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Cardiovascular Research 2001 52(1):120-129; doi:10.1016/S0008-6363(01)00360-1
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Cardioprotection with adenosine metabolism inhibitors in ischemic–reperfused mouse heart

Jason Pearta, G. Paul Matherneb, Rachael J. Cerniwayb and John P. Headricka,*

aHeart Foundation Research Centre, Griffith University Gold Coast Campus, Southport, QLD 4217 Australia
bDepartment of Pediatrics and the Cardiovascular Research Center, University of Virginia Health Sciences Center, Charlottesville, VA, USA

j.headrick{at}mailbox.gu.edu.au

* Corresponding author. Tel.: +61-7-5552-8292; fax: +61-7-5552-8908

Objectives: 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 µM erythro-2-(2-hydroxy-3-nonyl)adenine; EHNA) adenosine kinase inhibition (10 µM iodotubercidin; IODO), or 10 µM adenosine. Hearts overexpressing A1 adenosine receptors (A1ARs) 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 µM adenosine. Protection with EHNA was reversed by co-infusion of IODO or 50 µM 8-{rho}-sulfophenyltheophylline (adenosine receptor antagonist), but unaltered by 20 µM inosine+10 µm hypoxanthine. Similarly, effects of iodotubercidin were inhibited by EHNA and 8-{rho}-sulfophenyltheophylline. A1AR 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.

KEYWORDS Adenosine; Contractile function; Ischemia; Reperfusion; Stunning


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