Class la antiarrhythmic drugs, including procainamide (PROC), are associated with cardiac sodium channel blockade, delayed ventricular repolarisation and with a risk of ventricular pro-arrhythmia. The HERG K+ channel is frequently linked to drug-induced pro-arrhythmia. Therefore, in this study, interactions between PROC and HERG K+ channels were investigated, with particular reference to potency and mechanism of drug action. Whole-cell patch-clamp recordings of HERG current (I-HERG) were made at 37degreesC from human embryonic kidney (HEK 293) cells stably expressing the HERG channel. Following activating pulses to +20 mV, I-HERG tails were inhibited by PROC with an IC50 value of similar to139 muM. I-HERG blockade was found to be both time- and voltage-dependent, demonstrating contingency upon HERG channel gating. However, I-HERG inhibition by PROC was relieved by depolarisation to a highly positive membrane potential (+80 mV) that favoured HERG channel inactivation. These data suggest that PROC inhibits the HERG K+ channel by a primarily 'open' or 'activated' channel state blocking mechanism and that avidity of drug-binding is decreased by extensive I-HERG inactivation. The potency Of IHERG blockade by PROC is much lower than for other Class la agents that have been studied previously under analogous conditions (quinidine and disopyramide), although the blocking mechanism appears similar. Thus, differences between the chemical structure of PROC and other Class la antiarrhythmic drugs may help provide insight into chemical determinants of blocking potency for agents that bind to open/activated HERG channels. (C) 2003 Elsevier Science (USA). All rights reserved.