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Research ArticleCARDIOVASCULAR

Effects of Anorexinogen Agents on Cloned Voltage-Gated K+ Channel hKv1.5

Loı̈c Perchenet, Laurence Hilfiger, Jacques Mizrahi and Odile Clément-Chomienne
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 1108-1119;
Loı̈c Perchenet
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Laurence Hilfiger
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Jacques Mizrahi
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Odile Clément-Chomienne
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Abstract

Appetite suppressants have been associated with primary pulmonary hypertension (PPH), inhibition of voltage-gated potassium channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells. In cells taken from pulmonary arteries of primary pulmonary hypertensive patients, voltage-gated potassium channels appear to be dysfunctional and in particular, reduced hKv1.5 gene transcription and hKv1.5 mRNA instability have been shown. We have compared the effects of anorexinogen agents on hKv1.5 channels stably expressed in mammalian cell line. We found that aminorex, phentermine, dexfenfluramine, sibutramine, and fluoxetine cause a dose-dependent inhibition of hKv1.5 current. Aminorex, phentermine, and dexfenfluramine had a KD of inhibition greater than to 300 μM and are not potent inhibitors of hKv1.5. Sibutramine and fluoxetine inhibited hKv1.5 current with lowerKD values of 41 and 21 μM, respectively. Block by both drugs increased rapidly between −20 and +10 mV, coincident with channel opening and suggested an open channel block mechanism. This was confirmed by a slower deactivation time course resulting in a “crossover” phenomenon when tail currents recorded under control conditions and in the presence of either drug were superimposed. Single channel experiments demonstrated that open probability and open duration of hKv1.5 were decreased by fluoxetine and sibutramine. These results indicate that among the anorexinogen agents tested, sibutramine and fluoxetine are the most potent toward hKv1.5 channel, which they preferentially block in the open state. Nevertheless, their inhibitory effects do not correlate with their ability to produce PPH neither with their previously reported therapeutic plasma concentrations.

Footnotes

  • Abbreviations:
    PPH
    primary pulmonary hypertension
    DFF
    dexfenfluramine
    5-HT
    5-hydroxytryptamine or serotonin
    Kv
    voltage-gated potassium channel
    PASMC
    pulmonary arterial smooth muscle cell
    hKv1.5
    human cardiac Kv1.5 channel
    CHO
    Chinese hamster ovary
    • Received December 22, 2000.
    • Accepted May 31, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleCARDIOVASCULAR

Effects of Anorexinogen Agents on Cloned Voltage-Gated K+ Channel hKv1.5

Loı̈c Perchenet, Laurence Hilfiger, Jacques Mizrahi and Odile Clément-Chomienne
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1108-1119;

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Research ArticleCARDIOVASCULAR

Effects of Anorexinogen Agents on Cloned Voltage-Gated K+ Channel hKv1.5

Loı̈c Perchenet, Laurence Hilfiger, Jacques Mizrahi and Odile Clément-Chomienne
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1108-1119;
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