title: How to determine cardiac ion channels targeted by drugs using the isolated rabbit ventricular wedge model.
abstract: BACKGROUND
  The rabbit left ventricular wedge (RLVW) has been demonstrated as a highly sensitive and specific preclinical model in assessing drug-induced QT prolongation and proarrhythmias. However, there is a need to determine drugs' cardiac ion channel profiles beyond QT measurement. In this study, we present an approach to determine cardiac ion channels targeted by drugs with analyzing a few key ECG parameters plus a contractility parameter obtained from the RLVW.
  
  
  METHODS
  The RLVW assay was used for testing 18 drugs with well-known ion channel profiles. A transmural ECG and isometric contractility were recorded. Five parameters including QRS, QT, Tp-e/QT ratio, QT-BCL slope and the positive staircase response of contractility were analyzed.
  
  
  RESULTS
  There were distinguished drug-induced ECG and contractility changes from which targeted cardiac ion channels by drugs could be determined. Inhibition of sodium channel resulted in rate-dependent QRS widening, QT and Tp-e shortening and a reduced QT-BCL slope. Although both IKr and IKs blockers prolonged QT interval, IKr blockers but not IKs increased Tp-e/QT ratio. Both potassium channel openers and calcium channel blockers markedly shortened QT and Tp-e intervals, but only calcium channel blockers could reverse the positive staircase response of contractility.
  
  
  CONCLUSIONS
  The results in the present study are correlated closely to the drugs' well-known clinical profiles. This indicates that the RLVW assay with an adequate experimental protocol plus analysis of 5 key parameters is highly valuable in preclinical assessment of drug candidates for their detailed ion channel activities, proarrhythmic risks and other adverse effects. The limitations of the RLVW assay are also addressed.
authors.affiliation: The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Lankenau Institute for Medical Research, Lankenau Medical Center, Wynnewood, PA, USA.
authors.forename: Guizhi
authors.initials: G
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Lankenau Institute for Medical Research, Lankenau Medical Center, Wynnewood, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Lankenau Institute for Medical Research, Lankenau Medical Center, Wynnewood, PA, USA.
authors.forename: Tengxian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Lankenau Institute for Medical Research, Lankenau Medical Center, Wynnewood, PA, USA; The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China. Electronic address: yanganxin@comcast.net.
authors.forename: Gan-Xin
authors.initials: GX
authors.lastname: Yan
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D007537:Isometric Contraction / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced
chemical_list: D002121:Calcium Channel Blockers; D007473:Ion Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers
keywords: Calcium channel blocker; Drug safety; I(Kr) blocker; Positive staircase response of contractility; Potassium channel activator; QT-BCL slope; Rabbit ventricular wedge assay; Tp-e/QT ratio; Use-dependency