Effects of the antianginal drug fendiline on Ca2+ movement in hepatoma cells

Abstract

This study investigated the effect of the anti-anginal drug, fendiline, on intracellular free Ca²⁺ levels ([Ca²⁺]_i)inHA/ 22 human hepatoma cells by using fura-2 as a fluorescent Ca²⁺ dye. Fendiline (1-100 μM) increased [Ca²⁺]_i with an EC₅₀ of 25 μM. Removal of extracellular Ca²⁺ reduced the [Ca²⁺]_i signals by 51-5%. Fendiline (10 μM)-induced Ca²⁺release was abolished by pretreatment with 1 μM thapsigargin (an endoplasmic reticulum Ca²⁺ pump inhibitor). Inhibition of phospholipase C with 2 μM 1-(6-((17β 3 methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H pyrrole-2,5-dione (U73122) did not alter 10 μM fendilineinducedCa²⁺ release.Severalothercalmodulinantagonists, such as phenoxybenzamine (100-200 μM), trifluoperazine (5-50 μM),andfluphenazine N-chloroethane(2-100 μM), hadno effect on[Ca²⁺]_i. Together, it wasfound that fendiline increased [Ca²⁺]_i in human hepatoma cells by discharging Ca²⁺ from the endoplasmic reticulum in an inositol 1,4,5 trisphosphate-independent manner and by inducing Ca²⁺entry. This effect of fendiline does not appear to be via antagonism of calmodulin.