Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs
Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs
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DOI：
10.1113/jphysiol.2013.261198
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发表时间：
2013-09-01
影响因子：
5.5
通讯作者：
Nattel, Stanley
中科院分区：
文献类型：
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作者：
Jost, Norbert;Virag, Laszlo;Nattel, Stanley
复极的物种特异性决定因素知之甚少。本研究比较了不同电流对犬和人心室肌复极的贡献。采用常规微电极、全细胞膜片钳、分子生物学和数学模拟技术。选择性I-Kr阻断（50-100 nmol l（-1）多非利特）使人在90%复极时的AP持续时间（APD（90））比狗延长>3倍，表明人的复极储备较小。选择性I-K1阻滞（10 mol l（-1）BaCl 2）和I-Ks阻滞（1 mol l（-1）HMR-1556）增加犬右心室乳头肌APD（90）的幅度大于人右心室乳头肌。离体心肌细胞的离子电流测量结果表明，I-K1和I-Ks密度分别是3倍和4.5倍，比人类的狗。人与狗的I-Kr密度和动力学相似。人的I-Ca和I-to分别约大30%和约小29%，Na+-Ca ~（2+）交换电流相当。在人与狗中，主要I-K1离子通道亚基Kir2.1和I-Ks辅助亚基minK的心脏mRNA水平显著较低，但ERG和KvLQT 1（I-Kr和I-Ks-亚基）的mRNA表达无显著差异。免疫组化结果显示，与犬相比，人心肌细胞Kir2.1和minK表达较低，KvLQT 1蛋白表达较高。I-K1和I-Ks抑制使犬I-Kr阻滞的APD延长效应（分别为56%和49%）高于人（34%和16%），表明两种电流均有助于犬复极储备增加。结合观察到的人-犬离子电流差异的数学模型证实了I-K1和I-Ks在复极储备差异中的作用。因此，人类表现出更大的复极延迟效应的I-Kr阻滞比狗，因为较低的复极储备贡献I-K1和I-Ks，强调物种特异性的决定因素复极和人类疾病的动物模型的局限性。
The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective I-Kr block (50-100 nmol l(-1) dofetilide) lengthened AP duration at 90% of repolarization (APD(90)) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective I-K1 block (10 mol l(-1) BaCl2) and I-Ks block (1 mol l(-1) HMR-1556) increased APD(90) more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that I-K1 and I-Ks densities were 3- and 4.5-fold larger in dogs than humans, respectively. I-Kr density and kinetics were similar in human versus dog. I-Ca and I-to were respectively approximate to 30% larger and approximate to 29% smaller in human, and Na+-Ca2+ exchange current was comparable. Cardiac mRNA levels for the main I-K1 ion channel subunit Kir2.1 and the I-Ks accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (I-Kr and I-Ks-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. I-K1 and I-Ks inhibition increased the APD-prolonging effect of I-Kr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human-canine ion current differences confirmed the role of I-K1 and I-Ks in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of I-Kr block than dogs, because of lower repolarization reserve contributions from I-K1 and I-Ks, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.