title: Cardioprotection with adenosine metabolism inhibitors in ischemic-reperfused mouse heart.
abstract: OBJECTIVE
  To characterize the 'anti-ischemic' effects of adenosine metabolism inhibition in ischemic-reperfused myocardium.
  
  
  METHODS
  Perfused C57/B16 mouse hearts were subjected to 20 min ischemia 40 min reperfusion in the absence or presence of adenosine deaminase inhibition (50 microM erythro-2-(2-hydroxy-3-nonyl)adenine; EHNA) adenosine kinase inhibition (10 microM iodotubercidin; IODO), or 10 microM adenosine. Hearts overexpressing A(1) adenosine receptors (A(1)ARs) were also studied.
  
  
  RESULTS
  EHNA treatment reduced ischemic contracture and post-ischemic diastolic pressure (14+/-2 vs. 20+/-1 mmHg), increased recovery of developed pressure (66+/-3 vs. 53+/-2%) and reduced LDH efflux (8.9+/-1.6 vs. 18.0+/-1.7 I.U./g). IODO also improved functional recovery (to 60+/-2%) and reduced LDH efflux (5.3+/-1.7 I.U./g), as did treatment with 10 microM adenosine. Protection with EHNA was reversed by co-infusion of IODO or 50 microM 8-rho-sulfophenyltheophylline (adenosine receptor antagonist), but unaltered by 20 microM inosine+10 microm hypoxanthine. Similarly, effects of iodotubercidin were inhibited by EHNA and 8-rho-sulfophenyltheophylline. A(1)AR overexpression exerted similar effects to EHNA and EHNA or IODO alone enhanced recovery while EHNA+IODO reduced recovery in transgenic hearts. Functional recoveries and xanthine oxidase reactant levels were unrelated in the groups studied.
  
  
  CONCLUSIONS
  Adenosine deaminase or kinase inhibition protects from ischemia-reperfusion. Cardioprotection via these enzyme inhibitors requires a functioning purine salvage pathway and involves enhanced adenosine receptor activation. Reduced formation of inosine is unimportant in EHNA-mediated protection.
authors.affiliation: Heart Foundation Research Centre, Griffith University Gold Coast Campus, QLD 4217, Southport, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Peart
authors.forename: G P
authors.initials: GP
authors.lastname: Matherne
authors.forename: R J
authors.initials: RJ
authors.lastname: Cerniway
authors.forename: J P
authors.initials: JP
authors.lastname: Headrick
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000241:Adenosine / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology*; D010477:Perfusion; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000235:genetics; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C010192:9-(2-hydroxy-3-nonyl)adenine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D000248:Adenosine Kinase; D000225:Adenine; D000241:Adenosine; D014372:Tubercidin