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CARDIOVASCULAR

Propafenone and Its Metabolites Preferentially Inhibit I_Krin Rabbit Ventricular Myocytes

Department of Pediatrics and Child Health, University of Manitoba, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada

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.

Address correspondence to: Dr. Gil J. Gross, Cardiology Division, Room 1503F, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: ggross{at}sickkids.ca

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