{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T19:30:26Z","timestamp":1785526226363,"version":"3.56.0"},"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/E527098\/1"],"award-info":[{"award-number":["BB\/E527098\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["080268"],"award-info":[{"award-number":["080268"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    <jats:sc>\n                      <jats:italic>L<\/jats:italic>\n                    <\/jats:sc>\n                    -Arginine is the physiological substrate for the nitric oxide synthase (NOS) family, which synthesises nitric oxide (NO) in endothelial and neuronal cells. NO synthesis can be inhibited by endogenous asymmetric dimethylarginine (ADMA). NO has explicit roles in cellular signalling and vasodilation. Impaired NO bioavailability represents the central feature of endothelial dysfunction associated with vascular diseases. Interestingly, dietary supplementation with\n                    <jats:italic>L<\/jats:italic>\n                    -arginine has been shown to alleviate endothelial dysfunctions caused by impaired NO synthesis. In this study the transport kinetics of [\n                    <jats:sup>3<\/jats:sup>\n                    H]-arginine and [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA into the central nervous system (CNS) were investigated using physicochemical assessment and the\n                    <jats:italic>in situ<\/jats:italic>\n                    brain\/choroid plexus perfusion technique in anesthetized mice. Results indicated that\n                    <jats:italic>L<\/jats:italic>\n                    -arginine and ADMA are tripolar cationic amino acids and have a gross charge at pH 7.4 of 0.981.\n                    <jats:italic>L<\/jats:italic>\n                    -Arginine (0.00149\u00b10.00016) has a lower lipophilicity than ADMA (0.00226\u00b10.00006) as measured using octanol-saline partition coefficients. The\n                    <jats:italic>in situ<\/jats:italic>\n                    perfusion studies revealed that [\n                    <jats:sup>3<\/jats:sup>\n                    H]-arginine and [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA can cross the blood-brain barrier (BBB) and the blood-CSF barrier. [\n                    <jats:sup>3<\/jats:sup>\n                    H]-Arginine (11.6nM) and [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA (62.5nM) having unidirectional transfer constants (K\n                    <jats:sub>in<\/jats:sub>\n                    ) into the frontal cortex of 5.84\u00b10.86 and 2.49\u00b10.35 \u03bcl.min\n                    <jats:sup>-1<\/jats:sup>\n                    .g\n                    <jats:sup>-1<\/jats:sup>\n                    , respectively, and into the CSF of 1.08\u00b10.24 and 2.70\u00b10.90 \u03bcl.min\n                    <jats:sup>-1<\/jats:sup>\n                    .g\n                    <jats:sup>-1<\/jats:sup>\n                    , respectively. In addition, multiple-time uptake studies revealed the presence of CNS-to-blood efflux of ADMA. Self- and cross-inhibition studies indicated the presence of transporters at the BBB and the blood-CSF barriers for both amino acids, which were shared to some degree. Importantly, these results are the first to demonstrate: (i) saturable transport of [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA at the blood-CSF barrier (choroid plexus) and (ii) a significant CNS to blood efflux of [\n                    <jats:sup>3<\/jats:sup>\n                    H]-ADMA. Our results suggest that the arginine paradox, in other words the clinical observation that NO-deficient patients respond well to oral supplementation with\n                    <jats:italic>L<\/jats:italic>\n                    -arginine even though the plasma concentration is sufficient to saturate endothelial NOS, could be related to altered ADMA transport (efflux).