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Article: Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane

TitleIonic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane
Authors
KeywordsArrhythmogenic effect
Cardiac toxicity
Multiple ion channel blockade
Trichloromethane
Ventricular fibrillation
Issue Date2011
PublisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/toxicol
Citation
Toxicology, 2011, v. 290 n. 2-3, p. 296-305 How to Cite?
AbstractTrichloromethane (chloroform) is widely used for industrial chemical synthesis and also as an organic solvent in laboratories or ingredient of pesticides. Sudden death resulted from cardiac arrhythmias has been reported in clinic with acute trichloromethane intoxication. The present study was designed to investigate ionic mechanisms underlying arrhythmogenic effect (cardiac toxicity) of trichloromethane in isolated rat hearts and ventricular myocytes and HEK 293 cells stably expressing human Nav1.5, HCN2, or hERG channel using conventional electrophysiological approaches. It was found that trichloromethane (5mM) induced bradycardia and atrial-ventricular conduction blockade or ventricular fibrillation, and inhibited cardiac contractile function in isolated rat hearts. It shortened action potential duration (APD) in isolated rat ventricular myocytes, and increased the threshold current for triggering action potential, but had no effect on the inward rectifier K + current I K1. However, trichloromethane significantly inhibited the L-type calcium current I Ca.L and the transient outward potassium current I to in a concentration-dependent manner (IC 50s: 1.01 and 2.4mM, respectively). In HEK 293 cells stably expressing cardiac ion channel genes, trichloromethane reduced hNav1.5, HCN2, and hERG currents with IC 50s of 8.2, 3.3, and 4.0mM, respectively. These results demonstrate for the first time that trichloromethane can induce bradycardia or ventricular fibrillation, and the arrhythmogenic effect of trichloromethane is related to the inhibition of multiple ionic currents including I Ca.L, I to, I Na, HCN2, and hERG channels. © 2011 Elsevier Ireland Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/143373
ISSN
2014 Impact Factor: 3.621
2013 SCImago Journal Rankings: 1.196
ISI Accession Number ID
Funding AgencyGrant Number
Sun Chieh Yeh Heart Foundation of Hong Kong
University of Hong Kong
Funding Information:

The work was supported in part by a grant from Sun Chieh Yeh Heart Foundation of Hong Kong. Yuan Zhou and Hui-Jun Wu are supported by a postgraduate studentship from the University of Hong Kong. The authors thank Dr. G. Robertson for providing the hERG/pcDNA3, Dr. Carol A. Vandenberg for providing the human Kir2.1/pcDNA3, Dr. J. Makielski for providing the human SCNA5/pcDNA3, and Dr. A. Ludwig for providing the human HCN2/pCDNA3. We thank Mr. Chi-Pui Mok for the excellent technical support.

References

 

DC FieldValueLanguage
dc.contributor.authorZhou, Yen_HK
dc.contributor.authorWu, HJen_HK
dc.contributor.authorZhang, YHen_HK
dc.contributor.authorSun, HYen_HK
dc.contributor.authorWong, TMen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2011-11-24T10:04:11Z-
dc.date.available2011-11-24T10:04:11Z-
dc.date.issued2011en_HK
dc.identifier.citationToxicology, 2011, v. 290 n. 2-3, p. 296-305en_HK
dc.identifier.issn0300-483Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/143373-
dc.description.abstractTrichloromethane (chloroform) is widely used for industrial chemical synthesis and also as an organic solvent in laboratories or ingredient of pesticides. Sudden death resulted from cardiac arrhythmias has been reported in clinic with acute trichloromethane intoxication. The present study was designed to investigate ionic mechanisms underlying arrhythmogenic effect (cardiac toxicity) of trichloromethane in isolated rat hearts and ventricular myocytes and HEK 293 cells stably expressing human Nav1.5, HCN2, or hERG channel using conventional electrophysiological approaches. It was found that trichloromethane (5mM) induced bradycardia and atrial-ventricular conduction blockade or ventricular fibrillation, and inhibited cardiac contractile function in isolated rat hearts. It shortened action potential duration (APD) in isolated rat ventricular myocytes, and increased the threshold current for triggering action potential, but had no effect on the inward rectifier K + current I K1. However, trichloromethane significantly inhibited the L-type calcium current I Ca.L and the transient outward potassium current I to in a concentration-dependent manner (IC 50s: 1.01 and 2.4mM, respectively). In HEK 293 cells stably expressing cardiac ion channel genes, trichloromethane reduced hNav1.5, HCN2, and hERG currents with IC 50s of 8.2, 3.3, and 4.0mM, respectively. These results demonstrate for the first time that trichloromethane can induce bradycardia or ventricular fibrillation, and the arrhythmogenic effect of trichloromethane is related to the inhibition of multiple ionic currents including I Ca.L, I to, I Na, HCN2, and hERG channels. © 2011 Elsevier Ireland Ltd.en_HK
dc.languageengen_US
dc.publisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/toxicolen_HK
dc.relation.ispartofToxicologyen_HK
dc.subjectArrhythmogenic effecten_HK
dc.subjectCardiac toxicityen_HK
dc.subjectMultiple ion channel blockadeen_HK
dc.subjectTrichloromethaneen_HK
dc.subjectVentricular fibrillationen_HK
dc.subject.meshBradycardia - chemically induced-
dc.subject.meshChloroform - administration and dosage - toxicity-
dc.subject.meshIon Channels - antagonists and inhibitors-
dc.subject.meshSolvents - administration and dosage - toxicity-
dc.subject.meshVentricular Fibrillation - chemically induced-
dc.titleIonic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethaneen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.tox.2011.10.009en_HK
dc.identifier.pmid22024336en_US
dc.identifier.scopuseid_2-s2.0-84858619354en_HK
dc.identifier.hkuros197773en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84858619354&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume290en_HK
dc.identifier.issue2-3en_HK
dc.identifier.spage296en_HK
dc.identifier.epage305en_HK
dc.identifier.isiWOS:000298534700092-
dc.publisher.placeIrelanden_HK
dc.identifier.scopusauthoridZhou, Y=53880860200en_HK
dc.identifier.scopusauthoridWu, HJ=53880675900en_HK
dc.identifier.scopusauthoridZhang, YH=53880889500en_HK
dc.identifier.scopusauthoridSun, HY=53265070800en_HK
dc.identifier.scopusauthoridWong, TM=7403531434en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK
dc.identifier.citeulike9932027-

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