title: Pleiotropic, heart rate-independent cardioprotection by ivabradine.
abstract: OBJECTIVE
  In pigs, ivabradine reduces infarct size even when given only at reperfusion and in the absence of heart rate reduction. The mechanism of this non-heart rate-related cardioprotection is unknown. Hence, in the present study we assessed the pleiotropic action of ivabradine in more detail.
  
  
  METHODS
  Anaesthetized mice were pretreated with ivabradine (1.7 mg · kg(-1) i.v.) or placebo (control) before a cycle of coronary occlusion/reperfusion (30/120 min ± left atrial pacing). Infarct size was determined. Isolated ventricular cardiomyocytes were exposed to simulated ischaemia/reperfusion (60/5 min) in the absence and presence of ivabradine, viability was then quantified and intra- and extracellular reactive oxygen species (ROS) formation was detected. Mitochondria were isolated from mouse hearts and exposed to simulated ischaemia/reperfusion (6/3 min) in glutamate/malate- and ADP-containing buffer in the absence and presence of ivabradine respectively. Mitochondrial respiration, extramitochondrial ROS, mitochondrial ATP production and calcium retention capacity (CRC) were assessed.
  
  
  RESULTS
  Ivabradine decreased infarct size even with atrial pacing. Cardiomyocyte viability after simulated ischaemia/reperfusion was better preserved with ivabradine, the accumulation of intra- and extracellular ROS decreased in parallel. Mitochondrial complex I respiration was not different without/with ivabradine, but ivabradine significantly inhibited the accumulation of extramitochondrial ROS, increased mitochondrial ATP production and increased CRC.
  
  
  CONCLUSIONS
  Ivabradine reduces infarct size independently of a reduction in heart rate and improves ventricular cardiomyocyte viability, possibly by reducing mitochondrial ROS formation, increasing ATP production and CRC.
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Centre Essen, University of Essen Medical School, Essen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Kleinbongard
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Centre Essen, University of Essen Medical School, Essen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Gedik
authors.affiliation: Discipline of Pathology, The Charles Perkins Centre, The University of Sydney Medical School, Sydney, NSW, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Witting
authors.affiliation: Concord Repatriation General Hospital, Vascular Biology Group, ANZAC Research Institute, Concord, NSW, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Freedman
authors.affiliation: Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Klöcker
authors.affiliation: Institute for Pathophysiology, West German Heart and Vascular Centre Essen, University of Essen Medical School, Essen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Heusch
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D000077550:Ivabradine; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000378:metabolism / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001552:Benzazepines; D002316:Cardiotonic Agents; D000077550:Ivabradine