Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs

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.