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Article: Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists

TitleInhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists
Authors
Issue Date2007
PublisherElsevier 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?
AbstractDihydropyridine-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 Identifierhttp://hdl.handle.net/10722/171356
ISSN
2015 Impact Factor: 2.73
2015 SCImago Journal Rankings: 1.115
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, RWSen_US
dc.contributor.authorTse, CMen_US
dc.contributor.authorMan, RYKen_US
dc.contributor.authorVanhoutte, PMen_US
dc.contributor.authorLeung, GPHen_US
dc.date.accessioned2012-10-30T06:13:33Z-
dc.date.available2012-10-30T06:13:33Z-
dc.date.issued2007en_US
dc.identifier.citationEuropean Journal Of Pharmacology, 2007, v. 568 n. 1-3, p. 75-82en_US
dc.identifier.issn0014-2999en_US
dc.identifier.urihttp://hdl.handle.net/10722/171356-
dc.description.abstractDihydropyridine-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.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejpharen_US
dc.relation.ispartofEuropean Journal of Pharmacologyen_US
dc.rightsEuropean Journal of Pharmacology. Copyright © Elsevier BV.-
dc.subject.meshCalcium Channel Blockers - Pharmacologyen_US
dc.subject.meshCalcium Channels - Metabolismen_US
dc.subject.meshCell Lineen_US
dc.subject.meshDihydropyridines - Pharmacologyen_US
dc.subject.meshEquilibrative Nucleoside Transporter 1 - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshEquilibrative-Nucleoside Transporter 2 - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshTransfectionen_US
dc.subject.meshUridine - Metabolismen_US
dc.titleInhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonistsen_US
dc.typeArticleen_US
dc.identifier.emailMan, RYK:rykman@hkucc.hku.hken_US
dc.identifier.emailVanhoutte, PM:vanhoutt@hku.hken_US
dc.identifier.emailLeung, GPH:gphleung@hkucc.hku.hken_US
dc.identifier.authorityMan, RYK=rp00236en_US
dc.identifier.authorityVanhoutte, PM=rp00238en_US
dc.identifier.authorityLeung, GPH=rp00234en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.ejphar.2007.04.033en_US
dc.identifier.pmid17512522-
dc.identifier.scopuseid_2-s2.0-34250858008en_US
dc.identifier.hkuros136321-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34250858008&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume568en_US
dc.identifier.issue1-3en_US
dc.identifier.spage75en_US
dc.identifier.epage82en_US
dc.identifier.isiWOS:000248154800009-
dc.publisher.placeNetherlandsen_US
dc.identifier.scopusauthoridLi, RWS=7404722884en_US
dc.identifier.scopusauthoridTse, CM=7103295076en_US
dc.identifier.scopusauthoridMan, RYK=7004986435en_US
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_US
dc.identifier.scopusauthoridLeung, GPH=35963668200en_US

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