Selective activation of vascular K v 7.4/K v 7.5 K + channels by fasudil contributes to its vasorelaxant effect

Background and Purpose K 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 Approach A 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 Results Fasudil 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 Implications These 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.