Selective adenosine A3 receptor stimulation reduces ischemic myocardial injury in the rabbit heart.
OBJECTIVE
The aim of this study was to determine whether selective activation of the adenosine A3 receptor reduces infarct size in a Langendorff model of myocardial ischemia-reperfusion injury.


METHODS
Buffer-perfused rabbit hearts were exposed to 30 min regional ischemia and 120 min of reperfusion. Infarct size was measured by tetrazolium staining and normalized for area-at-risk (IA/AAR).


RESULTS
Preconditioning by 5 min global ischemia and 10 min reperfusion reduced infarct size (IA/AAR) to 19 +/- 4% (controls: 67 +/- 5%). Replacing global ischemia with 5 min perfusion of the rabbit A3-selective agonist, IB-MECA (A3 Ki: 2 nM; A1 Ki: 30 nM) elicited a concentration-dependent reduction in infarct size; 50 nM IB-MECA reduced IA/AAR to 24 +/- 4%. The A1-selective agonist, R-PIA (25 nM) reduced IA/AAR to a similar extent (21 +/- 6%). However, while the cardioprotective effect of R-PIA was significantly inhibited (54 +/- 7% IA/AAR) by the rabbit A1-selective antagonist, BWA1433 (50 nM), the IB-MECA-dependent cardioprotection was unaffected (28 +/- 6% IA/AAR). A non-selective (A1 vs. A3) concentration of BWA1433 (5 microM) significantly attenuated the IB-MECA-dependent cardioprotection (61 +/- 7% IA/AAR).


CONCLUSIONS
These data clearly demonstrate that selective A3 receptor activation provides cardioprotection from ischemia-reperfusion injury in the rabbit heart. Furthermore, the degree of A3-dependent cardioprotection is similar to that provided by A1 receptor stimulation or ischemic preconditioning.
Tracey
W R
WR
Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, CT 06340, USA. w_ross_tracey@groton.pfizer.com
Magee
W
W
Masamune
H
H
Kennedy
S P
SP
Knight
D R
DR
Buchholz
R A
RA
Hill
R J
RJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010660:Phenylisopropyladenosine / Q000627:therapeutic use*; D011817:Rabbits; D011983:Receptors, Purinergic / Q000187:drug effects*; D013268:Stimulation, Chemical
D011983:Receptors, Purinergic; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D010660:Phenylisopropyladenosine; D000241:Adenosine