Skip Navigation

Cardiovascular Research 2001 49(4):697-712; doi:10.1016/S0008-6363(00)00267-4
© 2001 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Mendes Ribeiro, A.C.
Right arrow Articles by Mann, G.E.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Mendes Ribeiro, A.C.
Right arrow Articles by Mann, G.E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2001, European Society of Cardiology

Abnormalities in L-arginine transport and nitric oxide biosynthesis in chronic renal and heart failure

A.C. Mendes Ribeiroa,b,*, T.M.C. Bruninia, J.C. Ellorya and G.E. Mannb

aUniversity Laboratory of Physiology, South Parks Road, Oxford OX1 3PT, UK
bCentre for Cardiovascular Biology and Medicine, GKT School of Biomedical Sciences, King's College London, London SE1 1UL, UK

* Corresponding author. Tel.: +44-1865-272-442; fax: +44-1865-272-469 cribeiro{at}physiol.ox.ac.uk

Received 30 August 2000; accepted 19 October 2000


   Abstract
Top
 Abstract
1 Introduction
 2 l-Arginine transport in...
 3 l-Arginine transport and...
 4 Modulation of the...
 5 Modulation of the...
 6 Activation of system...
 7 Summary
 References
 
Patients with chronic renal and heart failure present with hypertension and widespread vasoconstriction, respectively. Although systemic release of nitric oxide (NO) may be elevated in both pathological syndromes, enhanced production of NO fails to overcome endothelial dysfunction. Plasma concentrations of L-arginine, a cationic amino acid precursor for NO synthesis, are reduced whilst levels of the endogenous L-arginine analogues, asymmetric and symmetric dimethyl arginine and NG-monomethyl-L-arginine, seem to be elevated. We have reported that transport of L-arginine via the cationic amino acid transporters y+/CAT and/or y+L are up-regulated in erythrocytes, peripheral blood mononuclear cells and platelets from both patients with either chronic renal or heart failure. A possible explanation why NO serves as a failing counter-regulatory mechanism in both these pathologies is that availability of L-arginine for NO production is reduced despite the observed increase in membrane transport. This review examines the mechanisms underlying alterations in NO production in chronic renal and heart failure, and the possible role of L-arginine transport in vascular and platelet dysfunction observed in both syndromes.

KEYWORDS Cytokines; Heart failure; Ion transport; Nitric oxide; Leukocytes; Renal function; Platelets


   1 Introduction
Top
 Abstract
 1 Introduction
2 l-Arginine transport in...
 3 l-Arginine transport and...
 4 Modulation of the...
 5 Modulation of the...
 6 Activation of system...
 7 Summary
 References
 
Chronic renal and heart failure are accompanied by endothelial dysfunction and there is controversy as to whether systemic production of nitric oxide (NO) is increased in these disease states [1–19], since some reports do not confirm these findings [20–27]. The prolonged bleeding time in patients with chronic renal failure (uraemia) may be the consequence of increased NO synthesis, since in animal models this altered coagulation state can be reversed by infusions of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) [28]. Moreover, plasma concentrations of nitrates are elevated in patients with chronic renal failure, further supporting the hypothesis that NO production is up-regulated in uraemia [6,12,14,16,18]. Increased plasma concentrations of endogenous arginine analogues such as L-NMMA, symmetric and asymmetric dimethylarginine (SDMA and ADMA, respectively) together with reduced arginine levels may in part explain impaired responses to NO in patients with chronic renal or heart failure [25,29–40]. Transport of L-arginine (precursor of NO) is elevated in red blood cells and peripheral blood mononuclear cells [40–44], suggesting that uraemia and heart failure induce adaptive increases in the activity of the cationic amino acid transport system y+. By contrast, transport of L-arginine in platelets is mediated by the very high affinity transport system y+L; the observed activation of this system in uraemic platelets may be crucial to the enhanced synthesis of NO by these cells observed in renal failure [45]. This review examines the mechanisms underlying alterations in NO production in chronic renal and heart failure, and considers the evidence, based on studies in circulating blood cells, that elevated cytokine levels and altered substrate availability due to diminished plasma L-arginine and increased L-arginine analogues levels activate the L-arginine–NO signalling pathway in circulating blood cells and most likely vascular cells.


   2 L-Arginine transport in circulating blood cells
Top
 Abstract
 1 Introduction
 2 l-Arginine transport in...
3 l-Arginine transport and...
 4 Modulation of the...
 5 Modulation of the...
 6 Activation of system...
 7 Summary
 References
 
Membrane transport of cationic amino acids, initially assigned to the classical Na+-independent system y+ [46], has now been shown to be mediated by at least five Na+-independent transport pathways [47–52]: (cationic amino acid transporter, CAT-1 or system y+), CAT-2A (low affinity variant of CAT-1, expressed predominantly in liver), CAT-2B (inducible isoform of CAT-1, induced in T cells, macrophages, lung and testis), system y+L (transports leucine and cationic amino acids with high affinity) and systems b0,+ and B0,+ (broad specificity for neutral and cationic amino acids). The murine and human isoforms of CAT-2A and CAT-2B differ only in a stretch of 42 amino acids and are likely to be the product of differently spliced mRNAs [53–56]. Transport of arginine, lysine and ornithine via system y+ (CAT-1) is relatively pH-independent, sensitive to trans-stimulation and saturable at circulating plasma concentrations (~0.1–0.2 mM). System y+ is also sensitive to changes in membrane potential [57–60], with hyperpolarization increasing cationic amino acid transport influx. A new member of the CAT family (rCAT3) has recently been isolated from rat brain and expresses y+ transport activity [61]. Unlike the other CAT isoforms, transport properties of a newly identified CAT-4 isoform have yet to be described in detail [62].

L-Arginine transport in red blood cells and peripheral blood mononuclear cells is mediated via the cationic amino acid transport systems y+ and y+L [40–44,48,50,51,63]. System y+L, identified in human erythrocytes, exhibits a much higher affinity for cationic amino acids (KM for lysine ~10 µM) than any other cationic amino acid transporter [48,64]. System y+L mediates high-affinity, Na+-independent cationic and Na+-dependent neutral amino acid transport. Recently, y+L amino acid transporters (y+LAT1 and y+LAT2) have been identified and it seems that y+LAT and 4F2hc combine to induce y+L transport activity [65–67]. Systems B0,+ and b0,+ (Na+-dependent and Na+-independent isoforms, respectively) initially described in early mouse embryos [47,50,51,68] have not been described in human red blood cells or peripheral blood mononuclear cells.


   3 L-Arginine transport and nitric oxide production
Top
 Abstract
 1 Introduction
 2 l-Arginine transport in...
 3 l-Arginine transport and...
4 Modulation of the...
 5 Modulation of the...
 6 Activation of system...
 7 Summary
 References
 
3.1 Synthesis and metabolism of arginine
Metabolism of arginine by mammalian cells has been reviewed in detail [69]. L-Arginine is involved in the synthesis of proteins, creatinine, urea, agmatime and polyamines and modulates the delivery of hormones and the synthesis of pyrimidine bases [70]. L-Arginine produced by the liver is metabolised locally and does not contribute significantly to circulating plasma L-arginine levels (80–120 µmol/l), which are mainly dependent on dietary intake of L-arginine (1–2 g/day) and synthesis by the proximal tubule of the kidney. In humans, the conversion of L-citrulline to L-arginine is independent of the intake of L-arginine or protein [70], but in disease states, where synthesis of L-arginine is decreased and catabolism increased, L-arginine may become an essential amino acid [70].

3.2 Activity of the L-arginine–NO pathway in circulating blood cells
In mammalian cells, NO is formed from L-arginine by a family of NO synthases: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS, from activated macrophages) [71–73]. L-Arginine augments collagen-induced increases in platelet cyclic GMP levels and inhibits platelet aggregation, suggesting that L-arginine transport and NO production may be coupled [74]. NO may also react directly with oxyhaemoglobin forming nitrate and metahaemoglobin, and with haemoglobin to form nitrosylhaemoglobin [75]. Thus, red blood cells can inactivate NO under conditions where NO-mediated vasodilatation is undesired such as haemorrhage [76]. Recent evidence suggests that erythrocytes can release NO bound to haemoglobin in the microcirculation under low oxygen tension [77]. Although human erythrocytes appear to express both iNOS and eNOS [78–80], further studies are necessary to substantiate these claims. Nevertheless, red blood cells are capable of producing NO from nitrovasodilators such as isosorbide dinitrate [81].

NO production by human mononuclear cells has been difficult to demonstrate in vitro, and a clear role for NO in responses to infection remains controversial. In human leukocytes, some studies have concluded that iNOS message, protein or enzymatic activity is not detectable [82,83], whilst others have reported that leukocytes from human urine infected with bacteria express active iNOS localised to the membrane fraction of leukocytes [84]. Non-activated human monocytes/macrophages express eNOS and iNOS at rest or following stimulation, respectively [82,85,86]. Constitutive, low levels of iNOS have been detected in Epstein–Barr virus transformed human B lymphocytes, and the inhibition of apoptosis by NO is largely independent of cGMP and mediated by the cellular redox status [87]. Platelets express both constitutive and inducible forms of NO synthase [74,88,89], and iNOS activity is induced within 30 min and is maximal 2 h after stimulation with LPS and cytokines [88].

