Abstract

Propafenone is an antiarrhythmic agent with recognized cardiac myocyte repolarizing K⁺ current inhibitory effects. It has two known electropharmacologically active metabolites, 5-hydroxy- and N-depropylpropafenone, whose K⁺ current inhibitory effects are less thoroughly elucidated than those of the parent compound. This study characterizes and directly compares the pharmacologic interaction of all three compounds with two key repolarizing K⁺ currents, the rapidly activating delayed rectifier I_Kr and the transient outward current I_to, using the whole-cell patch-clamp technique in isolated rabbit ventricular myocytes. All three agents potently inhibited I_Kr with IC₅₀ values of 0.80 ±0.14, 1.88 ±0.21, and 5.78 ±1.24 μM for propafenone, 5-hydroxypropafenone, andN-depropylpropafenone, respectively, based on reduction of peak tail current amplitude following repolarization from +50 mV to -30 mV. I_Kr inhibition was concentration- and weakly voltage-dependent, with a time course from channel activation that was well described by a single exponential model and consistent with open channel block. Propafenone and its 5-hydroxy and N-depropyl metabolites also blocked I_to with IC₅₀ values of 7.27 ±0.53, 40.29 ±7.55, and 44.26 ±5.73 μM, respectively, at +50 mV. No significant drug effects were observed with respect to I_to voltage dependence of steady-state inactivation or time course of recovery from inactivation. The preferential interaction of propafenone and its metabolites with I_Kr relative to I_to in ventricular myocytes sheds new light on the anti- and proarrhythmic activity of propafenone in vivo.