Late Sodium Current in Canine, Guinea Pig and Human Left Ventricular Myocardium

Abstract

The late sodium current (INa,late) has been known to contribute to cardiac action potentials (AP), and lately it was also considered as a possible antiarrhythmic target. However, many aspects of this current are still poorly understood. Our aim was to study the true profile of INa,late in canine and guinea pig left ventricular cells and compare them to INa,late recorded in undiseased human cardiomyocytes. INa,late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp (APVC) conditions using either canonic- or self-action potentials as command signals. INa,late was also recorded using conventional voltage clamp. Under APVC conditions the density of canine and human INa,late monotonically decreased, whereas in guinea pig, it continuously increased during the AP plateau. The “decreasing” profile of canine INa,late could not be converted to an “increasing” morphology by application of isoproterenol, calmodulin, AP-like ramp voltage command or command APs recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the “increasing” INa,late profile in guinea pig is determined by the slow decay of INa,late in this species. INa,late was increased by isoproterenol but not by calmodulin in canine myocytes. When APs were recorded from multicellular ventricular preparations with sharp microelectrode, tetrodotoxin decreased AP duration in a reverse rate-dependent manner, which effect was the largest in human, while smaller in canine and the smallest in guinea pig preparations. The shape of INa,late under the AP is likely determined by the different inactivation kinetics of the sodium channels that generate INa,late. Variances between different species in the actual sodium channel subtypes that contribute to INa,late might underlie the differences observed in the macroscopic current. Canine myocytes seems to be the best model of human ventricular cells regarding INa,late.