Inhibitory effects of class I and IV antiarrhythmic drugs on the Na+-activated K+ channel current in guinea pig ventricular cells

Recently we have reported that class III antiarrhythmic drugs including ami odarone inhibit the Na+-activated K+ (K-Na) channels in isolated cardiac ce lls. In this study effects of antiarrhythmic drugs having class I and/or IV properties on the single K-Na channel current were examined in inside-out membrane patches of guinea pig ventricular cells by using patch clamp techn iques. 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 mu M), mexiletine (100 mu M) and flecainide (10 mu M) were selected as representa tive of class Ia, Ib and Ic drugs, respectively. These drugs at relatively high concentrations incompletely inhibited the K-Na channel by decreasing t he open time (flickering block). The class IV drug verapamil inhibited the K-Na channel current mainly by decreasing the open probability although the IC50 value of verapamil (3.36 mu M) was higher than the therapeutic concen trations. Bepridil and SD-3212, antiarrhythmic drugs having both class I an d IV properties, potently inhibited the K-Na channel current by decreasing the open probability. The IC50 values of bepridil and SD-3212 for inhibitin g the K-Na channel current was 0.51 mu M and 0.53 mu M, respectively, both of which are within the therapeutic range. Most antiarrhythmic drugs inhibi t cardiac K-Na channels by different modes and at different concentrations. The K-Na channel blocking action of bepridil and SD-3212 may partly contri bute to the prolongation of the action potential duration by these drugs at rapid stimulation rates.