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 microM and 9.2+/-1.6 microM, 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) x 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) x 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.