EVIDENCE THAT THE ADENOSINE A(3) RECEPTOR MAY MEDIATE THE PROTECTION AFFORDED BY PRECONDITIONING IN THE ISOLATED RABBIT HEART

Objective: Agonists selective for the A(1) adenosine receptor mimic the protective effect of ischaemic preconditioning against infarction in the rabbit heart. Unselective adenosine antagonists block this protection but, paradoxically, the A(1) adenosine receptor selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) does not. The aim of this study was to test the hypothesis that the newly described A(3) adenosine receptor, which has an agonist profile similar to the A(1) receptor but is insensitive to DPCPX, might mediate preconditioning. Methods: Isolated rabbit hearts perfused with Krebs buffer experienced 30 min of regional ischaemia followed by 120 min of reperfusion. Infarct size was measured by tetrazolium staining. Results: In control hearts infarction was 32.2(SEM 1.5)% of the risk zone. Preconditioning by 5 min ischaemia and 10 min reperfusion reduced infarct size to 8.8(2.3)%. Replacing the regional ischaemia with 5 min perfusion with 10 mu M adenosine or 65 nM N-6-[2-(4-aminophenyl)ethyl]adenosine (APNEA), an adenosine A(3) receptor agonist, was equally protective. The unselective antagonist 8-p-sulphophenyl theophylline at 100 mu M abolished protection by preconditioning, adenosine, and APNEA, but 200 nM DPCPX did not block protection by any of the interventions. Likewise the potent but unselective A(3) receptor antagonist 8-(4-carboxyethenylphenyl)-1,3-dipropylxanthine (BW A1433) completely blocked protection from ischaemic preconditioning. Conclusions: Because protection against infarction afforded by ischaemic preconditioning, adenosine, or the A(3) receptor agonist APNEA could not be blocked by DPCPX and because the potent A(3) receptor antagonist BW A1433 blocked protection from ischaemic preconditioning, these data indicate that the protection of preconditioning is not exclusively mediated by the adenosine A(1) receptor in rabbit heart and could involve the A(3) receptor.