title: Combined application of class I antiarrhythmic drugs causes "additive", "reductive", or "synergistic" sodium channel block in cardiac muscles.
abstract: OBJECTIVE
  The aim was to study the differences in cardiac sodium channel block among combinations of class I antiarrhythmic drugs.
  
  
  METHODS
  Conventional glass microelectrode techniques were used to record transmembrane action potentials and their maximum upstroke velocity (dV/dtmax) reflecting the sodium channel availability, during treatment of the preparations with mexiletine (20, 40 microM) in combination with aprindine (5 microM), disopyramide (40 microM), and flecainide (5 microM).
  
  
  METHODS
  Guinea pig papillary muscles (n = 6.8 per experiment) were used for the study.
  
  
  RESULTS
  In preparations constantly stimulated at 1 Hz, a shortening of action potential duration by aprindine was further enhanced, while prolongation by disopyramide or flecainide was reduced, after additional application of mexiletine. Trains of stimuli (0.5-2.0 Hz) were applied following a long quiescent period to evaluate "tonic" and "use dependent" decrease (block) of dV/dtmax. Additional application of mexiletine to the other three drugs resulted in an enhancement of tonic block. Use dependent block by aprindine at 0.5-1.0 Hz was reduced by 8-9% after admixture of mexiletine, reflected in net increase in dV/dtmax at steady states (reductive effect). Dual exponential components of dV/dtmax recovery from use dependent block in presence of both drugs suggest their competitive interaction on a common receptor site associated with sodium channels. Use dependent block by flecainide at 0.5-2.0 Hz was increased (p less than 0.01) after admixture of mexiletine. Steady state dV/dtmax was therefore largely inhibited by the drug combination (synergistic effect). Use dependent block in the presence of both disopyramide and mexiletine was similar to that predicted from the algebraic sum of each treatment.
  
  
  CONCLUSIONS
  Combined application of class I antiarrhythmic drugs causes not only additive but also reductive or synergistic effects on dV/dtmax through modulation of use dependent block.
authors.affiliation: Department of Internal Medicine, Nagoya University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawamura
authors.forename: I
authors.initials: I
authors.lastname: Kodama
authors.forename: J
authors.initials: J
authors.lastname: Toyama
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001073:Aprindine / Q000494:pharmacology; D004206:Disopyramide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004558:Electric Stimulation; D005260:Female; D005424:Flecainide / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008801:Mexiletine / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels; D008801:Mexiletine; D001073:Aprindine; D004206:Disopyramide; D005424:Flecainide