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Article: 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

TitleEffects 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
Authors
KeywordsAction Potential
Antiarrhythmic Drugs
Biophysics
Cardiac Arrhythmias
Potassium Channels
Issue Date1998
PublisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.org
Citation
Cardiovascular Research, 1998, v. 38 n. 2, p. 441-450 How to Cite?
AbstractObjectives: The slow component of the delayed rectifier K+ current (I(Ks)) 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 (I(K)) 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 I(K) 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 I(K) correspond to those of I(Kr) and I(Ks) 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 I(Ks) 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 I(Ks) blocker, and the frequency dependence of APD prolongation caused by this I(Ks) blocker is different from that caused by I(Kr) blockade: 293B may be an interesting tool to study the physiologic role of I(Ks) and the antiarrhythmic potential of I(Ks) blockade.
Persistent Identifierhttp://hdl.handle.net/10722/162251
ISSN
2015 Impact Factor: 5.465
2015 SCImago Journal Rankings: 2.897
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorBosch, RFen_US
dc.contributor.authorGaspo, Ren_US
dc.contributor.authorBusch, AEen_US
dc.contributor.authorLang, HJen_US
dc.contributor.authorLi, GRen_US
dc.contributor.authorNattel, Sen_US
dc.date.accessioned2012-09-05T05:18:24Z-
dc.date.available2012-09-05T05:18:24Z-
dc.date.issued1998en_US
dc.identifier.citationCardiovascular Research, 1998, v. 38 n. 2, p. 441-450en_US
dc.identifier.issn0008-6363en_US
dc.identifier.urihttp://hdl.handle.net/10722/162251-
dc.description.abstractObjectives: The slow component of the delayed rectifier K+ current (I(Ks)) 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 (I(K)) 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 I(K) 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 I(K) correspond to those of I(Kr) and I(Ks) 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 I(Ks) 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 I(Ks) blocker, and the frequency dependence of APD prolongation caused by this I(Ks) blocker is different from that caused by I(Kr) blockade: 293B may be an interesting tool to study the physiologic role of I(Ks) and the antiarrhythmic potential of I(Ks) blockade.en_US
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.orgen_US
dc.relation.ispartofCardiovascular Researchen_US
dc.subjectAction Potential-
dc.subjectAntiarrhythmic Drugs-
dc.subjectBiophysics-
dc.subjectCardiac Arrhythmias-
dc.subjectPotassium Channels-
dc.subject.meshAction Potentials - Drug Effectsen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCalcium Channels - Drug Effectsen_US
dc.subject.meshChromans - Pharmacologyen_US
dc.subject.meshGuinea Pigsen_US
dc.subject.meshHumansen_US
dc.subject.meshMyocardium - Metabolismen_US
dc.subject.meshPatch-Clamp Techniquesen_US
dc.subject.meshPotassium Channels - Drug Effectsen_US
dc.subject.meshSodium Channels - Drug Effectsen_US
dc.subject.meshSulfonamides - Pharmacologyen_US
dc.titleEffects 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 myocytesen_US
dc.typeArticleen_US
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_US
dc.identifier.authorityLi, GR=rp00476en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/S0008-6363(98)00021-2en_US
dc.identifier.pmid9709405-
dc.identifier.scopuseid_2-s2.0-0032076162en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0032076162&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume38en_US
dc.identifier.issue2en_US
dc.identifier.spage441en_US
dc.identifier.epage450en_US
dc.identifier.isiWOS:000074585800018-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridBosch, RF=7102263519en_US
dc.identifier.scopusauthoridGaspo, R=6603283635en_US
dc.identifier.scopusauthoridBusch, AE=7101774552en_US
dc.identifier.scopusauthoridLang, HJ=7402486161en_US
dc.identifier.scopusauthoridLi, GR=7408462932en_US
dc.identifier.scopusauthoridNattel, S=36048738800en_US

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