\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0305318","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T13:59:45Z","timestamp":1729778385000},"page":"e0305318","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["L-Arginine and asymmetric dimethylarginine (ADMA) transport across the mouse blood-brain and blood-CSF barriers: Evidence of saturable transport at both interfaces and CNS to blood efflux"],"prefix":"10.1371","volume":"19","author":[{"given":"Mehmet","family":"Fidanboylu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-0154","authenticated-orcid":true,"given":"Sarah Ann","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,24]]},"reference":[{"key":"pone.0305318.ref001","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/0006-8993(94)91503-2","article-title":"Role of nitric oxide in regulation of cerebral microvascular tone and autoregulation of cerebral blood flow in cats","volume":"667","author":"M Kobari","year":"1994","journal-title":"Brain Res"},{"key":"pone.0305318.ref002","doi-asserted-by":"crossref","first-page":"L371","DOI":"10.1152\/ajplung.00175.2004","article-title":"Constitutive eNOS-derived nitric oxide is a determinant of endothelial junctional integrity","volume":"289","author":"D Predescu","year":"2005","journal-title":"American Journal of Physiology-Lung Cellular and Molecular Physiology"},{"key":"pone.0305318.ref003","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0022-510X(02)00289-7","article-title":"Microvascular damage and platelet abnormalities in early Alzheimer\u2019s disease","volume":"203\u2013204","author":"B Borroni","year":"2002","journal-title":"J Neurol Sci"},{"key":"pone.0305318.ref004","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1161\/01.HYP.23.6.1121","article-title":"Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions","volume":"23","author":"U F\u00f6rstermann","year":"1994","journal-title":"Hypertension"},{"key":"pone.0305318.ref005","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ymgme.2007.04.017","article-title":"Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of l-arginine on its metabolism.","volume":"91","author":"DEL Wilcken","year":"2007","journal-title":"Mol Genet Metab"},{"key":"pone.0305318.ref006","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/0140-6736(92)90865-Z","article-title":"Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure","volume":"339","author":"P Vallance","year":"1992","journal-title":"Lancet"},{"key":"pone.0305318.ref007","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1097\/00005344-199204002-00018","article-title":"Endogenous Dimethylarginine as an Inhibitor of Nitric Oxide Synthesis","volume":"20","author":"P Vallance","year":"1992","journal-title":"J Cardiovasc Pharmacol"},{"key":"pone.0305318.ref008","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/333664a0","article-title":"Vascular endothelial cells synthesize nitric oxide from L-arginine","volume":"333","author":"RMJ Palmer","year":"1988","journal-title":"Nature"},{"key":"pone.0305318.ref009","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1006\/bbrc.1996.0279","article-title":"Elevated L-arginine\/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits","volume":"219","author":"SM Bode-B\u00f6ger","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0305318.ref010","doi-asserted-by":"crossref","first-page":"12230","DOI":"10.3390\/ijms160612230","article-title":"The Arginine\/ADMA Ratio Is Related to the Prevention of Atherosclerotic Plaques in Hypercholesterolemic Rabbits When Giving a Combined Therapy with Atorvastatine and Arginine.","volume":"16","author":"SJH Brinkmann","year":"2015","journal-title":"Int J Mol Sci."},{"key":"pone.0305318.ref011","doi-asserted-by":"crossref","first-page":"e0178710","DOI":"10.1371\/journal.pone.0178710","article-title":"Cellular interactions between L-arginine and asymmetric dimethylarginine: Transport and metabolism","volume":"12","author":"S Shin","year":"2017","journal-title":"PLoS One"},{"key":"pone.0305318.ref012","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.brainres.2016.07.026","article-title":"The transporter and permeability interactions of asymmetric dimethylarginine (ADMA) and L-arginine with the human blood\u2013brain barrier in vitro.","volume":"1648","author":"CP Watson","year":"2016","journal-title":"Brain Res"},{"key":"pone.0305318.ref013","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1161\/01.CIR.83.3.1057","article-title":"Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta","volume":"83","author":"JP Cooke","year":"1991","journal-title":"Circulation"},{"key":"pone.0305318.ref014","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1172\/JCI118632","article-title":"Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults","volume":"97","author":"P