USE-DEPENDENT BLOCK OF NA-CHANNEL LEVEL IN GUINEA-PIG VENTRICULAR MYOCYTES( CURRENTS BY MEXILETINE AT THE SINGLE)

1 The mechanism of use-dependent block of Na+ current by mexiletine wa s studied at the single channel level in guinea-pig ventricular myocyt es by the patch-clamp techniques. All experiments were performed using stimulation protocols to enable us to analyze the strict dependence o f changes in channel properties on channel use. 2 In cell-attached pat ches, bath or pipette application of mexiletine (40 mum) produced a us e-dependent reduction of the peak average current without changes in s ingle channel conductance. Null sweeps were increased and the number o f openings per sweep decreased with successive pulses, whereas no sign ificant change in the mean open time was detected during the train. 3 Block by mexiletine became greater when pulse duration was extended be yond the period in which channels were open, suggesting that block pro gressed without channel opening. 4 At near threshold potentials, mexil etine decreased the later occurrence of first openings. Additionally, late openings were reduced in a use-dependent way. 5 We conclude that mexiltine binds to the inactivated closed states of the Na+ channel an d then causes a failure of late openings as well as early, which resul ts in null sweeps on subsequent depolarization.