In several cell types, NOS and the y+/CAT transport system seem to be regulated in parallel. L-Lysine, a competitive inhibitor of L-arginine transport, inhibits NO production in rat cardiac myocytes exposed to cytokines [52]. In rat astrocytes there is evidence of a coordinated regulation of iNOS and L-arginine transport [90]. Treatment of endothelial or smooth muscle cells with cytokines induces iNOS and increases the expression of mRNA for CAT-1 and CAT-2B L-arginine transporters [91–95]. However, there are reports of independent mechanisms regulating the transcription of CAT transporters and iNOS in endothelial and smooth muscle cells [93–95] and macrophages [96]. Dexamethasone inhibits the transcription of L-arginine transporters, and it has been suggested that glucocorticoids may modulate NO synthesis partially by limiting intracellular L-arginine availability [92,96]. Insulin has been shown to up-regulate NO production and L-arginine transport via CAT-1 in human endothelial cells and cardiac myocytes [52,97]. Moreover, in activated rat macrophages, induction of L-arginine transport is required to sustain elevated NO synthesis [96,98].


   4 Modulation of the L-arginine–NO pathway in chronic renal failure
Top
 Abstract
 1 Introduction
 2 l-Arginine transport in...
 3 l-Arginine transport and...
 4 Modulation of the...
5 Modulation of the...
 6 Activation of system...
 7 Summary
 References
 
The alterations in blood pressure observed in chronic renal failure patients seem to be partially related to a dysfunction in the modulation of the L-arginine–NO signalling pathway in the vasculature of animals models and uraemic patients (see Tables 1 and 2Go) [99]. Indeed, chronic renal failure patients exhibit endothelial cell damage, and an impairment in endothelium-dependent relaxation, that presents in very early stages of the syndrome [100–105], although these findings do not seem to be present in rat models of uraemia [106,107]. This endothelial dysfunction seems to be reversed by infusion of L-arginine and renal dialysis [105].


View this table:
[in this window]
[in a new window]

  		Table 1 Modulation of the L-arginine–nitric oxide pathway in animal models of chronic renal failure

 

View this table:
[in this window]
[in a new window]

  		Table 2 Modulation of the L-arginine–NO pathway in patients with chronic renal failure

 
NO is one of the key regulators of renal haemodynamics and in the kidney NO is produced by endothelial, mesangial and inflammatory cells [108–111]. The status of NO in chronic renal failure is complex with indirect evidence suggesting that NO production is increased [1,4–9,12–14,16,18]. The prolonged bleeding time observed in patients with chronic renal failure appears to be reversed in uraemic rats following infusion of the NOS inhibitor, L-NMMA [1,28]. Moreover, the systemic production of NO based on the concentration of nitrites/nitrates in plasma seems to be increased in uraemic rats [110,112]. Platelets from uraemic patients synthesise more NO than control cells [1], and uraemic plasma increases the production of NO by endothelial cells [1]. Interestingly, platelets from uraemic patients seem to have a diminished response to NO, implying that NO synthesis in these cells may already be up-regulated [113].

Recently, we have demonstrated that the transport of L-arginine in platelets is mediated by the high affinity system y+L [45]. The very low KM of this system (~10 µM) suggests that under conditions of low circulating plasma L-arginine levels and elevated L-NMMA, SDMA and ADMA levels, as reported in heart and renal failure, intracellular supply of L-arginine may be limited due to low substrate availability and competition for transport. We also have shown that the transport of L-arginine via system y+L in human platelets is up-regulated in uraemia [45]. Recently, we have demonstrated that, in platelets, inhibition of L-arginine transport via y+L system by both neutral and cationic amino acids inhibits NO platelet synthesis (unpublished data). This activation of transport may provide a mechanism whereby uraemic platelets maintain their production of NO in spite of the reduced plasma availability of L-arginine. Moreover, synthesis of NO by uraemic platelets may provide a protective mechanism against increased aggregation and accelerated atherosclerosis characteristic of renal failure.

The gastric hyperaemia and increased susceptibility to gastric lesions observed in chronic renal failure patients may be related to an enhanced synthesis of NO, since gastric blood flow, in a rat model of uraemia, returns to normal after the administration of nitro-L-arginine methyl ester (L-NAME) [114,115]. Nevertheless, it is worth noting that a decreased expression of eNOS has been detected in the gastric mucosa of uraemic rats [116]. Accumulation of nitrates in peripheral blood from uraemic patients on haemodialysis is increased compared to controls [4,6,12,14,18]. This increase in NO production is related to the type of dialysis membrane used in treatment and has been reported more frequently in patients who present with hypotension during dialysis [4–6,12–14].

Although upregulation of vascular NOS activity is a homeostatic adaptation to prevent kidney damage [117], the production of NO by the kidney seems to be reduced in chronic renal failure [110–112]. In rats, inhibition of NO production leads to systemic hypertension, a diminution of the glomerular filtration rate and, if the inhibition persists, uraemia [118–121]. Administration of L-arginine in animal models improves kidney function in several conditions known to lead to chronic renal failure, such as obstructive nephropathy, hypertension, partial renal ablation and diabetes mellitus [70]. Recent studies have further demonstrated that formation of NO and expression of iNOS are reduced in parallel in uraemic renal tissue from rats, whereas the activity and expression of eNOS and iNOS appear to be up-regulated in the systemic vasculature [112].

A guanidino analogue of L-arginine (asymmetric dimethyl arginine) was reported to be increased in uraemic plasma, and these authors suggested that inhibition of NO synthesis contributed to the hypertension and immune dysfunction observed in chronic renal failure [29–35,37–39]. As summarised in Table 3, we have reported that plasma levels of L-arginine are reduced significantly in uraemic subjects predialysis, whilst plasma levels of L-citrulline were increased [31]. We have also demonstrated that plasma levels of L-arginine correlated with renal function indexes in undialysed patients with chronic renal failure (Fig. 1; unpublished data). There are several studies of plasma amino acid levels in uraemic patients, which have reported increased, unaltered or decreased levels of L-arginine [122–128]. However, it is clear that in uraemia the total amino acid pool is depleted and that L-arginine may become an essential amino acid in this pathological state [70].


View this table:
[in this window]
[in a new window]

  		Table 3 Plasma and intracellular red blood cell concentration of cationic amino acids and citrulline in chronic heart failure (CHF) and uraemic patients not yet on dialysis, on haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD)

 

Figure 1
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Dependence of plasma L-arginine concentration on glomerular filtration rate in undialysed chronic renal failure patients (n = 9). (unpublished data).

 
The activity of a large number of other membrane transporters is also altered in erythrocytes from uraemic patients [129–131]. Transport of L-arginine via system y+ but not y+L is increased in erythrocytes and peripheral blood mononuclear cells from uraemic patients (Figs. 2–4GoGo (see Refs. [42–44]). Dialysis partially reverses this stimulation in fresh red blood cells and peripheral blood mononuclear cells. The transport of L-arginine in erythrocytes from uraemic patients not yet on dialysis correlates with indexes of renal function and plasma concentration of L-arginine (Fig. 5; unpublished data). Rats with uraemia secondary to partial nephrectomy present with unaltered plasma L-arginine levels compared to controls and under these conditions transport of L-arginine and L-lysine in brain microvessels and red blood cells is unaffected [132,133]. These findings further support the hypothesis that decreased plasma L-arginine levels may trigger up-regulation of L-arginine transport observed in human circulating blood cells [40,42].


Figure 2
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 L-Arginine influx via the cationic amino acid transport systems y+ and y+L in red blood cells from control ({blacksquare}, n = 5) and chronic renal failure patients on haemodialysis, before (bullet, n = 9) and after (n, n = 9) one session of dialysis. Data denote the mean±S.E. Replotted from Mendes Ribeiro et al. [42].

 

Figure 3
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Comparison of the Vmax for L-arginine transport via cationic amino acid transport systems y+ and y+L in red blood cells obtained from control (n = 15) and uraemic patients: undialyzed (n = 11), continuous ambulatory peritoneal dialysis (n = 17), pre-haemodialysis (n = 9) and post-haemodialysis (3–4 h, n = 9). Data denote the mean±S.E. Replotted from Refs. [42,44] and unpublished data.

 

Figure 4
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Comparison of the initial rate of L-arginine influx (2 µM) via systems y+ and y+L in human peripheral blood mononuclear cells from control (n = 10) and uraemic patients: continuous ambulatory peritoneal dialysis (n = 6), pre-haemodialysis (n = 10) and post-haemodialysis (3–4 h, n = 10). Data denote the mean±S.E. Replotted from Mendes Ribeiro et al. [43,44].

