VOLTAGE-DEPENDENT AND TIME-DEPENDENT BLOCK BY PERHEXILINE OF K-TYPE CLONED CHANNEL( CURRENTS IN HUMAN ATRIUM AND IN CELLS EXPRESSING A KV1.5)

Perhexiline maleate is an antianginal drug that has been shown to have antiarrhythmic effects in humans. To examine whether some of these cl inical observations could be caused by block of cardiac K+ channels, w e examined the effects of perhexiline on a rapidly activating delayed rectifier K+ channel (Kv1.5) cloned from human heart and stably expres sed in human embryonic kidney cells as well as a corresponding K+ curr ent (the ultra-rapid delayed rectifier, I-Kur) in human atrial myocyte s. With the use of inside-out macropatches, we found that perhexiline inhibited Kv1.5 current in a time- and voltage-dependent manner with a n Ic(50) value of 1.5 x 10(-6) M at + 50 mV. Perhexiline reduced Kv1.5 tail current amplitude and slowed its decay relative to control. Thes e data are consistent with blockade of open channels, probably from th e intracellular surface. Perhexiline (3 mu M) also blocked I-Kur in hu man atrial myocytes. The block that was observed was both time- and vo ltage-dependent in qualitatively similar ways to block of Kv1.5 channe ls. However, the time-dependent block of I-Kur by perhexiline was some what slower and its voltage-dependence steeper relative to its effects on Kv1.5. These data indicate that perhexiline blocks both cloned and native human cardiac K+ channels. Blockade of one or more types of vo ltage-dependent K+ channels may explain some of the electrophysiologic al effects of perhexiline observed in humans.