Distinctive property and pharmacology of voltage-gated sodium current in rat atrial vs ventricular myocytes

BACKGROUND Several mammalian species display distinct biophysical properties between atrial and ventricular voltage-gated sodium current (I-Na); however, the potential mechanism behind this phenomenon is unknown. OBJECTIVE The purpose of this study was to investigate the potential molecular identities of the different INa in atrial and ventricular myocytes of rat hearts. METHODS Whole-cell patch voltage-damp and molecular biology techniques were used in the study. RESULTS Ventricular I-Na exhibited a slower inactivation, more positive potential of inactivation, and quicker recovery from inactivation compared to atrial I-Na. Real-time polymerase chain reaction and western blot analysis revealed that mRNA and protein levels of Na-v beta 2 and Na-v beta 4 subunits, but not Na(v)1.5, were greater in ventricular myocytes than in atrial myocytes. INa in heterologous HEK 293 cell expression system with coexpressing hNa(v)1.5 and hNa(v)beta 2/hNa(v)beta 4 showed similar biophysical properties to ventricular INa. Greater protein expression of Na-v beta 2 and Na-v beta 4 subunits was also observed in human ventricles. Interestingly, pharmacologic study revealed that the antiarrhythmic drug dronedarone (10 mu M) inhibited atrial I-Na more (by 73%) than ventricular I-Na (by 42%), and shifted its inactivation to more negative voltages (-4.6 mV) compared to ventricular I-Na CONCLUSION The results of this study demonstrate the novel information that the distinctive biophysical properties of INa in atrial and ventricular myocytes can be attributed to inhomogeneous expression of Na-v beta 2 and Na-v beta 4 subunits, and that atrial I-Na is more sensitive to inhibition by dronedarone.