Fendiline mobilizes intracellular Ca²⁺ in Chang liver cells

1. The effects of the antianginal drug fendiline (N-[3,3-diphenylpropyl]-α-methyl-benzylamine) on intracellular free Ca²⁺ levels ([Ca²⁺]_i) in Chang liver cells were evaluated using fura-2 as a fluorescent Ca²⁺ indicator. 2. Fendiline (1-100 μmol/L) increased [Ca²⁺]_i in a concentration-dependent manner, with an EC₅₀ of 25 μmol/L. 3. The [Ca²⁺]_i response was composed of an initial rise and a slow decay to a sustained phase. Removal of extracellular Ca²⁺ partly reduced the [Ca²⁺]_i signals. 4. Fendiline (10 μmol/L)-induced release of intracellular Ca²⁺ was reduced by 65% following pretreatment with 1 μmol/L thapsigargin (an endoplasmic reticulum Ca²⁺ pump inhibitor) to deplete Ca²⁺ stored in the endoplasmic reticulum. 5. After pretreatment with 10 μmol/L fendiline in Ca²⁺-free medium for several minutes, addition of 3 mmol/L Ca²⁺ induced an increase in [Ca²⁺]_i of a magnitude four-fold greater than control. This increase in [Ca²⁺]_i was not reduced by 10 μmol/L SKF96365, econazole, nifedipine or verapamil. 6. Fendiline (10 μmol/L)-induced release of intracellular Ca²⁺ was not altered by inhibition of phospholipase C with 2 μmol/L1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino) hexyl)-1H-pyrrole-2,5-dione (U73122). 7. The results of the present study show that fendiline induces an increase in [Ca²⁺]_i in Chang liver cells by releasing stored Ca²⁺ in an inositol 1,4,5-trisphosphate-independent manner and by causing extracellular Ca²⁺ influx.