title: Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations.
abstract: BACKGROUND
  Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2).
  
  
  OBJECTIVE
  To test a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs).
  
  
  METHODS
  Intracellular Ca(2+) and membrane voltage were simultaneously recorded by using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue VK-II-36, which does not have significant beta-blocking effects.
  
  
  RESULTS
  Spontaneous intracellular Ca(2+) elevations (SCaEs) during diastole were induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496(+/-) mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs by using a rabbit model of acquired long QT syndrome, in which phase 2 and phase 3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase 2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase 3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied.
  
  
  CONCLUSIONS
  A carvedilol analogue, VK-II-36, inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by the suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs.
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xiao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Kannan
authors.initials: K
authors.lastname: Vembaiyan
authors.forename: Su-Kiat
authors.initials: SK
authors.lastname: Chua
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart-von der Lohe
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Back
authors.forename: S R Wayne
authors.initials: SR
authors.lastname: Chen
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D002227:Carbazoles; D009025:Morpholines; D011412:Propanolamines; C581749:VK-II-36 compound; D000077261:Carvedilol; D007545:Isoproterenol; D002118:Calcium