Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm.
Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm.
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DOI：
10.1097/fjc.0b013e3182771708
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发表时间：
2013-01
影响因子：
3
通讯作者：
Byron KL
中科院分区：
文献类型：
--
作者：
Mani BK;O'Dowd J;Kumar L;Brueggemann LI;Ross M;Byron KL
蛛网膜下腔出血（SAH）后的脑血管痉挛的特征是基底动脉的长期严重收缩，这通常导致缺血性脑损伤。局部浓度升高的致痉挛物质诱导基底动脉中的肌细胞持续去极化，导致钙（Ca 2+）通过电压敏感性Ca 2+通道和肌细胞收缩持续流入。钾（K+）通道开放剂可具有对抗膜去极化、扩张动脉和减少缺血的治疗效用。在这里，我们研究了血管Kv 7 K+通道参与脑血管痉挛的发病机制，并测试了Kv 7通道开放剂是否是SAH大鼠模型的有效治疗药物。膜片钳实验表明，三种不同的痉挛剂（5-羟色胺，内皮素和加压素）抑制Kv 7电流和去极化新鲜分离的大鼠基底动脉肌细胞。在Kv 7通道开放剂瑞替加滨的存在下，这些作用显著降低。Retigabine（10 μmol/L）也显著阻断L-型Ca ~（2+）通道，使内向电流峰值降低> 50%。在存在选择性Kv 7通道阻滞剂XE 991的情况下，致痉挛剂不产生使用压力肌描记术测量的附加收缩反应。Kv 7通道开放剂（瑞替加滨或塞来昔布）可显著减轻实验诱导SAH大鼠的基底动脉痉挛。总之，我们确定Kv 7通道作为血管收缩剂痉挛的共同目标，并作为脑血管痉挛的治疗干预的候选人。
Cerebral vasospasm following subarachnoid hemorrhage (SAH) is characterized by prolonged severe constriction of the basilar artery, which often leads to ischemic brain damage. Locally elevated concentrations of spasmogenic substances induce persistent depolarization of myocytes in the basilar artery, leading to continuous influx of calcium (Ca2+) through voltage-sensitive Ca2+ channels and myocyte contraction. Potassium (K+) channel openers may have therapeutic utility to oppose membrane depolarization, dilate the arteries, and reduce ischemia. Here, we examined the involvement of vascular Kv7 K+ channels in the pathogenesis of cerebral vasospasm and tested whether Kv7 channel openers are effective therapeutic agents in a rat model of SAH. Patch-clamp experiments revealed that three different spasmogens (serotonin, endothelin and vasopressin) suppressed Kv7 currents and depolarized freshly isolated rat basilar artery myocytes. These effects were significantly reduced in the presence of a Kv7 channel opener, retigabine. Retigabine (10 μmol/L) also significantly blocked L-type Ca2+ channels, reducing peak inward currents by >50%. In the presence of a selective Kv7 channel blocker, XE991, the spasmogens did not produce additive constriction responses measured using pressure myography. Kv7 channel openers (retigabine or celecoxib) significantly attenuated basilar artery spasm in rats with experimentally-induced SAH. In conclusion, we identify Kv7 channels as common targets of vasoconstrictor spasmogens and as candidates for therapeutic intervention for cerebral vasospasm.