Abstract
1. In order to quantify the time- and voltage-dependent block of sodium channels by quinidine, we voltage clamped guinea-pig papillary muscles and measured the maximum upstroke velocity (Vmax) of the cardiac action potential. 2. Quinidine reduces Vmax presumably by blocking cardiac sodium channels. In therapeutic concentrations, quinidine causes a small amount of tonic block. Upon depolarization of the cardiac cell membrane, a use-dependent block develops. 3. A slow component of use-dependent block has time- and voltage-dependence similar to that of slow inactivation, develops for the duration of the depolarization or until a steady state is reached. 4. In addition, closely associated with the action potential upstroke, a fraction of the channels blocks very quickly. This represents block of activated or open channels. 5. Near the normal resting potential, channels recover from block with a time constant of 3 to 8 s. At more negative membrane potentials recovery from block occurs slightly faster, while at more positive potentials recovery from block proceeds somewhat more slowly. 6. In terms of the modulated receptor hypothesis, quinidine has a low affinity for the rested state, avidly blocks open sodium channels, but does not bind significantly to inactivated channels. In addition, quinidine blocks channels as they exhibit slow inactivation.