Objective: The aim was to assess the effects of various antiarrhythmic drugs on 2,4-dinitrophenol (DNP) induced outward current (IDNP), presumably the ATP sensitive K+ current (IK,ATP), of isolated cardiac cells and to discuss mechanisms involved in the hypoglycaemia which occurs in patients on these drugs. Methods: The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular cells was measured using whole cell voltage clamp techniques with a ramp pulse programme. The effects of seven different antiarrhythmic drugs on IDNP were examined. Action potentials were elicited at a rate of 0.2 Hz by an intracellular current injection. Results: DNP (50 μmol·litre−1) increased the quasi-steady state outward current at potentials positive to about -60 mV. This current (IDNP) was completely inhibited by the subsequent application of glibenclamide (1 μmol·litre−1), thereby suggesting that the IDNP is probably IK,ATP. Cibenzoline (10 μmol·litre−1, class Ia), disopyramide (30 μmol·litre−1, class Ia), and procainamide (100 μmol·litre−1, class Ia) significantly inhibited the IDNP by 95.5(SD 11.3)%, 77.8(21.2)%, and 76.4(23.9)% respectively. Flecainide (class Ic) inhibited the IDNP by 66.9(23.9)% at 10 μmol·litre−1 but not at 2 μmol·litre−1. Mexiletine (30 μmol·litre−1, class Ib), pilsicainide (50 μmol·litre−1, class Ic), and E4031 (10 μmol·litre−1, class III) at concentrations as high as approximately fivefold the clinically effective blood levels, did not suppress IDNP. Except for 10 μmol·litre−1 flecainide, all the concentrations listed above which blocked IDNP were within twofold of the clinical blood concentrations ducumented to be effective for suppression of arrhythmias. Cibenzoline, disopyramide, and procainamide, but not flecainide, belong to class la antiarrhythmic drugs. All these class la antiarrhythmic drugs "shortened" the action potential duration of guinea pig ventricular cells, an opposite change to that noted for multicellular preparations, eg, guinea pig papillary muscles. Conclusions: Class la antiarrhythmic drugs (cibenzoline, disopyramide, and procainamide) inhibit IDNP (presumably IK,ATP) in guinea pig ventricular cells within a range of therapeutic concentrations. This inhibitory effect of IK,ATP can probably explain the hypoglycaemia which occurs in some patients receiving these drugs, and the prolongation of the action potential duration alleged to occur in "superfused" papillary muscles. Cardiovascular Research 1992;26:1095-1101