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

Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Life Sciences (Impact Factor: 2.7). 01/2001; 68(3):345-51. DOI: 10.1016/S0024-3205(00)00932-2
Source: PubMed


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.

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    • "Inhibition is frequency-dependent, with an increasing potency at higher stimulation frequencies. In fact, in myocardial cells, efonidipine was shown to inhibit native T-type calcium currents in a frequency-dependent manner with IC 50 values of 13 nM, 2 mM, and 6.3 mM with stimulation frequencies of 1, 0.2, and 0.05 Hz, respectively [Masumiya et al., 2000]. Clinically, efonidipine decreases heart rate and has favourable effects on the nervous system supporting its significance in improving the prognosis in patients with hypertension and its protective influence on the heart and other organs [Harada et al., 2003]. "
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