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 -20mV (APD20) in the presence of fendiline (1-320 microM), 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 microM), 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.
Gautam
M
M
Physiology Division, Central Drug Research Institute, Chhattar Manzil Palace, Lucknow, India.
Tewari
A
A
Singh
S
S
Dixit
C
C
Raghu
K G
KG
Prakash
P
P
Tripathi
O
O
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D005275:Fendiline / Q000494:pharmacology*; D051379:Mice; D009132:Muscles / Q000187:drug effects* / Q000502:physiology
D002121:Calcium Channel Blockers; D005275:Fendiline