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

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.