Electrophysiological effects of the combination of imipramine and desipramine in guinea pig papillary muscles.

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 (Vmax) 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 Vmax block that was augmented at higher stimulation rates. At each driving rate, the Vmax 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 Vmax block, but the total amount of Vmax block was similar to that produced by desipramine alone. In the presence of imipramine alone, the recovery of Vmax 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 Vmax block, imipramine and desipramine can be classified as sodium channel blockers with intermediate and slow kinetics, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)