Inhibition of voltage-dependent K⁺ channels by antimuscarinic drug fesoterodine in coronary arterial smooth muscle cells

Figures

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  Fig. 1. Effects of fesoterodine on vascular voltage-dependent K+ (Kv) currents in coronary arterial smooth muscle cells. Representative traces from vascular smooth muscle cells depolarized from –80 mV to various potentials before (A) and after (B) fesoterodine exposure. (C) Summary of current-voltage (I–V) relationships at steady-state Kv currents in the absence (○) and presence (●) of fesoterodine. n = 8. Only one cell was used from a rabbit to reduce individual differences. *p < 0.05 (control vs. fesoterodine, at each voltage).

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  Fig. 2. Concentration dependence of fesoterodine-induced voltage-dependent K+ (Kv) current inhibition. Whole-cell Kv currents were elicited by 600 ms step depolarization to +60 mV from a holding potential of –80 mV. (A) Superimposed traces of Kv currents with increasing concentrations of fesoterodine. (B) Concentration-dependent Kv current inhibition by fesoterodine was measured at a steady-state. The percentage inhibition of Kv currents was plotted against the fesoterodine concentration. The smooth line was fitted to the Hill equation. n = 7.

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  Fig. 3. Changes in steady-state activation and inactivation curves by fesoterodine. (A) Activation curves of the voltage-dependent K+ (Kv) currents in the absence (○) and presence (●) of 3 μM fesoterodine. The tail currents were activated by a returning potential of –40 mV after short depolarizing pulses (20–50 ms) at different voltages. n = 7. (B) Inactivation curves of the Kv currents in the absence (○) and presence (●) of 3 μM fesoterodine. The curves were elicited by a test step to +40 mV after 7 s depolarizing pulses at different voltages. n = 6. *p < 0.05 (control vs. fesoterodine, at each voltage).

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  Fig. 4. Use (state)-dependence of fesoterodine effects on voltage-dependent K+ (Kv) channels. Twenty repetitive depolarizing one-step pulses from –80 mV to +60 mV were applied at frequencies of 1 Hz (A) and 2 Hz (B) in the absence (○) and presence (●) of 3 μM fesoterodine. Train pulse-induced Kv currents were normalized to the peak current elicited by the first train pulse, and plotted against the pulse number. All n = 6. *p < 0.05 (control vs. fesoterodine, at each pulse number).

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  Fig. 5. Effects of fesoterodine on the voltage-dependent K+ (Kv) recovery kinetics from inactivation. The recovery time constant was measured by applying identical twin pulses from –80 mV to +60 mV with extension of intervals from 30 ms to 7 s. Solid lines indicate recovery kinetics from Kv channel inactivation in the absence (○) and presence (●) of 3 μM fesoterodine. n = 5. *p < 0.05 (control vs. fesoterodine at each interval).

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  Fig. 6. The role of voltage-dependent K+ (Kv)1.5, Kv2.1, and Kv7 subtypes in the inhibitory effects of fesoterodine. The Kv currents were evoked by 600 ms step depolarization to +60 mV from a holding potential of –80 mV. (A) Superimposed Kv currents under control conditions, in the presence of DPO-1, and fesoterodine + DPO-1. (B) Summary data obtained from (A). n = 4. NS, not significant (DPO-1 vs. fesoterodine + DPO-1). (C) Superimposed Kv currents under control conditions, in the presence of guangxitoxin, and fesoterodine + guangxitoxin. (D) Summary data obtained from (C). n = 5. *p < 0.05 (guangxitoxin vs. fesoterodine + guangxitoxin). (E) Superimposed Kv currents under control conditions, in the presence of linopirdine, and fesoterodine + linopirdine. (F) Summary data obtained from (E). n = 5. *p < 0.05 (linopirdine vs. fesoterodine + linopirdine).