Frequency- and time-dependent effects of fendiline on action potentials ofguinea pig papillary muscle

The action of fendiline on cardiac electrical activity was investigated in guinea pig papillary muscle by monitoring frequency- and time-dependent cha nges in membrane potential, action potential (AP) configuration and conduct ion velocity. Isolated guinea pig papillary muscles driven at 0.1 to 3 Hz s howed a concentration-dependent reduction of +V-max, overshoot, and AP dura tion at -20 mV (APD(20)) in the presence of fendiline (1 - 320 mu M), refle cting inhibition of Na+ and L-type Ca2+ channels, respectively. No signific ant change in resting potential and AP duration at 90% repolarization (APD( 90)) were observed. Inhibition of + V-max and APD(20) was more prominent at higher frequency of stimulation (2 Hz) than at lower ones (0.2 Hz), demons trating frequency-dependent block of Na+ and Ca2+ channels including an ope n channel block. A good relationship between changes in + V-max and APD(20) suggested some commonality in the mechanism of inhibition of Na+ and Ca2channels by fendiline. Time-dependence of effects of fendiline, observed in presence of bolus dose (200 mu M), showed an earlier onset of inhibition o f + V-max and APD(20), particularly at higher frequencies. Missed beats and conduction block also appeared earlier in preparations driven at higher fr equency. These findings suggest a frequency-dependent (and open channel) bl ock of Na+ and Ca2+ channels by fendiline, leading to inhibition of fast an d slow conduction in addition to its reported inactivated Ca2+ channel bloc k.