title: A step towards characterisation of electrophysiological profile of torsadogenic drugs.
abstract: BACKGROUND
  In a previous study, two electrophysiological patterns for torsadogenic drugs were characterised in the model of isolated canine Purkinje fibres from their respective effects on action potential. This study was designed to elucidate the possible mechanisms underlying these two electrophysiological profiles.
  
  
  METHODS
  Effects of representative torsadogenic agents and non torsadogenic drugs on I(Kr), I(Ks), I(K1), I(Na) and I(CaL) were studied in transfected HEK 293 cells using the path-clamp method as well as in conscious beagle dogs and cynomolgus monkeys by telemetry.
  
  
  RESULTS
  Patch-clamp studies confirmed that torsadogenic molecules could be discriminated into at least two subgroups. The first subgroup can be defined as apparently pure I(Kr) blockers. The second subgroup can be defined as I(Kr) blockers with ancillary properties on sodium and/or calcium channels which counterbalance the I(Kr) prolongation component. This discrimination is transposable to the telemetered cynomolgus monkey model in terms of QT prolongation but not to the telemetered beagle dog model. This latter inter-species difference could be related to the sympathetic/parasympathetic balance and could involve reserve repolarisation dependent mechanisms.
  
  
  CONCLUSIONS
  The confirmation that torsadogenic drugs might have at least two different electrophysiological profiles should be taken into consideration in preclinical safety pharmacology studies because it increases the value of the cynomolgus monkey model in two particular situations: firstly when an NCE causes sympathetic activation and secondly, when an NCE exhibits a pure I(Kr) blocker pattern independently of its potency to block HERG channels.
authors.affiliation: Centre de Recherches Biologiques, CERB, Chemin de Montifault, 18800 Baugy, France. pascal.champeroux@cerb.fr
authors.forename: Pascal
authors.initials: P
authors.lastname: Champeroux
authors.forename: Aude
authors.initials: A
authors.lastname: Ouillé
authors.forename: Eric
authors.initials: E
authors.lastname: Martel
authors.forename: John Sinclair Lawrence
authors.initials: JS
authors.lastname: Fowler
authors.forename: Anne
authors.initials: A
authors.lastname: Maurin
authors.forename: Serge
authors.initials: S
authors.lastname: Richard
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013686:Telemetry; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels