Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts

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Title Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts
Author Willems, Laura; Reichelt, Melissa Elizabeth; Molina, Jose G; Sun, Chun-Xiao; Chunn, Janci L; Ashton, Kevin John; Schnermann, Jurgen; Blackburn, Michael R; Headrick, John Patrick
Journal Name Cardiovascular Research
Editor Hans Michael Piper
Year Published 2006
Place of publication Netherlands
Publisher Elsevier BV
Abstract OBJECTIVE: Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A(1)AR) deficiency on AR-mediated responses and ischaemic tolerance. METHODS: Normoxic function and responses to 20 or 25min ischaemia and 45min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A(1)ARs. RESULTS: Neither ADA or A(1)AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A(1)AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A(1)AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25min ischaemia, reducing ventricular diastolic pressure (by 45%; 21+/-4 vs. 38+/-3mm Hg) and lactate dehydrogenase (LDH) efflux (by 40%; 0.12+/-0.01 vs. 0.21+/-0.02U/g/min ischaemia), and enhancing pressure development (by 35%; 89+/-6 vs. 66+/-5mm Hg). Similar protection was evident after 20min ischaemia, and was mimicked by the ADA inhibitor EHNA (5muM). Deletion of ADA also enhanced tolerance in A(1)AR deficient hearts, though effects on diastolic pressure were eliminated. CONCLUSIONS: Deficiency of ADA does not alter sensitivities of cardiovascular A(1) or A(2)ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A(1)AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A(1)AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.
Peer Reviewed Yes
Published Yes
Volume 71
Issue Number 1
Edition 2006
Page from 79
Page to 87
ISSN 0008-6363
Date Accessioned 2006-07-02
Language en_AU
Research Centre Heart Foundation Research Centre; Griffith Health Institute
Faculty Griffith Health Faculty
Subject Cell Metabolism; Systems Physiology
URI http://hdl.handle.net/10072/14271
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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