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Cardiovascular Research 2000 46(1):151-161; doi:10.1016/S0008-6363(99)00430-7
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes

Lixia Yue, Jian Lin Feng, Zhiguo Wang and Stanley Nattel*

Department of Pharmacology and Therapeutics, McGill University, Department of Medicine, University of Montreal, and Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8

* Corresponding author. Tel.: +1-514-376-3330; fax: +1-514-376-1355 nattel{at}icm.umontreal.ca

Objective: A dog atrial ultra-rapid delayed rectifier current (IKur.d) is involved in canine atrial repolarization and shares similarities with the human atrial ultra-rapid delayed rectifier (IKur). Almost no information is available about the actions of antiarrhythmic drugs on IKur.d. This study evaluated effects of ambasilide, quinidine, flecainide and verapamil on IKur.d in isolated canine atrial myocytes. Methods: Standard whole-cell patch clamp techniques were used to study the effects of multiple concentrations of each drug. Results: All drugs produced reversible concentration-, voltage- and time-dependent IKur.d inhibition. Significant effects of quinidine, flecainide and ambasilide were noted at atrial-effective antiarrhythmic concentrations in the dog. Upon the onset of a depolarizing pulse, block developed exponentially in relation to time, with the blocking rate-constant increasing with drug concentration, consistent with open-channel blockade and permitting the calculation of forward and reverse rate-constants. For all drugs, the 50% blocking concentration (EC50) showed significant voltage-dependence, decreasing at more positive potentials. The magnitude of voltage-dependent block was directly related to the degree of drug-induced shift in the voltage dependence of activation (r=0.97), pointing to open-channel block as a mechanism for voltage-dependent action. An additional component of voltage-dependence suggested that blocking sites were subjected to 17–21% of the transmembrane voltage field. Conclusions: Ambasilide, quinidine, flecainide and verapamil inhibit IKur.d, with preferential action on the open state. IKur.d inhibition may play a role in antiarrhythmic effects in canine atrial arrhythmia models. Comparisons between the effects of these drugs on IKur.d and previously studied effects on IKur suggest potential opportunities for investigating the molecular structural determinants of drug-blocking action on atrial-specific ultrarapid delayed rectifiers.

KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Ion channels; K-channel; Supraventricular arrhythmia


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