IMIPRAMINE BLOCKS RAPIDLY ACTIVATING AND DELAYS SLOWLY ACTIVATING K+ CURRENT ACTIVATION IN GUINEA-PIG VENTRICULAR MYOCYTES

Imipramine is a tricyclic antidepressant drug that also exhibits antiarrhythmic effects and whose clinical spectrum of activity is similar to that of quinidine. It has been previously demonstrated that imipramine inhibits the aggregate time-dependent outward K+ current (I(K)). I(K) is composed of at least two components: a slowly activating La3+-resistant delayed rectifying current (I(k,s)) and a rapidly activating La3+-sensitive current (I(K,r)). To assess the effects of imipramine on I(K,r) and I(K,s), single guinea pig ventricular myocytes were studied using the nystatin-perforated patch-clamp technique in the absence and in the presence of La3+. Imipramine inhibited I(K,r) and I(K,s) in a concentration-dependent manner. The effects of imipramine on the aggregate time-dependent outward current were more marked than those on I(K,s) alone. Thus, 1 mumol/L imipramine decreased the tail currents elicited on return to -30 mV after long depolarizing pulses (5 seconds, from -40 to +50 mV) in the absence and in the presence of La3+ by 27+/-4% and 15+/-3% (n=6), respectively. Moreover, the inhibition induced by imipramine was greater after short (0.5-second) pulses than after 5-second depolarizing pulses, both in the absence and in the presence of La3+ (53+/-3% and 30+/-5%, respectively; n=6; P<.05). Imipramine did not significantly modify either the activation midpoint or the slope factor of the aggregate I(K) and I(K,s) activation curves. The reduction of I(K,s) by imipramine was voltage dependent and was more marked at negative membrane potentials. In the presence of 1 mumol/L imipramine, the ratio of tail current to time-dependent current remained constant at 0.37+/-0.03, regardless of the test pulse duration at +50 mV. Thus, the envelope-of-tails test was satisfied in the presence of 1 mumol/L imipramine, which indicates that imipramine, at this concentration, blocks I(K,r) Imipramine (1, 5, and 10 mumol/L) had no effect on the kinetics of the later phase of I(K) activation but delayed the beginning of the activation of I(K,s) by 62+/-22, 74+/-23, and 155+/-53 milliseconds in the presence of 1, 5, and 10 mumol/L imipramine, respectively. These results suggest that imipramine preferentially blocks rapidly activating K+ channels. In addition, experiments performed in the presence of 30 mumol/L La3+ suggest that the drug preferentially binds, but maybe not exclusively, to a closed state of the slowly activating K+ channel.