Referenced in: none

Automatically associated channels: HCN3 , Kir6.1 , Kir6.2 , Slo1

Title: Blockade of cardiac ATP-sensitive K+ channel by cibenzoline targets its pore-forming subunit.

Authors: M Horie, M Watanuki, K Tsuji, H Ishida, A Ishida-Takahashi, Y Yuzuki, Y Seino, S Sasayama

Journal, date & volume: J. Cardiovasc. Pharmacol., 2000 Mar , 35, 434-42

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/10710130

Abstract
Several antiarrhythmic agents with Na-channel blocking action have been shown to inhibit cardiac K(ATP) channels. We used cibenzoline to examine its precise target site using patch-clamp techniques and receptor binding assays in guinea-pig ventricular myocytes. Exposure of myocytes to a glucose-free perfusate containing 1 mM cyanide produced a time-dependent shortening of the action potential duration (APD) in the current-clamp mode. Cibenzoline (30 microM) slowed the development of APD shortening (APD90 to approximately 91% vs. approximately 55% control 16 min after metabolic inhibition) at pHo 7.4, but not at pHo 6.4 (to approximately 60%). The pinacidil (30 microM)-induced K(ATP) currents were inhibited by cibenzoline in a pHo-dependent manner: the higher the pHo, the stronger the blocking effect of cibenzoline. The binding of [3H]-labeled cibenzoline was prevented by cibenzoline, but not by glibenclamide. Alkalinization produces a higher concentration of the uncharged form of cibenzoline, which can more easily permeate the cell membrane than the charged form. In NIH3T3 cells stably expressing Kir6.1, a putative pore-forming subunit of K(ATP) channel, cibenzoline but not glibenclamide inhibited the K conductance. Thus cibenzoline interacts with the channel pore-forming subunit of the K(ATP) channel (Kir6.2), but not the sulfonylurea receptor, from the cytosolic side after it permeates into the cell interior via the membrane lipid bilayer.