|Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT).|
|PMID: 15302679 Owner: NLM Status: MEDLINE|
|1. The aim was to test the hypothesis that nitric oxide (NO) donor drugs can inhibit the 5-hydroxytryptamine (5-HT) transporter, SERT. 2. The NO donors, MAHMA/NO (a NONOate; (Z)-1-[N-methyl-N-[6-(N-methylammoniohexyl)-amino]]diazen-1-ium-1,2-diolate), SIN-1 (a sydnonimine; 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride), FK409 (an oxime; (+/-)-(4-ethyl-2E-(hydroxyimino)-5-nitro-3E-hexenamide)) and peroxynitrite, but not Angeli's salt (source of nitroxyl anion) or sodium nitrite, caused concentration-dependent inhibition of the specific uptake of [3H]-5-HT in COS-7 cells expressing human SERT. 3. Superoxide dismutase (150 U ml(-1)) plus catalase (1200 U ml(-1)), used to remove superoxide and hence prevent peroxynitrite formation, prevented the inhibitory effect of SIN-1 (which generates superoxide) but not of MAHMA/NO or FK409. 4 The inhibitory effects of the NO donors were not affected by the free radical scavenger, hydroxocobalamin (1 mM) or the guanylate cyclase inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 3 microM). 5. L-Cysteine (1 mM; source of excess thiol residues) abolished or markedly reduced the inhibitory effects of MAHMA/NO, SIN-1, FK409 and peroxynitrite. 6. It is concluded that inhibition of SERT by the NO donors cannot be attributed exclusively to NO free radical nor to nitroxyl anion. It does not involve guanosine-3',5'-cyclic monophosphate, but may involve nitrosation of cysteine residues on the SERT protein. Peroxynitrite mediates the effect of SIN-1, but not the other drugs. 7. Data in mice with hypoxic pulmonary hypertension suggest that SERT inhibitors may attenuate pulmonary vascular remodelling. Thus, NO donors may be useful in pulmonary hypertension, not only as vasodilators, but also because they inhibit SERT, provided they display this effect in vivo at appropriate doses.|
|Lesley J Bryan-Lluka; Marisa H Papacostas; Filip A Paczkowski; Janet C Wanstall|
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|Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2004-08-09|
|Title: British journal of pharmacology Volume: 143 ISSN: 0007-1188 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2004 Sep|
|Created Date: 2004-09-03 Completed Date: 2005-02-09 Revised Date: 2013-06-09|
Medline Journal Info:
|Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England|
|Languages: eng Pagination: 63-70 Citation Subset: IM|
|Department of Physiology & Pharmacology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.|
|APA/MLA Format Download EndNote Download BibTex|
Biological Transport / drug effects
Catalase / pharmacology
Cysteine / pharmacology
DNA, Complementary / genetics, metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Free Radical Scavengers / pharmacology
Guanylate Cyclase / antagonists & inhibitors
Hydroxocobalamin / pharmacology
Membrane Glycoproteins / antagonists & inhibitors*, metabolism*
Membrane Transport Modulators*
Membrane Transport Proteins / antagonists & inhibitors*, metabolism*
Nerve Tissue Proteins / antagonists & inhibitors*, metabolism*
Nitric Oxide Donors / pharmacology*
Nitro Compounds / pharmacology
Oxadiazoles / pharmacology
Peroxynitrous Acid / pharmacology
Piperazines / pharmacology
Quinoxalines / pharmacology
Serotonin / metabolism*
Serotonin Plasma Membrane Transport Proteins
Superoxide Dismutase / pharmacology
|0/1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; 0/Culture Media; 0/DNA, Complementary; 0/Enzyme Inhibitors; 0/Free Radical Scavengers; 0/Membrane Glycoproteins; 0/Membrane Transport Modulators; 0/Membrane Transport Proteins; 0/Nerve Tissue Proteins; 0/Nitric Oxide Donors; 0/Nitro Compounds; 0/Oxadiazoles; 0/Piperazines; 0/Quinoxalines; 0/SLC6A4 protein, human; 0/Serotonin Plasma Membrane Transport Proteins; 13422-51-0/Hydroxocobalamin; 14691-52-2/Peroxynitrous Acid; 50-67-9/Serotonin; 52-90-4/Cysteine; 67469-78-7/vanoxerine; 92454-60-9/FK 409; EC 22.214.171.124/Catalase; EC 126.96.36.199/Superoxide Dismutase; EC 188.8.131.52/Guanylate Cyclase|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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