Evidence for a role for both the adenosine A(1) and A(3) receptors in protection of isolated human atrial muscle against simulated ischaemia

Objective: Adenosine receptor activation has been implicated in the mechanism of ischaemic preconditioning protection, Evidence suggests adenosine A(1) receptor involvement, and possibly A(3) receptor involvement in the rabbit, This study investigated the roles of these receptors in human preconditioning. Human A(1)- and A(3)-selective compounds were chosen based on K-i values for inhibition of N-6-(4-amino-3-[I-125]iodobenzyl)adenosine (I-125-ABA) binding to stably expressed recombinant human A(1) and A(3) receptors, Cyclopentyladenosine (CPA), a 194-fold selective A(1) agonist, and iodobenzylmethyicarboxamidoadenosine (IBMECA), a 10-fold selective A(3) agonist were used alone and in combination with dipropylcyclopentylxanthine (DPCPX) a 62-fold selective A(1) antagonist, Methods: Human atrial trabeculae were superfused with oxygenated Tyrode's solution. After-stabilisation, muscles underwent one of 8 protocols (n = 6 per group), followed by 90 min of simulated ischaemia and 120 min of reoxygenation. The experimental endpoint was recovery of contractile function, presented as percentage baseline function. Results: 5 nM CPA (52.2 +/- 3.1%), 30 nM IBMECA (49.7 +/- 3.8%) and preconditioning (55.3 +/- 2.5%) produced similar functional recoveries at 120 min of reoxygenation; significantly different to controls (27.7 +/- 1.0%: P < 0.05, ANOVA). When DPCPX (200 nM) was added prior to 5 nM CPA, protection was lost (31.8 +/- 0.9%), but when added prior to 30 nM IBMECA. muscles continued to be significantly protected (41.5 +/- 2.3%). Conclusions: In human atrium both A(1) and A(3) receptor stimulation appears to mimic ischaemic preconditioning. This may represent the first evidence for A(3) receptor involvement in 'pharmacological' preconditioning of human myocardium. (C) 1997 Elsevier Science B.V.