 

Figure 5
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Correlation of the Vmax for L-arginine transport via system y+ in red blood cells with glomerular filtration rate (A) and plasma L-arginine levels (B) in undialysed chronic renal failure patients (n = 9–11) (unpublished data).

 
Platelet function is partially mediated by endogenous production of NO by platelets and previous studies have demonstrated that uraemic platelets generate more NO than control platelets. Recent observations support a role for platelet-derived NO production in the regulation of primary homeostasis. Freedman et al. have demonstrated that the bleeding time is significantly reduced in mice lacking platelet eNOS compared to mice with normal platelets [134]. The same group has also shown that platelets from patients with acute coronary syndromes produce less NO, suggesting that impaired platelet-derived NO production may contribute to thrombus formation in these syndromes [135].

Recently, we demonstrated that L-arginine transport in platelets is solely mediated by system y+L, which is up-regulated in platelets from chronic renal failure patients in dialysis [45] (Fig. 6). Since the transport of L-arginine via system y+L is critically dependent on plasma L-arginine concentrations, up-regulation of transport in uraemic platelets may be essential to maintain NO synthesis. The activation of L-arginine uptake in uraemic platelets is most probably involved in haemostatic alterations in this syndrome and may also be protective against atherothrombosis.


Figure 6
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 L-Arginine influx via system y+L in platelets from controls ({square}, n = 8) and chronic renal failure patients on haemodialysis ({blacksquare}, n = 10). Data denote the mean±S.E. Taken from Mendes Ribeiro et al. [45].

 

   5 Modulation of the L-arginine–NO pathway in chronic heart failure
Top
 Abstract
 1 Introduction
 2 l-Arginine transport in...
 3 l-Arginine transport and...
 4 Modulation of the...
 5 Modulation of the...
6 Activation of system...
 7 Summary
 References
 
Heart failure is a complex clinical syndrome broadly defined as a condition in which cardiac output is insufficient to maintain adequate perfusion of tissues [136]. The endothelium-dependent dilatation of arteries [137–150], but not the microvasculature [151], is impaired and related to the clinical severity of heart failure. NO synthase is expressed constitutively in the vascular endothelium, cardiac conduction tissue and myocytes [139], and iNOS has been detected in endothelium, infiltrating inflammatory cells, vascular smooth cells and myocytes in the presence of cytokines [139,152–158]. Recent evidence suggests that endothelial dysfunction could result from a decreased release or enhanced activation of NO [157–160] (see Tables 4 and 5Go). Clinical and experimental studies have reported increased plasma levels of the L-arginine analogue, ADMA, which could impair endothelium-dependent relaxation [11,36]. In contrast, several clinical studies have demonstrated that patients with heart failure exhibit an increased responsiveness to inhibitors of NO synthesis and elevated plasma levels of stable NO breakdown products [2,3,10,15], suggesting that NO synthesis is increased rather than decreased. Thus, increased release of NO in chronic heart failure may represent another failing counter-regulatory mechanism in the face of increased synthesis of vasoconstrictor mediators [152]. However, there is no direct evidence for increased synthesis of NO, and blood flow responses to endothelium-independent vasodilators such as nitroglycerin are preserved [139].


View this table:
[in this window]
[in a new window]

  		Table 4 Modulation of the L-arginine–NO pathway in animal models with chronic heart failure

 

View this table:
[in this window]
[in a new window]

  		Table 5 Modulation of the L-arginine–NO pathway in patients with chronic heart failure

 
It seems that NO synthesis and activity are abnormal in patients with heart failure, with the release of NO increased in heart conductance vessels although endothelium-dependent responses are blunted [139]. Increased oxidative stress and reduced antioxidant reserve have been demonstrated in heart failure subjects which can accelerated the inactivation of NO [161–165]. It is interesting to note that the antioxidant vitamin ascorbic acid improves endothelium-dependent relaxation in patients with heart failure [165]. The efficacy of oral L-arginine supplementation in endothelial function in heart failure remains controversial [166–168]. In the heart, NO has negative inotropic effects and plays a role in morphologic alterations such as hypertrophy and apoptosis on cardiomyocytes [169,170]. The presence of nNOS, eNOS and iNOS has been demonstrated within the myocardium of heart failure patients [169–173]. There are reports of increased expression of eNOS [169,171], iNOS [152–156,170,174–177] or both [178] in the failing myocardium. The putative deleterious actions of the negative inotropic effect of NO on ventricular contractility is counter-balanced by a reduction in myocardial oxygen consumption and enhanced coronary blood flow, preventing deterioration in myocardial performance [179]. Recently, it has been reported that an increase in endomyocardial iNOS and eNOS expression augments cardiac output in patients with dilated cardiomyopathy [180]. It has been suggested that in chronic heart failure increased plasma levels of circulating cytokines, especially TNF-{alpha}, may be responsible for a blunted endothelial response to agonists such as acetylcholine via a direct impairment of NO release, and destabilising of endothelial NOS mRNA levels [181]. At the same time, cytokines will induce iNOS and thereby NO release [153]. In this context, IL1-β and interferon-{gamma} pretreated myocytes express both iNOS and CAT transporters for L-arginine [52].

We have reported that erythrocytes and peripheral blood mononuclear cells from chronic heart failure patients exhibit an increased transport capacity for arginine via system y+/CAT [40,41] (see Fig. 7). We have also reported that plasma concentrations of L-arginine are reduced in chronic heart failure patients (see Table 3 and Ref. [40]). Our findings demonstrate a reduced supply of endogenous L-arginine which are consistent with reports of an improvement of blood flow and clinical conditions in chronic heart failure patients following L-arginine supplementation [182].


Figure 7
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 7 L-Arginine influx via systems y+ and y+L in red blood cells from control ({square}, n = 10) and chronic heart failure patients ({blacksquare}, n = 15). Data denote the mean±S.E. Replotted from Hanssen et al. [40].

 

   6 Activation of system y+ in uraemia and heart failure: a failing counter-regulatory mechanism
Top
 Abstract
 1 Introduction
 2 l-Arginine transport in...
 3 l-Arginine transport and...
 4 Modulation of the...
 5 Modulation of the...
 6 Activation of system...
7 Summary
 References
 
The fact that a similar increase in transport capacity for L-arginine was observed in chronic renal and heart failure, syndromes with a very different aetiology, argues against a specific effect of a uraemic toxin. In both chronic renal and heart failure, increased concentrations of circulating cytokines (IL-1, IL-6, TNF-{alpha}) may induce the expression of CAT-2 transporters and/or iNOS in peripheral mononuclear cells, platelets and erythroblasts. The up-regulation of NO synthesis in blood cells would further deplete the intracellular concentration of L-arginine, which together with the presence of arginine metabolites within the cell may trigger the activation of L-arginine transport. Since uraemia and heart failure are pre-thrombotic pathological conditions characterised by platelet activation, stimulation of L-arginine transport in these cells may be essential to minimise platelet aggregation and adhesion and therefore thrombotic events. Moreover, an adequate balance of the L-arginine–NO signalling pathway between platelets, white cells and endothelium seems to be essential to maintain an adequate vascular haemostasis.

It is also possible that the same adaptive mechanism is present in endothelial cells yet, as in circulating blood cells, the compensatory increase in L-arginine transport via y+/CAT-1 may not be sufficient to maintain an adequate synthesis of NO. This could contribute to the endothelial dysfunction characteristic of both pathologies. The failure of iNOS-mediated increases in NO synthesis to reverse the widespread vasoconstriction in chronic heart failure and hypertension in uraemia may be explained partially by an insufficient availability of L-arginine for eNOS in endothelial cells. The increase of L-arginine influx in red blood cells and peripheral mononuclear cells observed in chronic renal and heart failure may be associated with low plasma L-arginine. Indeed limited L-arginine availability has been reported to up-regulate L-arginine transport in endothelial cells via system y+ [60] and amino acid starvation has been reported to increase CAT-1 mRNA 3-fold in Fao cells [183].


   7 Summary
Top
 Abstract
 1 Introduction
 2 l-Arginine transport in...
 3 l-Arginine transport and...
 4 Modulation of the...
 5 Modulation of the...
 6 Activation of system...
 7 Summary
References
 
In both chronic renal and heart failure, endothelium-dependent relaxation is impaired whilst it seems likely that there is an increased systemic production of NO. If the up-regulation of L-arginine membrane transport in blood cells reported by our group is present in other cell types and tissues, this may provide a mechanism by which vascular cells compensate for the reduced vascular pool of L-arginine in uraemia and heart failure. The endothelial dysfunction present in both chronic renal and heart failure and its reversal by L-arginine supplementation may be of relevance to atherogenesis and hypertension in chronic renal failure and the widespread vasoconstriction observed in chronic heart failure. The observed low L-arginine and elevated arginine analogue plasma concentrations coupled with increased levels of cytokines and NO production would lead to up-regulation of L-arginine transport. Nevertheless, the increased transport of L-arginine and enhanced NO production appears to be a failing counter-regulatory mechanism in both chronic renal and heart failure.

