Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs

Norbert Jost, László Virág, Philippe Comtois, Balázs Ördög, Viktória Szuts, György Seprényi, Miklós Bitay, Zsófia Kohajda, István Koncz, Norbert Nagy, Tamás Szél, János Magyar, Mária Kovács, László G. Puskás, Csaba Lengyel, Erich Wettwer, Ursula Ravens, Péter P. Nánási, Julius G. Papp, András VarróStanley Nattel

Research output: Article

73 Citations (Scopus)

Abstract

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+-Ca2+ 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 IKsα-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.

Original languageEnglish
Pages (from-to)4189-4206
Number of pages18
JournalJournal of Physiology
Volume591
Issue number17
DOIs
Publication statusPublished - szept. 1 2013

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ASJC Scopus subject areas

  • Physiology

Cite this

Jost, N., Virág, L., Comtois, P., Ördög, B., Szuts, V., Seprényi, G., Bitay, M., Kohajda, Z., Koncz, I., Nagy, N., Szél, T., Magyar, J., Kovács, M., Puskás, L. G., Lengyel, C., Wettwer, E., Ravens, U., Nánási, P. P., Papp, J. G., ... Nattel, S. (2013). Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs. Journal of Physiology, 591(17), 4189-4206. https://doi.org/10.1113/jphysiol.2013.261198