Inhibitory actions by ibandronate sodium, a nitrogen-containing bisphosphonate, on calcium-activated potassium channels in Madin–Darby canine kidney cells

The nitrogen-containing bisphosphonates used for management of the patients with osteoporosis were reported to influence the function of renal tubular cells. However, how nitrogen-containing bisphosphates exert any effects on ion currents remains controversial. The effects of ibandronate (Iban), a nitrogen-containing bisphosphonate, on ionic channels, including two types of Ca(2+)-activated K(+) (K(Ca)) channels, namely, large-conductance K(Ca) (BK(Ca)) and intermediate-conductance K(Ca) (IK(Ca)) channels, were investigated in Madin–Darby canine kidney (MDCK) cells. In whole-cell current recordings, Iban suppressed the amplitude of voltage-gated K(+) current elicited by long ramp pulse. Addition of Iban caused a reduction of BK(Ca) channels accompanied by a right shift in the activation curve of BK(Ca) channels, despite no change in single-channel conductance. Ca(2+) sensitivity of these channels was modified in the presence of this compound; however, the magnitude of Iban-mediated decrease in BK(Ca)-channel activity under membrane stretch with different negative pressure remained unchanged. Iban suppressed the probability of BK(Ca)-channel openings linked primarily to a shortening in the slow component of mean open time in these channels. The dissociation constant needed for Iban-mediated suppression of mean open time in MDCK cells was 12.2 μM. Additionally, cell exposure to Iban suppressed the activity of IK(Ca) channels, and DC-EBIO or 9-phenanthrol effectively reversed its suppression. Under current-clamp configuration, Iban depolarized the cells and DC-EBIO or PF573228 reversed its depolarizing effect. Taken together, the inhibitory action of Iban on K(Ca)-channel activity may contribute to the underlying mechanism of pharmacological or toxicological actions of Iban and its structurally similar bisphosphonates on renal tubular cells occurring in vivo.