V. Leuranguer et al., Inhibition of T-type and L-type calcium channels by mibefradil: Physiologic and pharmacologic bases of cardiovascular effects, J CARDIO PH, 37(6), 2001, pp. 649-661
Citations number
47
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Ca2+ channel antagonists of the dihydropyridine. benzothiazepine, and pheny
lalkylamine: classes have selective effects on L-type versus T-type Ca2+ ch
annels. In contrast, mibefradil was reported to be more selective for T-typ
e 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 neg
ative 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 ventr
icular 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 b
oth I-CaT and I-CaL. In addition, inhibition was enhanced by increasing the
duration of the step-depolarizations. Similar effects were observed in hum
an atrial and rabbit sinoatrial cells. In conclusion, mibefradil combines t
he voltage- and use-dependent effects of dihydropyridines and benzothiazepi
nes on I-CaL. Inhibit ion of I-CaL, which has probably been underestimated
before, may contribute to most of the cardiovascular effects of mibefradil.