Abstract
The slowly inactivating or late Na+ current, INa-L, can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na+ influx corresponding to INa-L significantly increases intracellular Na+, [Na+]i; and the resulting reduction in the electrochemical driving force for Na+ reduces and (may reverse) Na+/Ca2+ exchange. These changes increase intracellular Ca2+, [Ca2+]i; which may further enhance INa-L due to calmodulin-dependent phosphorylation of the Na+ channels. This paper is based on mathematical simulations using the O’Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca2+]i homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (≤ 1.5 mM) in [Na+]i even when INa-L is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na+]i when INa-L was increased. Based on our simulations, the major short-term effect of markedly augmenting INa-L is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca2+ current, ICa-L. Furthermore, this action potential prolongation does not contribute to [Na+]i increase.
Highlights
Precise tuning and homeostatic regulation of intracellular Na+ levels, [Na+]i, are known to be essential elements of a number of very important regulatory physiological processes in mammalian heart cells
INa-L was increased 2-fold to approximate the changes in INa-L utilized in a number of different experimental settings that have evaluated repolarization variability caused by changes in INa-L [3,23]
Note that in response under steady-state conditions: (i) the action potential lengthens substantially (A), (ii) [Na+]i increases by only approx. 0.1 mM (D); and (iii) there are small changes in the Na+/K+ pump current (C), as well as the L-type Ca2+ current ICa-L (E) and the Na+/Ca2+ exchanger current, INCX (F)
Summary
Precise tuning and homeostatic regulation of intracellular Na+ levels, [Na+]i, are known to be essential elements of a number of very important regulatory physiological processes in mammalian heart cells (cf. [1,2,3]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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