Angiotensin II Potentiates the Slow Component of Delayed Rectifier K+ Current via the AT1 Receptor in Guinea Pig Atrial Myocytes
Angiotensin II Potentiates the Slow Component of Delayed Rectifier K+ Current via the AT1 Receptor in Guinea Pig Atrial Myocytes
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DOI：
10.1161/circulationaha.104.530592
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发表时间：
2006-03
期刊：
影响因子：
37.8
通讯作者：
D. Zankov;M. Omatsu-Kanbe;T. Isono;F. Toyoda;W. Ding;H. Matsuura;M. Horie
中科院分区：
文献类型：
--
作者：
D. Zankov;M. Omatsu-Kanbe;T. Isono;F. Toyoda;W. Ding;H. Matsuura;M. Horie
背景-血管紧张素II(Ang II)对心脏电活动有多种作用。然而，关于血管紧张素转换酶II对心脏复极的即刻电生理效应的信息很少。方法和结果：采用全细胞膜片钳技术，观察Ang II对豚鼠心房肌细胞延迟整流钾电流慢分量(Iks)和动作电位的即刻效应。应用血管紧张素转换酶II可呈浓度依赖性地增加IKs(EC_(50)，6.16nmol/L)的幅值。稳定的类似物Sar1-Ang II也能有效地增加iKs。这些激动剂对IKS激活的电压依赖性和失活动力学无明显影响。血管紧张素Ⅱ1型受体拮抗剂valsartan(1m ol/L)可阻断IKs的增强作用，而βS(2mmoL/L)可明显减弱IKs的增强作用，提示IKs参与了G蛋白偶联的AT1受体的作用。磷脂酶C抑制剂化合物48/80(100m ol/L)、蛋白激酶C抑制剂双吲哚马来酰亚胺I(200nm o l/L)和H-7(10m o l/L)也可显著降低这种刺激作用，提示AT1受体是通过磷脂酶C-蛋白激酶C信号转导途径增强Iks的。根据对IKs的刺激作用，Sar1-Ang II明显缩短动作电位时程，并可被valsartan逆转。结论：心房肌细胞通过AT1刺激使IKs增强，同时动作电位时程缩短，提示Ang II水平升高可能促进心力衰竭时房颤的发生，值得进一步研究。
Background— Angiotensin II (Ang II) has diverse actions on cardiac electrical activity. Little information is available, however, regarding immediate electrophysiological effects of Ang II on cardiac repolarization. Methods and Results— The present study investigated the immediate effects of Ang II on the slow component of delayed rectifier K+ current (IKs) and action potentials in guinea pig atrial myocytes using the whole-cell patch-clamp technique. Bath application of Ang II increased the amplitude of IKs (EC50, 6.16 nmol/L) concentration dependently. The stable analogue Sar1–Ang II was also effective at increasing IKs. The voltage dependence of IKs activation and the kinetics of deactivation were not significantly affected by these agonists. The enhancement of IKs was blocked by the Ang II type 1 (AT1) receptor antagonist valsartan (1 mol/L) and was markedly attenuated by inclusion of GDPβS (2 mmol/L) in the pipette, indicating an involvement of G protein–coupled AT1 receptor. The stimulatory effect was also significantly reduced by the phospholipase C inhibitor compound 48/80 (100 mol/L) and the protein kinase C inhibitors bisindolylmaleimide I (200 nmol/L) and H-7 (10 mol/L), suggesting that AT1 receptor acts through phospholipase C–protein kinase C signaling cascade to potentiate IKs. As expected from its stimulatory action on IKs, Sar1–Ang II markedly shortened the action potential duration, which could be reversed by valsartan. Conclusions— The potentiation of IKs via AT1 stimulation in atrial myocytes, accompanied by a shortening of the action potential duration, suggests a potential mechanism by which elevated levels of Ang II may promote atrial fibrillation in heart failure and warrants further investigation.