INHIBITION OF ATP-SENSITIVE K-MUSCLE BY DISOPYRAMIDE( CHANNELS OF MOUSE SKELETAL)

Single ATP-sensitive K+ channels (K-ATP channels) were studied in insi de-out membrane patches excised from mouse skeletal muscle. The class Ia antiarrhythmic, disopyramide (5-100 mu M), applied to the cytoplasm ic membrane surface inhibited K-ATP channels at -40 and +40 mV. Channe l inhibition by disopyramide started slowly and reached an almost stat ionary level within 1 min. Recovery from channel inhibition by disopyr amide was incomplete. At pH 7.4, the disopyramide concentrations produ cing 50% channel inhibition were 8.1 mu M at -40 mV and 7.1 mu M at +4 0 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 low ering the pH to 6.5 greatly potentiated the inhibition of K-ATP channe ls by the antiarrhythmic. Thus the open probabilities of K-ATP channel s at -40 mV and in the presence of disopyramide (20 mu M) were smaller by a factor of 18 at pH 6.5 than at pH 7.4. The results suggest that disopyramide interacts with K-ATP channels through the lipid phase of the membrane and that lowering the intracellular pH increases the affi nity of K-ATP channels to disopyramide. Thus disopyramide at therapeut ic concentrations (6-15 mu M) affects muscular K-ATP channels, in part icular at reduced intracellular pH values that occur under ischaemic c onditions and during fatiguing exercise.