Open channel block of A-type, K_v4.3, and delayed rectifier K⁺ channels, K_v1.3 and K_v3.1, by sibutramine

The effects of sibutramine on voltage-gated K⁺ channel (K _v)4.3, K_v1.3, and K_v3.1, stably expressed in Chinese hamster ovary cells, were investigated using the whole-cell patch-clamp technique. Sibutramine did not significantly decrease the peak K_v4.3 currents, but it accelerated the rate of decay of current inactivation in a concentration-dependent manner. This phenomenon was effectively characterized by integrating the total current over the duration of a depolarizing pulse to +40 mV. The IC₅₀ value for the sibutramine block of K_v4.3 was 17.3 μM. Under control conditions, the inactivation of K_v4.3 currents could be fit to a biexponential function, and the time constants for the fast and slow components were significantly decreased after the application of sibutramine. The association (k₊₁) and dissociation (k _-1) rate constants for the sibutramine block of K_v4.3 were 1.51 μM^-1s^-1 and 27.35 s^-1, respectively. The theoretical K_D value, derived from k_-1/k₊₁, yielded a value of 18.11 μM. The block of K_v4.3 by sibutramine displayed a weak voltage dependence, increasing at more positive potentials, and it was use-dependent at 2 Hz. Sibutramine did not affect the time course for the deactivating tail currents. Neither steady-state activation and inactivation nor the recovery from inactivation was affected by sibutramine. Sibutramine caused the concentration-dependent block of the K_v1.3 and K _v3.1 currents with an IC₅₀ value of 3.7 and 32.7 μM, respectively. In addition, sibutramine reduced the tail current amplitude and slowed the deactivation of the tail currents of K_v1.3 and K _v3.1, resulting in a crossover phenomenon. These results indicate that sibutramine acts on K_v4.3, K_v1.3, and K _v3.1 as an open channel blocker.