Add time:09/25/2019         Source:sciencedirect.com

The effect of Fendiline (cas 13042-18-7), a documented inhibitor of L-type Ca2+ channels and calmodulin, on Ca2+ signaling in Madin Darby canine kidney (MDCK) cells was investigated using fura-2 as a Ca2+ probe. Fendiline at 5–100 μM significantly increased [Ca2+]i concentration-dependently. The [Ca2+]i rise consisted of an initial rise and a slow decay. External Ca2+ removal partly inhibited the Ca2+ signals induced by 25–100 μM fendiline by reducing both the initial rise and the decay phase. This suggests that fendiline triggered external Ca2+ influx and internal Ca2+ release. In Ca2+-free medium, pretreatment with 50 μM fendiline nearly abolished the [Ca2+]i rise induced by 1 μM-thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor, and vice versa, pretreatment with thapsigargin prevented fendiline from releasing internal Ca2+. This indicates that the internal Ca2+ source for fendiline overlaps with that for thapsigargin. At a concentration of 50 μM, fendiline caused Mn2+ quench of fura-2 fluorescence at the 360 nm excitation wavelenghth, which was inhibited by 0.1 mM La3+ by 50%, implying that fendiline-induced Ca2+ influx has two components separable by La3+. Consistently, 0.1 mM La3+ pretreatment suppressed fendiline-induced [Ca2+]i rise, and adding La3+ during the rising phase immediately inhibited the signal. Addition of 3 mM Ca2+ increased [Ca2+]i after preincubation with 50–100 μM fendiline in Ca2+-free medium. However, 50–100 μM fendiline inhibited 1 μM thapsigargin-induced capacitative Ca2+ entry. Pretreatment with 40 μM aristolochic acid to inhibit phospholipase A2 inhibited 50 μM fendiline-induced internal Ca2+ release by 48%, but inhibition of phospholipase C with 2 μM U73122 or inhibition of phospholipase D with 0.1 mM propranolol had no effect. Collectively, we have found that fendiline increased [Ca2+]i in MDCK cells by releasing internal Ca2+ in a manner independent of inositol-l,4,5-trisphosphate (IP3), followed by external Ca2+ influx.

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