Downregulation of Kv7.4 Channel Activity in Primary and Secondary Hypertension
Downregulation of Kv7.4 Channel Activity in Primary and Secondary Hypertension
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DOI：
10.1161/circulationaha.111.032136
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发表时间：
2011-08-02
期刊：
影响因子：
37.8
通讯作者：
Greenwood, Iain A.
中科院分区：
文献类型：
--
作者：
Jepps, Thomas A.;Chadha, Preet S.;Greenwood, Iain A.
背景-由KCNQ基因编码的电压门控性钾(K+)通道(KV7通道)已在各种啮齿动物和人类血管中被确定为血管张力的关键调节因子；然而，这些通道在血管疾病中的功能影响尚不清楚。我们研究了3种不同结构的Kv7.2~Kv7.5通道激动剂(BMS-204352、S-1和雷替加宾)对正常血压和高血压动物血管的作用。方法和结果：3种KV7激动剂均能松弛正常血压大鼠的胸主动脉和肠系膜动脉，其作用强度为BMS-204352=S-1和雷替加宾。我们还使用朗宁多夫心脏制剂在冠脉循环中测试了这些药物。S-204352和S-1在0.1mU/L~10mU/L浓度范围内呈剂量依赖性地增加冠脉灌注量，而瑞格他滨在1~10mU/L浓度范围内呈剂量依赖性增加冠脉灌注量。此外，S-1还可使离体肠系膜动脉肌细胞钾电流增加。在自发性高血压大鼠(SHR)分离的组织中，这些药物松弛预收缩的血管、增加冠脉流量或增强K+电流的能力显著受损。在5个KCNQ基因中，只有KCNQ4在SHR中的表达降低(约3.7倍)。自发性高血压大鼠的主动脉和肠系膜动脉中Kv7.4蛋白水平比正常血压大鼠低约50%。与正常血压对照组相比，血管紧张素II诱导的高血压小鼠肠系膜动脉对S-1的反应减弱，Kv7.4降低。结论：在两种不同的高血压大鼠和小鼠模型中，KV7通道的功能影响显著下调。(发行量。2011；124：602-611。)
Background-Voltage-gated potassium (K+) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3 structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals.Methods and Results-Precontracted thoracic aorta and mesenteric artery segments from normotensive rats were relaxed by all 3 Kv7 activators, with potencies of BMS-204352 = S-1>retigabine. We also tested these agents in the coronary circulation using the Langendorff heart preparation. BMS-204352 and S-1 dose dependently increased coronary perfusion at concentrations between 0.1 and 10 mu mol/L, whereas retigabine was effective at 1 to 10 mu mol/L. In addition, S-1 increased K+ currents in isolated mesenteric artery myocytes. The ability of these agents to relax precontracted vessels, increase coronary flow, or augment K+ currents was impaired considerably in tissues isolated from spontaneously hypertensive rats (SHRs). Of the 5 KCNQ genes, only the expression of KCNQ4 was reduced (approximate to 3.7 fold) in SHRs aorta. Kv7.4 protein levels were approximate to 50% lower in aortas and mesenteric arteries from spontaneously hypertensive rats compared with normotensive vessels. A similar attenuated response to S-1 and decreased Kv7.4 were observed in mesenteric arteries from mice made hypertensive by angiotensin II infusion compared with normotensive controls.Conclusions-In 2 different rat and mouse models of hypertension, the functional impact of Kv7 channels was dramatically downregulated. (Circulation. 2011;124:602-611.)