Frequency-dependent blockade of T-type Ca2+ current by efonidipine in cardiomyocytes

Efonidipine is a dihydropyridine Ca2+ antagonist with inhibitory effects on both L-type and T-type Ca2+ channels and potent bradycardiac activity espe cially in patients with high heart rate. In the present study, we examined the frequency dependence of efonidipine action on the T-type Ca2+ channel i n isolated guinea-pig ventricular myocytes. The potency of efonidipine to i nhibit the T-type Ca2+ current was higher under higher stimulation frequenc ies. The IC50 values were 1.3 X 10(-8), 2.0 X 10(-6) and 6.3 X 10(-6) M und er stimulation frequencies of 1, 0.2 and 0.05 Hz, respectively. The reducti on of T-type Ca2+ current amplitude was not accompanied by change in the ti me course of current decay. Efonidipine (10 muM) inhibited T-type Ca2+ curr ent elicited by depolarization from holding potentials ranging from -90 to -30 mV by about 30%; the voltage-dependence of steady-state inactivation wa s not changed by the drug. Efonidipine slowed the recovery from inactivatio n 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 inactiva ted state of the channel. (C) 2000 Elsevier Science Inc. All rights reserve d.