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Frequency-dependent blockade of T-type Ca2+ current by efonidipine in cardiomyocytes
1Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Abstract:
Efonidipine is a dihydropyridine Ca2+ antagonist with inhibitory effects on both L-type and T-type Ca2+ channels and potent bradycardiac activity especially in patients with high heart rate. In the present study, we examined the frequency dependence of efonidipine action on the T-type Ca2+ channel in isolated guinea-pig ventricular myocytes. The potency of efonidipine to inhibit the T-type Ca2+ current was higher under higher stimulation frequencies. The IC50 values were 1.3 x 10(-8), 2.0 x 10(-6) and 6.3 x 10(-6) M under stimulation frequencies of 1, 0.2 and 0.05 Hz, respectively. The reduction of T-type Ca2+ current amplitude was not accompanied by change in the time course of current decay. Efonidipine (10 microM) inhibited T-type Ca2+ current elicited by depolarization from holding potentials ranging from -90 to -30 mV by about 30%; the voltage-dependence of steady-state inactivation was not changed by the drug. Efonidipine slowed the recovery from inactivation following an inactivating prepulse. In conclusion, efonidipine was shown to have frequency-dependent inhibitory effects on the T-type Ca2+ channel, which could be explained by slow dissociation of the drug from the inactivated state of the channel.
Insights
Efonidipine, a calcium channel blocker, shows increased effectiveness in inhibiting T-type calcium channels at higher heart rates. This frequency-dependent action is attributed to the drug
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Physiology
Background:
- Efonidipine is a dihydropyridine calcium (Ca2+) antagonist.
- It inhibits both L-type and T-type Ca2+ channels.
- Efonidipine exhibits bradycardiac activity, particularly in individuals with elevated heart rates.
Purpose of the Study:
- To investigate the frequency-dependent effects of efonidipine on T-type Ca2+ channels.
- To elucidate the mechanism behind efonidipine's action on T-type Ca2+ channels in cardiac myocytes.
Main Methods:
- Isolated guinea-pig ventricular myocytes were utilized.
- T-type Ca2+ currents were measured under varying stimulation frequencies (0.05 Hz, 0.2 Hz, 1 Hz).
- Inhibition, inactivation, and recovery kinetics of T-type Ca2+ currents were analyzed.
Main Results:
- Efonidipine's potency in inhibiting T-type Ca2+ current increased with higher stimulation frequencies.
- IC50 values demonstrated a significant decrease at higher frequencies (1.3 x 10^-8 M at 1 Hz).
- The drug slowed the recovery of T-type Ca2+ channels from inactivation, suggesting slow dissociation from the inactivated state.
Conclusions:
- Efonidipine exhibits frequency-dependent inhibition of T-type Ca2+ channels.
- This effect is likely due to slow drug dissociation from the channel's inactivated state.
- The findings provide insights into the electrophysiological effects of efonidipine in cardiac tissue.