Clarkson","year":"1996","journal-title":"Journal of Clinical Investigation"},{"key":"pone.0305318.ref015","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/S0006-291X(05)80876-9","article-title":"Substrate-dependent regulation of intracellular amino acid concentrations in cultured bovine aortic endothelial cells","volume":"173","author":"AR Baydoun","year":"1990","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0305318.ref016","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1074\/jbc.M603606200","article-title":"Evidence for the Pathophysiological Role of Endogenous Methylarginines in Regulation of Endothelial NO Production and Vascular Function","volume":"282","author":"AJ Cardounel","year":"2007","journal-title":"Journal of Biological Chemistry"},{"key":"pone.0305318.ref017","first-page":"1","article-title":"Removal of intracellular asymmetric dimethyl-l-arginine (ADMA) requires system y+L membrane transporter-despite significant activity of the metabolising enzyme dimethylarginine dimethylaminohydrolase (DDAH).","volume":"383","author":"A Slenzka","year":"2011","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"pone.0305318.ref018","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.yjmcc.2012.06.002","article-title":"Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1).","volume":"53","author":"J Strobel","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"pone.0305318.ref019","first-page":"329","article-title":"Pentamidine movement across the murine blood-brain and blood-cerebrospinal fluid barriers: Effect of trypanosome infection, combination therapy, P-glycoprotein, and multidrug resistance-associated protein","author":"L Sanderson","year":"2009","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"pone.0305318.ref020","doi-asserted-by":"crossref","first-page":"3136","DOI":"10.1128\/AAC.00372-07","article-title":"Distribution of suramin, an antitrypanosomal drug, across the blood-brain and blood-cerebrospinal fluid interfaces in wild-type and P-glycoprotein transporter-deficient mice","volume":"51","author":"L Sanderson","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0305318.ref021","article-title":"MarvinSketch.","author":"MarvinSketch","year":"2022","journal-title":"ChemAxon version 22.9.0"},{"key":"pone.0305318.ref022","doi-asserted-by":"crossref","DOI":"10.1016\/S0006-8993(96)00930-4","article-title":"Identification of a saturable uptake system for deoxyribonucleosides at the blood-brain and blood-cerebrospinal fluid barriers","volume":"741","author":"SA Thomas N\u00e9e Williams","year":"1996","journal-title":"Brain Res"},{"key":"pone.0305318.ref023","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1111\/j.1471-4159.1990.tb04886.x","article-title":"Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins","volume":"54","author":"D Triguero","year":"1990","journal-title":"J Neurochem"},{"key":"pone.0305318.ref024","doi-asserted-by":"crossref","first-page":"H299","DOI":"10.1152\/ajpheart.1978.235.3.H299","article-title":"Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat","volume":"235","author":"K Ohno","year":"1978","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"pone.0305318.ref025","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/0006-8993(79)90546-8","article-title":"Drug entry into the brain","volume":"172","author":"SI Rapoport","year":"1979","journal-title":"Brain Res"},{"key":"pone.0305318.ref026","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1111\/j.1471-4159.1986.tb01760.x","article-title":"Measurement of solute transport across the blood-brain barrier in the perfused guinea pig brain: method and application to N-methyl-alpha-aminoisobutyric acid","volume":"46","author":"V Zlokovi\u0107 B","year":"1986","journal-title":"J Neurochem"},{"key":"pone.0305318.ref027","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1046\/j.1471-4159.1996.66031289.x","article-title":"Passage of a delta-opioid receptor selective enkephalin, [D-penicillamine2,5] enkephalin, across the blood-brain and the blood-cerebrospinal fluid barriers","volume":"66","author":"SA Williams","year":"1996","journal-title":"J Neurochem"},{"key":"pone.0305318.ref028","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1111\/j.1471-4159.1981.tb00587.x","article-title":"High\u2010 