title: Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS.
abstract: BACKGROUND
  Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212-2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial-type nitric oxide synthase (eNOS) expression.
  
  
  METHODS
  Male 20-week-old Zucker diabetic fatty rats were treated with vehicle, WIN, the selective CB1 or CB2 receptor antagonists AM251 and AM630, respectively, AM251 + WIN or AM630 + WIN. Hearts were isolated from these rats, and the cardiac functional response to ischaemia/reperfusion injury was evaluated. In addition, cardiac iNOS and eNOS expression were determined by western blot.
  
  
  RESULTS
  WIN significantly improved cardiac recovery after ischaemia/ reperfusion in the hearts from Zucker diabetic fatty rats by restoring coronary perfusion pressure and heart rate to preischaemic levels. Additionally, WIN decreased cardiac iNOS expression and increased eNOS expression after ischaemia/reperfusion in diabetic hearts. WIN-induced cardiac functional recovery was completely blocked by the CB2 antagonist AM630. However, changes in NOS isoenzyme expression were not affected by the CB antagonists.
  
  
  CONCLUSIONS
  This study shows a cardioprotective effect of a cannabinoid agonist on ischaemia/reperfusion injury in an experimental model of a metabolic disorder. The activation mainly of CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect. These initial studies have provided the basis for future research in this field.
authors.affiliation: Universidad Rey Juan Carlos, Facultad Ciencias de la Salud, Dpto. Farmacología y Nutrición, Alcorcón, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: González
authors.forename: Esperanza
authors.initials: E
authors.lastname: Herradón
authors.forename: Raquel
authors.initials: R
authors.lastname: Abalo
authors.forename: Gema
authors.initials: G
authors.lastname: Vera
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Pérez-Nievas
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Leza
authors.forename: Ma Isabel
authors.initials: MI
authors.lastname: Martín
authors.forename: Visitación
authors.initials: V
authors.lastname: López-Miranda
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D003331:Coronary Vessels / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009281:Naphthalenes / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D002316:Cardiotonic Agents; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C094023:iodopravadoline