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

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Abstract
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. Propafenone and 5‐hydroxy‐propafenone inhibited in a concentration‐dependent manner the hKv1.5 current with KD values of 4.4±0.3 μM and 9.2±1.6 μM, respectively. 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). The apparent association (k) and dissociation (l) rate constants for propafenone were (8.9±0.9)×106 M−1 s−1 and 39.5±4.2 s−1, respectively. For 5‐hydroxy‐propafenone these values averaged (2.3±0.3)×106 M−1 s−1 and 21.4±3.1 s−1, respectively. 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. 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. 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