The effects of four 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 four drugs on the blocking of slow action potentials (using [Formula: see text] 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 × 10−9 M for nifedipine, 3.1 × 10−7 M for diltiazem, 1.2 × 10−6 M for verapamil, and 5.1 × 10−6 M for bepridil. The effect of all four 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 utilizing a 5-min rest period in the presence of the drugs, nifedipine blocked and bepridil exhibited some depression of the first action potential elicited, i.e., use-independent effect, indicating that these drugs may also act on resting channels. Thus, these four Ca antagonists have a prominent use-dependent component in their actions, and one or two may also have a use-independent component.
Stimulation of slow action potentials in guinea pig papillary muscle cells by intracellular injection of cAMP, Gpp(NH)p, and cholera toxin.