A. Varró: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Dóm tér 12, PO Box 427, Hungary.
J Physiol. 2013 Sep 1;591(17):4189-206. doi: 10.1113/jphysiol.2013.261198. Epub 2013 Jul 22.
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 IKr block (50-100 nmol l(-1) dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 μmol l(-1) BaCl2) and IKs block (1 μmol l(-1) HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na(+)-Ca(2+) exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKs α-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. IK1 and IKs inhibition increased the APD-prolonging effect of IKr 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 IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.
心脏复极的种属特异性决定因素尚不清楚。本研究比较了犬和人心室复极中各种电流的贡献。应用常规微电极、全细胞膜片钳、分子生物学和数学建模技术。选择性 IKr 阻断（50-100nmol l(-1) 多非利特）使人心室复极 90%时的动作电位时程（APD90）延长>3 倍，提示人心室复极储备较小。选择性 IK1 阻断（10μmol l(-1) 氯化钡）和 IKs 阻断（1μmol l(-1) HMR-1556）使人心室比犬心室乳头状肌的 APD90 延长更大。在分离的心肌细胞中进行的离子电流测量显示，IK1 和 IKs 的密度分别是犬的 3 倍和 4.5 倍。人和犬的 IKr 密度和动力学相似。在人心室，ICa 和 Ito 分别大30%和小29%，而钠钙交换电流相当。人和犬的主要 IK1 离子通道亚基 Kir2.1 和 IKs 辅助亚基 minK 的心脏 mRNA 水平显著降低，但 IKr 和 IKs α 亚基的 ERG 和 KvLQT1 的 mRNA 表达无显著差异。免疫染色提示人心室和犬心室心肌细胞中 Kir2.1 和 minK 表达较低，KvLQT1 蛋白表达较高。IK1 和 IKs 抑制使犬的 IKr 阻断的 APD 延长作用增加（分别增加 56%和 49%）比人心室（增加 34%和 16%）更大，提示这两种电流均有助于增加犬的复极储备。一个纳入观察到的人心-犬离子电流差异的数学模型证实了 IK1 和 IKs 在复极储备差异中的作用。因此，与犬相比，人对 IKr 阻断的复极延迟作用更大，因为 IK1 和 IKs 对复极储备的贡献较低，强调了复极的种属特异性决定因素和动物模型对人类疾病的局限性。
