Electrophysiological and functional effects of the KCNQ channel blocker XE991 on murine portal vein smooth muscle cells

The effect of the KCNQ channel blockers XE991, chromanol 293B and linopirdine, was studied on voltage-dependent K+ currents in smooth muscle cells dissociated freshly from mouse portal vein (mPV) and isometric tension recordings from whole mPV. Voltage clamp experiments showed XE991 inhibited an outward current in a concentration-dependent manner with an IC50 of 5.8 microM. Block was voltage independent. Chromanol 293B and linopirdine also blocked the voltage-dependent K+ current but were less potent than XE991. At least two components--a linear (I(linear)) and an outward relaxation (I(out))--contributed to the XE991-sensitive conductance. XE991-sensitive currents were sustained at all test potentials and XE991 inhibited the enhanced holding current at -60 mV produced by bathing cells in an external solution containing 36 mM KCl. Current clamp experiments in the perforated-patch configuration showed XE991 and linopirdine depolarised the resting membrane potential and augmented the evoked response in a concentration-dependent manner. In functional experiments the spontaneous contractile activity of the mPV was increased significantly by XE991 and linopirdine. The stimulatory effect of XE991 was not affected by the presence of 4-AP, glibenclamide nor paxilline. These data provide evidence for an important role for KCNQ channels in governing cellular excitability in mPV smooth muscle cells.