© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes
aDepartment of Medicine and Research Center, Montreal Heart Institute, 5000 Bélanger Street E., Montreal, Quebec H1T 1C8, Canada
bDepartment of Medicine, University of Montreal, Montreal, Quebec, Canada
cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
dThe Institute of Physiology, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
eHoechst AG, Frankfurt, Germany
* Corresponding author. Tel.: +1 (514) 376 3330; Fax: +1 (514) 376 1355; E-mail: nattel@icm.umontreal.ca
Objectives: The slow component of the delayed rectifier K+ current (IKs) is believed to be important in cardiac repolarization, and may be a potential target for antiarrhythmic drugs, but its study has been limited by a lack of specific blockers. The chromanol derivate 293B blocks currents expressed by minK and not HERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials. We aimed to establish the effects of 293B on K+, Na+ and Ca2+ currents and action potentials in human and guinea pig cardiomyocytes. Methods: Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36°C. Results: Delayed rectifier current (IK) elicited by pulses to +60 mV from a holding potential of –50 mV in guinea pig myocytes was strongly inhibited by 293B (maximum inhibition 96.9±0.8%; 50% inhibitory concentration, EC50, 1.02 µM), but IK during pulses to –10 mV was unaffected (3.9±8.4% inhibition at 50 µM). Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug-sensitive IK correspond to those of IKr and IKs respectively. Inward rectifier K+ current, Na+ current and L-type Ca2+ current were unaffected by 293B. Transient outward current in human ventricular myocytes was inhibited by 293B at an EC50 of 24 µM, less than one twentieth the potency for IKs inhibition in guinea pig myocytes. While dofetilide prolonged action potential duration (APD) with strong reverse use dependence, 293B prolonged guinea pig and human ventricular APD to a similar fractional extent at all frequencies. Conclusions: 293B is a selective IKs blocker, and the frequency dependence of APD prolongation caused by this IKs blocker is different from that caused by IKr blockade: 293B may be an interesting tool to study the physiologic role of IKs and the antiarrhythmic potential of IKs blockade.
KEYWORDS Potassium channels; Action potential; Biophysics; Cardiac arrhythmias; Antiarrhythmic drugs
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