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      Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

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          Abstract

          The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na +, K +-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na +, K +-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na +, K +-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na +, K +-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.

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          Most cited references37

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          Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial.

          Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested.
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            Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2.

            LAT1 and LAT2 are heterodimeric large amino acid transporters that are expressed in various tissues, including the intestinal wall, blood-brain barrier, and kidney. These transporters consist of membrane spanning light chain and heavy chain, and they act as 1:1 exchangers in concert with other amino acid transporters. Only a few drugs (less than 10) are substrates of LAT1 and LAT2, including L-DOPA, alpha-methyldopa, melphalan, and gabapentin. The mechanisms and substrates have been mostly elucidated using mammalian cells and Xenopus oocytes. The in vivo relevance of LAT1 and LAT2 in pharmacokinetics is obscure, because contradictory findings have been reported. It is difficult to make quantitative pharmacokinetic conclusions about LAT1 and LAT2. This is due to the possible involvement of other transporters (including cross-linked heterodimers of light chain with different heavy chains, other overlapping transporters, for example TAT1), competing endogenous amino acids, and saturation phenomena. This review presents the current functional knowledge on LAT1 and LAT2 with emphasis on their potential involvement in pharmacokinetics.
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              Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3).

              For the elimination of environmental toxins and metabolic waste products, the body is equipped with a range of broad-specificity transporters that are generally present in the liver, kidney, and intestine. The polyspecific organic cation transporters OCT1, 2, and 3 (SLC22A1-3) mediate the facilitated transport of a variety of structurally diverse organic cations, including many drugs, toxins, and endogenous compounds. OCT1 and OCT2 are found in the basolateral membrane of hepatocytes, enterocytes, and renal proximal tubular cells. OCT3 has a more widespread tissue distribution and is considered to be the major component of the extraneuronal monoamine transport system (or uptake-2), which is responsible for the peripheral elimination of monoamine neurotransmitters. Studies with knockout mouse models have directly demonstrated that these transporters can have a major impact on the pharmacological behavior of various substrate organic cations. The recent identification of polymorphic genetic variants of human OCT1 and OCT2 that severely affect transport activity thus suggests that some of the interpatient differences in response and sensitivity to cationic drugs may be caused by variable activity of these transporters.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                8 July 2016
                2016
                : 11
                : 7
                : e0157487
                Affiliations
                [1 ]Cardiological Research Institute, National Scientific and Technical Research Council, Buenos Aires, Argentina
                [2 ]Pathophysiology and Clinical Biochemistry Institute, Buenos Aires, Argentina
                [3 ]Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
                [4 ]Department of General Surgery, Johns Hopkins Hospital, Baltimore, Maryland, United States of America
                [5 ]Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
                [6 ]Deutsch Hospital, Buenos Aires, Argentina
                [7 ]Department of Anatomy and Histology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
                [8 ]Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
                University of Geneva, SWITZERLAND
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BEF MRC. Performed the experiments: NMK NLRM MCK BML SG MRC. Analyzed the data: JET MRC. Contributed reagents/materials/analysis tools: AC JDM MP MMG. Wrote the paper: NMK NLRM BEF MRC.

                Author information
                http://orcid.org/0000-0003-2909-8534
                Article
                PONE-D-15-52493
                10.1371/journal.pone.0157487
                4938554
                27392042
                79bb1f4a-f7a3-457d-8619-b245dcc01581
                © 2016 Kouyoumdzian et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 December 2015
                : 30 May 2016
                Page count
                Figures: 6, Tables: 3, Pages: 17
                Funding
                Funded by: Agencia Nacional de Promoción Científica y Tecnológica (PICT)
                Award ID: 2012-01775
                Award Recipient :
                Funded by: Universidad de Buenos Aires (UBACyT)
                Award ID: 20020110200048
                Award Recipient :
                Funded by: Universidad de Buenos Aires (UBACyT)
                Award ID: 20020130200105BA
                Award Recipient :
                Funded by: Stimulus Grant for Research on Hypertension
                Award ID: 2014-2015
                Award Recipient :
                The work was supported by the following: PICT (Proyectos de Investigación Científica y Tecnológica), 2012-01775 MRC; UBACyT (Universidad de Buenos Aires Ciencia y Técnica), 20020130200105BA MRC; SAHA 2014-2015 MRC; Hansang Latinoamérica (Confederación Latinoamericana de Empresarios Coreanos). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amines
                Catecholamines
                Dopamine
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amines
                Catecholamines
                Dopamine
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