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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

Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed... AbstractObjectives: 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cardiovascular Research Oxford University Press

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

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References (60)

Publisher
Oxford University Press
Copyright
Copyright © 1998, European Society of Cardiology
ISSN
0008-6363
eISSN
1755-3245
DOI
10.1016/S0008-6363(98)00021-2
Publisher site
See Article on Publisher Site

Abstract

AbstractObjectives: 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.

Journal

Cardiovascular Research – Oxford University Press

Published: May 1, 1998

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