title: Acadesine extends the window of protection afforded by ischaemic preconditioning in conscious rabbits.
abstract: OBJECTIVE
  Ischaemic preconditioning protects myocardium from infarction if the reperfusion interval between the brief and prolonged ischaemic intervals is less than 1 h. In anaesthetised rabbits acadesine (5-amino-4-imidazolecarboxamide riboside, AICAR), an adenosine enhancer which increases tissue adenosine during ischaemia, prolongs the window of protection to 2 h. The aim of this study was to try to determine the maximum extension of this window of protection, using chronically instrumented, unsedated rabbits.
  
  
  METHODS
  Rabbits were instrumented with a balloon occluder around a major branch of the left coronary artery for reversible coronary occlusion. Five to seven days after surgery all animals underwent a 30 min coronary occlusion. Animals were randomised to one of seven groups: (1) No additional treatment (control); (2) Ischaemic preconditioning with 5 min regional ischaemia followed by 10 min reperfusion before the 30 min coronary occlusion; (3) and (4) Ischaemic preconditioning followed by 2 or 4 h of reperfusion before the 30 min occlusion, respectively; (5) Treatment with acadesine (2.5 mg.kg-1.min-1 intravenously for 5 min and then 0.5 mg.kg-1.min-1 beginning 45 min before and continuing until 30 min after release of the 30 min occlusion) without ischaemic preconditioning; (6) and (7) Treatment with the higher dose of acadesine for 5 min beginning 35 min before the 5 min ischaemic period, and then the lower dose continuing until 30 min after release of the 30 min coronary occlusion in rabbits with 4 or 6 h reperfusion intervals, respectively.
  
  
  RESULTS
  Rabbits with ischaemic preconditioning with 10 min reperfusion preceding the 30 min coronary occlusion (group 2) had only 5.6(SEM 1.1)% infarction of the ischaemic zone. Ischaemic preconditioning followed by 2 h reperfusion (group 3) offered continued protection [18.2(2.2)% infarction] as compared to control animals [37.7(2.6)% infarction]. However, protection waned if ischaemic preconditioning was followed by 4 h reperfusion (group 4) [36.7(3.0)% infarction]. Additionally, treatment with acadesine alone did not modify infarct size (group 7) [39.5(4.0)%], but acadesine largely restored the protection of ischaemic preconditioning despite a 4 h reperfusion interval (group 5) [20.4(3.0)% infarction, P < 0.01 v control]. However, when reperfusion was extended to 6 h (group 6) acadesine could no longer restore protection [36.2(0.9)% infarction].
  
  
  CONCLUSIONS
  The protection afforded by a 5 min ischaemic preconditioning period lasts from 2 to 4 h in the awake, unsedated rabbit, and acadesine can extend the duration of this window of protection to at least 4 h but not to 6 h.
authors.affiliation: Department of Medicine, University of South Alabama, College of Medicine, Mobile 36688, USA.
authors.forename: B
authors.initials: B
authors.lastname: Burckhartt
authors.forename: X M
authors.initials: XM
authors.lastname: Yang
authors.forename: A
authors.initials: A
authors.lastname: Tsuchida
authors.forename: K M
authors.initials: KM
authors.lastname: Mullane
authors.forename: J M
authors.initials: JM
authors.lastname: Downey
authors.forename: M V
authors.initials: MV
authors.lastname: Cohen
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D009203:Myocardial Infarction / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000378:metabolism; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D011817:Rabbits; D012263:Ribonucleosides / Q000627:therapeutic use*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000517:prevention & control
chemical_list: D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D000241:Adenosine