebo), respectively. Outcome variables were the changes in DAS 28, the number of tender and swollen joints, morning stiffness, and supply with different nutrients (e.g. serum concentration of EPA, AA and vitamin E), as well as blood lipid levels. Results: Sixty-four participants were included in this analysis: 30 receiving verum and 34 placebo. After twelve weeks of intervention, little but not significant improvements were observed in the DAS 28 and other clinical factors. Subgroup analysis revealed that the effect was much more pronounced in patients who were at least at a moderate activity of illness. Regarding the nutritional status, the serum concentration of EPA (P < 0.001), vitamin E (P < 0.01), SOD (P < 0.05), and GPx (P < 0.001) increased significantly, while AA (P < 0.001) decreased after supplementation. The concentration of triglycerides decreased significantly in the verum group (P < 0.05) but not in the placebo group. Conclusions: A twelve week add-on supplementation of a combined food supplement (ω-3 FA + antioxidants) effected modest but not significant changes in the clinical parameters in RA. Though vitamin E, SOD and GPx improved significantly, equivalent to an increased antioxidant defence. This supplementation was dedicated to enhance the nutritional status of critical nutrients in RA, especially with regard to an increased risk of cardiovascular disease in these patients