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Research ArticleArticle

Inhibition of Delayed Rectifier K+ Channels by Dexfenfluramine (Redux)

Shiling Hu, Shuya Wang, Joyce Gibson and Timothy A. Gilbertson
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 480-486;
Shiling Hu
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Shuya Wang
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Joyce Gibson
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Timothy A. Gilbertson
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Abstract

In light of recent reports linking K+ channel modulation with food intake and macronutrient preference, we investigated the effect of anorectic agent dexfenfluramine (d-FF), a 5-HT reuptake inhibitor and releasing agent, on the delayed rectifier K+ (DRK) channels in rat lingual taste cells using the patch-clamp technique in whole-cell configuration. In a concentration-dependent manner, d-FF caused a reduction of the DRK currents in taste cells with an IC50 of 30.5 μM. Other anorectics that promote 5-HT activity such as fenfluramine, sibutramine and m-chlorophenylpiperazine (a specific 5-HT2C receptor agonist) produced inhibition of DRK currents of a similar pattern with a respective IC50 of 69.0, 8.6 and 95.4 μM. The actions of all compounds had rapid onset and were readily reversible. The inhibitory effects were not secondary to their stimulation of 5-HT, because direct application of 5-HT up to 1 mM did not alter DRK current. In addition, d-FF-induced current reduction was not prevented by either the 5-HT synthesis inhibitorp-chlorophenylalanine or 5-HT receptor antagonist metergoline. d-FF was also tested in cardiac ventricular myocytes that are reportedly abundant in DRK channels and was found to depress the DRK currents concentration-dependently with an IC50 of 250.9 μM. These results indicate an important pharmacological role for d-FF as an inhibitor of the DRK channels. The common inhibitory effect on DRK channels in oral taste cells and cardiac cells by this class of compounds might contribute to the anorectic and some of the detrimental cardiovascular effect associated with long-term exposure.

Footnotes

  • Send reprint requests to: Dr. Shiling Hu, Research Department, Novartis Pharmaceuticals Corp., 556 Morris Avenue, Summit, NJ 07901. E-mail: shiling.hu{at}pharma.novartis.com

  • ↵1 Present address: Louisiana State University, Baton Rouge, LA 70808.

  • Abbreviations:
    d-FF
    dexfenfluramine
    FF
    fenfluramine
    SB
    sibutramine
    mCPP
    m-chlorophenylpiperazine
    PCPA
    p-chlorophenylalanine
    MTG
    metergoline
    DRK
    delayed rectifier K+
    • Received March 17, 1998.
    • Accepted June 18, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Inhibition of Delayed Rectifier K+ Channels by Dexfenfluramine (Redux)

Shiling Hu, Shuya Wang, Joyce Gibson and Timothy A. Gilbertson
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 480-486;

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Research ArticleArticle

Inhibition of Delayed Rectifier K+ Channels by Dexfenfluramine (Redux)

Shiling Hu, Shuya Wang, Joyce Gibson and Timothy A. Gilbertson
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 480-486;
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