title: Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig.
abstract: BACKGROUND
  Assessment of the propensity of novel drugs to cause proarrhythmia is essential in the drug development process. It is increasingly recognized, however, that QT prolongation alone is an imperfect surrogate marker for Torsades de Pointes (TdP) arrhythmia prediction. In the present study we investigated the behavior of a novel surrogate marker for TdP, the electro-mechanical (E-M) window, prior to triggering of TdP episodes with sympathetic stimulation after administration of a number of reference compounds.
  
  
  METHODS
  Experiments were carried out in closed chest pentobarbital anesthetized guinea pigs. Test compounds were administered intravenously together with a specific I(Ks) blocker (JNJ303; 0.2 mgkg(-1)min(-1) for 3 min) and adrenaline (0.06 mgkg(-1)min(-1) for 2 min) was applied to trigger TdP. ECG, blood- and left ventricular pressure signals were measured continuously throughout the experiments. The E-M window i.e. the duration of the mechanical systole (QLVP(end) interval) minus the duration of the electrical activity (QT interval) was assessed for individual beats.
  
  
  RESULTS
  Drugs with documented TdP liability (quinidine, haloperidol, domperidone, terfenadine, moxifloxacin, ciprofloxacin and dofetilide) produced TdP in the protocol after adrenaline infusion, whereas negative control compounds (verapamil, ranolazine, amiodarone and saline) did not cause TdP arrhythmia, even though increases in repolarization times were observed. TdP were typically preceded by large (greater than -50 ms) negative electro-mechanical windows and were accompanied by aftercontractions.
  
  
  CONCLUSIONS
  The present study in anesthetized guinea pigs indicates that negative E-M windows are a prerequisite for sympathetically-driven TdP induction after the administration of various agents with known proarrhythmic potential. These data are a first step in the validation of this novel protocol; however we believe that this proarrhythmia model in small animals might be a valuable additional tool in the prediction of TdP risk of new chemical entities at the early stages of drug discovery.
authors.affiliation: Bio-Plus Safety Pharmacology, Vlasmeer 5/0003, B-2400 Mol, Belgium. pg@bio-plus.org
authors.forename: P-J
authors.initials: PJ
authors.lastname: Guns
authors.forename: D M
authors.initials: DM
authors.lastname: Johnson
authors.forename: E
authors.initials: E
authors.lastname: Weltens
authors.forename: J
authors.initials: J
authors.lastname: Lissens
mesh_terms: D000758:Anesthesia; D000818:Animals; D004195:Disease Models, Animal; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004837:Epinephrine