Cooperative Cardioprotection Through Adenosine A1 and A2A Receptor Agonism in Ischemia-Reperfused Isolated Mouse Heart

Recent reports have shown that adenosine A(1) receptor-mediated cardioprotection requires concomitant A(2) receptor activation, but no study thus far has shown that this phenomenon occurs using A(1) agonists at reperfusion. Thus, we compared adenosine A(2A) receptor knockout (A(2A)KO) and wild-type mouse hearts (n = 9-11) subjected to global ischemia (30 minutes) and reperfusion (60 minutes) in the presence and absence of the A(1) agonist N-6-cyclopentlyadenosine (CPA). We also determined the effects of selective antagonists at A(2A) and A(2B) receptors on CPA-induced protection. In wild-type hearts, CPA (100 nM) significantly (P < 0.05) improved contractility (52.7 +/- 6.2% versus 23.9 +/- 4.9% of preischemia), left ventricular developed pressure, end diastolic pressure; reduced infarct size (7.9 +/- 1.7% versus 23.9 +/- 6.6% area at risk); decreased lactate dehydrogenase efflux; and increased ERK1/2 phosphorylation at 60 minutes of reperfusion. Adenosine A(2A) (ZM241385, 50 nM) and A(2B) (MRS1754, 100 nM) receptor antagonists abolished CPA-mediated cardioprotection in wild-type groups as did the A(1) receptor antagonist DPCPX (P < 0.05). In A(2A)KO hearts, CPA did not improve functional parameters and protective signaling with the exception of end diastolic pressure. In this model, using a clinically relevant mode of pharmacologic intervention, pERK 1/2-dependent A(1)-mediated cardioprotection requires a cooperative activation of A(2) receptors, presumably through endogenous adenosine.