Résumé
Ca channel antagonists of the dihydropyridine, benzothiazepine, and phenylalkylamine classes have selective effects on L-type versus T-type Ca 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 Ca currents (ICaT and ICaL) recorded at physiologic extracellular Ca in different cardiac cell types. At a stimulation rate of 0.1 Hz, mibefradil blocked ICaT evoked from negative holding potentials (HPs) (-100 mV to -80 mV) with an IC50 of 0.1 μM in rat atrial cells. This concentration had no effect on ICaL in rat ventricular cells (IC50~3 μM). However, block of ICaL was enhanced when the HP was depolarized to -50 mV (IC50~0.1 μM). Besides a resting block, mibefradil displayed voltage- and use-dependent effects on both ICaT and ICaL. In addition, inhibition was enhanced by increasing the duration of the stepdepolarizations. 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 ICaL. Inhibition of ICaL, which has probably been underestimated before, may contribute to most of the cardiovascular effects of mibefradil.