Abstract
The effect of the antianginal drug bepridil on Ca 2+ signaling in Madin–Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca 2+ probe. Bepridil at 10–50 μM evoked a significant rise in cytosolic free Ca 2+ concentration ([Ca 2+] i) in a dose-dependent manner. The [Ca 2+] i rise consisted of an immediate initial rise and a slow decay. Removal of external Ca 2+ partly inhibited the Ca 2+ signals by reducing both the initial rise and the decay phase, suggesting that bepridil activated both external Ca 2+ influx and internal Ca 2+ release. In Ca 2+-free medium, pretreatment with 50 μM bepridil nearly abolished the Ca 2+ release induced by thapsigargin (1 μM), an endoplasmic reticulum Ca 2+ pump inhibitor, and vice versa, pretreatment with thapsigargin inhibited most of the bepridil-induced Ca 2+ release, suggesting that the thapsigargin-sensitive Ca 2+ store was the main source of bepridil-induced Ca 2+ release. Bepridil (50 μM) induced considerable Mn 2+ quench of fura-2 fluorescence at an excitation wavelength of 360 nm, which was partly inhibited by La 3+ (0.1 mM). Consistently, La 3+ (0.1 mM) pretreatment significantly inhibited the bepridil-induced [Ca 2+] i rise. Addition of 3 mM Ca 2+ induced a significant [Ca 2+] i rise after prior incubation with 10–50 μM bepridil in Ca 2+-free medium, suggesting that bepridil induced dose-dependent capacitative Ca 2+ entry. However, 50 μM bepridil inhibited 1 μM thapsigargin-induced capacitative Ca 2+ entry by 38%. Pretreatment with aristolochic acid (40 μM) so as to inhibit phospholipase A 2 inhibited 50 μM bepridil-induced internal Ca 2+ release by 42%, but inhibition of phospholipase C with U73122 (2 μM) or inhibition of phospholipase D with propranolol (0.1 mM) had little effect, suggesting that bepridil induced internal Ca 2+ release in an inositol 1,4,5-trisphosphate-independent manner that could be modulated by phospholipase A 2-coupled events. This is the first report providing evidence that bepridil, currently used as an antianginal drug, induced a rise in [Ca 2+] i in a non-excitable cell line.
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