Time for primary review 28 days.


   Acknowledgements
 
We gratefully acknowledge the financial support of the British Heart Foundation (PG/95102) and CAPES (Brazil), and thank our colleagues Dr. Magdi Yaqoob, Dr. Norman Roberts, Mr. Clive Lane, Ms. Daniele Fricke and Dr. Henner Hanssen for their collaboration in the cited work in uraemia and chronic heart failure.


   References
Top
 Abstract
 1 Introduction
 2 l-Arginine transport in...
 3 l-Arginine transport and...
 4 Modulation of the...
 5 Modulation of the...
 6 Activation of system...
 7 Summary
 References
 

  1. Noris M., Benigni A., Boccardo P., et al. Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension. Kidney Int (1993) 44:445–450.[Web of Science][Medline]
  2. Habib F., Dutka D., Crossman D., et al. Enhanced basal nitric oxide production in heart failure: another failed counter-regulatory vasodilator mechanism? Lancet (1994) 344:371–373.[CrossRef][Web of Science][Medline]
  3. Winlaw D.S., Smythe G.A., Keogh A.M., et al. Increased nitric oxide production in heart failure. Lancet (1994) 344:373–374.[CrossRef][Web of Science][Medline]
  4. Yokokawa K., Mankus R., Saklayen M.G., et al. Increased nitric oxide production in patients with hypotension during hemodialysis. Ann Intern Med (1995) 123:35–37.[Abstract/Free Full Text]
  5. Amore A., Bonaudo R., Ghigo D., et al. Enhanced production of nitric oxide by blood-dialysis membrane interaction. J Am Soc Nephrol (1995) 6:1278–1283.[Abstract]
  6. Lin S.H., Chu P., Yu F.C., et al. Increased nitric oxide production in hypotensive hemodialysis patients. ASAIO J (1996) 42:M895–M899.[Web of Science][Medline]
  7. Rysz J., Luciak M., Kedziora J., et al. Nitric oxide release in the peripheral blood during hemodialysis. Kidney Int (1997) 51:294–300.[Web of Science][Medline]
  8. Kang E.S., Acchiardo S.R., Wang Y.B., et al. Hypotension during hemodialysis: role for nitric oxide. Am J Med Sci (1997) 313:138–146.[CrossRef][Web of Science][Medline]
  9. Roccatello D., Mengozzi G., Alfieri V., et al. Early increase in blood nitric oxide, detected by electron paramagnetic resonance as nitrosylhaemoglobin, in haemodialysis. Nephrol Dial Transplant (1997) 12:292–297.[Abstract/Free Full Text]
  10. Kaye D.M., Chin-Dusting J., Esler M.D., et al. The failing human heart does not release nitrogen oxides. Life Sci (1998) 62:883–887.[CrossRef][Web of Science][Medline]
  11. Usui M., Matsuoka H., Miyazaki H., et al. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci (1998) 62:2425–2430.[CrossRef][Web of Science][Medline]
  12. Nishimura M., Takahashi H., Maruyama K., et al. Enhanced production of nitric oxide may be involved in acute hypotension during maintenance hemodialysis. Am J Kidney Dis (1998) 31:809–817.[Web of Science][Medline]
  13. Noris M., Todeschini M., Casiraghi F., et al. Effect of acetate, bicarbonate dialysis, and acetate-free biofiltration on nitric oxide synthesis: implications for dialysis hypotension. Am J Kidney Dis (1998) 32:115–124.[Web of Science][Medline]
  14. Blum M., Yachnin T., Wollman Y., et al. Nitric oxide production in patients with chronic renal failure. Nephron (1998) 79:265–280.[CrossRef][Web of Science][Medline]
  15. Rakhit R.D., Tousoulis D., Lefroy D.C., et al. Differential nitric oxide synthase activity in ischemic and idiopathic dilated cardiomyopathy. Am J Cardiol (1999) 84:737–738.[CrossRef][Web of Science][Medline]
  16. De Nicola L., Bellizzi V., Minutolo R., et al. Randomized, double-blind, placebo-controlled study of arginine supplementation in chronic renal failure. Kidney Int (1999) 56:674–684.[CrossRef][Web of Science][Medline]
  17. Ramesh G., Varma J.S., Ganguly N.K., et al. Increased plasma nitrite level in cardiac failure. J Mol Cell Cardiol (1999) 31:1495–1500.[CrossRef][Web of Science][Medline]
  18. Hon W.M., Lee J.C., Lee K.H. Effect of hemodialysis on plasma nitric oxide levels. Artif Organs (2000) 24:387–390.[CrossRef][Web of Science][Medline]
  19. Orus J., Heras M., Morales-Ruiz M., et al. Nitric oxide synthase II mRNA expression in cardiac tissue of patients with heart failure undergoing cardiac transplantation. J Heart Lung Transplant (2000) 19:139–144.[CrossRef][Web of Science][Medline]
  20. Kubo S.H., Rector T.S., Bank A.J., et al. Lack of contribution of nitric oxide to basal vasomotor tone in heart failure. Am J Cardiol (1994) 74:1133–1136.[CrossRef][Web of Science][Medline]
  21. Koifman B., Wollman Y., Bogomolny N., Chernichowsky T., et al. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol (1995) 26:1251–1256.[Abstract]
  22. Mohri M., Egashira K., Tagawa T., et al. Basal release of nitric oxide is decreased in the coronary circulation in patients with heart failure. Hypertension (1997) 30:50–56.[Abstract/Free Full Text]
  23. Cooper C.J., Jevnikar F.W., Walsh T., Dickinson J., Mouhaffel A., Selwyn A.P. The influence of basal nitric oxide activity on pulmonary vascular resistance in patients with congestive heart failure. Am J Cardiol (1998) 82:609–614.[CrossRef][Web of Science][Medline]
  24. Wever R., Boer P., Hijmering M., Stroes E., et al. Nitric oxide production is reduced in patients with chronic renal failure. Arterioscler Thromb Vasc Biol (1999) 19:1168–1172.[Abstract/Free Full Text]
  25. Schmidt R.J., Domico J., Samsell L.S., et al. Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis (1999) 34:228–234.[Web of Science][Medline]
  26. Schmidt R.J., Yokota S., Tracy T.S., Sorkin M.I., Baylis C. Nitric oxide production is low in end-stage renal disease patients on peritoneal dialysis. Am J Physiol (1999) 276:F794–F797.[Web of Science][Medline]
  27. Sumino H., Sato K., Sakamaki T., et al. Reduced production of nitric oxide during haemodialysis. J Hum Hypertens (1999) 13:437–442.[CrossRef][Web of Science][Medline]
  28. Remuzzi G., Perico N., Zoja C., Corna D., Macconi D., Vigano G. Role of endothelium-derived nitric oxide in the bleeding tendency of uremia. J Clin Invest (1990) 86:1768–1811.[Web of Science][Medline]
  29. Vallance P., Leone A., Calver A., Collier J., Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet (1992) 339:572–575.[CrossRef][Web of Science][Medline]
  30. Arese M., Strasly M., Ruva C., et al. Regulation of nitric oxide synthesis in uraemia. Nephrol Dial Transplant (1995) 10:1386–1397.[Abstract/Free Full Text]
  31. Mendes Ribeiro A.C., Roberts N.B., Lane C., Yaqoob M., Ellory J.C. Accumulation of the endogenous analogue NG-monomethyl-L-arginine in human end-stage renal failure patients on regular haemodialysis. Exp Physiol (1996) 81:475–481.[Abstract]
  32. MacAllister R.J., Rambausek M.H., Vallance P., Williams D., Hoffmann K.H., Ritz E. Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant (1996) 11:2449–2452.[Abstract/Free Full Text]
  33. De Deyn P.P., Marescau B., D'Hooge R., Possemiers I., Nagler J., Mahler C. Guanidino compound levels in brain regions of non-dialyzed uremic patients. Neurochem Int (1995) 27:227–237.[CrossRef][Web of Science][Medline]
  34. Anderstam B., Katzarski K., Bergstrom J. Serum levels of NG,NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients. J Am Soc Nephrol (1997) 8:1437–1442.[Abstract]
  35. Marescau B., Nagels G., Possemiers I., et al. Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. Metabolism (1997) 46:1024–1031.[CrossRef][Web of Science][Medline]
  36. Feng Q., Lu X., Fortin A.J., et al. Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure. Cardiovasc Res (1998) 37:667–675.[Abstract/Free Full Text]
  37. Kang E.S., Tevlin M.T., Wang Y.B., et al. Hemodialysis hypotension: Interaction of inhibitors, iNOS, and the interdialytic period. Am J Med Sci (1999) 317:9–21.[CrossRef][Web of Science][Medline]
  38. Kielstein J.T., Boger R.H., Bode-Boger S.M., et al. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol (1999) 10:594–600.[Abstract/Free Full Text]
  39. Al Banchaabouchi M., Marescau B., Possemiers I., D'Hooge R., Levillain O., De Deyn P.P. NG, NG-dimethylarginine and NG, NG-dimethylarginine in renal insufficiency. Pflugers Arch (2000) 439:524–531.[CrossRef][Web of Science][Medline]
  40. Hanssen H., Brunini T.M.C., Conway M., et al. Increased L-arginine transport in human erythrocytes in chronic heart failure. Clin Sci (1998) 94:43–48.[Web of Science][Medline]
  41. Brunini T.M.C., Ellory J.C., Mann G.E., Mendes Ribeiro A.C. Chronic heart failure activates the L-arginine–nitric oxide signalling pathway in human peripheral blood mononuclear cells. J Vasc Res (1998) 35(2):43. abstract.
  42. Mendes Ribeiro A.C., Hanssen H., Kiessling K., Roberts N.B., Mann G.E., Ellory J.C. Transport of L-arginine and the nitric oxide inhibitor NG-Monomethyl-L-arginine in human erythrocytes in chronic renal failure. Clin Sci (1997) 93:57–64.[Web of Science][Medline]
  43. Mendes Ribeiro A.C., Brunini T.M.C., Yaqoob M., Ellory J.C., Mann G.E. Peripheral mononuclear cells from uraemic patients exhibit an increased transport of L-arginine via system y+(cat-1): implications for nitric oxide synthesis. J Physiol (Lond) (1998) 506:30P. abstract.
  44. Brunini T.M.C., Khoeler A.L., Yaqoob M., Mann G.E., Ellory J.C., Mendes Ribeiro A.C. Blood cells from patients on CAPD exhibit increased L-arginine influx via the cationic amino acid transport system y+(CAT-1). J Physiol (Lond) (1999) 517P:52 P. abstract.
  45. Mendes Ribeiro A.C., Brunini T.M.C., Yaqoob M., Aronson J.K., Mann G.E., Ellory J.C. Identification of system y+L as the high-affinity transporter for L-arginine in human platelets: up-regulation of L-arginine influx in uraemia. Pflugers Arch (1999) 438(4):573–575.[CrossRef][Web of Science][Medline]