and Low\u2010Affinity Transport of D\u2010Glucose from Blood to Brain","volume":"36","author":"A. Gjedde","year":"1981","journal-title":"J Neurochem"},{"key":"pone.0305318.ref029","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0165-0173(82)90018-2","article-title":"Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: A re-examination","volume":"4","author":"A. Gjedde","year":"1982","journal-title":"Brain Res Rev"},{"key":"pone.0305318.ref030","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/jcbfm.1983.1","article-title":"Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data.","volume":"3","author":"CS Patlak","year":"1983","journal-title":"Journal of Cerebral Blood Flow & Metabolism."},{"key":"pone.0305318.ref031","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/jcbfm.1983.2","article-title":"Transport of \u03b1-Aminoisobutyric Acid across Brain Capillary and Cellular Membranes.","volume":"3","author":"RG Blasberg","year":"1983","journal-title":"Journal of Cerebral Blood Flow & Metabolism."},{"key":"pone.0305318.ref032","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1111\/j.1471-4159.1993.tb13428.x","article-title":"Identification of the cationic amino acid transporter (system y+) of the rat blood-brain barrier.","volume":"60","author":"J Stoll","year":"1993","journal-title":"J Neurochem"},{"key":"pone.0305318.ref033","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1146\/annurev.pharmtox.41.1.79","article-title":"The Clinical Pharmacology of L-Arginine","volume":"41","author":"RH B\u00f6ger","year":"2001","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"pone.0305318.ref034","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.clnu.2003.09.003","article-title":"Acute reduction of circulating arginine in mice does not compromise whole body NO production.","volume":"23","author":"MM Hallemeesch","year":"2004","journal-title":"Clinical Nutrition"},{"key":"pone.0305318.ref035","doi-asserted-by":"crossref","first-page":"e7337","DOI":"10.1371\/journal.pone.0007337","article-title":"Dimethylarginine Dimethylaminohydrolase-1 Transgenic Mice Are Not Protected from Ischemic Stroke.","volume":"4","author":"F Leypoldt","year":"2009","journal-title":"PLoS One"},{"key":"pone.0305318.ref036","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.neulet.2012.06.076","article-title":"The CSF concentration of ADMA, but not of ET-1, is correlated with the occurrence and severity of cerebral vasospasm after subarachnoid hemorrhage","volume":"524","author":"CS Jung","year":"2012","journal-title":"Neurosci Lett"},{"key":"pone.0305318.ref037","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1046\/j.1365-201x.1999.00587.x","article-title":"Regulation of macrophage nitric oxide synthesis by endothelial cells: a role for N G, N G \u2010dimethylarginine","volume":"167","author":"Holden Fickling","year":"1999","journal-title":"Acta Physiol Scand"},{"key":"pone.0305318.ref038","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1021\/mp2004127","article-title":"The Involvement of a Na +\u2014and Cl\u2212-Dependent Transporter in the Brain Uptake of Amantadine and Rimantadine","volume":"9","author":"SAA Kooijmans","year":"2012","journal-title":"Mol Pharm"},{"key":"pone.0305318.ref039","doi-asserted-by":"crossref","first-page":"14913","DOI":"10.1074\/jbc.270.25.14913","article-title":"Neutral Amino Acid Transport Characterization of Isolated Luminal and Abluminal Membranes of the Blood-Brain Barrier","volume":"270","author":"MMS del Pino","year":"1995","journal-title":"Journal of Biological Chemistry"},{"key":"pone.0305318.ref040","doi-asserted-by":"crossref","first-page":"E412","DOI":"10.1152\/ajpendo.00007.2006","article-title":"Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+.","author":"RL O\u2019Kane","year":"2006","journal-title":"American Journal of Physiology\u2014Endocrinology and Metabolism"},{"key":"pone.0305318.ref041","doi-asserted-by":"crossref","first-page":"S1016","DOI":"10.1093\/jn\/130.4.1016S","article-title":"Transport of Glutamate and Other Amino Acids at the Blood-Brain Barrier","volume":"130","author":"QR Smith","year":"2000","journal-title":"J Nutr"},{"key":"pone.0305318.ref042","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0304-4157(85)90015-2","article-title":"The transport of cationic amino acids across the plasma membrane of mammalian cells","volume":"822","author":"MF White","year":"1985","journal-title":"Biochimica et Biophysica Acta (BBA)\u2014Reviews on Biomembranes."