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 th e protective effect of ischaemic preconditioning against infarction in the rabbit heart. Unselective adenosine antagonists block this protec tion but, paradoxically, the A(1) adenosine receptor selective antagon ist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) does not. The aim of th is study was to test the hypothesis that the newly described A(3) aden osine receptor, which has an agonist profile similar to the A(1) recep tor but is insensitive to DPCPX, might mediate preconditioning. Method s: Isolated rabbit hearts perfused with Krebs buffer experienced 30 mi n of regional ischaemia followed by 120 min of reperfusion. Infarct si ze was measured by tetrazolium staining. Results: In control hearts in farction 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)%. R eplacing the regional ischaemia with 5 min perfusion with 10 mu M aden osine or 65 nM N-6-[2-(4-aminophenyl)ethyl]adenosine (APNEA), an adeno sine A(3) receptor agonist, was equally protective. The unselective an tagonist 8-p-sulphophenyl theophylline at 100 mu M abolished protectio n by preconditioning, adenosine, and APNEA, but 200 nM DPCPX did not b lock protection by any of the interventions. Likewise the potent but u nselective A(3) receptor antagonist 8-(4-carboxyethenylphenyl)-1,3-dip ropylxanthine (BW A1433) completely blocked protection from ischaemic preconditioning. Conclusions: Because protection against infarction af forded by ischaemic preconditioning, adenosine, or the A(3) receptor a gonist APNEA could not be blocked by DPCPX and because the potent A(3) receptor antagonist BW A1433 blocked protection from ischaemic precon ditioning, these data indicate that the protection of preconditioning is not exclusively mediated by the adenosine A(1) receptor in rabbit h eart and could involve the A(3) receptor.