Targeted deletion of A(3) adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium.
A(3) adenosine receptors (A(3)ARs) have been implicated in regulating mast cell function and in cardioprotection during ischemia-reperfusion injury. The physiological role of A(3)ARs is unclear due to the lack of widely available selective antagonists. Therefore, we examined mice with targeted gene deletion of the A(3)AR together with pharmacological studies to determine the role of A(3)ARs in myocardial ischemia-reperfusion injury. We evaluated the functional response to 15-min global ischemia and 30-min reperfusion in isovolumic Langendorff hearts from A(3)AR(-/-) and wild-type (A(3)AR(+/+)) mice. Loss of contractile function during ischemia was unchanged, but recovery of developed pressure in hearts after reperfusion was improved in A(3)AR(-/-) 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 A(3)AR(-/-) hearts (4.5 +/- 1 vs. 7.5 +/- 1 U/g). The adenosine receptor antagonist BW-A1433 (50 microM) decreased functional recovery following ischemia in A(3)AR(-/-) 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 A(3)AR(-/-) hearts. In summary, targeted deletion of the A(3)AR improved functional recovery and tissue viability during reperfusion following ischemia. These data suggest that activation of A(3)ARs contributes to myocardial injury in this setting in the rodent. Since A(3)ARs are thought to be present on resident mast cells in the rodent myocardium, we speculate that A(3)ARs may have proinflammatory actions that mediate the deleterious effects of A(3)AR activation during ischemia-reperfusion injury.
Cerniway
R J
RJ
Department of Pediatrics and the Cardiovascular Research Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.
Yang
Z
Z
Jacobson
M A
MA
Linden
J
J
Matherne
G P
GP
D000222:Adaptation, Physiological; D000241:Adenosine / Q000037:antagonists & inhibitors; D000818:Animals; D006321:Heart / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009203:Myocardial Infarction / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology
D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D014970:Xanthines; C056346:BW A1433; D000241:Adenosine