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- Publisher Website: 10.1016/j.ejphar.2007.04.033
- Scopus: eid_2-s2.0-34250858008
- PMID: 17512522
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Article: Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists
Title | Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists |
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Authors | |
Keywords | Adenosine Dihydropyridine Nucleoside Transporter |
Issue Date | 2007 |
Publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar |
Citation | European Journal Of Pharmacology, 2007, v. 568 n. 1-3, p. 75-82 How to Cite? |
Abstract | Dihydropyridine-type calcium channel antagonists, in addition to having a vasodilatory effect, are known to inhibit cellular uptake of nucleosides such as adenosine. However, the nucleoside transporter subtypes involved and the mechanism by which this occurs are not known. Therefore, we have studied the inhibitory effects of dihydropyridines on both human equilibrative nucleoside transporters, hENT-1 and hENT-2, which are the major transporters mediating nucleoside transport in most tissues. Among the dihydropyridines tested, nimodipine proved to be the most potent inhibitor of hENT-1, with an IC 50 value of 60 ± 31 μM, whereas nifedipine, nicardipine, nitrendipine, and felodipine exhibited 100-fold less effective inhibitory activity. Nifedipine, nitrendipine, and nimodipine inhibited hENT-2 with IC 50 values in the micromolar range; however, nicardipine and felodipine had no significant effect on hENT-2. Removal of the 4-aryl ring or changing the nitro group at the 4-aryl ring proved not to be detrimental to the inhibitory effects of dihydropyridines on hENT-1, but resulted in a drastic decrease in their inhibitory effects on hENT-2. Kinetic studies revealed that nimodipine and nifedipine reduced V max of [ 3H]uridine transport without affecting K m. The inhibitory effects of nimodipine and nifedipine could be washed out. In addition, nimodipine and nifedipine inhibited the rate of NBTGR-induced dissociation of [ 3H]NBMPR from hENT-1 cell membrane. We conclude that dihydropyridines are non-competitive inhibitors of hENT-1 and hENT-2, probably working through reversible interactions with the allosteric sites. The inhibitory potencies of dihydropyridines may be associated with the structure of the 4-aryl ring, as well as the ester groups at the C-3 and C-5 positions. © 2007 Elsevier B.V. All rights reserved. |
Persistent Identifier | http://hdl.handle.net/10722/171356 |
ISSN | 2023 Impact Factor: 4.2 2023 SCImago Journal Rankings: 1.055 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
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dc.contributor.author | Li, RWS | en_US |
dc.contributor.author | Tse, CM | en_US |
dc.contributor.author | Man, RYK | en_US |
dc.contributor.author | Vanhoutte, PM | en_US |
dc.contributor.author | Leung, GPH | en_US |
dc.date.accessioned | 2012-10-30T06:13:33Z | - |
dc.date.available | 2012-10-30T06:13:33Z | - |
dc.date.issued | 2007 | en_US |
dc.identifier.citation | European Journal Of Pharmacology, 2007, v. 568 n. 1-3, p. 75-82 | en_US |
dc.identifier.issn | 0014-2999 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/171356 | - |
dc.description.abstract | Dihydropyridine-type calcium channel antagonists, in addition to having a vasodilatory effect, are known to inhibit cellular uptake of nucleosides such as adenosine. However, the nucleoside transporter subtypes involved and the mechanism by which this occurs are not known. Therefore, we have studied the inhibitory effects of dihydropyridines on both human equilibrative nucleoside transporters, hENT-1 and hENT-2, which are the major transporters mediating nucleoside transport in most tissues. Among the dihydropyridines tested, nimodipine proved to be the most potent inhibitor of hENT-1, with an IC 50 value of 60 ± 31 μM, whereas nifedipine, nicardipine, nitrendipine, and felodipine exhibited 100-fold less effective inhibitory activity. Nifedipine, nitrendipine, and nimodipine inhibited hENT-2 with IC 50 values in the micromolar range; however, nicardipine and felodipine had no significant effect on hENT-2. Removal of the 4-aryl ring or changing the nitro group at the 4-aryl ring proved not to be detrimental to the inhibitory effects of dihydropyridines on hENT-1, but resulted in a drastic decrease in their inhibitory effects on hENT-2. Kinetic studies revealed that nimodipine and nifedipine reduced V max of [ 3H]uridine transport without affecting K m. The inhibitory effects of nimodipine and nifedipine could be washed out. In addition, nimodipine and nifedipine inhibited the rate of NBTGR-induced dissociation of [ 3H]NBMPR from hENT-1 cell membrane. We conclude that dihydropyridines are non-competitive inhibitors of hENT-1 and hENT-2, probably working through reversible interactions with the allosteric sites. The inhibitory potencies of dihydropyridines may be associated with the structure of the 4-aryl ring, as well as the ester groups at the C-3 and C-5 positions. © 2007 Elsevier B.V. All rights reserved. | en_US |
dc.language | eng | en_US |
dc.publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar | en_US |
dc.relation.ispartof | European Journal of Pharmacology | en_US |
dc.rights | European Journal of Pharmacology. Copyright © Elsevier BV. | - |
dc.subject | Adenosine | - |
dc.subject | Dihydropyridine | - |
dc.subject | Nucleoside | - |
dc.subject | Transporter | - |
dc.subject.mesh | Calcium Channel Blockers - Pharmacology | en_US |
dc.subject.mesh | Calcium Channels - Metabolism | en_US |
dc.subject.mesh | Cell Line | en_US |
dc.subject.mesh | Dihydropyridines - Pharmacology | en_US |
dc.subject.mesh | Equilibrative Nucleoside Transporter 1 - Antagonists & Inhibitors - Genetics - Metabolism | en_US |
dc.subject.mesh | Equilibrative-Nucleoside Transporter 2 - Antagonists & Inhibitors - Genetics - Metabolism | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Transfection | en_US |
dc.subject.mesh | Uridine - Metabolism | en_US |
dc.title | Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists | en_US |
dc.type | Article | en_US |
dc.identifier.email | Man, RYK:rykman@hkucc.hku.hk | en_US |
dc.identifier.email | Vanhoutte, PM:vanhoutt@hku.hk | en_US |
dc.identifier.email | Leung, GPH:gphleung@hkucc.hku.hk | en_US |
dc.identifier.authority | Man, RYK=rp00236 | en_US |
dc.identifier.authority | Vanhoutte, PM=rp00238 | en_US |
dc.identifier.authority | Leung, GPH=rp00234 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1016/j.ejphar.2007.04.033 | en_US |
dc.identifier.pmid | 17512522 | - |
dc.identifier.scopus | eid_2-s2.0-34250858008 | en_US |
dc.identifier.hkuros | 136321 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-34250858008&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 568 | en_US |
dc.identifier.issue | 1-3 | en_US |
dc.identifier.spage | 75 | en_US |
dc.identifier.epage | 82 | en_US |
dc.identifier.isi | WOS:000248154800009 | - |
dc.publisher.place | Netherlands | en_US |
dc.identifier.scopusauthorid | Li, RWS=7404722884 | en_US |
dc.identifier.scopusauthorid | Tse, CM=7103295076 | en_US |
dc.identifier.scopusauthorid | Man, RYK=7004986435 | en_US |
dc.identifier.scopusauthorid | Vanhoutte, PM=7202304247 | en_US |
dc.identifier.scopusauthorid | Leung, GPH=35963668200 | en_US |
dc.identifier.issnl | 0014-2999 | - |