Tonic and frequency-dependent Vmax block induced by imipramine in guinea pig ventricular muscle fibers

The effects of imipramine (IMI) on transmembrane action potentials were studied in isolated guinea pig papillary muscles. In muscles driven at 0.02 and 1 Hz, IMI (10(-7) to 5 X 10(-5) M) produced a concentration-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential, but it had no effect on the resting membrane potential. In the presence of 10(-5) M IMI, trains of stimuli at rates between 0.5 and 2 Hz led to an exponential decline in Vmax to a new steady-state level (K = 0.230 +/- 0.09 AP-1 at 2 Hz). This frequency-dependent Vmax block was augmented at higher stimulation frequencies and at higher drug concentrations. The time constant of the recovery of Vmax from the frequency-dependent block was 2.5 s, this value being independent of the drug concentration. These values of onset and offset kinetics of IMI lie between those of drugs with fast and intermediate kinetic properties. IMI also shifted the curve relating membrane potential and Vmax in hyperpolarizing directions. These results suggested that IMI exhibited a frequency- and voltage-dependent inhibition of the fast sodium channels similar to that exhibited by other class Ib antiarrhythmics. The possible role of this frequency- and voltage-dependent Vmax inhibition in the pro-antiarrhythmic effects of IMI is discussed.