A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes

Abstract

Diastolic depolarization (DD) of atrial myocytes can lead to spontaneous action potentials (APs) and, potentially, atrial tachyarrhythmias. This study examined the hypotheses that 1) a slowly inactivating component of the Na⁺ current (referred to as late I_Na) may contribute to DD and initiate AP firing and that 2) blocking late I_Na will reduce spontaneous and induced firing of APs by atrial myocytes. Guinea pig atrial myocytes without or with DD and spontaneous AP firing were studied using the whole cell patch-clamp technique. In experiments using cells with a stable resting membrane potential (no spontaneous DD or firing), hydrogen peroxide (H₂O₂, 50 μmol/l) caused DD and AP firing. The H₂O₂-induced activity was suppressed by the late I_Na inhibitors tetrodotoxin (TTX, 1 μmol/l) and ranolazine (5 μmol/l). In cells with DD but no spontaneous APs, the late I_Na enhancer anemone toxin II (ATX-II, 10 nmol/l) accelerated DD and induced APs. In cells with DD and spontaneous AP firing, TTX and ranolazine (both, 1 μmol/l) significantly reduced the slope of DD by 81 ± 12% and 75 ± 11% and the frequency of spontaneous firing by 70 ± 15% and 74 ± 9%, respectively. Ramp voltage-clamp simulating DD elicited a slow inward current. TTX at 1, 3, and 10 μmol/l inhibited this current by 41 ± 4%, 73 ± 2%, and 91 ± 1%, respectively, suggesting that a slowly inactivating I_Na underlies the DD. ATX-II and H₂O₂ increased the amplitude of this current, and the effects of ATX-II and H₂O₂ were attenuated by ranolazine or TTX. In conclusion, late I_Na can contribute to the DD of atrial myocytes and the inhibition of this current suppresses atrial DD and spontaneous APs.