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

    Author(s)
    Willems, Laura
    Reichelt, Melissa E
    Molina, Jose G
    Sun, Chun-Xiao
    Chunn, Janci L
    Ashton, Kevin J
    Schnermann, Jurgen
    Blackburn, Michael R
    Headrick, John P
    Griffith University Author(s)
    Headrick, John P.
    Ashton, Kevin J.
    Reichelt, Melissa E.
    Willems, Laura
    Year published
    2006
    Metadata
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    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 ...
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    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.
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    Journal Title
    Cardiovascular Research
    Volume
    71
    Issue
    1
    Subject
    Cardiovascular medicine and haematology
    Publication URI
    http://hdl.handle.net/10072/14271
    Collection
    • Journal articles

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