  46. White M.F. The transport of cationic amino acids across the plasma membrane of mammalian cells. Biochim Biophys Acta (1985) 822:355–374.[Medline]
  47. Bertran J., Werner A., Stange G., et al. Expression of Na(+)-independent amino acid transport in Xenopus laevis oocytes by injection of rabbit kidney cortex mRNA. Biochem J (1992) 281:717–723.[Web of Science][Medline]
  48. Deves R., Chavez P., Boyd C.A. Identification of a new transport system (y+L) in human erythrocytes that recognizes lysine and leucine with high affinity. J Physiol (Lond.) (1992) 454:491–501.[Abstract/Free Full Text]
  49. Palacin M. A new family of proteins (rBAT and 4F2hc) involved in cationic and zwitteronic amino acid transport: a tale of two proteins in search of a transport function. J Exp Biol (1994) 196:124–137.
  50. Deves R., Boyd C.A. Transporters for cationic amino acids in animal cells: discovery, structure, and function. Physiol Rev (1998) 78:487–545.[Abstract/Free Full Text]
  51. Palacin M., Estevez R., Bertran J., Zorzano A. Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev (1998) 78:969–1054.[Abstract/Free Full Text]
  52. Simmons W.W., Closs E.I., Cunningham J.M., Smith T.W., Kelly R.A. Cytokines and insulin induce cationic amino acid transporter (CAT) expression in cardiac myocytes. J Biol. Chem. (1996) 271:11694–11702.[Abstract/Free Full Text]
  53. Closs E.L., Lyons C.R., Kelly C., Cunningham J.M. Characterization of the third member of the M.C.A.T. family of cationic amino acid transporters. Identification of a domain that determines the transport properties of the MCAT proteins. J Biol. Chem. (1993) 268:20796–20800.[Abstract/Free Full Text]
  54. Macleod C.L., Finley K.D., Kakuda D.K. y+-type cationic amino acid transport: expression and regulation of the mCAT genes. J Exp Biol (1996) 196:109–121.
  55. Closs E.I. CATs, a family of three distinct mammalian cationic amino acid transporters. Amino Acids (1996) 11:193–208.[Web of Science]
  56. Closs E.L., Graf P., Habermeier A., Cunningham J.M., Fostermann U. Human cationic amino acid transporters hCAT-1, hCAT-2A and hCAT-2B: three related carriers with distinct transport proteins. Biochemistry (1997) 36:6462–6468.[CrossRef][Web of Science][Medline]
  57. Bussolati O., Laris P.C., Nucci F.A., et al. Influx of L-arginine is an indicator of membrane potential in human fibroblasts. Am J Physiol (1989) 256:C930–C935.[Web of Science][Medline]
  58. Kavanaugh M.P. Voltage dependence of facilitated arginine flux mediated by the system y+ basic amino acid transporter. Biochemistry (1993) 32:5781–5785.[CrossRef][Web of Science][Medline]
  59. Sobrevia L., Cesare P., Yudilevich D.L., Mann G.E. Diabetes-induced activation of system y+ and nitric oxide synthase in human endothelial cells: association with membrane hyperpolarization. J Physiol (Lond) (1995) 489:183–192.[Abstract/Free Full Text]
  60. Bogle R.G., Baydoun A.R., Pearson J.D., Mann G.E. Regulation of L-arginine transport and nitric oxide release in superfused porcine aortic endothelial cells. J Physiol (Lond) (1996) 490:229–241.[Abstract/Free Full Text]
  61. Hosokawa H., Sawamura T., Kobayashi S., Ninomiya H., Miwa S., Masaki T. Cloning and characterization of a brain-specific cationic amino acid transporter. J Biol Chem (1997) 272:8717–8722.[Abstract/Free Full Text]
  62. Sperandeo M.P., Borsani G., Incerti B., et al. The gene encoding a cationic amino acid transporter (SLC7A4) maps to the region deleted in the velocardiofacial syndrome. Genomics (1998) 49:230–236.[CrossRef][Web of Science][Medline]
  63. Ellory J.C. Amino acid transport in animal cells. Yudilevich D.L., Boyd C.A.R., eds. (1987) Manchester: Manchester University Press. 106–119.
  64. Deves R., Angelo S., Chavez P. N-Ethylmaleimide discriminates between two lysine transport systems in human erythrocytes. J Physiol (Lond) (1993) 468:753–766.[Abstract/Free Full Text]
  65. Torrents D., Estevez R., Pineda M., et al. Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L A candidate gene of lysinuric protein intolerance. J Biol Chem (1998) 273(49):32437–32445.[Abstract/Free Full Text]
  66. Torrents D., Mykkenen J., Pineda M., et al. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. Nat Genet (1999) 21(3):293–296.[CrossRef][Web of Science][Medline]
  67. Pfeiffer R., Rossier G., Spindler B., Meier C., Kuhn L., Verrey F. Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family. EMBO J (1999) 18(1):49–57.[CrossRef][Web of Science][Medline]
  68. Van Winkle L.J., Campione A.L., Gorman J.M. Na+-independent transport of basic and zwitterionic amino acids in mouse blastocysts by a shared system and by processes which distinguish between these substrates. J Biol Chem (1988) 263:3150–3163.[Abstract/Free Full Text]
  69. Barbul A. Arginine: biochemistry, physiology, and therapeutic implications. J Parent Enteral Nutr (1986) 10:227–232.[Free Full Text]
  70. Reyes A.A., Karl I.E., Klahr S. Role of L-arginine in health and renal disease. Am J Physiol (1994) 267:F331–F346.[Web of Science][Medline]
  71. Ignarro L.J. Biosynthesis and metabolism of endothelium-derived nitric oxide. Ann Rev Pharmacol Toxicol (1990) 30:535–560.[CrossRef][Web of Science][Medline]
  72. Knowles R.G., Moncada S. Nitric oxide synthases in mammals. Bioch J (1994) 298:249–258.
  73. Gross S.S. Nitric oxide and the kidney: physiology and pathophysiology. Goligorsky M.S., Gross S.S., eds. (1997) New York: Chapman and Hall. 52–65.
  74. Radomski M.W., Palmer R.M., Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA (1990) 87:5193–5197.[Abstract/Free Full Text]
  75. Wennmalm A., Benthin G., Edlund A., et al. Metabolism and excretion of nitric oxide in humans. An experimental and clinical study. Circ. Res (1993) 73:1121–1127.[Abstract/Free Full Text]
  76. Huot A.E., Schiffeleers E., Kruszyna H., Kruszyna R., Smith R.P., Hacker M.P. The biology of nitric oxide. In: Enzymology, Biochemistry and Immunology—Moncada S., Marletta M.A., Hibbs J.B. Jr., Higgs E.A., eds. (1992) 2. London: Portland Press. 159–162.
  77. Pawloski J.R., Swaminathan R.V., Stamler J.S. Cell-free and erythrocytic S-nitrosohemoglobin inhibits human platelet aggregation. Circulation (1998) 97:263–267.[Abstract/Free Full Text]
  78. Jubelin B.C., Gierman J.L. Erythrocytes may synthesize their own nitric oxide. Am J Hyperten (1996) 12:1214–1219.
  79. Deliconstantinos G., Villiotou V., Stavrides J.C., Salemes N., Gogas J. Nitric oxide and peroxynitrite production by human erythrocytes. A causative factor of toxic anemia in breast cancer patients. Anticancer Res (1995) 15:1435–1446.[Web of Science][Medline]
  80. Chen L.Y., Mehta J.L. Evidence for the presence of L-arginine–nitric oxide pathway in human red blood cells: relevance in the effects of red blood cells on platelet function. J Cardiovasc Pharmacol (1998) 32:57–61.[CrossRef][Web of Science][Medline]
  81. Kosaka H., Tanaka S., Yoshii T., Kumura E., Seiyama A., Shiga T. Direct proof of nitric oxide formation from a nitrovasodilator metabolised by erythrocytes. Biochem Biophys Res Commun (1994) 204:1055–1060.[CrossRef][Web of Science][Medline]
  82. Chesrown S.E., Monnier J., Visner G., Nick H.S. Regulation of inducible nitric oxide synthase mRNA levels by LPS, INF-{gamma}, TGF-β and IL-10 in murine macrophage cell lines and rat peritoneal macrophages. Biochem Biophys Res Commun (1994) 200:126–134.[CrossRef][Web of Science][Medline]
  83. Miles A.M., Owens M.W., Milligan S., et al. Nitric oxide synthase in circulating vs. extravasated polymorphonuclear leukocytes. J Leuk Biol (1995) 58:616–622.[Abstract]
  84. Wheeler M.A., Smith S.D., Weiss E.D., Sessa W.C., Weis R.M. Characterization of nitric oxide synthase (NOS) activity in leukocytes enriched from human infected urine. FASEB J (1995) 9:A679. abstract.
  85. Reiling N., Ulmer A.J., Duchrow M., Ernst M., Flad H.D., Hauschildt S. Nitric oxide synthase: mRNA expression of different isoforms in human monocytes/macrophages. Eur J Immunol (1994) 24:1941–1944.[Web of Science][Medline]
  86. De Maria R., Cifone M.G., Trotta R., et al. Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. J Exp Med (1994) 180(5):1999–2004.[Abstract/Free Full Text]
  87. Mannick J.B., Asano K., Izumi K., Kieff E., Stamler J.S. Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein–Barr virus reactivation. Cell (1994) 79:1137–1146.[CrossRef][Web of Science][Medline]
  88. Mehta J.L., Chen L.Y., Kone B.C., Mehta P., Turner P. Identification of constitutive and inducible forms of nitric oxide synthase in human platelets. J Lab Clin Med (1995) 125:370–377.[Web of Science][Medline]
  89. Berkels R., Stockklauser K., Rosen P., Rosen R. Current status of platelet NO synthases. Thromb. Res (1997) 87:51–55.[CrossRef][Web of Science][Medline]
  90. Stevens B.R., Kakuda D.K., Yu K., Waters M., Vo C.B., Raizada M.K. Induced nitric oxide synthesis is dependent on induced alternatively spliced CAT-2 encoding L-arginine transport in brain astrocytes. J Biol Chem (1996) 271:24017–24022.[Abstract/Free Full Text]
  91. Pan M., Wasa M., Yan U., Souba W. Lipopolysaccharide and tumor necrosis factor stimulate lung microvascular arginine uptake, a response attenuated by dexamethasone. J Parent Enteral Nutr (1996) 20:50–55.[Abstract/Free Full Text]
