Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery

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BACKGROUND AND PURPOSECerebral vasospasm is the persistent constriction of large conduit arteries in the base of the brain. This pathologically sustained contraction of the arterial myocytes has been attributed to locally elevated concentrations of vasoconstrictor agonists (spasmogens). We assessed the presence and function of KCNQ (Kv7) potassium channels in rat basilar artery myocytes, and determined the efficacy of Kv7 channel activators in relieving spasmogen-induced basilar artery constriction.EXPERIMENTAL APPROACHExpression and function of Kv7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to Kv7 channel modulators were studied in intact artery segments using pressure myography.KEY RESULTSAll five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. Kv currents were attributed to Kv7 channel activity based on their voltage dependence of activation (V0.5˜−34 mV), lack of inactivation, enhancement by flupirtine (a selective Kv7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective Kv7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced Kv7 currents but also inhibited voltage-sensitive Ca2+ currents. In arteries pre-constricted with spasmogens, both celecoxib and flupirtine were more effective in dilating artery segments than was nimodipine, a selective L-type Ca2+ channel blocker.CONCLUSIONS AND IMPLICATIONSKv7 channels are important determinants of basilar artery contractile status. Targeting the Kv7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm.

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