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Calcium antagonist blockade of slow action potentials in cultured chick heart cells
Abstract:
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 Vmax 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 X 10(-9) M for nifedipine, 3.1 X 10(-7) M for diltiazem, 1.2 X 10(-6) M for verapamil, and 5.1 X 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.
Insights
This study compared four calcium channel blockers on slow channels in chick heart cells. Nifedipine was the most potent, with all drugs showing frequency-dependent effects on action potentials.
Area of Science:
- Cardiovascular Pharmacology
- Electrophysiology
- Cell Biology
Background:
- Calcium (Ca) channels play a crucial role in cardiac action potential generation.
- Calcium channel antagonists are widely used in treating cardiovascular diseases.
- Understanding the differential effects of these drugs is vital for optimizing therapy.
Purpose of the Study:
- To investigate and compare the effects of four calcium channel antagonists (bepridil, diltiazem, nifedipine, verapamil) on cardiac slow channels.
- To determine the potency and mechanism of action of these drugs on slow action potentials in a controlled experimental setting.
Main Methods:
- Cultured cell reaggregates from embryonic chick hearts were used.
- Fast sodium channels were inactivated by partial depolarization using 22 mM KCl.
- Slow action potentials were induced by isoproterenol and electrical stimulation.
- Dose-response curves were analyzed using Hill plots to determine drug potency (IC50 values).
Main Results:
- Nifedipine exhibited the highest potency (5.2 x 10^-9 M), followed by diltiazem (3.1 x 10^-7 M), verapamil (1.2 x 10^-6 M), and bepridil (5.1 x 10^-6 M).
- All four calcium antagonists demonstrated use-dependent effects, becoming more potent at higher stimulation frequencies.
- Nifedipine and bepridil also showed some use-independent effects, suggesting action on resting channels.
Conclusions:
- The four calcium channel antagonists exhibit varying potencies in blocking cardiac slow channels.
- A significant use-dependent component characterizes the action of these drugs, with potential use-independent effects observed for nifedipine and bepridil.
- These findings highlight differential pharmacological profiles of common calcium channel blockers on cardiac electrophysiology.