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

Imipramine is a tricyclic antidepressant drug that also exhibits antia rrhythmic effects and whose clinical spectrum of activity is similar t o that of quinidine. It has been previously demonstrated that imiprami ne inhibits the aggregate time-dependent outward K+ current (I(K)). I( K) is composed of at least two components: a slowly activating La3+-re sistant delayed rectifying current (I(k,s)) and a rapidly activating L a3+-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 studie d using the nystatin-perforated patch-clamp technique in the absence a nd 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 agg regate time-dependent outward current were more marked than those on I (K,s) alone. Thus, 1 mumol/L imipramine decreased the tail currents el icited 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 o f 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 reducti on of I(K,s) by imipramine was voltage dependent and was more marked a t negative membrane potentials. In the presence of 1 mumol/L imipramin e, the ratio of tail current to time-dependent current remained consta nt at 0.37+/-0.03, regardless of the test pulse duration at +50 mV. Th us, the envelope-of-tails test was satisfied in the presence of 1 mumo l/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 beginn ing of the activation of I(K,s) by 62+/-22, 74+/-23, and 155+/-53 mill iseconds in the presence of 1, 5, and 10 mumol/L imipramine, respectiv ely. These results suggest that imipramine preferentially blocks rapid ly activating K+ channels. In addition, experiments performed in the p resence 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.