Mibefradil dihydrochloride

Mibefradil dihydrochloride is an blocker of calcium channel with moderate selectivity for T-type Ca2+ channels (T-type and L-type currents with IC50s of 2.7 μM and 18.6 μM, respectively) . Mibefradil dihydrochloride inhibits reversibly the T- and L-type currents with IC50 values of 2.7 and 18.6 μM, respectively..Mibefradil inhibited Orai1, Orai2, and Orai3 currents dose-dependently. The IC50 for Orai1, Orai2, and Orai3 channels was 52.6, 14.1, and 3.8 μM respectively. Outside-out patch demonstrated that perfusion of 10-μM mibefradil to the extracellular surface completely blocked Orai3 currents and single channel activity evoked by 2-APB. Intracellular application of mibefradil did not alter Orai3 channel activity. Mibefradil at higher concentrations (>50 μM) inhibited Ca2+ release but had no effect on cytosolic STIM1 translocation evoked by thapsigargin. Inhibition on Orai channels by mibefradil was structure-related, as other T-type Ca2+ channel blockers with different structures, such as ethosuximide and ML218, had no or minimal effects on Orai channels. Moreover, mibefradil inhibited cell proliferation, induced apoptosis, and arrested cell cycle progression.Compared with the saline-treated group, rats receiving Mibefradil or Ethosuximide show significant lower CaV3.2 expression in the spinal cord and DRG.