Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel

Propafenone has been shown to affect the delayed-rectifier potassium curren ts in cardiomyocytes of different animal models. In this study we investiga ted effects and mechanisms of action of propafenone on HERG potassium chann els in oocytes of Xenopus laevis with the two-electrode voltage-clamp techn ique. Propafenone decreased the currents during voltage steps and the tail currents. The block was voltage-dependent and increased with positive going potentials (from 18% block of tail current amplitude at -40 mV to 69% at 40 mV with 100 mu mol/l propafenone). The voltage dependence of block could be fitted with the sum of a monoexponential and a linear function. The fra ctional electrical distance was estimated to be delta =0.20. The block of c urrent during the voltage step increased with time starting from a level of 83% of the control current. Propafenone accelerated the increase of curren t during the voltage step as well as the decay of tail currents (time const ants of monoexponential fits decreased by 65% for the currents during the v oltage step and by 37% for the tail currents with 100 mu mol/l propafenone) . The threshold concentration of propafenone effect was around 1 mu mol/l a nd the concentration of half-maximal block (ICS,) ranged between 13 mu mol/ l and 15 mu mol/l for both current components. With high extracellular pota ssium concentrations, the IC50 value rose to 80 mu mol/l. Acidification of the extracellular solution to pH 6.0 increased the IC50 value to 123 mu mol /l, alkalization to pH 8.0 reduced it to 10 mu mol/l and coexpression of th e beta -subunit minK had no statistically significant effect on the concent ration dependence. In conclusion, propafenone has been found to block HERG potassium channels. The data suggest that propafenone affects the channels in the open state a nd give some hints for an intracellular site of action.