The voltage-gated sodium channel Nav1.5 is highly expressed in cardiac myocytes. Depolarization causes these channels to open briefly, allowing a large entry of Na+ ions that peaks within ~ 2-3 ms and further depolarizes the cell to generate the upstroke of the cardiac action potential (phase 0). After opening, most channels quickly inactivate to prevent further movement of Na+ and remain inactivated throughout the duration of the action potential. However, some channels continue to conduct, or even reactivate at relatively positive membrane potentials during the plateau and repolarization phases (Pourrier et al, 2014).
Na channel late openings allow influx of Na+ that creates a small, “late current” (late INa or INa,L) that persists throughout the action potential plateau and repolarization. In a variety of pathophysiological settings (inherited and acquired), the number of Na+ channel late openings and thus the amplitude of INa,L is significantly increased, resulting in slowed repolarization and prolonged action potential duration (Zaza et al, 2008). Under these conditions, prolonged action potential duration can lead to after depolarizations and triggered activity.
In physiologic conditions, block of INa,L can have a protective effect by counteracting the effect of IhERG inhibition (Orth et al, 2006). As a result, drugs inhibiting both INa,L and IhERG are not considered pro-arrhythmic. The importance of testing the effects of compounds beyond hERG is now widely recognized. And INa,L is now accepted as part of the cardiac ionic current panel for drug testing. More recently, it has been proposed to use human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to assess the pro-arrhythmic liability of novel compounds in safety studies. In this regard, it is important to demonstrate that all the ionic currents contributing to the human action potential are present in this model. At present, it is unclear whether or not INa,L is present in commercially available hiPSC-CM. Thus, the goal of this study is to record INa,L from Cor.4U® cells (Axiogenesis AG), to determine its pharmacologic properties as well as its importance in shaping the action potential morphology
We tested the hypothesis that:
- INa,L is present in Cor.4U® cardiomyocytes.
- INa,L recorded from Cor.4U® cells is inhibited by Na channel inhibitors such as TTX, ranolazine and flecainide.
- Enhancement of late INa by ATXII results in prolongation of the action potential recorded from Cor.4U® cells.
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