Inhibition of ATP-sensitive K+ channels of mouse skeletal muscle by disopyramide

Single ATP-sensitive K+ channels (KATP channels) were studied in inside-out membrane patches excised from mouse skeletal muscle. The class Ia antiarrhythmic, disopyramide (5-100 microM), applied to the cytoplasmic membrane surface inhibited KATP channels at -40 and +40 mV. Channel inhibition by disopyramide started slowly and reached an almost stationary level within 1 min. Recovery from channel inhibition by disopyramide was incomplete. At pH 7.4, the disopyramide concentrations producing 50% channel inhibition were 8.1 microM at -40 mV and 7.1 microM at +40 mV. The Hill coefficients of the concentration-response curves were close to unity at both potentials. Raising the internal pH from 7.4 to 8.0 had no significant effect on the actions of disopyramide, but lowering the pH to 6.5 greatly potentiated the inhibition of KATP channels by the antiarrhythmic. Thus the open probabilities of KATP channels at -40 mV and in the presence of disopyramide (20 microM) were smaller by a factor of 18 at pH 6.5 than at pH 7.4. The results suggest that disopyramide interacts with KATP channels through the lipid phase of the membrane and that lowering the intracellular pH increases the affinity of KATP channels to disopyramide. Thus disopyramide at therapeutic concentrations (6-15 microM) affects muscular KATP channels, in particular at reduced intracellular pH values that occur under ischaemic conditions and during fatiguing exercise.