OBJECTIVE The aim was to examine the effects of flecainide, a class Ic antiarrhythmic drug, on the ATP sensitive potassium channel (KATP channel) current in guinea pig ventricular cells, using the inside-out patch clamp technique. METHODS KATP channel activities were recorded from inside-out membrane patches with 140 mM KCl solution bathing both the external and internal surfaces of the membrane (20-22 degrees C). Flecainide was added to the intracellular medium (ATP-free, pH = 7.3). RESULTS Flecainide (1-300 microM) inhibited the outward KATP channel current evoked at the holding potential of +40 mV, in a concentration dependent manner. The flecainide concentration for half maximum inhibition of the channel activity (IC50) and Hill coefficient of the flecainide inhibition were estimated to be 17.3 microM and 1.1, respectively. However, flecainide did not affect the inwardly directed KATP channel current measured at the potential of -40 mV. When the inhibitory effects of flecainide on the outward current were examined under conditions in which pH was decreased from 7.3 (control) to 6.8, the IC50 and Hill coefficient became 27.3 microM and 1.2, respectively. Furthermore, in the presence of 0.1 mM ADP on the cytosolic side of the membrane (pH = 7.3), flecainide blocked the outward currents with the IC50 of 47.0 microM and a Hill coefficient of 0.9. After 1 min exposure of the cytoplasmic side of the membrane to trypsin (1 mg.ml-1), glibenclamide (2 microM) did not inhibit the KATP channel currents, while flecainide (30 microM) reversibly inhibited this trypsin enhanced KATP channel activity. CONCLUSIONS Flecainide at relatively high concentrations blocks the cardiac KATP channels only when the currents are directed outward, and in a concentration dependent manner. The potency of flecainide in blocking KATP channels decreased under conditions of increased H+ or ADP concentrations on the cytosolic side of the membrane, as may occur in myocardial ischaemia or hypoxia.