Copyright © 2006, European Society of Cardiology
Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts
aHeart Foundation Research Center, Griffith University, Southport, QLD 4217, Australia
bDepartment of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Medical School, Houston, TX 77030, USA
cNational Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
* Corresponding author. Tel.: +61 7 5552 8292; fax: +61 7 5552 8802. Email address: J.Headrick{at}griffith.edu.au
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 A1AR) 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 A1ARs.
Results Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR 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 (5µM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated.
Conclusions Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.
KEYWORDS Experimental; Heart; Organ; Biochemistry; General physiology; Pharmacology; Adenosine deaminase; Adenosine receptor; Gene knockout; Ischemia
1 The first two authors contributed equally to this study and manuscript.
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