},{"key":"pone.0305318.ref043","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1111\/j.1471-4159.1985.tb07209.x","article-title":"Kinetic Constants for Blood\u2014Brain Barrier Amino Acid Transport in Conscious Rats","volume":"45","author":"LP Miller","year":"1985","journal-title":"J Neurochem"},{"key":"pone.0305318.ref044","doi-asserted-by":"crossref","first-page":"F1288","DOI":"10.1152\/ajprenal.1990.258.5.F1288","article-title":"Kinetics and Na independence of amino acid uptake by blood side of perfused sheep choroid plexus","volume":"258","author":"MB Segal","year":"1990","journal-title":"American Journal of Physiology-Renal Physiology"},{"key":"pone.0305318.ref045","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0006-8993(92)90731-N","article-title":"The uptake of anionic and cationic amino acids by the isolated perfused sheep choroid plexus","volume":"581","author":"JE Preston","year":"1992","journal-title":"Brain Res"},{"key":"pone.0305318.ref046","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1016\/S0021-9258(18)91787-4","article-title":"Cationic Amino Acid Transport in the Rabbit Reticulocyte","volume":"244","author":"HN Christensen","year":"1969","journal-title":"Journal of Biological Chemistry"},{"key":"pone.0305318.ref047","doi-asserted-by":"crossref","first-page":"4450","DOI":"10.1016\/S0021-9258(18)34743-4","article-title":"Cationic amino acid transport into cultured animal cells. II. Transport system barely perceptible in ordinary hepatocytes, but active in hepatoma cell lines","volume":"257","author":"MF White","year":"1982","journal-title":"Journal of Biological Chemistry"},{"key":"pone.0305318.ref048","doi-asserted-by":"crossref","first-page":"4443","DOI":"10.1016\/S0021-9258(18)34742-2","article-title":"Cationic amino acid transport into cultured animal cells. I. Influx into cultured human fibroblasts","volume":"257","author":"MF White","year":"1982","journal-title":"J Biol Chem"},{"key":"pone.0305318.ref049","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/352729a0","article-title":"Cell-surface receptor for ecotropic murine retroviruses is a basic amino-acid transporter","volume":"352","author":"H Wang","year":"1991","journal-title":"Nature"},{"key":"pone.0305318.ref050","doi-asserted-by":"crossref","DOI":"10.3389\/fddev.2023.1113493","article-title":"Identification of transport systems involved in eflornithine delivery across the blood-brain barrier.","volume":"3","author":"CP Watson","year":"2023","journal-title":"Frontiers in Drug Delivery."},{"key":"pone.0305318.ref051","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/0042-6822(91)90748-Z","article-title":"Molecular cloning and characterization of a novel human gene homologous to the murine ecotropic retroviral receptor","volume":"185","author":"T Yoshimoto","year":"1991","journal-title":"Virology"},{"key":"pone.0305318.ref052","doi-asserted-by":"crossref","first-page":"20796","DOI":"10.1016\/S0021-9258(19)36854-1","article-title":"Characterization of the third member of the MCAT family of cationic amino acid transporters. Identification of a domain that determines the transport properties of the MCAT proteins","volume":"268","author":"EI Closs","year":"1993","journal-title":"Journal of Biological Chemistry"},{"key":"pone.0305318.ref053","doi-asserted-by":"crossref","first-page":"6462","DOI":"10.1021\/bi962829p","article-title":"Human Cationic Amino Acid Transporters hCAT-1, hCAT-2A, and hCAT-2B: Three Related Carriers with Distinct Transport Properties","volume":"36","author":"EI Closs","year":"1997","journal-title":"Biochemistry"},{"key":"pone.0305318.ref054","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.pharmthera.2007.03.002","article-title":"The l-arginine paradox: Importance of the l-arginine\/asymmetrical dimethylarginine ratio","volume":"114","author":"S Bode-Boger","year":"2007","journal-title":"Pharmacol Ther"},{"key":"pone.0305318.ref055","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.phrs.2009.08.002","article-title":"Cellular ADMA: Regulation and action","volume":"60","author":"T Teerlink","year":"2009","journal-title":"Pharmacol