BLOCKAGE BY TERFENADINE OF THE ADENOSINE-TRIPHOSPHATE (ATP)-SENSITIVEK+ CURRENT IN RABBIT VENTRICULAR MYOCYTES

We examined the blocking effects of terfenadine, an antihistaminic age nt, on the ATP-sensitive K+ current (I-K,I-ATP) in rabbit ventricular cells. I-K,I-ATP was induced by cromakalim or NaCN. Terfenadine blocke d the I-K,I-ATP with an IC50 of 1.7 mu M at -10 mV. This blockage was voltage dependent; depolarization induced a stronger blockage. Accordi ng 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 cytopla smic surface, terfenadine applied to the cytoplasmic solution potently inhibited the single-channel activity for I-K,I-ATP in the inside-out configuration (IC50 0.19 mu M). In contrast, terfenadine applied to t he external solution did not affect the channel activity in the cell-a ttached 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) terfenad ine blocks the ATP-sensitive K+ channel in the open state, 2) the bind ing site is near the internal membrane surface and 3) terfenadine is p oorly diffusible into the lipid biomembrane and accesses the binding s ite via the hydrophilic pathway. Terfenadine also inhibited the transi ent outward K+ current, inward rectifier K+ current and E4031-sensitiv e rectifier K+ current. However, the inhibition of these repolarizatio n currents by terfenadine at 1 mu M was not sufficient to prolong the action potential duration significantly. Whereas, terfenadine (1 mu M) prolonged the action potential duration which had been shortened by c romakalim. Terfenadine may modify the ischemia-induced arrhythmias by blocking I-K,I-ATP.