Effect of phenytoin on the sodium current in isolated rat ventricular cells

The mode of action of the antiarrhythmic drug, phenytoin, on the cardiac sodium current was investigated using isolated rat ventricular cells, under voltage clamp conditions. It was found that the blocking effect of phenytoin on INa displays both voltage- and use-dependence. At a concentration of 20 mumol/l, it produced a tonic block of INa measuring 18% of control. After a train of 10 depolarizing pulses of 500 ms duration (applied at a frequency of 1 Hz), the degree of block was increased to 45% of control. Phenytoin also shifted the steady-state inactivation curve of INa to more hyperpolarized potentials by 5.4 mV. The blocking effects of phenytoin during repetitive depolarizing voltage steps suggest that phenytoin binds preferentially to inactivated channels, and that removal of this block may primarily occur from resting channels; moreover, the removal of block is strongly voltage-dependent.