Previous work demonstrated that several anti-arrhythmic agents and antidepressive drugs block transient outward K+ current (Ito) in rat ventricular myocytes. The anti-arrhythmic drug, disopyramide, and the tricyclic antidepressants, imipramine and amitriptyline, block the Ito channel mainly when it is in the open state. The rate of recovery from block induced by disopyramide is so slow that the drug produces a use-dependent block at 1 Hz, whereas the rate of recovery from block in the presence of imipramine and amitriptyline is fast enough so as not to induce any use-dependent block at this frequency. We studied the effects of the combinations of disopyramide-imipramine and disopyramide-amitriptyline on Ito to detect possible interactions between the drugs on Ito blockade. The effects of imipramine and amitriptyline on the use-dependent effect induced by disopyramide and on the rate of recovery of the channels blocked by this drug allow us to conclude that there is only one common receptor site in the channel molecule for the three drug molecules.