Effects of propafenone and 5‐hydroxy‐propafenone on hKv1.5 channels

1 The goal of this study was to analyse the effects of propafenone and its major metabolite, 5‐hydroxy‐propafenone, on a human cardiac K + channel (hKv1.5) stably expressed in Ltk − cells and using the whole‐cell configuration of the patch‐clamp technique. 2 Propafenone and 5‐hydroxy‐propafenone inhibited in a concentration‐dependent manner the hKv1.5 current with K D values of 4.4±0.3 μ M and 9.2±1.6 μ M , respectively. 3 Block induced by both drugs was voltage‐dependent consistent with a value of electrical distance (referenced to the cytoplasmic side) of 0.17±0.55 ( n =10) and 0.16±0.81 ( n =16). 4 The apparent association ( k ) and dissociation ( l ) rate constants for propafenone were (8.9±0.9)×10 6   M −1  s −1 and 39.5±4.2 s −1 , respectively. For 5‐hydroxy‐propafenone these values averaged (2.3±0.3)×10 6   M −1  s −1 and 21.4±3.1 s −1 , respectively. 5 Both drugs reduced the tail current amplitude recorded at −40 mV after 250 ms depolarizing pulses to +60 mV, and slowed the deactivation time course resulting in a ‘crossover’ phenomenon when the tail currents recorded under control conditions and in the presence of each drug were superimposed. 6 Both compounds induced a small but statistically significant use‐dependent block when trains of depolarizations at frequencies between 0.5 and 3 Hz were applied. 7 These results indicate that propafenone and its metabolite block hKv1.5 channels in a concentration‐, voltage‐, time‐ and use‐dependent manner and the concentrations needed to observe these effects are in the therapeutical range.British Journal of Pharmacology (1998) 125 , 969–978; doi: 10.1038/sj.bjp.0702129