  92. Simmons W.W., Ungureanu-Longrois D., Smith G.K., Smith T.W., Kelly R.A. Glucocorticoids regulate inducible nitric oxide synthase by inhibiting tetrahydrobiopterin synthesis and L-arginine transport. J Biol Chem (1996) 271:23928–23937.[Abstract/Free Full Text]
  93. Durante W., Liao L., Schafer A.L. Differential regulation of L-arginine transport and inducible NOS. in cultured vascular smooth muscle cells. Am J Physiol (1995) 268:1158–1164.
  94. Durante W., Liao L., Iftikkar I., O'Brien W.E., Schafer A.L. Differential regulation of L-arginine transport and nitric oxide production by vascular smooth muscle and endothelium. Circ. Res (1996) 78:1075–1082.[Abstract/Free Full Text]
  95. Baydoun A.R., Wileman S.M., et al. Transmembrane signalling mechanisms regulating the expression of cationic amino acid transporters and inducible nitric oxide synthase in vascular smooth muscle cells. Biochem J (1999) 344:265–272.[CrossRef][Web of Science][Medline]
  96. Baydoun A.R., Bogle R.G., Pearson J.D., Mann G.E. Selective inhibition by dexamethasone of induction of NO synthase, but not of induction of L-arginine transport, in activated murine macrophages J774 cells. Br J Pharmacol (1993) 110:1401–1406.[Web of Science][Medline]
  97. Sobrevia L., Nadal A., Yudilevich D.L., Mann G.E. Activation of L-arginine transport (system y+) and nitric oxide synthase by elevated D-glucose and insulin in human endothelial cells. J Physiol (1996) 490:775–781.[Abstract/Free Full Text]
  98. Shibazaki T., Fujiwara M., Sato H., Fujiwara K., Abe K., Bannai S. Relevance of the L-arginine transport activity to the nitric oxide synthesis in mouse peritoneal macrophages stimulated with bacterial lipopolysaccharide. Biochim Biophys Acta (1996) 1311:150–154.[Medline]
  99. Morgan A.G. The kidney: physiology and pathology. Seldin D.W., Giebisch G., eds. (1985) New York: Raven Press. 1901–1943.
  100. Gris J.C., Branger B., Vecina F., Al Sabadani B., Fourcade J., Schved J.F. Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. Kidney Int (1994) 46:807–813.[Web of Science][Medline]
  101. Kari J.A., Donald A.E., Vallance D.T., et al. Physiology and biochemistry of endothelial function in children with chronic renal failure. Kidney Int (1997) 52:468–472.[Web of Science][Medline]
  102. Joannides R., Bakkali E.H., Le Roy F., et al. Altered flow-dependent vasodilation of conduit arteries in maintenance haemodialysis. Nephrol Dial Transplant (1997) 12:2623–2628.[Abstract/Free Full Text]
  103. Mezzano D., Tagle R., Pais E., et al. Endothelial cell markers in chronic uremia: relationship with hemostatic defects and severity of renal failure. Thromb Res (1997) 88:465–472.[CrossRef][Web of Science][Medline]
  104. Thambyrajah J., Landray M.J., McGlynn F.J., Jones H.J., Wheeler D.C., Townend J.N. Abnormalities of endothelial function in patients with predialysis renal failure. Heart (2000) 83:205–209.[Abstract/Free Full Text]
  105. Hand M.F., Haynes W.G., Webb D.J. Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction. Kidney Int (1998) 53:1068–1077.[CrossRef][Web of Science][Medline]
  106. Wang S.P., West M.W., Dresner L.S., et al. Effects of diabetes and uremia on mesenteric vascular reactivity. Surgery (1996) 120:328–335.[CrossRef][Web of Science][Medline]
  107. Thuraisingham R.C., Raine A.E.G. Maintenance of normal agonist-induced endothelium-dependent relaxation in uraemic and hypertensive resistance vessels. Nephrol Dial Transplant (1999) 14:70–75.[Abstract/Free Full Text]
  108. Cattel V., Cook H.T. Nitric oxide: role in the physiology and pathology of the glomerulus. Exp Nephrol (1993) 1:265–280.[Web of Science][Medline]
  109. Raij L., Shultz P.J. Endothelium derived relaxing factor, nitric oxide: effects on and production by mesangial cells and the glomerulus. J Am Soc Nephrol (1993) 3:1435–1441.[Abstract]
  110. Ashab I., Peer G., Blum M., et al. Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production. Kidney Int (1995) 47:1515–1521.[Web of Science][Medline]
  111. Wilcox C.S., Welch W.J., Murad F., Gross S.S., Taylor G., Levi R., Schmidt H.H. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci USA (1992) 89:11993–11997.[Abstract/Free Full Text]
  112. Aiello S., Noris M., Todeschini M., et al. Renal and systemic nitric oxide synthesis in rats with renal mass reduction. Kidney Int (1997) 52:171–181.[Web of Science][Medline]
  113. Gordge M.P., Neild G.H. Platelets from patients on haemodialysis show impaired responses to nitric oxide. Clin Sci (1992) 83:313–318.[Web of Science][Medline]
  114. Quintero E., Guth P.H. Nitric oxide-mediated gastric hyperemia decreases ethanol-induced gastric mucosal injury in uremic rats. Dig Dis Sci (1992) 37:1324–1328.[CrossRef][Web of Science][Medline]
  115. Mendez A., Fernandez M., Barrios Y., et al. Constitutive NOS. isoforms account for gastric mucosal NO overproduction in uremic rats. Am J Physiol (1997) 272:G894–901.[Web of Science][Medline]
  116. Tomikawa M., Ohta M., Vaziri N.D., et al. Decreased endothelial nitric oxide synthase in gastric mucosa of rats with chronic renal failure. Am J Physiol (1998) 274:F1102–1108.[Web of Science][Medline]
  117. Bataineh A., Raij L. Angiotensin II, nitric oxide, and end-organ damage in hypertension. Kidney Int Suppl (1998) 68:S14–19.[CrossRef][Medline]
  118. Arnal J.F., Warin L., Michel J.B. Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. J Clin Invest (1992) 90:647–652.[Web of Science][Medline]
  119. Baylis C., Mitruka B., Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest (1992) 90:278–281.[Web of Science][Medline]
  120. Vaziri N.D., Ni Z., Wang X.Q., Oveisi F., Zhou X.J. Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH. Am J Physiol (1998) 274:F642–649.[Web of Science][Medline]
  121. Vaziri N.D., Oveisi F., Ding Y. Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension. Kidney Int (1998) 53:1748–1754.[CrossRef][Web of Science][Medline]
  122. Young G.A., Swanepoel C.R., Croft M.R., Hobson S.M., Parsons F.M. Anthropometry and plasma valine, amino acids, and proteins in the nutritional assessment of hemodialysis patients. Kidney Int (1982) 21:492–499.[CrossRef][Web of Science][Medline]
  123. Alvestrand A., Furst P., Bergstrom J. Intracellular amino acids in uremia. Kidney Int Suppl. (1983) 16:S9–16.[Medline]
  124. Bergstrom J., Alvestrand A., Furst P. Plasma and muscle free amino acids in maintenance hemodialysis patients without protein malnutrition. Kidney Int (1990) 38:108–114.[Web of Science][Medline]
  125. Jungers P., Chaveau P., Ceballos I., Bardet J., Parvy P., Hannedouche T., Kamoun P. Plasma and free amino acid alterations from early to end stage chronic renal failure. J Nephrol (1996) 7:48–54.
  126. Divino-Filho J.C., Barany P., Stehle P., Furst P., Bergstrom J. Free amino-acid levels simultaneously collected in plasma, muscle, and erythrocytes of uraemic patients. Nephrol Dial Transplant (1997) 12:2339–2348.[Abstract/Free Full Text]
  127. Alvestrand A., Defronzo R.A., Smith D., Wahren J. Influence of hyperinsulinaemia on intracellular amino acid levels and amino acid exchange across splanchnic and leg tissues in uraemia. Clin Sci (1988) 74:155–163.[Web of Science][Medline]
  128. Bergstrom J. Toxicity of uraemia: physiopathology and clinical signs. Contrib. Nephrol (1989) 71:1–9.[Medline]
  129. Hendry B.M. Advanced renal medicine. Raine A.E.G., ed. (1992) Oxford: Oxford University Press. 16–23.
  130. Fervenza F.C., Harvey C.M., Hendry B.M., Ellory J.C. Increased lysine transport capacity in erythrocytes from patients with chronic renal failure. Clin Sci (1989) 76:419–422.[Web of Science][Medline]
  131. Fervenza F.C., Meredith D., Ellory J.C., et al. A study of the membrane transport of amino acids in erythrocytes from patients on haemodialysis. Nephrol Dial Transplant (1990) 5:594–599.[Abstract]
  132. Cangiano C., Cardelli-Cangiano P., Cascino A., et al. Uptake of amino acids by brain microvessels isolated from rats with experimental chronic renal failure. J Neurochem (1988) 51:1675–1681.[CrossRef][Web of Science][Medline]
  133. Brunini T.M.C., Roberts N., Yaqoob M., Ellory J.D., Mann G.E., Mendes Ribeiro A.C. L-Arginine–nitric oxide pathway in a rat model of uraemia. J Physiol (1998) 506:33P. abstract.[CrossRef]
  134. Freedman J.E., Sauter R., Battinelli E.M., Ault K., Knowles C., Huang P.L., Loscalzo J. Deficient platelet-derived nitric oxide and enhanced hemostasis in mice lacking the NOSIII gene. Circ Res (1999) 84:1416–1421.[Abstract/Free Full Text]
  135. Freedman J.E., Ting B., Hankin B., Loscalzo J., Keaney J.F. Jr., Vita J.A. Impaired platelet production of nitric oxide predicts presence of acute coronary syndromes. Circulation (1998) 98:1481–1486.[Abstract/Free Full Text]
  136. Packer M. Pathophysiology of chronic heart failure. Lancet (1992) 340:88–92.[CrossRef][Web of Science][Medline]
  137. Drexler H., Lu W. Endothelial dysfunction of hindquarter resistance vessels in experimental heart failure. Am J Physiol (1992) 262:H1640–1645.[Web of Science][Medline]
  138. Wang J., Sevedi N., Xu X.B., Wolin M.S., Hintze T.H. Defective endothelium-mediated control of coronary circulation in conscious dogs after heart failure. Am J Physiol (1994) 266:H670–680.[Web of Science][Medline]
  139. Drexler H., Hayoz D., Munzel T., Hornig B., Just H., Brunner H.R., Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol (1992) 69:1596–1601.[CrossRef][Web of Science][Medline]
  140. Drexler H., Hornig B. Importance of endothelial function in chronic heart failure. J Cardiovasc Pharmacol (1996) 27(2):S9–S12.[CrossRef][Web of Science][Medline]
