title: Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine.
abstract: OBJECTIVE
  This study tested the hypothesis that brief cycles of iterative ischemia-reperfusion at onset of reperfusion (termed "postconditioning", post-con) delays washout of intravascular adenosine and thereby increases endogenous adenosine receptor (AR) activation during the early moments of reperfusion (R).
  
  
  METHODS
  Isolated mouse hearts were subjected to 20 min global ischemia (I) and 30 min R with or without post-con (3 or 6 cycles of 10 s R&I). Intravascular purines in coronary effluent were analyzed by HPLC. To assess the functional role of endogenous AR activation in post-con, an open-chest rat model of myocardial infarction was employed. Rats were randomly divided into 11 groups: control, no intervention at R; post-con, three cycles of 10 s R followed by 10 s LCA re-occlusion immediately upon R. In the following interventions, drugs (or vehicle) were administered 5 min before R in the absence or presence (+/-) of post-con. Vehicle (DMSO < 300 microl/kg); 8-SPT (non-selective AR antagonist, 10 mg/kg) +/- post-con; DPCPX (A(1A)R antagonist, 0.1 mg/kg) +/- post-con; ZM241385 (A(2A)AR antagonist, 0.2 mg/kg) +/- post-con; MRS1523 (A(3)AR antagonist, 2 mg/kg) +/- post-con.
  
  
  RESULTS
  In isolated mouse hearts, post-con reduced diastolic pressure during both early (26+/-3* vs. 37+/-3 mmHg at 5 min) and late (22+/-3* vs. 34+/-3 mmHg at 30 min) R. Post-con also hastened the early recovery of contractile function (developed pressure 39+/-6* vs. 16+/-2 mmHg at 5 min R), although differences did not persist at 30 min R. Importantly, post-con was associated with reduced adenosine washout (58+/-5* vs. 155+/-16 nM/min/g) at 2 min R suggesting greater retention time of intravascular adenosine. In rats, post-con significantly attenuated infarct size compared to control (40+/-3% vs. 53 +/- 2%* in control), an effect that was unaltered by DPCPX (42 +/- 2%) but was abrogated by 8-SPT (50 +/- 2%), ZM241385 (49 +/- 3%) or MRS1523 (52 +/- 1%) (P < 0.02).
  
  
  CONCLUSIONS
  These data suggest that post-con involves endogenous activation of A(2A) and A3 but not A1AR subtypes. This activation may be linked to the delay in the washout of intravascular adenosine during the early minutes of R during which post-con is applied.
authors.affiliation: Department of Cardiothoracic Surgery, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University School of Medicine, 550 Peachtree Street, NE Atlanta, GA 30308-2225, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kin
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Zatta
authors.forename: Mark T
authors.initials: MT
authors.lastname: Lofye
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Amerson
authors.forename: Michael E
authors.initials: ME
authors.lastname: Halkos
authors.forename: Faraz
authors.initials: F
authors.lastname: Kerendi
authors.forename: Zhi-Qing
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: Robert A
authors.initials: RA
authors.lastname: Guyton
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.forename: Jakob
authors.initials: J
authors.lastname: Vinten-Johansen
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D058915:Purinergic P1 Receptor Antagonists; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; C031433:8-(4-sulfophenyl)theophylline; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000241:Adenosine