Heterogeneous Distribution Of I_Na-L Determines Regional Differences In Rate Adaptation Of Repolarization

(First Part)BACKGROUND: The QT interval, an index of ventricular repolarization, is rate-dependent. An exaggerated rate-dependence of ventricular repolarization is arrhythmogenic. It is unknown if there are regional differences in rate-dependent repolarization. Thus the purpose of this study was to determine whether there are regional differences in rate-dependent repolarization, and if so, to investigate the late sodium current(INa-L) in those differences, and resultant dispersion of repolarization.METHODS: Action potential duration(APD), its rate-adaptation, INa-L and regional responses to pharmacological agents were studied in rabbit myocytes isolated from the four heart chambers. Action potentials(APs) were recorded using standard microelectrode techniques, and INa-L was recorded using the whole-cell patch clamp technique.RESULTS: There were distinct regional differences in APDs and their rate-adaptations in myocytes from the four heart chambers. Left ventricular myocytes exhibited the longest APD with the greatest rate-dependence, whereas right and left atrial myocytes had the shortest APD with the smallest rate-dependence. Interestingly, the INa-L densities distributed heterogeneously and matched to regional APDs and rate-dependences as follows: left ventricle > right ventricle > left/right atria. Both dofetilide(an IKr blocker) and ATX-II(a specific INa-L enhancer) amplified the APD rate-adaptation preferentially in the left ventricle and therefore exacerbated regional dispersion of repolarization. In contrast, the atria exhibited blunted responses to both QT-prolonging agents. Ranolazine(an INa-L blocker) at 30 μM blunted the APD rate-adaptation preferentially in the ventricles and markedly reduced bradycardia-dependent regional dispersion of repolarization.CONCLUSIONS: Our results demonstrate that the heterogeneous distribution of INa-L contributes importantly to the regional heterogeneity of repolarization in response to rate changes and to APD/QT prolonging agents.(Second Part)BACKGROUND: In our first part of the study,we found that late sodium current distributed differently in the four chamber of heart.The distribution is as follow:LV>RV>LA/RA. Heterogeneous distribution in(INa-L) is responsible for regional differences in rate-dependent repolarization.But,we didn,t dtudy that difference in wede-shape preparation.This study was to study the regional differences in rate-dependent repolarization using wedge-shape preparation.METHODS: Action potential duration(APD), QT intervals and their rate-adaptation were studied in arterially-perfused ventricular and atrial wedge preparations.RESULTS:Same with the first part of our study, there were distinct regional differences in repolarization and its rate-adaptations among different cardiac chambers: the left ventricle exhibited the longest QT and APD with the greatest rate-dependence, followed by the right ventricle; whereas the atria had the shortest APD without significant rate-dependence.CONCLUSIONS: Our results demonstrate that the heterogeneous distribution of INa-L contributes importantly to the regional heterogeneity of repolarization in response to rate changes and to APD/QT prolonging agents.