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

Abstract

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 + V_max, overshoot, and AP duration at −20mV(APD₂₀)in the presence of fendiline(1−320μM), 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 + V_max 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 + V_max 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(200μM), showed an earlier onset of inhibition of + V_max 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.