title: Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles.
abstract: BACKGROUND
  Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs.
  
  
  OBJECTIVE
  To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles.
  
  
  METHODS
  We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Ca(i)) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats.
  
  
  RESULTS
  SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02-0.06] vs 0.23 arbitrary units [95% confidence interval 0.18-0.28] at baseline; n = 6 hearts; P <.001). Lidocaine also significantly reduced the SCaE but was significantly (P <.05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of I(Na).
  
  
  CONCLUSIONS
  Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.
authors.affiliation: Department of Medicine, Krannert Institute of Cardiology and Division of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Po Cheng
authors.initials: PC
authors.lastname: Chang
authors.forename: Hyung Wook
authors.initials: HW
authors.lastname: Park
authors.forename: Kyoung-Suk
authors.initials: KS
authors.lastname: Rhee
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Hsueh
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Hwang
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000032:analysis*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D004357:Drug Synergism; D006352:Heart Ventricles; D008012:Lidocaine / Q000494:pharmacology; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D008012:Lidocaine; D002118:Calcium