Propafenone and its metabolites preferentially inhibit IKr in rabbit ventricular myocytes

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 muM for propafenone, 5-hydroxypropafenone, and N-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 muM, 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.