Accumulation of the endogenous L‐arginine analogue NG‐monomethyl‐L‐arginine in human end‐stage renal failure patients on regular haemodialysis

Ribeiro, A Mendes; Roberts, N. B.; Lane, Catherine; Yaqoob, Muhammad; Ellory, J. Clive

doi:10.1113/expphysiol.1996.sp003950

Cited by 41 publications

(18 citation statements)

References 9 publications

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“…As the kidney is involved in regulating circulating arginine concentrations, potential derangement of arginine metabolism could occur in end-stage renal failure. This has been shown in dialysis patients where plasma citrulline concentrations are high and arginine concentrations low [22,23]. This, however, may not be physiological relevant, as arginine transport into cells is increased in uraemia [24,25].…”

Section: Scheme 1 Inhibition Of Arginase By Uraemia Results In Increamentioning

confidence: 95%

Altered l-arginine metabolism results in increased nitric oxide release from uraemic endothelial cells

THURAISINGHAM¹,

ROBERTS²,

WILKES³

et al. 2002

Clinical Science

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A B S T R A C TResults regarding the nitric oxide (NO) system in uraemia are contradictory. L-Arginine, the precursor of NO, is also metabolized by arginase to form ornithine and urea. In the present study, endothelial NO production and arginine metabolism in uraemia were assessed. In addition an in vivo model was used to examine excess consumption of NO in uraemia. NO and amino acid measurements were made from basal and stimulated (by bradykinin) uraemic and control endothelial cells. Reverse-transcriptase PCR was used to assess endothelial NO synthase (eNOS) and inducible NOS (iNOS) expression. Finally, aortae of uraemic rats were stained for nitrotyrosine (a marker of peroxynitrite). Basal uraemic cells produced more NO than the control cells. L-Arginine levels were greater in uraemic (supernatants/cells), but ornithine levels were higher in control (supernatants/cells). Following stimulation, NO levels in supernatants were similar, but the rise in NO production was greater in control compared with uraemic cells; L-arginine levels still remained higher in uraemic supernatants/cells. Differences in ornithine concentration (supernatants/cells) disappeared following bradykinin stimulation, due to a rise in ornithine levels in the uraemic group. There was no difference in eNOS expression, nor was iNOS detected in either group. Only aortae from uraemic rats showed evidence for nitrotyrosine staining. These studies demonstrated increased basal NO release in uraemic endothelial cells, perhaps by inhibition of arginase and hence diversion of arginine to the NO pathway. The increased NO produced under basal conditions may be inactive due to excessive consumption, resulting in peroxynitrite formation. Interestingly, bradykinin appears to restore arginase activity in uraemia, resulting in normalization of NO production.

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Section: Scheme 1 Inhibition Of Arginase By Uraemia Results In Increamentioning

confidence: 95%

Altered l-arginine metabolism results in increased nitric oxide release from uraemic endothelial cells

THURAISINGHAM¹,

ROBERTS²,

WILKES³

et al. 2002

Clinical Science

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“…In ESRD patients, the short-term effect of a single HD session on the plasma levels of l-arginine has been extremely variable between studies, with some finding no change [27,28,32,38] while others reported decreases ranging from 10-70 % of pre-dialysis values [26,[39][40][41]. The present study clearly belongs to the second category (Figure 2), although the results differed considerably between patients, possibly because of a variable redistribution of l-arginine between intracellular and extracellular pools (keeping in mind that the former is by far the larger) [42].…”

Section: Acute Impact Of Hdmentioning

confidence: 99%

Haemodialysis acutely reduces the plasma levels of ADMA without reversing impaired NO-dependent vasodilation

et al. 2009

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End-stage renal disease patients have endothelial dysfunction and high plasma levels of ADMA (asymmetric omega-NG,NG-dimethylarginine), an endogenous inhibitor of NOS (NO synthase). The actual link between these abnormalities is controversial. Therefore, in the present study, we investigated whether HD (haemodialysis) has an acute impact on NO-dependent vasodilation and plasma ADMA in these patients. A total of 24 patients undergoing maintenance HD (HD group) and 24 age- and gender-matched healthy controls (Control group) were enrolled. The increase in forearm SkBF (skin blood flow) caused by local heating to 41 degrees C (SkBF41), known to depend on endothelial NO production, was determined with laser Doppler imaging. SkBF41 was expressed as a percentage of the vasodilatory reserve obtained from the maximal SkBF induced by local heating to 43 degrees C (independent of NO). In HD patients, SkBF41 was assessed on two successive HD sessions, once immediately before and once immediately after HD. Plasma ADMA was assayed simultaneously with MS/MS (tandem MS). In the Control group, SkBF41 was determined twice, on two different days, and plasma ADMA was assayed once. In HD patients, SkBF41 was identical before (82.2+/-13.1%) and after (82.7+/-12.4%) HD, but was lower than in controls (day 1, 89.6+/-6.1; day 2, 89.2+/-6.9%; P<0.01 compared with the HD group). In contrast, plasma ADMA was higher before (0.98+/-0.17 micromol/l) than after (0.58+/-0.10 micromol/l; P<0.01) HD. ADMA levels after HD did not differ from those obtained in controls (0.56+/-0.11 micromol/l). These findings show that HD patients have impaired NO-dependent vasodilation in forearm skin, an abnormality not acutely reversed by HD and not explained by ADMA accumulation.

