Adenosine A2A and A2B receptors work in concert to induce a strong protection against reperfusion injury in rat hearts

We aimed to test if stimulation of both adenosine A(2A) and A(2B) receptors is required to produce an effective cardioprotection against reperfusion injury. Isolated rat hearts were subjected to 30-min regional ischemia followed by 2 h of reperfusion. The adenosine A(1)/A(2) receptor agonist 5'-(N-ethylcarboxamido) adenosine (NECA) given at reperfusion reduced infarct size, an effect that was reversed by both the adenosine A2A antagonist SCH58261 and the A(2B) antagonist MRS1706. The A(2B) agonist BAY 60-6583 but not the selective A(2A) agonist CGS21680 reduced infarct size. Interestingly, a combination of BAY 60-6583 and CGS21680 further reduced infarct size. These results suggest that both A(2A) and A(2B) receptors are involved in NECA's anti-infarct effect at reperfusion. NECA attenuated mitochondrial swelling upon reperfusion and this was blocked by both SCH58261 and MRS1706, indicating that activation of A(2) receptors with NECA can modulate reperfusion-induced mitochondrial permeability transition pore (mPTP) opening In support. NECA also prevented oxidant-induced loss of mitochondrial membrane potential (Delta Psi(m)) and matrix Ca2+ overload in cardiomyocytes via both the A(2) receptors. In addition, NECA increased mitochondrial glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylation upon reperfusion and this was again blocked by SCH58261 and MRS1706. In conclusion, A(2A) and A(2B) receptors work in concert to prevent reperfusion injury in rat hearts treated with NECA. NECA may protect the heart by modulating the mPTP opening through inactivating mitochondrial GSK-3 beta. A simultaneous stimulation of A(2A) and A(2B) receptors at reperfusion is required to produce a strong cardioprotection against reperfusion injury. (C) 2009 Elsevier Inc. All rights reserved.