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

Rachel W.S. Li, Chung Ming Tse, Ricky Y.K. Man, Paul M. Vanhoutte, George P.H. Leung

Research output: Contribution to journalArticlepeer-review

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 IC50 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 IC50 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 Vmax of [3H]uridine transport without affecting Km. 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.

Original languageEnglish (US)
Pages (from-to)75-82
Number of pages8
JournalEuropean Journal of Pharmacology
Volume568
Issue number1-3
DOIs
StatePublished - Jul 30 2007

Keywords

  • Adenosine
  • Dihydropyridine
  • Nucleoside
  • Transporter

ASJC Scopus subject areas

  • Pharmacology

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