Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT)

Bryan-Lluka, Lesley J., Papacostas, Marisa H., Paczkowski, Filip A. and Wanstall, Janet C. (2004) Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT). British Journal of Pharmacology, 143 1: 63-70. doi:10.1038/sj.bjp.0705904

Author Bryan-Lluka, Lesley J.
Papacostas, Marisa H.
Paczkowski, Filip A.
Wanstall, Janet C.
Title Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT)
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
Publication date 2004-01-01
Sub-type Article (original research)
DOI 10.1038/sj.bjp.0705904
Open Access Status Not Open Access
Volume 143
Issue 1
Start page 63
End page 70
Total pages 8
Editor H.P. Rang
Place of publication London, England
Publisher Nature Publishing Group
Language eng
Subject C1
320502 Basic Pharmacology
730106 Cardiovascular system and diseases
320602 Cell Physiology
Abstract 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 [H-3]- 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 muM). 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.
Keyword Pharmacology & Pharmacy
5-ht Transporter (sert)
Dopamine Transporter (dat)
Nitric Oxide Donors
Transfected Cos-7 Cells
Human Serotonin Transporter
Human Dopamine Transporter
H-3 Dopamine
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 14:51:07 EST