Effects of anorexinogen agents on cloned voltage-gated K+ channel hKv1.5

Appetite suppressants have been associated with primary pulmonary hypertens ion (PPH), inhibition of voltage-gated potassium channels, membrane depolar ization, and calcium entry in pulmonary artery smooth muscle cells. In cell s taken from pulmonary arteries of primary pulmonary hypertensive patients, voltage-gated potassium channels appear to be dysfunctional and in particu lar, reduced hKv1.5 gene transcription and hKv1.5 mRNA instability have bee n shown. We have compared the effects of anorexinogen agents on hKv1.5 chan nels stably expressed in mammalian cell line. We found that aminorex, phent ermine, dexfenfluramine, sibutramine, and fluoxetine cause a dose-dependent inhibition of hKv1.5 current. Aminorex, phentermine, and dexfenfluramine h ad a K-D of inhibition greater than to 300 muM and are not potent inhibitor s of hKv1.5. Sibutramine and fluoxetine inhibited hKv1.5 current with lower K-D values of 41 and 21 muM, respectively. Block by both drugs increased r apidly between -20 and +10 mV, coincident with channel opening and suggeste d an open channel block mechanism. This was confirmed by a slower deactivat ion time course resulting in a "crossover" phenomenon when tail currents re corded under control conditions and in the presence of either drug were sup erimposed. Single channel experiments demonstrated that open probability an d open duration of hKv1.5 were decreased by fluoxetine and sibutramine. The se results indicate that among the anorexinogen agents tested, sibutramine and fluoxetine are the most potent toward hKv1.5 channel, which they prefer entially block in the open state. Nevertheless, their inhibitory effects do not correlate with their ability to produce PPH neither with their previou sly reported therapeutic plasma concentrations.