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 IKr and the transient outward current Ito, using the whole-cell patch-clamp technique in isolated rabbit ventricular myocytes. All three agents potently inhibited IKr 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. IKr 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 Ito 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 Ito voltage dependence of steady-state inactivation or time course of recovery from inactivation. The preferential interaction of propafenone and its metabolites with IKr relative to Ito in ventricular myocytes sheds new light on the anti- and proarrhythmic activity of propafenone in vivo.
Footnotes
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This work was supported by an operating grant from the Manitoba Medical Service Foundation.
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DOI: 10.1124/jpet.103.057844.
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ABBREVIATIONS:HERG, human ether-à-go-go related gene; IKr, rapidly activating delayed rectifier potassium current; IKs, slowly activating delayed rectifier potassium current; Ito, transient outward potassium current; IKur, ultrarapidly activating delayed rectifier potassium current; HBS, HEPES-buffered saline.
- Received August 1, 2003.
- Accepted September 18, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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