title: Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs.
abstract: BACKGROUND
  Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal arrhythmic disorder caused by mutations in the type-2 ryanodine receptor (RyR2). Mutant RyR2 cause abnormal Ca2+leak from the sarcoplasmic reticulum (SR), which is associated with the development of arrhythmias.
  
  
  OBJECTIVE
  To determine whether derivatives of tetracaine, a local anesthetic drug with known RyR2 inhibiting action, could prevent CPVT induction by suppression of RyR2-mediated SR Ca2+leak.
  
  
  RESULTS
  Confocal microscopy was used to assess the effects of tetracaine and 9 derivatives (EL1-EL9) on spontaneous Ca2+sparks in ventricular myocytes isolated from RyR2-R176Q/+ mice with CPVT. Whereas each derivative suppressed the Ca2+spark frequency, derivative EL9 was most effective at the screening dose of 500nmol/L. At this high dose, the Ca2+transient amplitude was not affected in myocytes from WT or R176Q/+ mice. The IC50of EL9 was determined to be 13nmol/L, which is about 400× time lower than known RyR2 stabilizer K201. EL9 prevented the induction of ventricular tachycardia observed in placebo-treated R176Q/+ mice, without affecting heart rate or cardiac contractility.
  
  
  CONCLUSIONS
  Tetracaine derivatives represent a novel class of RyR2 stabilizing drugs that could be used for the treatment of the potentially fatal disorder catecholaminergic polymorphic ventricular tachycardia.
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Physics, Portland State University, Portland, OR 97207, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Sibrian-Vazquez
authors.affiliation: Department of Physics, Portland State University, Portland, OR 97207, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Klipp
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Julia O
authors.initials: JO
authors.lastname: Reynolds
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tarah A
authors.initials: TA
authors.lastname: Word
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Scott
authors.affiliation: Department of Medicine, Heart and Vascular Institute, University of Pittsburgh, Pittsburg, PA 15260, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
authors.affiliation: Department of Chemistry, Portland State University, Portland, OR 97207, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strongin
authors.affiliation: Department of Physics, Portland State University, Portland, OR 97207, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Abramson
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wehrens@bcm.edu.
authors.forename: Xander H T
authors.initials: XHT
authors.lastname: Wehrens
mesh_terms: D000779:Anesthetics, Local / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000235:genetics*; D013748:Tetracaine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000779:Anesthetics, Local; D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C000592748:ryanodine receptor 2. mouse; D013748:Tetracaine; C109183:K201 compound
keywords: Calcium leak; Catecholaminergic polymorphic ventricular tachycardia; Sarcoplasmic reticulum; Tetracaine; Type-2 ryanodine receptor