Distinctive density, biophysical properties, and pharmacology of voltage-gated sodium current in atrial and ventricular myocytes

Abstract

BACKGROUND AND OBJECTIVE: Our earlier study reported that heterogeneous voltage-gated sodium current (INa) in the density and biophysical properties is present in atrial and ventricular myocytes from guinea pig heart (Li et al, J Mol Cell Cardiol 2002;34:1185-1194). However, molecular contribution is not understood for the different properties of INa in atrial and ventricular myocytes of the heart. The present study was designed to investigate the properties, potential molecular contribution, and pharmacology of INa in atrial and ventricular myocytes of rat heart using approaches of electrophysiology and molecular biology. RESULTS: It was found the INa density (-35 mV) was greater in left atrial (n=17, -38.6±4.6 pA/pF) than that in left ventricular (n=35, -24.5±1.3 pA/pF, P<0.01) myocytes. Time constants of activation (τm) and inactivation (τh) of INa was smaller in atrial (0.23±0.02 ms and 1.05±0.04 ms) than those in ventricular (0.48±0.02 ms and 1.67±0.06 ms, P<0.01) myocytes. The V1/2 of INa availability (I/Imax) was more negative in atrial (n=15, -100.3±1.1 mV) than that in ventricular (n=18, -95.1±1.0 mV, P<0.05) myocytes. In addition, recovery of INa from inactivation was slower in atrial than that in ventricular myocytes. Molecular biological experiments revealed that mRNAs and proteins of SCN5A, SCN4A, SCN10A, SCN1B, SCN2B, and SCN3B were homogenously expressed in both atrial and ventricular myocytes. Interestingly, expression of SCN4B was greater (2.8 folds) in ventricular myocytes than that in atrial myocytes. The anti-arrhythmic drug quinidine inhibited INa with IC50 of 2.8 μM in atrial myocytes, while 7.2 μM in ventricular myocytes. CONCLUSIONS: Our results demonstrate for the first time to our knowledge that distinctive density and biophysical properties of INa are present in atrial and ventricular myocytes of from rat heart. The less expression of SCN4B in atrial myocytes likely contributes at least in part to the higher density, quicker activation and inactivation, negative potential of inactivation, slower recovery from inactivation of INa, and the more sensitive to inhibition by the anti-arrhythmic drug quinidine. The study further supports the notion that atrial INa may be a target for developing atrial selective anti-atrial fibrillation drug.