The states and sites of actions of flecainide on sodium channels were investigated in guinea-pig single cardiac cells, using the whole-cell voltage-clamp technique at 22 degrees C. External application of flecainide caused tonic and use-dependent block of the sodium current (INa). The tonic block and the steady state use-dependent block increased with increasing drug concentrations. The dose-response curve for the use-dependent block was fitted by the equation for 1:1 drug-receptor binding and yielded a KD of 7.0 microM flecainide. At 5 microM flecainide, the use-dependent block of INa with 10 and 200 ms depolarizing pulses at an interpulse interval of 400 ms was 31.1 +/- 2.7 (mean +/- S.E.) and 36.8 +/- 2.7%, respectively. The two values were not significantly different. The block developed as a single exponential function with onset rate of 0.041 +/- 0.005/pulse. Recovery from flecainide block consisted of two components as reported previously. The mean time constant of the initial fast component was 48 +/- 17 ms, which was comparable but significantly longer than that in the absence of the drug. The late slow component was only seen after drug application and the time constant was 26 +/- 7 s at -100 mV. Internal application of 5 and 50 microM flecainide for 30 min after rupture of the cell membrane produced a non-significant block and values of 1.7 +/- 0.8 and 6.9 +/- 2.4%, respectively, for the use-dependent block of INa.(ABSTRACT TRUNCATED AT 250 WORDS)