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...

Full description

Saved in:
Bibliographic Details
Main Authors: Jost Norbert László
Virág László
Comtois Philippe
Ördög Balázs
Szűts Viktória
Seprényi György
Bitay Miklós
Kohajda Zsófia
Koncz István
Nagy Norbert
Szél Tamás
Magyar János
Kovács Mária
Puskás László
Lengyel Csaba Attila
Wettwer Erich
Ravens Ursula
Nánási Péter Pál
Papp Gyula
Varró András
Nattel Stanley
Format: Article
Published: 2013-09-01
Series:The Journal of physiology 591 No. 17
doi:10.1113/jphysiol.2013.261198

mtmt:2359594
Online Access:http://publicatio.bibl.u-szeged.hu/9041
Description
Summary: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.
Physical Description:4189-206
ISSN:1469-7793