Pharmacological activation of plasma-membrane KATP channels reduces reoxygenation-induced Ca2+ overload in cardiac myocytes via modulation of the diastolic membrane potential
Pharmacological activation of plasma-membrane KATP channels reduces reoxygenation-induced Ca2+ overload in cardiac myocytes via modulation of the diastolic membrane potential
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DOI：
10.1038/sj.bjp.0705702
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发表时间：
2004-03-01
影响因子：
7.3
通讯作者：
Light, PE
中科院分区：
文献类型：
--
作者：
Baczkó, I;Giles, WR;Light, PE
1心肌细胞质膜ATP敏感性钾通道（pmK（ATP））开放对缺血再灌注损伤具有保护作用。我们最近证明心室肌细胞的静息膜电位（E-m）强烈调节再氧诱导的Ca 2+超负荷。这导致了一种假设，即pm（KATP）的激活可以通过心室肌细胞舒张期膜电位的超极化影响化学诱导缺氧（CIH）/复氧Ca 2+过载的程度。2使用穿孔膜片钳技术和DiBac（4）（3）成像测定分离的大鼠心肌细胞的膜电位（E-m）。使用FURA-2成像监测细胞内Ca 2+（[Ca 2 +]（i））。3 CIH/复氧引起E-m的显著去极化和[Ca 2 +]（i）的显著增加。K-ATP开放剂pinacidil（100 μ M）和pm（KATP）开放剂P-1075（100 μ M）使常氧心肌细胞的Em超极化。在复氧过程中应用吡那地尔（100 μ M）和P-1075（10和100 μ M），使E-m超极化，并防止复氧诱导的[Ca 2 +]增加（i）。4肌细胞过度收缩和死亡与10-15 mV的E-m去极化和[Ca 2 +]增加平行增加（i）。在这些条件下，选择性pm（KATP）通道抑制剂HMR 1098进一步使肌细胞膜电位去极化并增加过度收缩。5总之，pm（KATP）通道的激活可通过依赖于舒张期膜电位超极化的机制防止CIH/再氧合诱导的Ca 2+过载。向正常静息膜电位的超极化有利于Na+/Ca 2+交换的Ca 2+挤出模式。
1 The opening of cardiac plasma-membrane ATP-sensitive K+ channels (pmK(ATP)) can protect the heart against ischaemia/reperfusion injury. We recently demonstrated that the resting membrane potential (E-m) of ventricular myocytes strongly modulates reoxygenation-induced Ca2+ overload. This led to the hypothesis that activation of pm(KATP) can influence the extent of chemically induced hypoxia (CIH)/reoxygenation Ca2+ overload via hyperpolarization of the diastolic membrane potential of ventricular myocytes.2 The membrane potential (E-m) of isolated rat myocytes was determined using the perforated patch-clamp technique and DiBac(4)(3) imaging. Intracellular Ca2+ ([Ca2+](i)) was monitored using FURA-2 imaging.3 CIH/reoxygenation caused a significant depolarization of E-m and a substantial increase in [Ca2+](i). The K-ATP opener pinacidil (100 muM) and the pm(KATP) opener P-1075 (100 muM) hyperpolarized the Em of normoxic myocytes. Pinacidil (100 muM) and P-1075 (10 and 100 muM), applied during reoxygenation, hyperpolarized E-m and prevented reoxygenation-induced increases in [Ca2+](i).4 Myocyte hypercontracture and death increased in parallel with an E-m depolarization of 10-15 mV and increases in [Ca2+](i). Under these conditions, the selective pm(KATP) channel inhibitor HMR 1098 further depolarized myocyte membrane potential and increased hypercontracture.5 In conclusion, activation of pm(KATP) channels can prevent CIH/reoxygenation-induced Ca2+ overload via a mechanism that is dependent on hyperpolarization of diastolic membrane potential. Hyperpolarization toward normal resting membrane potential favours the Ca2+ extrusion mode of Na+/Ca2+ exchange.