Calcium antagonist blockade of slow action potentials in cultured chick heart cells

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Abstract
The effects of 4 Ca antagonists, bepridil, diltiazem, nifedipine and verapamil, on slow channels were studied in cultured cell reaggregates prepared from 14-day-old chick embryonic hearts. The cell membrane was partially depolarized to about -45 mV by using 22 mM KCl to inactivate the fast Na+ channels. Slow action potentials were induced by 10-6 M isoproterenol with electrical stimulation. Cumulative dose-response curves for the effect of the 4 drugs on the blocking of slow action (using .ovrhdot.Vmax [maximum voltage] as the indicator) were analyzed by Hill plots. The dose values for 50% of maximal effect, at a stimulation frequency of 60/min, were (in order of decreasing potencies) as follows: 5.2 .times. 10-9 M for nifedipine, 3.1 .times. 10-7 M for diltiazem, 1.2 .times. 10-6 M for verapamil and 5.1 .times. 10-6 M for bepridil. The effect of all 4 Ca antagonists showed use (or frequency)-dependency, i.e., the drugs were more effective at higher stimulation rates. This may reflect a blocking action of the drugs on the nonresting states of the channels and (or) a slowing of the recovery kinetics of the channels from the inactivated state back to the resting state. In a separate type of experiment using a 5-min rest period in the presence of the drugs, nifedipine blocked and bepridil exhibited some depression of the 1st action potential elicited, i.e., use-independent effect, indicating that these drugs may also act on resting channels. These 4 Ca antagonists have a prominent use-dependent component in their actions, and 1 or 2 may also have a use-independent component.