Jpn. J. Pharmacol. 83 (3), 175-181 (2000)

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

Mamta Gautam, Anoop Tewari, Soni Singh, Chetna Dixit, K. Gopalan Raghu,
Prem Prakash and Onkar Tripathi*


Physiology Division, Central Drug Research Institute, Chhattar Manzil Palace, Post Box 173, Lucknow-226 001, India
*ﾊTo whom correspondence should be addressed.

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ﾊHz showed a concentration-dependent reduction of +V_max, overshoot, and AP duration at -20ﾊmV (APD₂₀) in the presence of fendiline (1-320ﾊmM), 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ﾊHz) than at lower ones (0.2ﾊ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 (200ﾊmM), 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.

Keywords: Fendiline, Diphenylalkylamine, Na⁺ channel, Ca²⁺ channel blocker, Cardiac action potential