EFFECTS OF MEXILETINE ON ATP-SENSITIVE K-MUSCLE FIBERS - A STATE-DEPENDENT MECHANISM OF ACTION( CHANNEL OF RAT SKELETAL)

1 The effects of mexiletine were evaluated on the ATP-sensitive K+ cha nnel (K-ATP) of rat skeletal muscle fibres using patch clamp technique s. The effects of mexiletine were studied on macropatch currents 20 s (maximally activated), g min (early stage of rundown) and 15 min (late stage of rundown) after excision in the absence or in the presence of internal ADP (50-100 mu M) or UDP (500 mu M). In addition, the effect s of mexiletine were tested on single channel. 2 In the absence of ADP and UDP, mexiletine inhibited the current through maximally activated channels with an ICS, of -5.58 +/- 0.3 M. Nucleoside diphosphates shi fted the current versus mexiletine concentration relationship to the r ight on the log concentration axis. UDP (500 mu M) was more efficaciou s than ADP (50 - 100 mu M) in this effect. 3 At the early stage of run down, the sensitivity of the channel to mexiletine was reduced and nuc leoside diphosphates, particularly UDP, antagonized the effect of mexi letine. At the late stage of rundown, mexiletine did not affect the cu rrents. 4 At the single channel level, 1 mu M mexiletine reduced the m ean burst duration by 63% and prolonged the arithmetic mean closed tim e intervals between the bursts of openings without altering the open t ime and closed time distributions. Mexiletine did not affect the singl e channel conductance. 5 These results show that in skeletal muscle, m exiletine is a state-dependent K-ATP channel inhibitor which either ac ts through the nucleotide binding site or a site allosterically couple d to it.