Linked Life Data

15135665

Source:http://linkedlifedata.com/resource/pubmed/id/15135665

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2004-5-11
pubmed:abstractText
Lidoflazine is an antianginal calcium channel blocker that carries a significant risk of QT interval prolongation and ventricular arrhythmia. We investigated whether or not lidoflazine inhibits current through the rapid delayed rectifier K(+) channel alpha subunit (encoded by HERG - human ether-a-go-go-related gene), since this channel has been widely linked to drug-induced QT-prolongation. Lidoflazine inhibited potently HERG current (I(HERG)) recorded from HEK 293 cells stably expressing wild-type HERG (IC(50) of approximately 16 nM). It was approximately 13-fold more potent against HERG than was verapamil under similar conditions. On membrane depolarization, I(HERG) inhibition developed gradually, ruling out closed-channel state dependent inhibition. The effect of command voltage on the drug's action suggested that lidoflazine preferentially inhibits activated/open HERG channels. The S6 mutation Y652A largely eliminated the inhibitory action of lidoflazine, whilst the F656A mutation also reduced blocking potency. We conclude: first, that lidoflazine produces high affinity blockade of the alpha subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore and, second, that this is likely to represent the molecular mechanism of QT interval prolongation by this drug.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2828
pubmed:author
pubmed:issnType
Print
pubmed:volume
36
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
701-5
pubmed:dateRevised
2008-10-28
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Lidoflazine is a high affinity blocker of the HERG K(+)channel.
pubmed:affiliation
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't