  141. Takeshita A., Hirooka Y., Imaizumi T. Role of endothelium in control of forearm blood flow in patients with heart failure. J Card Fail (1996) 2(4):S209–215.[CrossRef][Medline]
  142. Baggia S., Perkins K., Greenberg B. Endothelium-dependent relaxation is not uniformly impaired in chronic heart failure. J Cardiovasc Pharmacol (1997) 29:389–396.[CrossRef][Web of Science][Medline]
  143. Veronneau M., Tanguay M., Fontaine E., Jasmin G., Dumont L. Reactivity to endothelium-dependent and -independent vasoactive substances is maintained in coronary resistance vessels of the failing hamster heart. Cardiovasc Res (1997) 33:623–630.[Abstract/Free Full Text]
  144. Crespo M.J., Altieri P.I., Escobales N. Altered vascular function in early stages of heart failure in hamsters. J Card Fail (1997) 3:311–318.[CrossRef][Medline]
  145. Wang J., Yi G.H., Knecht M., Cai B.L., et al. Physical training alters the pathogenesis of pacing-induced heart failure through endothelium-mediated mechanisms in awake dogs. Circulation. (1997) 96:2683–2692.[Abstract/Free Full Text]
  146. Berkenboom G., Crasset V., Giot C., Unger P., Vachiery J.L., LeClerc J.L. Endothelial function of internal mammary artery in patients with coronary artery disease and in cardiac transplant recipients. Am Heart J (1998) 135:488–494.[CrossRef][Web of Science][Medline]
  147. Maguire S.M., Nugent A.G., McGurk C., Johnston G.D., Nicholls D.P. Abnormal vascular responses in human chronic cardiac failure are both endothelium dependent and endothelium independent. Heart (1998) 80:141–145.[Abstract/Free Full Text]
  148. Hambrecht R., Fiehn E., Weigl C., et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation (1998) 98:2709–2715.[Abstract/Free Full Text]
  149. Varin R., Mulder P., Richard V., et al. Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress. Circulation (1999) 99:2951–2957.[Abstract/Free Full Text]
  150. Bank A.J., Lee P.C., Kubo S.H. Endothelial dysfunction in patients with heart failure: relationship to disease severity. J Card Fail (2000) 6:29–36.[CrossRef][Web of Science][Medline]
  151. Larosa G., Foster C. Altered vasodilator response of coronary microvasculature in pacing-induced congestive heart failure. Eur J Pharmacol (1996) 318(2–3):387–394.[CrossRef][Web of Science][Medline]
  152. Stewart D.J. Nitric oxide puzzles and paradoxes in heart failure: how to fit the pieces together. Clin Sci (1998) 94:3–4.[Web of Science][Medline]
  153. Birks E.J., Yacoub M.H. The role of nitric oxide and cytokines in heart failure. Coron. Artery Dis (1997) 8:389–402.[Web of Science][Medline]
  154. Riede U.N., Forstermann U., Drexler H. Inducible nitric oxide synthase in skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol (1998) 32:964–969.[Abstract/Free Full Text]
  155. Haywood G.A., Tsao P.S., Von der Leyen H.E., et al. Expression of inducible nitric oxide inhuman heart failure. Circulation (1996) 93:1087–1094.[Abstract/Free Full Text]
  156. Katz S.D., Ramanath R., Berman J.W., et al. Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive heart failure. Circulation (1994) 90:12–16.[Abstract/Free Full Text]
  157. Comini L., Bachetti T., Gaia G., et al. Aorta and skeletal muscle NO synthase expression in experimental heart failure. J Mol Cell Cardiol. (1996) 28:2241–2248.[CrossRef][Web of Science][Medline]
  158. Smith C.J., Sun D., Hoegler C., et al. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res (1996) 78:58–64.[Abstract/Free Full Text]
  159. Nasa Y., Toyoshima H., Ohaku H., Hashizume Y., Sanbe A., Takeo S. Impairment of cGMP- and cAMP-mediated vasorelaxations in rats with chronic heart failure. Am J Physiol (1996) 271:H2228–2237.[Web of Science][Medline]
  160. Katz S.D., Khan T., Zeballos G.A., et al. Decreased activity of L-arginine–nitric oxide metabolic pathway in patients with congestive heart failure. Circulation (1999) 27:2113–2117.
  161. Prasad K., Kalra J., Bharadwaj B. Increased chemiluminescence of polymorphonuclear leukocytes in dogs with volume overload heart failure. Br J Exp Pathol (1989) 70:463–468.[Web of Science][Medline]
  162. McMurray J., Chopra M., Abdullah I., Smith W.E., Dargie H.J. Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J (1993) 14:1493–1498.[Abstract/Free Full Text]
  163. Singh N., Dhalla A.K., Seneviratne C., Singal P.K. Oxidative stress and heart failure. Mol Cell Biochem (1995) 147:77–81.[CrossRef][Web of Science][Medline]
  164. Bauersachs J., Bouloumie A., Fraccarollo D., Hu K., Busse R., Ertl G. Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production. Circulation (1999) 100:292–298.[Abstract/Free Full Text]
  165. Hornig B., Arakawa N., Kohler C., Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation (1998) 97:363–368.[Abstract/Free Full Text]
  166. Chin-Dusting J.P.F., Kaye D.M., Lefkovitis J., Wong J., Bergin P., Jennings G.L. Dietary supplementation with L-arginine fails to restore endothelial function in forearm resistance arteries of patients with severe heart failure. J. Am Coll Cardiol (1996) 27:1207–1213.[Abstract]
  167. Rector T.S., Bank A.J., Mullen K.A., et al. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation (1996) 93:2135–2141.[Abstract/Free Full Text]
  168. Hambrecht R., Hilbrich L., Erbs S., et al. Correction of endothelial dysfunction in chronic heart failure:additional effects of exercise training and oral L-arginine. J Am Coll Cardiol (2000) 35:706–713.[Abstract/Free Full Text]
  169. Khadour F.H., O'Brien D.W., Fu Y., Armstrong P.W., Schulz R. Endothelial nitric oxide synthase increases in left atria of dogs with pacing-induced heart failure. Am J Physiol (1998) 275:H1971–1978.[Web of Science][Medline]
  170. Satoh M., Nakamura M., Tamura G. Inducible nitric oxide synthase and TNF{alpha} in myocardium in human cardiomyopathy. J Am Coll Cardiol (1997) 15:716–724.
  171. Stein B., Eschenhagen T., Rudiger J., Scholz H., Fostermann U., Gath I. Increased expression of constitutive nitric oxide synthase III. but not inducible nitric oxide synthase II, in human heart failure. J Am Coll Cardiol (1998) 32:1179–1186.[Abstract/Free Full Text]
  172. Schwarz P., Diem R., Dun J.N., Fostermann U. Endogenous and exogenous nitric oxide inhibits norepinephrine release from rat heart sympathetic nerves. Circ Res (1995) 77(4):841–848.[Abstract/Free Full Text]
  173. Hare J.M., Colucci W.S. Role of nitric oxide in the regulation of myocardium function. Prog Cardiovasc Dis (1995) 38:155–166.[CrossRef][Web of Science][Medline]
  174. Kelly R.A., Balligand J.L., Smith T.W. Nitric oxide and cardiac function. Circ Res (1996) 79:363–380.[Free Full Text]
  175. Vejlstrup N.G., Bouloumie A., Boesgaard S., et al. Inducible nitric oxide in the human heart: expression and localization in congestive heart failure. J Mol Cell Cardiol (1998) 30:1215–1223.[CrossRef][Web of Science][Medline]
  176. Drexler H., Kastner S., Strobel A., Studer R., Brodde O.E., Hasenfub G. Expression activity and functional significance of inducible nitric oxide in the failing human heart. J Am Coll Cardiol (1998) 32:955–963.[Abstract/Free Full Text]
  177. Habib F.M., Springhall D.R., Davies G.J., Oakley C.M., Yacoub M.H., Polak J.M. TNF and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet (1996) 27:1151–1155.
  178. Fukuchi M., Hussain S.N., Giaid A. Heterogeneous expression and activity of endothelial and inducible nitric oxide synthases in end-stage human heart failure: their relation to lesion site and β-adrenergic receptor therapy. Circulation (1998) 98(2):132–139.[Abstract/Free Full Text]
  179. Dusting G.J., MacDonald P.S. Endogenous nitric oxide in cardiovascular disease and transplantation. An Med (1995) 27:395–406.[CrossRef]
  180. Heymes C., Vanderheyden M., Bronzwaer J.G., Shah A.M., Paulus W.J. Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy. Circulation. (1999) 99(23):3009–3016.[Abstract/Free Full Text]
  181. Yoshizumi M., Perrella M.A., Burnett J.C. Jr., Lee M.E. Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ. Res (1993) 73:205–209.[Abstract]
  182. Koifman B., Wollman Y., Bogomolny N., et al. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol (1995) 26:1251–1256.[Abstract]
  183. Hyatt S.L., Aulak K.S., Malandro M., Kilberg M.S., Hatzoglou M. Adaptive regulation of the cationic amino acid transporter-1 (CAT-1) in Fao cells. J Biol Chem (1997) 272:19951–19957.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Physiol.Home page
E. N. Dedkova and L. A. Blatter
Characteristics and function of cardiac mitochondrial nitric oxide synthase
J. Physiol., February 15, 2009; 587(4): 851 - 872.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
S. S. Billecke, L. G. D'Alecy, R. Platel, S. E. Whitesall, K. A. Jamerson, R. L. Perlman, and C. A. Gadegbeku
Blood content of asymmetric dimethylarginine: new insights into its dysregulation in renal disease
Nephrol. Dial. Transplant., February 1, 2009; 24(2): 489 - 496.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
R. D. Peluffo
L-Arginine currents in rat cardiac ventricular myocytes
J. Physiol., May 1, 2007; 580(3): 925 - 936.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
T. M.C. Brunini, A. C. Mendes-Ribeiro, J. C. Ellory, and G. E. Mann
Platelet nitric oxide synthesis in uremia and malnutrition: A role for L-arginine supplementation in vascular protection?
Cardiovasc Res, January 15, 2007; 73(2): 359 - 367.
[Abstract] [Full Text] [PDF]

