Molecular Basis of Repolarization Reserve Differences between Dogs and Man

Dog models are often used for clinically related electrophysiology research, but their appropriateness and limitations are unclear. This study compared repolarization reserve and its molecular basis in dogs vs humans. Rapid (IKr) and slow (IKs) delayed rectifier and inward rectifier (IK1) K+ currents were measured in cardiomyocytes from normal dog and human tissue-donor hearts. IK1, IKr and IKs blocking effects on action potential duration (APD) were studied on human and dog papillary muscle preparations. Gene expression was measured by real time PCR. IKr densities were similar in dog and man (0.37±0.03 pA/pF vs 0.29±0.05 pA/pF, P=ns). IK1 was ~3-fold greater in canine vs human cells (eg at –60 mV: 1.72±0.07 pA/pF vs 0.65±0.1 pA/pF*; n=21–28, *P<0.05), and IKs was ~4-fold greater in dog cardiomyocytes (eg at ~40 mV: 0.72±0.11 pA/pF vs human 0.18±0.03 pA/pF*, n=10–15). IK1 inhibition (Ba2+) marginally increased APD in humans (by 4.8 ± 1.5 %) but caused larger increases in dogs (17.9 ± 2.1 %*). In contrast, IKr inhibition caused remarkable APD prolongation in humans (44 ± 4 %) versus dogs (16 ± 2 %*). IK1-inhibition potentiated APD-prolonging actions of IKr-blockade more in dogs (APD-increase augmented by 55%) than in humans (APD-increase enhanced by 33%) and IKs-inhibition enhanced APD-prolonging actions of IKr-blockade more in dogs (APD-increase augmented by 20%) than in humans (APD-increase enhanced by 9%), confirming the role of IK1 and IKs in limiting IKr-blocking effects in dogs. Kir2.1 subunit mRNA was significantly more abundant in dog compared to human (by ~4 fold), while Kir2.2, Kir2.3, Kir2.4, the IKr-subunit ERG and Ito-subunits (Kv1.4, Kv4.3 and KChIP2) were expressed at similar levels. One IKs-related gene (KvLQT1) was similarly expressed, while minK was more abundant (~ 7-fold) in dogs than humans. Smaller IK1 and IKs, possibly due to differential expression of the IK1 β-subunit Kir2.1 and the IKs β-subunit minK, limit repolarization reserve and exaggerate APD-prolongation by IKr-block in humans compared to dogs. These findings provide insights into species-specific determinants of responses to repolarization stress and are relevant to relating findings in dog studies to clinical phenomena in man.