Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA.
Br J Pharmacol. 2011 Sep;164(2):237-49. doi: 10.1111/j.1476-5381.2011.01273.x.
Cerebral 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 (K(v) 7) potassium channels in rat basilar artery myocytes, and determined the efficacy of K(v) 7 channel activators in relieving spasmogen-induced basilar artery constriction.
Expression and function of K(v) 7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to K(v) 7 channel modulators were studied in intact artery segments using pressure myography.
All five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. K(v) currents were attributed to K(v) 7 channel activity based on their voltage dependence of activation (V(0.5) ∼-34 mV), lack of inactivation, enhancement by flupirtine (a selective K(v) 7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective K(v) 7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced K(v) 7 currents but also inhibited voltage-sensitive Ca(2+) 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 Ca(2+) channel blocker.
K(v) 7 channels are important determinants of basilar artery contractile status. Targeting the K(v) 7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm.
To view two letters to the Editor regarding this article visit http://dx.doi.org/10.1111/j.1476-5381.2011.01454.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01457.x.
脑血管痉挛是大脑基底动脉大导管的持续收缩。这种动脉平滑肌细胞病理性持续收缩归因于局部升高的血管收缩剂（痉挛原）浓度。我们评估了大鼠基底动脉平滑肌细胞中 KCNQ（K(v)7）钾通道的存在和功能，并确定了 K(v)7 通道激活剂在缓解痉挛原诱导的基底动脉收缩中的疗效。
通过逆转录聚合酶链反应和全细胞电生理技术评估新分离的基底动脉平滑肌细胞中 K(v)7 通道的表达和功能。使用压力测微技术研究完整动脉段对 K(v)7 通道调节剂的功能反应。
在肌细胞中检测到所有五种哺乳动物 KCNQ 亚型（KCNQ1-5）。K(v)电流归因于 K(v)7 通道活性，其依据为激活的电压依赖性（V(0.5)∼-34 mV）、无失活、氟比洛芬（一种选择性 K(v)7 通道激活剂）增强和 10,10-双（吡啶-4-基甲基）蒽-9-酮（XE991；一种选择性 K(v)7 通道阻断剂）抑制。XE991 使肌细胞去极化并使完整的基底动脉收缩。塞来昔布，一种临床使用的抗炎药物，不仅增强了 K(v)7 电流，还抑制了电压敏感的 Ca(2+)电流。在预先用痉挛原收缩的动脉中，塞来昔布和氟比洛芬比尼莫地平（一种选择性 L 型 Ca(2+)通道阻断剂）更有效地扩张动脉段。
K(v)7 通道是基底动脉收缩状态的重要决定因素。使用氟比洛芬或塞来昔布靶向 K(v)7 通道可能为缓解脑血管痉挛患者的基底动脉收缩提供一种新策略。
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