Identification of system y+L as the high-affinity transporter for l-arginine in human platelets: up-regulation of l-arginine influx in uraemia

Abstract

Kinetic studies of L-arginine transport in human platelets have identified a high-affinity, low-capacity transport system [Michaelis-Menten constant (K m ) about 10 µM] for cationic amino acids that also transports neutral amino acids with high affinity in the presence of Na + but not K + . These characteristics, together with our kinetic cis-inhibition studies, indicate that saturable L-arginine transport in human platelets is mediated via the system y + L and not the classic cationic transporter system y + . We present here the first evidence that L-arginine transport via system y + L is increased twofold in platelets from patients with chronic renal failure. System y + L has been described in human erythrocytes, peripheral blood mononuclear cells and placenta, and up-regulation of system y + L activity in human platelets could explain the paradox of increased nitric oxide (NO) production by uraemic platelets under conditions of decreased plasma L-arginine and elevated N G -monomethyl-L-arginine (L-NMMA) concentrations.

Nitric Oxide Synthesis Requires Activity of the Cationic and Neutral Amino Acid Transport System y+L in Human Umbilical vein Endothelium

“…Our study shows that incubation of HUVECs with L-leucine in the presence of Na + leads to inhibition of NO synthesis and 1.5 mM L-arginine transport, suggesting that NO synthesis could depend on L-arginine uptake via system y + L. This is supported by the results showing that NEM itself did not alter NO synthesis under these experimental conditions. Our results also agree with the possibility that the elevated activity of system y + L exhibited by human platelets isolated from patients with chronic renal failure could be associated with increased NO synthesis (Mendes-Ribeiro et al 1999). It is unfortunate that in the latter study the authors did not perform experiments to directly demonstrate that NO synthesis in human platelets would depend on the system y + L activity.…”

“…Recent studies have shown that L-arginine transport is also mediated by the very high-affinity transport system y + L in HUVECs (Arancibia & Sobrevia, 1999;Sala et al 2002). System y + L was first described in human erythrocytes (Devés et al 1992) and then characterized in human placenta (Eleno et al 1994;Furesz & Smith, 1997), skin fibroblasts (Dall'Asta et al 2000), platelets (Mendes-Ribeiro et al 1999;Signorello et al 2003) and other cell types (Devés & Boyd, 1998Palacín et al 1998;Mann et al 2003). (Haynes et al 1981;Fei et al 1995;Palacín et al 1998;Torrents et al 1998;Pfeiffer et al 1999;Devés & Boyd, 2000;Sala et al 2002;Mann et al 2003).…”

Nitric oxide deficiency in chronic kidney disease

“…Defects in endothelial L-arginine transport in renal failure patients could explain the poor responses to both acute and chronic L-arginine supplementation in the renal failure population (14, 31, 34.143). It has been reported that increased L-arginine transport occurs into erythrocytes and platelets from ESRD patients, although whether this reflects ongoing acute inflammation or is routinely observed in the ESRD population remains to be determined (82,83).…”

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

“…37 By contrast, L-arginine transport into erythrocytes and platelets is enhanced in ESRD patients compared with controls. 38,39 The presence of inhibitors of endothelial L-arginine transport, low levels of endothelial transporters in ESRD patients, or both, could explain the poor response to supplementation with excess L-arginine in the patients with renal failure. Studies have shown that neither acute nor chronic administration of L-arginine improve arterial endothelial function in adults or children with chronic renal failure, 40,41 although acute L-arginine supplementation improves acetylcholine-induced venodilation in ESRD.…”