title: Clofilium in the isolated perfused rabbit heart: a new model to study proarrhythmia induced by class III antiarrhythmic drugs.
abstract: OBJECTIVE
  The clinical usefulness of class III antiarrhythmic drugs for the treatment of tachyarrhythmias is limited by their potential proarrhythmic effects, mainly torsades-depointes (TdP). The goal of this experimental study was to develop an isolated whole-heart model exhibiting typical characteristics of class III drug-induced ventricular arrhythmias.
  
  
  METHODS
  Isolated rabbit hearts were perfused with a Krebs-Henseleit buffer containing 10 microM clofilium and then exposed to a modified Krebs-Henseleit buffer with 2.0 mM K+ and 0.5 mM Mg2+. Hearts subjected to either clofilium alone or modified buffer alone were used as controls.
  
  
  RESULTS
  Under clofilium the QT interval increased from 187 +/- 16 to 282 +/- 33 ms. Within 8 to 25 s after the change of the perfusate, ventricular arrhythmias developed in all hearts associated with a further QT prolongation to 380 +/- 73 ms when the first ventricular extrasystole occurred. Simultaneously, the monophasic action potential durations increased relatively more during late repolarization; from 99 +/- 21 to 110 +/- 25 ms (+11%) at 50% repolarization, from 143 +/- 24 to 178 +/- 40 ms (+24%) at 70%, and from 200 +/- 30 to 275 +/- 53 ms (+38%) at 90%. The predominant rhythm was polymorphic with either two alternating or multiple QRS morphologies exhibiting the characteristic features of torsades-depointes. All control hearts stayed in normal sinus rhythm.
  
  
  CONCLUSIONS
  Under the conditions selected, the isolated perfused rabbit heart represents a useful experimental approach to study the proarrhythmic effects of class III agents. This model provides a convenient way to manipulate the ionic and pharmacologic milieu in a preparation conserving the functional anatomy of the whole organ without interference by cardiovascular reflexes. It might be useful for analyzing the conditions favoring and preventing drug-induced torsades-depointes.
authors.affiliation: Westfälische Wilhelms-Universität, Innere Medizin C, Münster, Germany. johna@uni-muenster.de
authors.forename: R
authors.initials: R
authors.lastname: Johna
authors.forename: H
authors.initials: H
authors.lastname: Mertens
authors.forename: W
authors.initials: W
authors.lastname: Haverkamp
authors.forename: L
authors.initials: L
authors.lastname: Eckardt
authors.forename: T
authors.initials: T
authors.lastname: Niederbröker
authors.forename: M
authors.initials: M
authors.lastname: Borggrefe
authors.forename: G
authors.initials: G
authors.lastname: Breithardt
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques / Q000379:methods*; D011188:Potassium / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D000644:Quaternary Ammonium Compounds; C022799:clofilium; D008274:Magnesium; D011188:Potassium