title: Regular dipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury: is it time to revisit PARIS?
abstract: BACKGROUND
  Increased activated Akt and eNOS expression coincide with this persistent cardioprotection. Emergent coronary reperfusion therapies are rarely carried out before considerable myocardial injury has occurred. Moreover, reperfusion after prolonged ischemia produces paradoxical ischemia-reperfusion injury, attenuating the efficacy of reperfusion therapies. This has provided impetus for identifying chronic therapies to protect against ischemia-reperfusion injury in those at risk. We previously found that regular dipyridamole therapy produces a chronic preconditioning-like effect mediated through adenosine A1 receptors.
  
  
  METHODS
  To determine how long this chronic preconditioning effect of dipyridamole remains present after discontinuing therapy, guinea pigs received 4 mg/kg/day in their water for 6 weeks. Ischemia-reperfusion was performed at 0, 2, 3, and 4 days after dipyridamole discontinuation (0 day, 2 days, 3 days and 4 days; n=8 per group). Left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), coronary flow (CF), infarct size, and western blot analyses for Akt and endothelial nitric oxide synthase (eNOS) were studied.
  
  
  RESULTS
  After ischemia-reperfusion, 0 day, 2 days and 3 days, but not 4 days, had significantly higher LVDP and lower LVEDP compared to control. Myocardial infarct size was significantly reduced at 0 day, 2 days and 3 days, but not 4 days, compared to control. Western blot analyses demonstrated upregulation of phospho-Akt and phospho-eNOS expression at 0 day, 2 days, and 3 days, but not 4 days.
  
  
  CONCLUSIONS
  A chronic preconditioning-like cardioprotection by regular dipyridamole treatment persists for 3 days after discontinuing therapy. Increased activated Akt and eNOS expression may play a role in this persistent cardioprotection.
authors.affiliation: Einstein Institute for Heart and Vascular Health, Einstein Medical Center, Philadelphia, United States; Jefferson Medical College, Thomas Jefferson University, Philadelphia, United States.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Figueredo
authors.affiliation: Department of Anesthesiology, Osaka Dental University, Osaka, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Okusa
authors.affiliation: Department of Anesthesiology, Osaka Dental University, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kaneda
authors.affiliation: Department of Anesthesiology, Osaka Dental University, Osaka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Inamura
authors.affiliation: Internal Medicine, Osaka Dental University, Osaka, Japan. Electronic address: miyamae0907@gmail.com.
authors.forename: Masami
authors.initials: M
authors.lastname: Miyamae
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D004176:Dipyridamole / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D004176:Dipyridamole; D001241:Aspirin
keywords: Adenosine; Akt; Dipyridamole; Endothelial nitric oxide synthase; Ischemia–reperfusion injury; Preconditioning