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
*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 3Hz showed a concentration-dependent reduction of +Vmax, overshoot, and AP duration at -20mV (APD20) in the presence of fendiline (1-320mM), 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 (2Hz) than at lower ones (0.2Hz), 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 (200mM), 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.

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

Copyright The Japanese Pharmacological Society 2000

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