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Vol. 298, Issue 3, 1108-1119, September 2001

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

Loïc Perchenet, Laurence Hilfiger, Jacques Mizrahi and Odile Clément-Chomienne

Preclinical Research, F. Hoffmann-La-Roche Ltd., Basel, Switzerland

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 lower KD 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.

0022-3565/01/2983-1108$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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