title: Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.
abstract: BACKGROUND
  Ranolazine (Ran) is known to inhibit multiple targets, including the late Na(+)current, the rapid delayed rectifying K(+)current, the L-type Ca(2+)current, and fatty acid metabolism. Functionally, Ran suppresses early afterdepolarization (EADs) and torsades de pointes (TdP) in drug-induced long QT type 2 (LQT2) presumably by decreasing intracellular [Na(+)](i) and Ca(2+)overload. However, simulations of EADs in LQT2 failed to predict their suppression by Ran.
  
  
  OBJECTIVE
  To elucidate the mechanism(s) whereby Ran alters cardiac action potentials (APs) and cytosolic Ca(2+)transients and suppresses EADs and TdP in LQT2.
  
  
  METHODS
  The known effects of Ran were included in simulations (Shannon and Mahajan models) of rabbit ventricular APs and Ca(2+)transients in control and LQT2 models and compared with experimental optical mapping data from Langendorff rabbit hearts treated with E4031 (0.5 μM) to block the rapid delayed rectifying K(+)current. Direct effects of Ran on cardiac ryanodine receptors (RyR2) were investigated in single channels and changes in Ca(2+)-dependent high-affinity ryanodine binding.
  
  
  RESULTS
  Ran (10 μM) alone prolonged action potential durations (206 ± 4.6 to 240 ± 7.8 ms; P <0.05); E4031 prolonged action potential durations (204 ± 6 to 546 ± 35 ms; P <0.05) and elicited EADs and TdP that were suppressed by Ran (10 μM; n = 7 of 7 hearts). Simulations (Shannon but not Mahajan model) closely reproduced experimental data except for EAD suppression by Ran. Ran reduced open probability (P(o)) of RyR2 (half maximal inhibitory concentration = 10 ± 3 μM; n = 7) in bilayers and shifted half maximal effective concentration for Ca(2+)-dependent ryanodine binding from 0.42 ± 0.02 to 0.64 ± 0.02 μM with 30 μM Ran.
  
  
  CONCLUSIONS
  Ran reduces P(o) of RyR2, desensitizes Ca(2+)-dependent RyR2 activation, and inhibits Ca(i) oscillations, which represents a novel mechanism for its suppression of EADs and TdP.
authors.affiliation: Department of Bioengineering, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Parikh
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Mantravadi
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kozhevnikov
authors.forename: Michael A
authors.initials: MA
authors.lastname: Roche
authors.forename: Yanping
authors.initials: Y
authors.lastname: Ye
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Owen
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Puglisi
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Abramson
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D008133:Long QT Syndrome / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D000069458:Ranolazine; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D019837:Ryanodine Receptor Calcium Release Channel; D000069458:Ranolazine