title: Reduced Arrhythmia Inducibility With Calcium/Calmodulin-dependent Protein Kinase II Inhibition in Heart Failure Rabbits.
abstract: BACKGROUND
  Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in heart failure (HF) and can contribute to arrhythmias induced by β-adrenergic receptor-mediated sarcoplasmic reticulum calcium leak.
  
  
  OBJECTIVE
  To evaluate the effect of CaMKII inhibition on ventricular tachycardia (VT) induction in conscious HF and naive rabbits.
  
  
  RESULTS
  Nonischemic HF was induced by aortic insufficiency and constriction. Electrocardiograms were recorded in rabbits pretreated with vehicle (saline) or the CaMKII inhibitor KN-93 (300 μg/kg); VT was induced by infusion of increasing doses of norepinephrine (1.56-25 μg·kg⁻¹·min⁻¹) in naive (n = 8) and HF (n = 7) rabbits. With saline, median VT dose threshold in HF was 6.25 versus 12.5 μg·kg⁻¹·min⁻¹ norepinephrine in naive rabbits (P = 0.06). Pretreatment with KN-93 significantly increased VT threshold in HF and naive rabbits (median = 25 μg·kg⁻¹·min⁻¹, P < 0.05 vs. saline for both groups). Mean cycle length of VT initiation was shorter in HF (221 ± 20 milliseconds) than naive (296 ± 23 milliseconds, P < 0.05) rabbits with saline; this difference was not significant after treatment with KN-93.
  
  
  CONCLUSIONS
  KN-93 significantly reduced arrhythmia inducibility and slowed initiation of VT, suggesting that CaMKII inhibition may have antiarrhythmic effects in the failing human heart.
authors.affiliation: *Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL; †Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; ‡Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; and §Department of Pharmacology, University of California Davis, Davis, CA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Hoeker
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Hanafy
authors.forename: Robert A
authors.initials: RA
authors.lastname: Oster
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pogwizd
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D004789:Enzyme Activation; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control*; D000096926:Benzenesulfonamides
chemical_list: D000889:Anti-Arrhythmia Agents; D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009638:Norepinephrine; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides