Abstract
Background: Nitric oxide (NO), a key endogenous mediator involved in the maintenance of platelet function, is synthesized from the amino acid L-arginine. We have shown that L-arginine transport in platelets is rate-limiting for NO synthesis. A disturbance in the L-arginine-NO pathway in platelets was previously described in chronic renal failure (CRF) patients. Methods: Detailed kinetic studies were performed in platelets from controls (n = 60) and hemodialysis patients (n = 26). Results: The transport of L-arginine in platelets is mediated via system y+L, which is competitively inhibited by L-leucine in the presence of Na+ and by the irreversible inhibitor pCMB. In platelets, system y+L is markedly stimulated by an Na+/K+-ATPase inhibitor, ouabain, and by changes in surface potential, while it is downregulated by intraplatelet amino acid depletion (zero-trans) and by thrombin. In CRF patients, activation of L-arginine transport was limited to well-nourished patients compared to malnourished patients and controls, where it was reduced and did not differ significantly among the groups under zero-trans conditions. Conclusion: Our results provide the first evidence that system y+L in platelets is modulated by zero-trans conditions, surface potential, thrombin and intraplatelet Na+ concentration. Our findings suggest that enhanced transport in CRF involves increased L-arginine exchange with intraplatelet neutral amino acids.
Journal Section:
Original Paper
References
1.
Morris SM Jr: Arginine metabolism: boundaries of our knowledge. J Nutr 2007;137:1602S–1609S.
[PubMed]
2.
Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109–142.
[PubMed]
3.
Morris SM Jr: Enzymes of arginine metabolism. J Nutr 2004;134:2743S–2747S.
[PubMed]
4.
Brunini TMC, da Silva CVD, Siqueira MAS, Moss MB, Santos SFF, Mendes-Ribeiro AC: Uraemia, atherothrombosis and malnutrition: the role of L-arginine-nitric oxide pathway. Cardiovasc Haematol Disord Drug Targets 2006;6:133–140.
5.
Berkels R, Stockklauser K, Rosen P, Rosen R: Current status of platelet NO synthases. Thromb Res 1997;87:51–55.
[PubMed]
6.
Mendes Ribeiro AC, Brunini TMC, Ellory JC, Mann GE: Abnormalities of nitric oxide biosynthesis in chronic renal and heart failure. Cardiovasc Res 2001;49:697–712.
[PubMed]
7.
Rotoli BM, Bussolati O, Sala R, Barillia A, Talarico E, Gazzola GC, Dall’Asta V: INF-γ stimulates arginine transport through system y+L in human monocytes. Am J Physiol 2004;571:177–181.
8.
Welt LG, Sachs JR, Macmanus TJ: An ion transport defect from uremic patients. Trans Assoc Am Physiol 1964;77:169–181.
9.
Flam BR , Hartmann PJ, Harrell-Booth M, Solomonson LP, Eichler DC: Caveolar localization of arginine regeneration enzymes, argininosuccinate synthase, and lyase, with endothelial nitric oxide synthase. Nitric Oxide 2001;5:187–197.
[PubMed]
10.
McDonald KK, Zharikov S, Block ER, Kilberg MS: A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the ‘arginine paradox’. J Biol Chem 1997;272:31213–31216.
[PubMed]
11.
Closs EI, Simon A, Vékony N, Rotmann A: Plasma membrane transporters for L-arginine. J Nutr 2004;134:2752S–2759S.
[PubMed]
12.
Devés R, Boyd AR: Transporters for cationic amino acids in animal cells: discovery, structure, and function. Physiol Rev 1998;78:487–544.
[PubMed]
13.
Mann GE, Yudilevich DL, Sobrevia L: Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev 2003;83:182–252.
14.
Mendes Ribeiro AC, Brunini TMC, Yaqoob M, Aronson JK, Mann GE, Elloy JC: Identification of system y+L as the high-affinity transporter for L-arginine in human platelets: up-regulation of L-arginine influx in uraemia. Pflügers Arch Eur J Physiol 1999;438:573–575.
15.
Cotton JR, Woodward T, Carter NW, Knochel JP: Resting skeletal muscle membrane potential as index uremic toxicity. J Clin Invest 1979;63:501–506.
[PubMed]
16.
Edmondson RP, Hilton PJ, Jones NF, Patrick J, Thomas RD: Leukocyte sodium transport in uraemia. Clin Sci Mol Med 1975;49:213–216.
[PubMed]
17.
Fervenza FC, Harvey CM, Hendry BM, Ellory: Increased lysine transport capacity in erythrocytes from patients with chronic renal failure. Clin Sci 1989;76:419–422.
[PubMed]
18.
Fraser CL, Sarnacki AP, Arieff AI: Abnormal sodium transport in synaptosomes from brain of uraemic rats. J Clin Invest 1985;75:2014–2023.
[PubMed]
19.
Vanholder R, Glorieux G, Lameire N: New insights in uremic toxicity. Contrib Nephrol. Basel, Karger, 2005, vol 149, pp 315–324.
20.
Vanholder R, Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clarck W, Cohen G, Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W: Review on uremic toxins: classification, concentration, and interindividual variability. Kid Int 2003;63:1934–1943.
[PubMed]
21.
Tepel M, Theilmeier G, Bachmann J, Barenbrock M, Spieker C, Ganten D, Rahn KH, Zidek W: Increased cytosolic sodium and reduced Na,K-ATPase activity in transgenic rats. Hypertension 1994;23(1 suppl):198–202.
22.
da Silva CD, Brunini TM, Reis PF, Moss MB, Santos SF, Roberts NB, Ellory JC, Mann GE, Mendes-Ribeiro AC: Effects of nutritional status on the L-arginine-nitric oxide pathway in platelets from haemodialysis patients. Kid Int 2005;68:2173–2179.
[PubMed]
23.
Chillarón J, Estévez R, Mora C, Wagner CA, Suessbrich H, Lang F, Gelpí JL, Testar X, Busch AE, Zorzano A, Palacín M: Amino acid Exchange via system b0, +-like and y+L-like: a tertiary active transport mechanism for renal reabsorption of cysteine and dibasic amino acids. J Biol Chem 1996;271:17761–17770.
[PubMed]
24.
Déves R, Angelo S: Changes in membrane and surface potential explain the opposite effects of low ionic strength on the two lysine transporters of human erythrocytes. J Biol Chem 1996;271:32034–32039.
[PubMed]
25.
Flores C, Rojas S, Aguayo C, Parodi J, Mann G, Pearson JD, Casanello P, Sobrevia L: Rapid stimulation of L-arginine transport by D-glucose involves p42/44(mapk) and nitric oxide in human umbilical vein endothelium. Circ Res 2003;92:64–72.
[PubMed]
26.
Giovine M, Signorello MG, Pozzolini M, Leoncini G: Regulation of L-arginine uptake by Ca2+ in human platelets. FEBS Letters 1999;461:43–46.
[PubMed]
27.
Visigalli R, Bussolati O, Sala R, Barilli A, Rotoli BM, Alessandro P, Alamanni F, Gazzola GC, Dall’Asta: The stimulation of arginine transport by TNFα in human endothelial cells depends on NF-κB activation. Biochim Biophys Acta 2004;1664:45–52.
[PubMed]
28.
Zharikov SI: Role of membrane potential in hypoxic inhibition of L-arginine uptake by lung endothelial cells. Am J Physiol 1997;272:L78–L84.
[PubMed]
29.
Sobrevia L, Nadal A, Yudilevich DL, Mann GE: Activation of L-arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. J.Physiol 1996;490:775–781.
[PubMed]
30.
Corona-de-la-Pena N, Uribe-Carvajal S, Barrientos-Rios R, Matias-Aguilar L, Montiel-Manzano G, Majluf-Cruz A: Polyamines inhibit both platelet aggregation and glycoprotein IIb/IIIa activation. J Cardiovasc Pharmacol 2005;46:216–221.
[PubMed]
31.
Brunini TMC, Yaqoob M, Novaes Malagris LE, Ellory JC, Mann GE, Mendes Ribeiro: Increased nitric oxide synthesis in uraemic platelets is dependent on L-arginine transport via system y(+)L. Pflügers Arch 2003;445:547–550.
32.
Estévez R, Camps M, Rojas AM, Testar X, Déves R, Hediger MA, Zorzano A, Palacín M: The amino acid transport system y+L/4F2hc is a heteromultimeric complex. FASEB J 1998;12:1319–1329.
[PubMed]
33.
Déves R, Chavez P, Boyd CAR: Identification of a new transport system (y+L) in human erythrocytes that recognizes lysine and leucine with high affinity. FASEB J 1992;454:491–501.
34.
Arancibia-Garavilla Y, Toledo F, Casanello P, Sobrevia L: Nitric oxide synthesis requires activity of the cationic and neutral amino acid transport system y+L in human umbilical vein endothelium. Exp Physiol 2003;88:699–710.
[PubMed]
35.
Sala R, Rotoli MB, Colla E, Visigalli R, Parolari A, Bussolati O, Gazzola GC, Daal’Asta V: Two-way arginine transport in human endothelial cells: TNF-α stimulation is restricted to system y+. Am J Physiol 2002;282:C134–C143.
36.
Radomki MW, Palmer RM, Moncada S: An L-arginine/ nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990;87:5193–5197.
[PubMed]
37.
Leoncini G, Bruzzese D, Signorello MG: The L-arginine/NO pathway in the early phases of platelet stimulation by collagen. Bioch Pharm 2005;29:289–296.
38.
Schoner W: Endogenous cardiac glycosides, a new class of steroid hormones. Eur J Biochem 2002;269:2440–2448.
[PubMed]
© 2007 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2007
You do not currently have access to this content.
