Tae-Seong Lee

Actions of Mibefradil, Efonidipine and Nifedipine Block of Recombinant T- and L-Type Ca2+ Channels with Distinct Inhibitory Mechanisms

We compared detailed efficacy of efonidipine and nifedipine, dihydropyridine analogues, and mibefradil using recombinant T- and L-type Ca²⁺ channels expressed separately in mammalian cells. All these Ca²⁺ channel antagonists blocked T-type Ca²⁺ channel currents (I_Ca(T)) with distinct blocking manners: I_Ca(T) was blocked mainly by a tonic manner by nifedipine, by a use-dependent manner by mibefradil, and by a combination of both manners by efonidipine. IC₅₀s of these Ca²⁺ channel antagonists to I_Ca(T) and L-type Ca²⁺ channel current (I_Ca(L)) were 1.2 µmol/l and 0.14 nmol/l for nifedipine; 0.87 and 1.4 µmol/l for mibefradil, and 0.35 µmol/l and 1.8 nmol/l for efonidipine, respectively. Efonidipine, a dihydropyridine analogue, showed high affinity to T-type Ca²⁺ channel.

Voltage-Dependent and Frequency-Independent Inhibition of Recombinant Cav3.2 T-Type Ca2+ Channel by Bepridil

Effects of bepridil on the low voltage-activated T-type Ca2+ channel (CaV3.2) current stably expressed in human embryonic kidney (HEK)-293 cells were examined using patch-clamp techniques. Bepridil potently inhibited ICa,T with a markedly voltage-dependent manner; the IC50 of bepridil was 0.4 µmol/l at the holding potential of –70 mV, which was 26 times as potent as that at –100 mV (10.6 µmol/l). Steady-state inactivation curve (8.4 ± 1.7 mV) and conductance curve (5.9 ± 1.9 mV) were shifted to the hyperpolarized potential by 10 µmol/l bepridil. Bepridil exerted the tonic blocking action but not the use-dependent block. Bepridil had no effect on the recovery from inactivation of T-type Ca2+ channels. Thus, high efficacy of bepridil for terminating atrial fibrillation and atrial flutter may be considered to be attributed, at least in a part, to the T-type Ca2+ channel-blocking actions.