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CARDIOVASCULAR

Open Channel Block of A-Type, K_v4.3, and Delayed Rectifier K⁺ Channels, K_v1.3 and K_v3.1, by Sibutramine

Departments of Physiology (S.E.K., H.S.A., H.-J.J., M.-J.K., D.-J.R., S.-H.Y., Y.-H.J., M.-S.K., S.J.H.) and Pharmacology (K.-W.S.), Medical Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea; and Department of Pharmacology, Chonbuk National University, Jeonju, Korea (B.H.C.)

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_v 4.3 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.

Address correspondence to: Dr. Sang June Hahn, Department of Physiology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea. E-mail: sjhahn{at}catholic.ac.kr

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