Effect of the class III antiarrhythmic agent E-4031 on the ATP-sensitive potassium channel in rabbit ventricular...

The class III antiarrhythmic drug E-4031, a known blocker of the delayed rectifier potassium channel (IK), might also be capable of blocking the ATP-sensitive potassium channel (IKATP). We examined this possibility by studying the effect of E-4031 on single IKATP channels in membrane patches excised from ventricular myocytes that were obtained by standard enzymatic dissociation techniques from New Zealand white rabbits. In inside-out patches, E-4031 caused a dose-dependent block of IKATP with an EC50 of 31 +/- 1 microM, Hill coefficient of 0.89 +/- 0.24 and no effect on channel conductance. Open dwell-time kinetics were fitted by two exponential components, with E-4031 causing reduction of the longer time constant. In outside-out patches, the concentration of E-4031 required to produce blockade was much higher. We conclude that E-4031 blocks the ATP-sensitive potassium channel and that it does so from within the cytoplasm, with one-to-one channel binding stoichiometry. Single channel conductance is unchanged, but the longer time constant for the open state is reduced, which suggests that E-4031 may be an open channel blocker of intermediate to slow time course.