Vol. 287, Issue 1, 293-300, October 1998

Blockage by Terfenadine of the Adenosine Triphosphate (ATP)-Sensitive K⁺ Current in Rabbit Ventricular Myocytes

Manabu Nishio, Yoshizumi Habuchi, Hideo Tanaka, Junichiro Morikawa, Taku Yamamoto and Kei Kashima

Departments of Internal Medicine III and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-0841, Japan

We examined the blocking effects of terfenadine, an antihistaminic agent, on the ATP-sensitive K⁺ current (I_K,ATP) in rabbit ventricular cells. I_K,ATP was induced by cromakalim or NaCN. Terfenadine blocked the I_K,ATP with an IC₅₀ of 1.7 µM at 10 mV. This blockage was voltage dependent; depolarization induced a stronger blockage. According to the transmembrane electrical field model, terfenadine interacts with the site located 15 to 18% from the cytoplasmic membrane surface. In line with the assumption that the binding site is near the cytoplasmic surface, terfenadine applied to the cytoplasmic solution potently inhibited the single-channel activity for I_K,ATP in the inside-out configuration (IC₅₀ 0.19 µM). In contrast, terfenadine applied to the external solution did not affect the channel activity in the cell-attached configuration, but inhibited it when applied into the pipette. The inhibition of the single channels by terfenadine was accompanied by flickering of the channels. These findings suggest that 1) terfenadine blocks the ATP-sensitive K⁺ channel in the open state, 2) the binding site is near the internal membrane surface and 3) terfenadine is poorly diffusible into the lipid biomembrane and accesses the binding site via the hydrophilic pathway. Terfenadine also inhibited the transient outward K⁺ current, inward rectifier K⁺ current and E4031-sensitive rectifier K⁺ current. However, the inhibition of these repolarization currents by terfenadine at 1 µM was not sufficient to prolong the action potential duration significantly. Whereas, terfenadine (1 µM) prolonged the action potential duration which had been shortened by cromakalim. Terfenadine may modify the ischemia-induced arrhythmias by blocking I_K,ATP.