Vol. 287, Issue 2, 480-486, November 1998

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

Shiling Hu, Shuya Wang, Joyce Gibson and Timothy A. Gilbertson¹

Research Department, Novartis Pharmaceuticals Corp., Summit, New Jersey

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-HT_2C 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 inhibitor p-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.