Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Pflugers Arch. 2009 Sep;458(5):837-49. doi: 10.1007/s00424-009-0669-8. Epub 2009 Apr 29.
A repolarizing conduction in the heart augmented by hyposmotic or mechanically induced membrane stretch is the slow component of delayed rectifier K(+) current (I (Ks)). I (Ks) upregulation is recognized as a factor promoting appearance of atrial fibrillation (AF) since gain-of-function mutations of the channel genes have been detected in congenital AF. Mechanical stretch activates angiotensin II type 1 (AT(1)) receptor in the absence of its physiological ligand angiotensin II. We investigated the functional role of AT(1) receptor in I (Ks) enhancement in hyposmotically challenged guinea pig atrial myocytes using the whole-cell patch-clamp method. In atrial myocytes exposed to hyposmotic solution with osmolality decreased to 70% of the physiological level, I (Ks) was enhanced by 84.1%, the duration of action potential at 90% repolarization (APD(90)) was decreased by 16.8%, and resting membrane potential was depolarized (+4.9 mV). The hyposmotic-induced effects on I (Ks) and APD(90) were significantly attenuated by specific AT(1) receptor antagonist candesartan (1 and 5 muM). Pretreatment of atrial myocytes with protein tyrosine kinase inhibitors tyrphostin A23 and A25 suppressed but the presence of tyrosine phosphatase inhibitor orthovanadate augmented hyposmotic stimulation of I (Ks). The above results implicate AT(1) receptor and tyrosine kinases in the hyposmotic modulation of atrial I (Ks) and suggest acute antiarrhythmic properties of AT(1) antagonists in the settings of stretch-related atrial tachyarrhythmias.
心脏中的复极化传导通过低渗或机械诱导的膜拉伸而增强，这是延迟整流钾电流（I（Ks））的缓慢成分。I（Ks）的上调被认为是促进心房颤动（AF）出现的一个因素，因为已经在先天性 AF 中检测到通道基因的功能获得性突变。机械拉伸在没有其生理配体血管紧张素 II 的情况下激活血管紧张素 II 型 1（AT（1））受体。我们使用全细胞膜片钳方法研究了低渗应激中海豚心房肌细胞中 AT（1）受体在 I（Ks）增强中的功能作用。在暴露于低渗溶液的心房肌细胞中，渗透压降低至生理水平的 70%，I（Ks）增强 84.1%，90%复极化时动作电位时程（APD（90））缩短 16.8%，静息膜电位去极化（+4.9 mV）。特定的 AT（1）受体拮抗剂坎地沙坦（1 和 5 μM）显著减弱了低渗诱导的 I（Ks）和 APD（90）的作用。用蛋白酪氨酸激酶抑制剂 tyrphostin A23 和 A25 预处理心房肌细胞可抑制，但存在酪氨酸磷酸酶抑制剂正钒酸钠可增强低渗对 I（Ks）的刺激。上述结果表明 AT（1）受体和酪氨酸激酶参与了心房 I（Ks）的低渗调节，并提示 AT（1）拮抗剂在与拉伸相关的心房性心动过速的情况下具有急性抗心律失常特性。
