Effects of Ibandronate Sodium a Bisphosphonate on the Activity of Calcium-Activated Potassium Channels in Madin-Darby Canine Kidney Cells

摘要

Ibandronate sodium (Iban) is a highly potent nitrogen-containing bisphosphonate and effective for the treatment of osteoporosis It was previously reported to influence the function of renal tubular cells According to previous studies Iban is not metabolized in either human or animal and it can then accumulate in the kidney; consequently it produces hypertrophy and hyperplasia of distal tubules and collecting ducts in the rats However whether this drug has any effects on membrane ion channels in kidney cells remains largely unclear This study was conducted to investigate the possible effects of this drug on ionic currents functionally expressed in MDCK renal tubular cells In whole-cell recordings Iban decreased the amplitude of voltage-dependent K+ current (Ik) in MDCK cells Iban-induced inhibition of IK was reversed by further addition of hydrogen sulfide (H2S) In cell-attached recordings cell exposure to Iban decreased the activity of large-conductance Ca2+-activated K+ (BKCa) channels in a concentration-dependent manner; however it suppressed BKCa channel activity with no modifications on single-channel conductance of these channels This compound caused a shift in the activation curve to a positive membrane potential by approximately 22 mV of BKCa channels in these cells However during exposure to it not only decreased probability of channel openings but also shortened slow component of mean open time for BKCa channels The magnitude of Iban-mediated inhibition of BKCa-channel activity did not differ significantly in membrane stretch with negative pressure Moreover Ca2+ sensitivity of these channels was modified in the presence of this compound Iban also effectively suppressed the activity of intermediate-conductance Ca2+-activated K+ (IKCa) channels and DCEBIO or 9-phenanthrol effectively reversed its effects In the RT-PCR experiment the mRNA expression of KCNN4 could be detected in these cells Under current-clamp recordings Iban caused membrane depolarization of MDCK cells and DCEBIO or PF573228 reversed Iban-induced depolarization Taken together our results clearly showed that the role of suppression by Iban on the activity of Ca2+-activated K+ channels may contribute to the understanding mechanism of pharmacological or toxicological actions of this compound and its structurally similar bisphosphonates on renal tubular cells if similar findings occur in vivo

獎項日期	2016 7月 20
原文	English
監督員	Sheng-Nan Wu (Supervisor)