Abstract
The effect of ketoconazole on Ca 2+ signaling in Madin–Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca 2+ probe. Ketoconazole evoked increases in cytosolic free Ca 2+ concentration ([Ca 2+] i) concentration dependently. The response was decreased by external Ca 2+ removal. In Ca 2+-free medium, pretreatment with ketoconazole abolished the [Ca 2+] i rise induced by thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2+ pump. Addition of 3 mM Ca 2+ induced a significant [Ca 2+] i rise after preincubation with 150 μM ketoconazole in Ca 2+-free medium. Pretreatment with aristolochic acid (40 μM) to inhibit phospholipase A 2 inhibited the 150-μM-ketoconazole-induced internal Ca 2+ release by 37%, but inhibition of phospholipase C with 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1 H-pyrrole-2,5-dione (U73122) (2 μM) had no effect. Collectively, we found that ketoconazole increases [Ca 2+] i in MDCK cells by releasing Ca 2+ from thapsigargin-sensitive pools in a manner independent of the production of inositol-1,4,5-trisphosphate, followed by Ca 2+ influx from the external space.
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