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1 Department of Pediatrics and the Cardiovascular Research Center, 2 Department of Biomedical Engineering, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; and 3 Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486
A3 adenosine receptors (A3ARs) have been
implicated in regulating mast cell function and in cardioprotection
during ischemia-reperfusion injury. The physiological role of
A3ARs is unclear due to the lack of widely available
selective antagonists. Therefore, we examined mice with targeted gene
deletion of the A3AR together with pharmacological studies
to determine the role of A3ARs in myocardial
ischemia-reperfusion injury. We evaluated the functional response to 15-min global ischemia and 30-min reperfusion in
isovolumic Langendorff hearts from A3AR
/
and wild-type (A3AR+/+) mice. Loss of
contractile function during ischemia was unchanged, but
recovery of developed pressure in hearts after reperfusion was improved
in A3AR/ compared with wild-type hearts
(80 ± 3 vs. 51 ± 3% at 30 min). Tissue viability assessed
by efflux of lactate dehydrogenase was also improved in
A3AR/ hearts (4.5 ± 1 vs. 7.5 ± 1 U/g). The adenosine receptor antagonist BW-A1433 (50 µM) decreased
functional recovery following ischemia in
A3AR/ but not in wild-type hearts. We also
examined myocardial infarct size using an intact model with 30-min left
anterior descending coronary artery occlusion and 24-h reperfusion.
Infarct size was reduced by over 60% in
A3AR/ hearts. In summary, targeted deletion
of the A3AR improved functional recovery and tissue
viability during reperfusion following ischemia. These data
suggest that activation of A3ARs contributes to myocardial injury in this setting in the rodent. Since A3ARs are
thought to be present on resident mast cells in the rodent myocardium, we speculate that A3ARs may have proinflammatory actions
that mediate the deleterious effects of A3AR activation
during ischemia-reperfusion injury.
knockout; myocardial infarction; inflammation; cardiac protection
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