Home page
 Vasc MedHome page
T. Teerlink
ADMA metabolism and clearance
Vascular Medicine, July 1, 2005; 10(1_suppl): S73 - S81.
[Abstract] [PDF]

Home page
 Vasc MedHome page
T. Teerlink
ADMA metabolism and clearance
Vascular Medicine, May 1, 2005; 10(2_suppl): S73 - S81.
[Abstract] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
J. Passauer, F. Pistrosch, E. Bussemaker, G. Lassig, K. Herbrig, and P. Gross
Reduced Agonist-Induced Endothelium-Dependent Vasodilation in Uremia Is Attributable to an Impairment of Vascular Nitric Oxide
J. Am. Soc. Nephrol., April 1, 2005; 16(4): 959 - 965.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
E. I. Closs, A. Simon, N. Vekony, and A. Rotmann
Plasma Membrane Transporters for Arginine
J. Nutr., October 1, 2004; 134(10): 2752S - 2759S.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Matsunaga, S. Kotamraju, S. V. Kalivendi, A. Dhanasekaran, J. Joseph, and B. Kalyanaraman
Ceramide-induced Intracellular Oxidant Formation, Iron Signaling, and Apoptosis in Endothelial Cells: PROTECTIVE ROLE OF ENDOGENOUS NITRIC OXIDE
J. Biol. Chem., July 2, 2004; 279(27): 28614 - 28624.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
G. E. Mann, D. L. Yudilevich, and L. Sobrevia
Regulation of Amino Acid and Glucose Transporters in Endothelial and Smooth Muscle Cells
Physiol Rev, January 1, 2003; 83(1): 183 - 252.
[Abstract] [Full Text] [PDF]

Home page
 Vasc MedHome page
D. Tousoulis, C. Antoniades, C. Tentolouris, G. Goumas, C. Stefanadis, and P. Toutouzas
L-Arginine in cardiovascular disease: dream or reality?
Vascular Medicine, August 1, 2002; 7(3): 203 - 211.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Mendes Ribeiro, A.C.
Right arrow Articles by Mann, G.E.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Mendes Ribeiro, A.C.
Right arrow Articles by Mann, G.E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?