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

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 micromol/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 micromol/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 micromol/L 8-rho-sulfophenyltheophylline) and mitochondrial K(ATP) channel inhibition (50 micromol/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.

journal_name

Clin Exp Pharmacol Physiol

journal_title

Clinical and experimental pharmacology & physiology

authors

Willems L,Headrick JP

doi

10.1111/j.1440-1681.2005.04168.x

keywords:

subject

Has Abstract

pub_date

2005-03-01 00:00:00

pages

179-83

issue

eissn

0305-1870

issn

1440-1681

pii

CEP4168

journal_volume

pub_type

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