Frequency- and Time-Dependent Effects of Fendiline on Action Potentials of Guinea Pig Papillary Muscle

The action of fendiline on cardiac electrical activity was investigated in guinea pig papillary muscle by monitoring frequency- and time-dependent changes in membrane potential, action potential (AP) configuration and conduction velocity. Isolated guinea pig papillary muscles driven at 0.1 to 3 Hz showed a concentration-dependent reduction of + Vmax, overshoot, and AP duration at -20 mV (APD20) in the presence of fendiline (1–320 μM), reflecting inhibition of Na+ and L-type Ca2+ channels, respectively. No significant change in resting potential and AP duration at 90% repolarization (APD90) were observed. Inhibition of + Vmax and APD20 was more prominent at higher frequency of stimulation (2 Hz) than at lower ones (0.2 Hz), demonstrating frequency-dependent block of Na+ and Ca2+ channels including an open channel block. A good relationship between changes in + Vmax and APD20 suggested some commonality in the mechanism of inhibition of Na+ and Ca2+ channels by fendiline. Time-dependence of effects of fendiline, observed in presence of bolus dose (200 μM), showed an earlier onset of inhibition of +Vmax and APD20, particularly at higher frequencies. Missed beats and conduction block also appeared earlier in preparations driven at higher frequency. These findings suggest a frequency-dependent (and open channel) block of Na+ and Ca2+ channels by fendiline, leading to inhibition of fast and slow conduction in addition to its reported inactivated Ca2+ channel block.