Selective Activation of Vascular K 7.4/K 7.5 K Channels by Fasudil Contributes to Its Vasorelaxant Effect

Background And Purpose: K 7 (K 7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests K 7.4/K 7.5 channels play a crucial role in regulating vascular smooth muscle contractility. Most of the reported K 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 7.4/K 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 7.4 channel. An isometric tension recording technique was used to assess the vascular tension.

Key Results: Fasudil selectively and potently enhanced K 7.4 and K 7.4/K 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 7.2 and K 7.2/K 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 in S5 and Ile in S6 segment of K 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 7 channel blocker XE991.

Conclusions And Implications: These results suggest that fasudil is a selective K 7.4/K 7.5 channel opener and provide a new dimension for developing selective K 7 modulators and a new prospective for the use, action and mechanism of fasudil.