Effects of chronic oral l-arginine administration on the l-arginine/NO pathway in patients with peripheral arterial occlusive disease or coronary artery disease: l-Arginine prevents renal loss of nitrite, the major NO reservoir

Abstract

Despite saturation of nitric oxide (NO) synthase (NOS) by its substrate L-arginine (Arg), oral and intravenous supplementation of Arg may enhance NO synthesis, a phenomenon known as "The L-arginine paradox". Yet, Arg is not only a source of NO, but is also a source for guanidine-methylated (N (G)) arginine derivatives which are all inhibitors of NOS activity. Therefore, Arg supplementation may not always result in enhanced NO synthesis. Concomitant synthesis of N (G)-monomethyl arginine (MMA), N (G),N (G)-dimethylarginine (asymmetric dimethylarginine, ADMA) and N (G),N (G´)-dimethylarginine (symmetric dimethylarginine, SDMA) from supplemented Arg may outweigh and even outbalance the positive effects of Arg on NO. Another possible, yet little investigated effect of Arg supplementation may be alteration of renal function, notably the influence on the excretion of nitrite in the urine. Nitrite is the autoxidation product of NO and the major reservoir of NO in the circulation. Nitrite and Arg are reabsorbed in the proximal tubule of the nephron and this reabsorption is coupled, at least in part, to the renal carbonic anhydrase (CA) activity. In the present placebo-controlled studies, we investigated the effect of chronic oral Arg supplementation of 10 g/day for 3 or 6 months in patients suffering from peripheral arterial occlusive disease (PAOD) or coronary artery disease (CAD) on the urinary excretion of nitrite relative to nitrate. We determined the urinary nitrate-to-nitrite molar ratio (UNOxR), which is a measure of nitrite-dependent renal CA activity before and after oral intake of Arg or placebo by the patients. The UNOxR was also determined in 6 children who underwent the Arg test, i.e., intravenous infusion of Arg (0.5 g Arg/kg bodyweight) for 30 min. Arg was well tolerated by the patients of the three studies. Oral Arg supplementation increased Arg (plasma and urine) and ADMA (urine) concentrations. No appreciable changes were seen in NO (in PAOD and CAD) and prostacyclin and thromboxane synthesis (in PAOD). In the PAOD study, UNOxR did not change in the Arginine group (480 ± 51 vs 486 ± 50), but fell in the Placebo group (422 ± 67 vs 332 ± 42, P = 0.025). In the CAD study, UNOxR did not change significantly in the Arginine group (518 ± 77 at start vs 422 ± 40 after 3 months vs 399 ± 66 after 6 months), but fell in the Placebo group (524 ± 69 vs 302 ± 36 vs 285 ± 31; P = 0.025 for 0 vs 3 months). Infusion of Arg tended to decrease the UNOxR in the children (317 ± 41 vs 208 ± 16, P = 0.06). We propose that oral long-term Arg supplementation prevents loss of NO bioactivity by saving nitrite. The optimum Arg dose needs to be elaborated and is likely to be less than 10 g per day in adults. Orally and intravenously administered arginine was well tolerated by the elderly patients and young children, respectively.

Results, meta-analysis and a first evaluation of UNOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings

“…Especially, intravenous administration of the carbonic anhydrase (CA) inhibitor acetazolamide to conscious rats increased UNOx by a factor of almost 3, strongly suggesting involvement of renal CA in the handling of nitrate/nitrite excretion/reabsorption (Sütö et al 1995). In humans, we have recently shown that renal CA isoforms are involved in the reabsorption of inorganic nitrite (NO2 -) and to a lesser extent of inorganic nitrate (ONO2 -) (Tsikas and Chobanyan-Jürgens 2010; Chobanyan-Jürgens et al 2012a;Tsikas et al 2014;Schneider et al 2015). This newly discovered role of renal CA isoforms is of particular importance, because nitrite is an important and abundant reservoir of NO in tissues and cells including erythrocytes (Gladwin et al 2006).…”

Homoarginine, arginine, and relatives: analysis, metabolism, transport, physiology, and pathology

“…Recent clinical investigations on these Arg metabolites in adults extend their key importance to other diseases in adults, including multiple sclerosis, chronic liver and kidney disease, obesity, rheumatoid arthritis, coronary artery disease, and peripheral arterial occlusive disease (Dimitroulas et al 2015;Frenay et al 2015a, b;Haghikia et al 2015;Kayacelebi et al 2015c;Kruszelnicka et al 2015;May et al 2015;Pilz et al 2015a;Schneider et al 2015;Sitar et al 2015). In childhood and adolescence, the significance of ADMA or hArg as cardiovascular risk factors is little investigated and incompletely understood.…”

“…The circulating concentration of ADMA in healthy children is more than two times higher than in healthy adults (Lücke et al 2007), suggesting that ADMA and presumably the whole Arg/NO pathway greatly differ between children/adolescents and adults, i.e., that children are not small adults. In the present work, emphasis was given to the Arg/NO pathway, including hArg in healthy children and adolescents, as well as in those suffering from type 1 diabetes mellitus, Duchenne muscular dystrophy, and growth hormone deficiency (GHD) (Carmann et al 2015;Hörster et al 2015;Langen et al 2015; see also Thum et al 2007).…”

“…Benefits from pharmacological or supplemental use of Arg are expected to be more than enhancement of NO synthesis by increasing the substrate availability of Arg (Wu et al 2009). Potential benefits of oral administration of Arg could be saving nitrite bioavailability due to improved reabsorption of nitrite in the proximal tubule of the nephron (Schneider et al 2015), as nitrite is the major NO reservoir (Gladwin et al 2006), and due to enhanced hArg biosynthesis in comparison to ADMA (Kayacelebi et al 2015b). This may be of particular importance because hArg and ADMA seem to act antagonistically at least in the circulatory system (Tsikas and Kayacelebi 2014).…”

Regulation of c-Jun N-Terminal Protein Kinase (JNK) Pathway in Apoptosis of Endothelial Outgrowth Cells Induced by Asymmetric Dimethylarginine

“…Under pathological conditions, ADMA concentrations significantly rise (3–5 μmol/l) and inhibit synthesis of NOS and NO, which leads to diastolic function depression of peripheral vascular and decreased cerebral blood perfusion [10,11]. Research shows that L-arginine-NO synthetic obstacles have a close relationship with hypertension and atherosclerosis [12,13]. In vivo , ADMA expression levels have obvious correlation with the occurrence and prognosis of acute cardiovascular and cerebrovascular diseases [14].…”