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

  1. A.C. Mendes Ribeiroa,b,*,
  2. T.M.C. Bruninia,
  3. J.C. Ellorya and
  4. G.E. Mannb
  1. aUniversity Laboratory of Physiology, South Parks Road, Oxford OX1 3PT, UK
  2. bCentre for Cardiovascular Biology and Medicine, GKT School of Biomedical Sciences, King's College London, London SE1 1UL, UK
  1. * Corresponding author. Tel.: +44-1865-272-442; fax: +44-1865-272-469 cribeiro{at}physiol.ox.ac.uk
  • Received August 30, 2000.
  • Accepted October 19, 2000.
 
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Abstract

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.

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Time for primary review 28 days.

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1 Introduction

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.

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2 l-Arginine transport in circulating blood cells

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.

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3 l-Arginine transport and nitric oxide production

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].

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4 Modulation of the l-arginine–NO pathway in chronic renal failure

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 2) [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].

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Table 2

Modulation of the l-arginine–NO pathway in patients with chronic renal failure

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Table 1

Modulation of the l-arginine–nitric oxide pathway in animal models of 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].

Fig. 1
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Fig. 1

Dependence of plasma l-arginine concentration on glomerular filtration rate in undialysed chronic renal failure patients (n = 9). (unpublished data).

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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)

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. 2–4 (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].

Fig. 2
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Fig. 2

l-Arginine influx via the cationic amino acid transport systems y+ and y+L in red blood cells from control (▪, n = 5) and chronic renal failure patients on haemodialysis, before (●, n = 9) and after (n, n = 9) one session of dialysis. Data denote the mean±S.E. Replotted from Mendes Ribeiro et al. [42].

Fig. 3
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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.

Fig. 4
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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].

Fig. 5
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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.

Fig. 6
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Fig. 6

l-Arginine influx via system y+L in platelets from controls (□, n = 8) and chronic renal failure patients on haemodialysis (▪, n = 10). Data denote the mean±S.E. Taken from Mendes Ribeiro et al. [45].

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5 Modulation of the l-arginine–NO pathway in chronic heart failure

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 5). 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].

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Table 5

Modulation of the l-arginine–NO pathway in patients with chronic heart failure

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Table 4

Modulation of the l-arginine–NO pathway in animal models 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-α, 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-γ 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].

Fig. 7
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Fig. 7

l-Arginine influx via systems y+ and y+L in red blood cells from control (□, n = 10) and chronic heart failure patients (▪, n = 15). Data denote the mean±S.E. Replotted from Hanssen et al. [40].

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6 Activation of system y+ in uraemia and heart failure: a failing counter-regulatory mechanism

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-α) 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].

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7 Summary

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.

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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.

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