Selective activation of vascular Kv7.4/Kv7.5 K+ channels by fasudil contributes to its vasorelaxant effect

Background and PurposeK(v)7 (K(v)7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests K(v)7.4/K(v)7.5 channels play a crucial role in regulating vascular smooth muscle contractility. Most of the reported K(v)7 openers have shown poor selectivity across these five subtypes. In this study, fasudil - a drug used for cerebral vasospasm - has been found to be a selective opener of K(v)7.4/K(v)7.5 channels. Experimental ApproachA perforated whole-cell patch technique was used to record the currents and membrane potential. Homology modelling and a docking technique were used to investigate the interaction between fasudil and the K(v)7.4 channel. An isometric tension recording technique was used to assess the vascular tension. Key ResultsFasudil selectively and potently enhanced K(v)7.4 and K(v)7.4/K(v)7.5 currents expressed in HEK293 cells, and shifted the voltage-dependent activation curve in a more negative direction. Fasudil did not affect either K(v)7.2 and K(v)7.2/K(v)7.3 currents expressed in HEK293 cells, the native neuronal M-type K+ currents, or the resting membrane potential in small rat dorsal root ganglia neurons. The Val(248) in S5 and Ile(308) in S6 segment of K(v)7.4 were critical for this activating effect of fasudil. Fasudil relaxed precontracted rat small arteries in a concentration-dependent fashion; this effect was antagonized by the K(v)7 channel blocker XE991. Conclusions and ImplicationsThese results suggest that fasudil is a selective K(v)7.4/K(v)7.5 channel opener and provide a new dimension for developing selective K(v)7 modulators and a new prospective for the use, action and mechanism of fasudil.