Single channel sodium current in rat cardiomyocytes: use-dependent block by ethacizin

Ethacizin is a phenothiazine derivative antiarrhythmic agent that blocks sodium current. The cell-attached patch clamp of single adult rat ventricular cells was used to investigate mechanisms of use-dependent block of sodium current. Under control conditions peak open probability, first latency, fraction of null sweeps, mean open time and single channel current amplitude were not different at both 1 and 4 Hz. Ethacizin (5 microM) caused a significant decrease in the peak open probability, a significant increase in the first latency and an increase in the fraction of null sweeps at 4 Hz compared with 1 Hz; mean open time and single channel current amplitude were unchanged. These observations support a model of antiarrhythmic action which proposes complete block of single channel conductance resulting from drug binding. A "runs analysis" revealed nonrandom clustering of null traces in the presence of ethacizin and no clustering in control patches. Increasing stimulation frequency makes this nonrandom behavior more apparent. We conclude that the relatively slow cycling of a few channels between blocked and unblocked states induces null sweeps clustering. The implications of these findings for mechanisms of drug block of the Na channel are discussed.