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 I Na in atrial and ventricular myocytes of rat hearts. Methods Whole-cell patch voltage-clamp 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 β2 and Na V β4 subunits, but not Na V 1.5, were greater in ventricular myocytes than in atrial myocytes. I Na in heterologous HEK 293 cell expression system with coexpressing hNa V 1.5 and hNa V β2/hNa V β4 showed similar biophysical properties to ventricular I Na . Greater protein expression of Na V β2 and Na V β4 subunits was also observed in human ventricles. Interestingly, pharmacologic study revealed that the antiarrhythmic drug dronedarone (10 μM) 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 I Na in atrial and ventricular myocytes can be attributed to inhomogeneous expression of Na V β2 and Na V β4 subunits, and that atrial I Na is more sensitive to inhibition by dronedarone.