Cardiac Sodium Channels Importance of Activation Unblocking to the Voltage Dependence of Recovery

Effects of flecainide, a potent antiarrhythmic agent, on sodium channel availability was investigated in guinea pig single cardiac cells by the whole-cell voltage-clamp technique. Sodium current (INa) experiments were performed at 170 C, and maximum upstroke velocity (Vmax) experiments were performed at 370 C. Flecainide (3 ,M) caused little tonic block, but reduced sodium channel availability in a use-dependent manner. The latter effect was accentuated by depolarization and attenuated by hyperpolarization. Long (200-msec) and short (10-msec) depolarizations yielded similar use-dependent block. These results indicate that flecainide has a low affinity for rested (R) and inactivated (I) channels but a high affinity for activated ones (A). In each of these states, the channels can bind to drug to form the corresponding RD, ID, and AD states. Recovery from flecainide block consisted of two components. An initial fast component was strongly voltage dependent: with increasing hyperpolarization, recovery developed more quickly and to a larger extent. At 170 C, the mean time constant shortened from 132±81.6 msec at -120 mV to 46.9±34.1 msec at ±160 mV (kinetics were too fast for accurate measurement at 370 C). A later slow component was largely voltage independent: at 370 C, the mean time constant was 9.8±3.2 seconds at -100 mV and 10.7±3.8 seconds at -75 mV. The slow component of recovery was similarly independent of voltage at 170 C. In terms of the modulated-receptor theory, our results indicate that the fast