title: Atrial-selective antiarrhythmic actions of novel Ikur vs. Ikr, Iks, and IKAch class Ic drugs and beta blockers in pigs.
abstract: BACKGROUND
  The Kv1.5 channel, underlying IKur, is supposed to be atrial selective in pigs and humans. We investigated the effects of different potassium channel blockers, i.e. the IKur blockers AVE 0118, S9947 and S20951, with amiodarone (AM), dofetilide (DO), azimilide (AZ), ibutilide (IB), the IKs blocker HMR 1556, atropine (ATR), flecainide (FL), propafenone (PR), d,l-sotalol (SO), atenolol (ATE), and esmolol (ES), on the left and right atrial and ventricular refractoriness and left atrial vulnerability (LAV) in vivo in pigs.
  
  
  METHODS
  In pentobarbital-anesthetized pigs (n=81), atrial and ventricular effective refractory periods (ERPs) were measured with the S1-S2-extrastimulus-method and QTc time from electrocardiograms. LAV was assessed after S2-extrastimulus to the left atrium.
  
  
  RESULTS
  All IKur blockers prolonged left stronger than right atrial ERP and did not change QTc. All IKr blockers predominantly prolonged the right vs. left atria. AM prolonged both atria equally, and ATR the left only. Pure beta blockers acted predominantly on the left atrium, as did FL and PR, while d,l-sotalol acted predominantly on the right. AVE 0118, S9947, S20951, ibutilide, and d,l-sotalol significantly decreased LAV (-100%, -100%, -82%, -53%, -42%; p<0.05), in contrast to all other drugs.
  
  
  CONCLUSIONS
  The IKur blockers exhibited stronger effects on the left atrium, which itself has shorter refractoriness, but strikingly with no effect on ventricular repolarization, while IKr blockers, IKs blockers, and d,l-sotalol exerted predominantly right atrial effects and known ventricular effects. IKur blockers inhibited atrial tachyarrhythmias stronger than all available drugs. Therefore, IKur blockers seem to be promising new atrial-selective antiarrhythmic drugs.
authors.affiliation: DG Cardiovascular Diseases, Aventis Pharma, Frankfurt am Main, Germany. Knobloch@thg.mh-hannover.de
authors.forename: Karsten
authors.initials: K
authors.lastname: Knobloch
authors.forename: Joachim
authors.initials: J
authors.lastname: Brendel
authors.forename: Björn
authors.initials: B
authors.lastname: Rosenstein
authors.forename: Markus
authors.initials: M
authors.lastname: Bleich
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Busch
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Wirth
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016275:Atrial Function / Q000187:drug effects* / Q000502:physiology; D001285:Atropine / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D005424:Flecainide / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000145:classification / Q000187:drug effects / Q000502:physiology; D011405:Propafenone / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology
chemical_list: D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D001713:Biphenyl Compounds; D002839:Chromans; C420023:HMR 1556; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011412:Propanolamines; D013449:Sulfonamides; C067192:ibutilide; D011405:Propafenone; C086123:azimilide; D001285:Atropine; D013015:Sotalol; D005424:Flecainide; C036604:esmolol; D000638:Amiodarone; C063533:dofetilide