Selective activation of vascular Kv7.4/Kv7.5 K+channels by fasudil contributes to its vasorelaxant effect.
Kv7 (Kv7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests Kv7.4/Kv7.5 channels play a crucial role in regulating vascular smooth muscle contractility. Most of the reported Kv7 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 Kv7.4/Kv7.5 channels.



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 Kv7.4 channel. An isometric tension recording technique was used to assess the vascular tension.



Fasudil selectively and potently enhanced Kv7.4 and Kv7.4/Kv7.5 currents expressed in HEK293 cells, and shifted the voltage-dependent activation curve in a more negative direction. Fasudil did not affect either Kv7.2 and Kv7.2/Kv7.3 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 Val248in S5 and Ile308in S6 segment of Kv7.4 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 Kv7 channel blocker XE991.



These results suggest that fasudil is a selective Kv7.4/Kv7.5 channel opener and provide a new dimension for developing selective Kv7 modulators and a new prospective for the use, action and mechanism of fasudil.
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.|Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China.|Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.
Xuan
X
Zhang
Key Laboratory of Molecular Biophysics, Hebei Province; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, China.
Hailong
H
An
Key Laboratory of Molecular Biophysics, Hebei Province; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, China.
Junwei
J
Li
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China.
Yuanyuan
Y
Zhang
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.|Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China.
Yang
Y
Liu
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
Zhanfeng
Z
Jia
Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.
Wei
W
Zhang
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China.
Li
L
Chu
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
Hailin
H
Zhang
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D015394:Molecular Structure; D024642:Potassium Channels, Voltage-Gated / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D024642:Potassium Channels, Voltage-Gated; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil
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