Contribution of late sodium current (INa-L) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents

BACKGROUND Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization. OBJECTIVE The purpose of this study was to examine the role of the late sodium current (INa-L) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents. METHODS The effects of INa-L blockade, INa-L enhancement, I-Kr blockade, and changes in extracellular potassium concentration ([K+](o)) on rate adaptation of the QT interval and action potential duration (APD) were examined in isolated rabbit ventricular wedges and single myocytes. Rate dependence of INa-L, delayed rectifier potassium current (I-K), and L-type calcium current (I-Ca) was determined using a whole-cell, voltage clamp technique. RESULTS At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when [K+](o) remained constant. The rate dependence of APD was significantly enhanced by reduction of [K+](o) from 4 to 1 mM or by INa-L enhancement but was markedly blunted by the selective sodium channel blocker tetrodotoxin. The I-Kr blocker dofetilide (3 nM) amplified the QT to basic cycle length slope (71.2 +/- 13.1 ms/s vs 35.1 +/- 8.8 ms/s in control, n = 4, P < .05). This reverse use-dependence was abolished by tetrodotoxin at 5 mu M (11.4 +/- 4.3 ms/s, n = 4, P < .01). There were no significant differences in I-Ca or I-K over the range of basic cycle lengths from 2,000 to 500 ms. However, INa-L exhibited a significant rate-dependent reduction. CONCLUSION INa-L is sensitive to rate change due to its slow inactivation and recovery kinetics and plays a central role in the rate dependence of APD/QT and in the reverse use-dependence of select APD/QT-prolonging agents.