Recently we have reported that class III antiarrhythmic drugs including amiodarone inhibit the Na+-activated K+ (KNa) channels in isolated cardiac cells. In this study effects of antiarrhythmic drugs having class I and/or IV properties on the single KNa channel current were examined in inside-out membrane patches of guinea pig ventricular cells by using patch clamp techniques. The KNa channel current, which was activated by increasing [Na+]i from 0 mM to 100 mM in the presence of 150 mM [K+]o, showed a large slope conductance (212 pS) and inward-going rectification. Quinidine (100 microM), mexiletine (100 microM) and flecainide (10 microM) were selected as representative of class Ia, Ib and Ic drugs, respectively. These drugs at relatively high concentrations incompletely inhibited the KNa channel by decreasing the open time (flickering block). The class IV drug verapamil inhibited the KNa channel current mainly by decreasing the open probability although the IC50 value of verapamil (3.36 microM) was higher than the therapeutic concentrations. Bepridil and SD-3212, antiarrhythmic drugs having both class I and IV properties, potently inhibited the KNa channel current by decreasing the open probability. The IC50 values of bepridil and SD-3212 for inhibiting the KNa channel current was 0.51 microM and 0.53 microM, respectively, both of which are within the therapeutic range. Most antiarrhythmic drugs inhibit cardiac KNa channels by different modes and at different concentrations. The KNa channel blocking action of bepridil and SD-3212 may partly contribute to the prolongation of the action potential duration by these drugs at rapid stimulation rates.