Modulation of voltage-dependent K+ channel activity by the muscarinic receptor antagonist solifenacin in native coronary arterial smooth muscle cells.

Several muscarinic receptor antagonists have been reported to modulate vascular voltage-dependent K+ (Kv) channels; however, the electrophysiological effects of solifenacin on these channels have not been fully characterized. We used the whole-cell patch-clamp technique to examine the effects of solifenacin on Kv currents in rabbit coronary arterial smooth muscle cells. Solifenacin suppressed arterial Kv currents in a concentration-dependent manner, with half-maximal inhibitory concentration (IC50) of 14.59 ± 4.78 μM and a Hill coefficient of 0.84 ± 0.15. Although 30 μM solifenacin did not significantly affect steady-state activation, it produced a pronounced leftward shift in the steady-state inactivation curve. These findings imply that solifenacin inhibits Kv channels through interaction with the inactivation gating machinery. Consistent with this interpretation, solifenacin displayed use (state)-dependent inhibition: repetitive stimulation at 1 Hz progressively reduced current amplitude, and the recovery time constant from inactivation was significantly prolonged. To determine the Kv subtypes involved, subtype-selective inhibitors were applied. The inhibitory effect of solifenacin was not significantly modified by the Kv2.1 inhibitor stromatoxin-1 or the Kv7 inhibitor linopirdine. By contrast, pretreatment with the Kv1.5 inhibitor DPO-1 partially attenuated inhibition of peak currents but had minimal effect on steady-state inhibition. These results indicate that solifenacin targets multiple Shaker-related (Kv1.x) channel subtypes, with Kv1.5 making a substantial contribution to the observed current suppression. Solifenacin inhibits arterial Kv channels in a concentration- and use (inactivated state)-dependent manner by modulating inactivation gating, predominantly involving the Kv1.5 subtype.