The electrophysiological effects of imipramine and its active metabolite desipramine, alone or in combination, were studied in isolated guinea pig papillary muscles. The maximum upstroke velocity (V(max)) of the action potential was used as an indirect index of the magnitude of the sodium inward current. In muscles driven at 0.02 Hz, imipramine alone (5 x 10(-6) M), desipramine alone (5 x 10(-6) M), or their combination had no effect on action potential characteristics. However, in the presence of imipramine or desipramine, trains of stimuli at rates between 0.5 and 3 Hz led to a frequency-dependent V(max) block that was augmented at higher stimulation rates. At each driving rate, the V(max) block produced by desipramine was significantly greater than that produced by imipramine. The combination of imipramine and desipramine increased the onset rate of the frequency-dependent V(max) block, but the total amount of V(max) block was similar to that produced by desipramine alone. In the presence of imipramine alone, the recovery of V(max) was a monoexponential process, the time constant (tau(re)) being 2.3 +/- 0.4 s, whereas in the presence of desipramine, it was better defined by a biexponential function (tau(re) = 1.5 +/- 0.4 and 15.8 +/- 2.8 s). In the presence of the combination, the recovery process was also defined by a biexponential function and the tau(re) values were similar to those found in the presence of desipramine alone. Thus, according to their onset and offset kinetics of the frequency-dependent V(max) block, imipramine and desipramine can be classified as sodium channel blockers with intermediate and slow kinetics, respectively. Therefore, the active metabolite desipramine can be responsible for some of the cardiodepressant effects previously attributed to its parent compound, imipramine.