IKs restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation
IKs restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation
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DOI：
10.1016/j.yjmcc.2009.08.033
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发表时间：
2010-01-01
影响因子：
5
通讯作者：
Volders, Paul G. A.
中科院分区：
文献类型：
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作者：
Johnson, Daniel M.;Heijman, Jordi;Volders, Paul G. A.
体内研究表明，心室复极持续时间（BVR）的逐搏变异性增加比单纯复极延长更能预测药物诱导的尖端扭转型室性心动过速。细胞BVR和它的动力学前programmic事件知之甚少。我们研究了在β-肾上腺素能受体刺激的影响下，单个肌细胞在I-Ks阻断与I-Kr阻断和晚期I-Na增强过程中BVR的差异反应。在不同的起搏频率下记录离体犬左心室中层肌细胞的跨膜动作电位。HMR 1556可阻断I-Ks，多非利特可阻断I-Kr。晚I-Na增强海葵毒素-II。加入异丙肾上腺素用于β-肾上腺素能受体刺激。BAPTA-AM缓冲细胞内Ca 2+。SEA 0400部分抑制Na+-Ca ~（2+）交换。将BVR定量为90%复极化时动作电位持续时间的变异性：30个连续动作电位的Sigma（竖线APD 90; i+1减去APD 90; i竖线）/[n次心跳x根2]。I-Kr阻滞和晚期I-Na增强显著增加了基线BVR，尤其是在缓慢起搏速率下。β-肾上腺素能刺激使这些BVR变化重新稳定。相比之下，与基线条件相比，I-Ks阻断引起复极的变化很小，但在β-肾上腺素能刺激期间，特别是在快速速率下，使肌细胞倾向于增加BVR。BAPTA-AM和SEA 0400降低了这种过度的BVR，并消除了早期后去极化。总之，β-肾上腺素能受体刺激在I-Ks阻断期间夸大BVR，表明β-肾上腺素能敏感I-Ks的BVR稳定作用。在这些条件下，I-Ks的丧失加上Ca 2+依赖性膜电流（包括内向Na+-Ca 2+交换电流）的覆盖，共同促进了BVR。(C)2009爱思唯尔公司All rights reserved.
In vivo studies have suggested that increased beat-to-beat variability of ventricular repolarization duration (BVR) is a better predictor of drug-induced torsades de pointes than repolarization prolongation alone. Cellular BVR and its dynamics before proarrhythmic events are poorly understood. We investigated differential responses of BVR in single myocytes during I-Ks blockade versus I-Kr blockade and late-I-Na augmentation, under the influence of beta-adrenergic receptor stimulation. Transmembrane action potentials were recorded from isolated canine left-ventricular midmyocytes at various pacing rates. I-Ks was blocked by HMR1556, I-Kr by dofetilide. Late I-Na was augmented by sea anemone toxin-II. Isoproterenol was added for beta-adrenergic receptor stimulation. BAPTA-AM buffered intracellular Ca2+. SEA0400 partially inhibited the Na+-Ca2+ exchanger. BVR was quantified as variability of action-potential duration at 90% repolarization: Sigma(vertical bar APD90; i+1 minus APD90; i vertical bar)/[nbeats x root 2] for 30 consecutive action potentials. Baseline BVR was significantly increased by I-Kr blockade and late-I-Na augmentation, especially at slow pacing rates. beta-adrenergic stimulation restabilized these BVR changes. In contrast, I-Ks blockade caused very little change in repolarization when compared to baseline conditions, but predisposed the myocyte to increased BVR during beta-adrenergic stimulation, especially at fast rates. BAPTA-AM and SEA0400 reduced this excessive BVR and eliminated early afterdepolarizations. In conclusion, beta-adrenergic receptor stimulation exaggerates BVR during I-Ks blockade, indicating a BVR-stabilizing role of beta-adrenergic-sensitive I-Ks. Loss of I-Ks plus overriding of Ca2+-dependent membrane currents, including inward Na+-Ca2+ exchange current, conspire to proarrhythmic BVR under these conditions. (C) 2009 Elsevier Inc. All rights reserved.