Inhibition of T-type and L-type calcium channels by mibefradil: Physiologic and pharmacologic bases of cardiovascular effects

Ca2+ channel antagonists of the dihydropyridine. benzothiazepine, and phenylalkylamine: classes have selective effects on L-type versus T-type Ca2+ channels. In contrast, mibefradil was reported to be more selective for T-type channels. We used the whole-cell patch-clamp technique to investigate the effects of mibefradil on T-type and L-type Ca2+ currents (I-CaT and I-CaL) recorded at physiologic extracellular Ca2+ in different cardiac cell types. At a stimulation rate of 0.1 Hz, mibefradil blocked I-CaT evoked from negative holding potentials (HPs) (-100 mV to -80 mV) with an IC50 of 0.1 muM in rat atrial cells. This concentration had no effect on I-CaL in rat ventricular cells (IC50: similar to3 muM). However, block of I-CaL was enhanced when the HP was depolarized to -50 mV (IC50: similar to0.1 muM). Besides a resting block, mibefradil displayed voltage- and use-dependent effects on both I-CaT and I-CaL. In addition, inhibition was enhanced by increasing the duration of the step-depolarizations. Similar effects were observed in human atrial and rabbit sinoatrial cells. In conclusion, mibefradil combines the voltage- and use-dependent effects of dihydropyridines and benzothiazepines on I-CaL. Inhibit ion of I-CaL, which has probably been underestimated before, may contribute to most of the cardiovascular effects of mibefradil.