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Effects of genetic deletion of adenosine deaminase and A1 receptors in normoxic and ischemic hearts
Author(s) -
Reichelt Melissa,
Willems Laura,
Schnermann Jurgen,
Blackburn Michael,
Headrick John
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a743
Subject(s) - adenosine , adenosine deaminase , medicine , adenosine receptor , ischemia , endocrinology , contractility , ischemic preconditioning , bradycardia , adenosine a1 receptor , ehna , biology , chemistry , receptor , heart rate , agonist , blood pressure
Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and receptor (AR) agonism and functionality. We assessed effects of ADA, A 1 AR, and dual ADA/A 1 AR knockout (KO) on AR‐mediated responses and ischemic tolerance (20–25 min ischemia 45 min reperfusion) in murine hearts. Neither ADA or A 1 AR KO modified basal contractility, though ADA KO reduced resting heart rate (an effect abrogated by A 1 AR KO). AR‐mediated bradycardia and dilation with 2‐chloroadenosine was unaltered by ADA KO, and A 1 AR KO eliminated bradycardia. Adenosine efflux was increased 10‐ to 20‐fold by ADA KO (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischemia, reducing diastolic pressure (21±4 vs. 38±3 mmHg) and LDH efflux (0.12±0.01 vs. 0.21±0.02 U/g/min ischemia), and enhancing pressure development (89±6 vs . 66±5 mmHg). Protection was also evident after 20 min ischemia, and mimicked by the ADA inhibitor EHNA (5 μM). ADA KO enhanced tolerance in A 1 AR KO hearts, though effects on diastolic function were eliminated. Summary Absence of ADA does not alter functional sensitivities of cardiovascular A 1 or A 2 ARs, despite enhanced adenosine levels, but enhances ischemic tolerance. Conversely, A 1 AR KO impairs ischemic tolerance. Effects of ADA KO on diastolic dysfunction are A 1 AR‐specific while other ARs contribute to changes in contractile recovery and cell death.