Late sodium current in human, canine and guinea pig ventricular myocardium

Highlights

• Marked interspecies differences exist in the profile of cardiac I_Na-late.

• In human and dog I_Na-late decreases, while in guinea pig increases during the AP.

• This is a consequence of the slower inactivation of I_Na-late in guinea pig.

• The ATX-II induced current is different from the native I_Na-late in dog.

• Dog ventricular myocyte is the best model for studying human I_Na-late.

Abstract

Although late sodium current (I_Na-late) has long been known to contribute to plateau formation of mammalian cardiac action potentials, lately it was considered as possible target for antiarrhythmic drugs. However, many aspects of this current are still poorly understood. The present work was designed to study the true profile of I_Na-late in canine and guinea pig ventricular cells and compare them to I_Na-late recorded in undiseased human hearts. I_Na-late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp conditions using either canonic- or self-action potentials as command signals. Under action potential voltage clamp conditions the amplitude of canine and human I_Na-late monotonically decreased during the plateau (decrescendo-profile), in contrast to guinea pig, where its amplitude increased during the plateau (crescendo profile). The decrescendo-profile of canine I_Na-late could not be converted to a crescendo-morphology by application of ramp-like command voltages or command action potentials recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the crescendo I_Na-late profile in guinea pig was due to the slower decay of I_Na-late in this species. When action potentials were recorded from multicellular ventricular preparations with sharp microelectrode, action potentials were shortened by tetrodotoxin, which effect was the largest in human, while smaller in canine, and the smallest in guinea pig preparations. It is concluded that important interspecies differences exist in the behavior of I_Na-late. At present canine myocytes seem to represent the best model of human ventricular cells regarding the properties of I_Na-late. These results should be taken into account when pharmacological studies with I_Na-late are interpreted and extrapolated to human. Accordingly, canine ventricular tissues or myocytes are suggested for pharmacological studies with I_Na-late inhibitors or modifiers. Incorporation of present data to human action potential models may yield a better understanding of the role of I_Na-late in action potential morphology, arrhythmogenesis, and intracellular calcium dynamics.

Introduction

Although late Na⁺ current (I_Na-late) is an important current flowing during the action potential (AP) plateau in mammalian cardiomyocytes with physiological and pathological significance recognized long ago [[1], [2], [3]], its pathophysiological role in LQT3 [4] and heart failure [[5], [6], [7], [8]] has been emphasized only in the last decades. I_Na-late - as an inward current - contributes to plateau formation and is responsible for largely half of the transmembrane Na⁺ entry [[9], [10], [11]]. As a consequence, the elevation of I_Na-late results in increased arrhythmia propensity (e.g. in heart failure) including prolongation of the action potential duration (APD), increased inhomogeneity of repolarization and occurrence of early as well as delayed afterdepolarizations [5,[12], [13], [14]]. Therefore, as a new concept, intensive efforts were made recently to develop selective inhibitors of I_Na-late [9,15,16].

Initially I_Na-late was believed to be a consequence of the overlapping steady-state activation and inactivation functions of the Na⁺ current (window Na⁺ current) [17], now it is better explained by the slow inactivation kinetics of a small fraction of cardiac Na⁺ channels (mode-II gating, bursting and late openings) [4,6]. In spite of its relative importance, many aspects of I_Na-late are still poorly understood. In contrast to the detailed data obtained in rabbit [18], guinea pig [19] and porcine [20] myocytes, we have only a limited number of recordings of native human and canine I_Na-late, since these experiments were typically performed using conventional voltage clamp arrangements and many of them at room temperature [7,8,[21], [22], [23]]. Self action potential voltage clamp measurements, delivering the cell's own AP as a command signal, are not available in the literature either for canine or human ventricular cardiomyocytes. Since canine ventricular cells are believed to be a good model for human ventricular myocytes in general regarding their cellular electrophysiological properties [[24], [25], [26]], our goal was to monitor and compare the profiles of I_Na-late in ventricular cells obtained from canine, guinea pig and undiseased human hearts. The rationale of our work is given by the very limited availibilty of undiseased human ventricular tissues for experimental purposes, and our results show that canine myocytes - but not guinea pig cells - are reasonably suitable preparations for studying the properties of human I_Na-late.