Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles.
Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles.
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DOI：
10.1161/circresaha.110.238386
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发表时间：
2011-04-15
影响因子：
20.1
通讯作者：
Chen PS
中科院分区：
文献类型：
--
作者：
Chua SK;Chang PC;Maruyama M;Turker I;Shinohara T;Shen MJ;Chen Z;Shen C;Rubart-von der Lohe M;Lopshire JC;Ogawa M;Weiss JN;Lin SF;Ai T;Chen PS
衰竭心室的纤颤-除颤发作可能伴随着动作电位持续时间（APD）缩短和复发性自发性心室颤动（SVF）。我们假设阿帕胺敏感的小电导Ca2+激活的K+ (SK)通道的激活是导致衰竭心室休克后APD缩短的原因。采用兔速搏性心力衰竭模型。在衰竭和非衰竭心室中同时进行细胞内Ca2+和膜电位（Vm）的光学定位。3例衰竭心室发生SVF （SVF组），9例未发生SVF（无SVF组）。10个未衰竭心室均未发生SVF。起搏频率和持续时间的增加增加了APD缩短的幅度。Apamin （1 μmol/L）可消除复发性SVF，使SVF组APD80从126±5 ms增加到153±4 ms (p<0.05)，使无SVF组APD80从147±2 ms增加到162±3 ms (p<0.05)，而非SVF组APD80无变化。36°C全细胞膜片钳研究显示，衰竭心肌中阿帕胺敏感K+电流（IKAS）密度明显大于正常心室心外膜肌细胞，心外膜IKAS密度明显高于心肌中、心内膜肌细胞。与正常对照细胞相比，衰竭细胞中IKAS的稳态Ca2+响应向左移动，表明衰竭心室中IKAS的Ca2+敏感性增加。衰竭肌细胞Kd为232±5 nM，正常肌细胞Kd为553±78 nM （p = 0.002）。心力衰竭不均匀地增加IKAS对细胞内Ca2+的敏感性，导致IKAS上调，休克后APD缩短和复发性SVF。
Fibrillation-defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). We hypothesized that activation of apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels are responsible for the postshock APD shortening in failing ventricles. A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca2+ and membrane potential (Vm) was performed in failing and non-failing ventricles. Three failing ventricles developed SVF (SVF group), 9 did not (no-SVF group). None of the 10 non-failing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF, increased postshock APD80 in SVF group from 126±5 ms to 153±4 ms (p<0.05), in no-SVF group from147±2 ms to 162±3 ms (p<0.05) but did not change of APD80 in non-failing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K+ current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density is significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca2+ response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca2+ sensitivity of IKAS in failing ventricles. The Kd was 232 ± 5 nM for failing myocytes and 553 ± 78 nM for normal myocytes (p = 0.002). Heart failure heterogeneously increases the sensitivity of IKAS to intracellular Ca2+, leading to upregulation of IKAS, postshock APD shortening and recurrent SVF.