Res"},{"key":"pone.0305318.ref056","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/352725a0","article-title":"Transport of cationic amino acids by the mouse ecotropic retrovirus receptor","volume":"352","author":"JW Kim","year":"1991","journal-title":"Nature"},{"key":"pone.0305318.ref057","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1006\/niox.1996.0106","article-title":"Interference ofL-Arginine Analogues withL-Arginine Transport Mediated by the y+Carrier hCAT-2B","volume":"1","author":"EI Closs","year":"1997","journal-title":"Nitric Oxide"},{"key":"pone.0305318.ref058","doi-asserted-by":"crossref","first-page":"F989","DOI":"10.1152\/ajprenal.2001.280.6.F989","article-title":"Uremic levels of urea inhibit l -arginine transport in cultured endothelial cells","volume":"280","author":"S Xiao","year":"2001","journal-title":"American Journal of Physiology-Renal Physiology"},{"key":"pone.0305318.ref059","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1046\/j.1471-4159.1995.65010068.x","article-title":"Characterization of l \u2010Arginine and Aminoguanidine Uptake into Isolated Rat Choroid Plexus: Differences in Uptake Mechanisms and Inhibition by Nitric Oxide Synthase Inhibitors","volume":"65","author":"DFE Stuhlmiller","year":"1995","journal-title":"J Neurochem"},{"key":"pone.0305318.ref060","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1046\/j.1365-2125.1999.00883.x","article-title":"Pharmacokinetics of intravenous and oral L\u2010arginine in normal volunteers","volume":"47","author":"O Tangphao","year":"1999","journal-title":"Br J Clin Pharmacol"},{"key":"pone.0305318.ref061","doi-asserted-by":"crossref","first-page":"H1381","DOI":"10.1152\/ajpheart.01231.2004","article-title":"Transport of extracellular l -arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production","volume":"289","author":"BG Zani","year":"2005","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"pone.0305318.ref062","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbrc.2011.09.112","article-title":"Intracellular l-arginine concentration does not determine NO production in endothelial cells: Implications on the \u201cl-arginine paradox.\u201d","volume":"414","author":"S Shin","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0305318.ref063","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/S0891-5849(01)00781-X","article-title":"Coordinate regulation of L-arginine uptake and nitric oxide synthase activity in cultured endothelial cells","volume":"32","author":"TA Hardy","year":"2002","journal-title":"Free Radic Biol Med"},{"key":"pone.0305318.ref064","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-5793(00)01686-0","article-title":"Endogenous nitric oxide synthase inhibitors are responsible for the L \u2010arginine paradox","volume":"478","author":"D Tsikas","year":"2000","journal-title":"FEBS Lett"},{"key":"pone.0305318.ref065","doi-asserted-by":"crossref","first-page":"2842S","DOI":"10.1093\/jn\/134.10.2842S","article-title":"Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Explains the \u201cL-Arginine Paradox\u201d and Acts as a Novel Cardiovascular Risk Factor.","volume":"134","author":"RH B\u00f6ger","year":"2004","journal-title":"J Nutr"},{"key":"pone.0305318.ref066","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1161\/01.CIR.98.18.1842","article-title":"Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction.","volume":"98","author":"RH B\u00f6ger","year":"1998","journal-title":"Circulation"},{"key":"pone.0305318.ref067","volume-title":"Blood-CNS transport mechanisms in pathophysiology and drug delivery","author":"M. Fidanboylu","year":"2013"},{"key":"pone.0305318.ref068","first-page":"036P","article-title":"CAATs at the mouse choroid plexus","volume":"7","author":"M Fidanboylu","year":"2009","journal-title":"Br J Pharmacol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305318","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T14:00:07Z","timestamp":1729778407000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305318"}},"subtitle":[],"editor":[{"given":"Emre","family":"Avci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,24]]},"references-count":68,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0305318","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.05.30.596616","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,24]]}}}