Frequency-dependent blockade of T-type Ca 2+ current by efonidipine in cardiomyocytes

Abstract

Efonidipine is a dihydropyridine Ca 2+ antagonist with inhibitory effects on both L-type and T-type Ca 2+ 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 Ca 2+ channel in isolated guinea-pig ventricular myocytes. The potency of efonidipine to inhibit the T-type Ca 2+ current was higher under higher stimulation frequencies. The IC 50 values were 1.3×10 −8, 2.0×10 −6 and 6.3×10 −6 M under stimulation frequencies of 1, 0.2 and 0.05 Hz, respectively. The reduction of T-type Ca 2+ current amplitude was not accompanied by change in the time course of current decay. Efonidipine (10 μM) inhibited T-type Ca 2+ 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 Ca 2+ channel, which could be explained by slow dissociation of the drug from the inactivated state of the channel.