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“…17,33 Concentrations of L-NMMA in healthy controls appear to be 10 times lower than that of ADMA 17,34 but are increased significantly (1.4ϫ10 Ϫ5 mol/L) in uremic patients. 34 These values in uremic patients are within the range of concentrations tested in the present study. Plasma ADMA levels in normotensive and hypertensive rats (0.7ϫ10 Ϫ6 mol/L) 25 are similar to those observed in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Effects of Some Guanidino Compounds on Human Cerebral Arteries

Segarra

Medina

Ballester

et al. 1999

Stroke

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Background and Purpose-Accumulation of endogenous guanidino-substituted analogues of L-arginine in chronic renal failure might contribute to some of the vascular and neurological disorders of this pathology. We tested the hypothesis that in human cerebral arteries, some guanidino compounds may increase vascular tone, through nitric oxide (NO) synthase inhibition, and impair endothelium-dependent relaxation. Methods-Rings of human middle cerebral artery were obtained during autopsy of 26 patients who had died 3 to 12 hours before. The rings were suspended in organ baths for isometric recording of tension. We then studied the responses to N G -monomethyl-L-arginine (L-NMMA), N G ,N G -dimethyl-L-arginine (asymmetrical dimethylarginine; ADMA), aminoguanidine (AG), and methylguanidine (MG). Results-L-NMMA (10Ϫ6 to 3ϫ10 Ϫ4 mol/L) and ADMA (10 Ϫ6 to 3ϫ10 Ϫ4 mol/L) caused concentration-and endothelium-dependent contractions (median effective concentrations [EC 50 ]ϭ1.1ϫ10Ϫ5 and 1.6ϫ10 Ϫ5 mol/L, respectively; E max ϭ35.5Ϯ7.9% and 43.9Ϯ5.9% of the response to 100 mmol/L KCl). AG (10 Ϫ5 to 3ϫ10 Ϫ3 mol/L) and MG (10 Ϫ5 to 3ϫ10 Ϫ3 mol/L) produced endothelium-independent contractions (E max ϭ44.3Ϯ8.8% and 45.7Ϯ5.8% of the response to 100 mmol/L KCl, respectively). L-Arginine (10 Ϫ3 mol/L) prevented the contractions by L-NMMA and ADMA but did not change contractions induced by AG and MG. L-NMMA and ADMA inhibited endothelium-dependent relaxation induced by acetylcholine in a concentration-dependent manner; AG and MG were without effect. Conclusions-The results suggest that the contractions induced by L-NMMA and ADMA are due to inhibition of endothelial NO synthase activity, whereas AG and MG do not affect the synthesis of NO. An increase in the plasma concentration of L-NMMA and ADMA associated with uremia is likely to represent a diminished release or effect of NO, and consequently, an increased cerebrovascular tone in uremic patients is highly conceivable. (Stroke. 1999;30:2206-2211.)Key Words: cerebral arteries Ⅲ endothelium Ⅲ nitric oxide N itric oxide (NO) synthesized from L-arginine accounts for the powerful vasodilator effects of endotheliumderived relaxing factor 1,2 and consequently plays a decisive role in determining vasomotor tone in several vascular beds, including the cerebral circulation. [3][4][5][6][7] The synthesis of NO can be specifically and competitively antagonized by arginine analogues such as N G -monomethyl-L-arginine (L-NMMA). 4,8 Histochemical studies have demonstrated the presence of NO synthase immunoreactivity in the adventitia of rat and human cerebral arteries. 9,10 Consistent with these observations, several reports have shown that NO from perivascular nerve endings mediates dilatation in the cerebral arteries through a nonadrenergic, noncholinergic mechanism, 11-13 whereas NO of endothelial origin can modulate contractile responses of isolated human cerebral arteries to sympathetic stimulation. 6 Uremia is an established risk factor for cardiovascular disease and cerebrovascular acciden...

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Accumulation of the endogenous L‐arginine analogue NG‐monomethyl‐L‐arginine in human end‐stage renal failure patients on regular haemodialysis

Cited by 41 publications

References 9 publications

Altered l-arginine metabolism results in increased nitric oxide release from uraemic endothelial cells

Altered l-arginine metabolism results in increased nitric oxide release from uraemic endothelial cells

Haemodialysis acutely reduces the plasma levels of ADMA without reversing impaired NO-dependent vasodilation

Effects of Some Guanidino Compounds on Human Cerebral Arteries

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