Protecting murine hearts from ischaemia–reperfusion using selective inhibitors of adenosine metabolism

Willems, Laura, and Headrick, John P. (2005) Protecting murine hearts from ischaemia–reperfusion using selective inhibitors of adenosine metabolism. Clinical and Experimental Pharmacology and Physiology, 32 (3). pp. 179-183.

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Abstract

1. By selectively modifying adenosine metabolism via adenosine deaminase or adenosine kinase inhibitors, it may be possible to enhance the receptor-mediated protective actions of adenosine in a site- and event-specific fashion.

2. We characterized cardioprotective actions of the adenosine deaminase inhibitor erythro-2-(2-hydroxy-3-non-yl)adenine (EHNA) and the adenosine kinase inhibitor iodotubercidin in C57/Bl6 mouse hearts subjected to 20 min global normothermic ischaemia and 40 min reperfusion.

3. Ventricular pressure development only recovered to 45 ± 2% of baseline levels (67 ± 5 mmHg) in untreated hearts, with sustained and pronounced diastolic contracture (25 ± 2 mmHg). Treatment with 20 µmol/L EHNA increased recovery of ventricular pressure (107 ± 9 mmHg), reduced postischaemic diastolic pressure (13 ± 1 mmHg) and reduced loss of lactate dehydrogenase (LDH; an indicator of necrotic damage) by 50% (9 ± 2 vs 19 ± 2 IU/g). Adenosine kinase inhibition with 10 µmol/L iodotubercidin also improved pressure development (to 100 ± 8 mmHg) and reduced LDH efflux (5 ± 2 IU/g).

4. Protective actions were mimicked by adenosine and inhibited by adenosine receptor antagonism (50 µmol/L 8-ρ-sulfophenyltheophylline) and mitochondrial KATP channel inhibition (50 µmol/L 5-hydroxydecanoate).

5. Coinfusion of the inhibitors, 'trapping' formed adenosine, failed to exert protection and, in some instances, was detrimental. Although substantial benefit was gained by these agents in hearts from young animals, neither inhibitor was effective in 'aged' hearts (18 months).

6. Our data demonstrate that adenosine deaminase or kinase inhibition substantially limits injury during ischaemia–reperfusion. Protection involves adenosine receptor activation. However, cardioprotection via either enzyme inhibitor requires an alternative purine-salvage pathway to be functional and was reduced in aged hearts known to be increasingly susceptible to ischaemic damage.

Item ID: 10109
Item Type: Article (Refereed Research - C1)
Keywords: adenosine deaminase, adenosine kinase, adenosine, ageing, ischaemia, mitochondrial K ATP channels, reperfusion
ISSN: 1440-1681
Date Deposited: 19 Apr 2010 04:03
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1199 Other Medical and Health Sciences > 119999 Medical and Health Sciences not elsewhere classified @ 50%
06 BIOLOGICAL SCIENCES > 0606 Physiology > 060699 Physiology not elsewhere classified @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 50%
97 EXPANDING KNOWLEDGE > 970102 Expanding Knowledge in the Physical Sciences @ 50%
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