Both A_2a and A_2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

Abstract

Pre- and postconditioning depend on the activation of adenosine receptors (ARs) at the end of the index ischemia. The aim of this study was to determine which receptor subtypes must be activated. In situ mouse hearts underwent 30 min of regional ischemia, followed by 2 h of reperfusion. As expected, either ischemic postconditioning (6 cycles of 10 s of reperfusion and 10 s of coronary occlusion) or infusion of the selective A(2b) adenosine receptor (A(2b)AR) agonist BAY60-6583 (BAY60) for 60 min, starting 5 min before reperfusion reduced infarct size in wild-type C57Bl/6N mice. Protection from either was abolished by the selective A(2b)AR antagonist MRS-1754, confirming a role for A(2b)AR. Additionally, the coadministration of ischemic postconditioning and a selective A(2a)AR antagonist led to the loss of protection as well. 5'-Ectonucleotidase (CD73) is thought to be necessary for the production of adenosine during ischemia. As predicted, ischemic postconditioning did not protect CD73 knockout mice. Selective agonists of either A(2b)AR (BAY60) or A(2a)AR (CGS-21680), as well as the coadministration of ischemic postconditioning and BAY60, also failed to protect hearts of the CD73 knockout mice. But the nonselective A(1)/A(2)AR agonist 5'-(N-ethylcarboxamido)adenosine (NECA) was protective, suggesting that the activation of multiple AR subtypes might be required. The coadministration of CGS-21680 and BAY60 also elicited profound protection, indicating that two AR subtypes, A(2a) and A(2b), must be simultaneously activated for protection to occur.

Adenosine A2A and A2B receptors are both required for adenosine A1 receptor-mediated cardioprotection

“…Much less is known about the role of A 2B receptors in myocardial ischemia-reperfusion injury, although there are reports (17,28,42) showing that A 2B receptor stimulation during reperfusion is cardioprotective. As stated above, our previous reports (19,33) demonstrating that ZM-241385 blocked A 1 cardioprotection could have been the result of antagonism of A 2B receptors due to the high affinity of this antagonist for A 2B receptors (1).…”

“…Activation of A 1 and A 3 receptors before ischemia is cardioprotective (2,19,20,24,30,33,37,38,41), whereas A 2A and A 2B receptors appear to exert their effects during reperfusion (10,13,17,18,28,34,42,43). Adenosine A 3 receptor activation during reperfusion has been reported to be cardioprotective (8), but there are conflicting reports on whether A 1 receptor activation during reperfusion is beneficial (3,7,30,39,40).…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Evidence that activation of both A 1 and A 2 receptors during hypoxia can attenuate myocardial injury was claimed (Stambaugh et al, 1997;Tracey et al, 1997;Liang and Jacobson, 1998). Endogenous adenosine makes a significant contribution to A 1 agonistmediated prevention of necrosis in a cardiac cell model of ischemia by cooperative interactions with both A 2A and A 2B receptors, but does not play a role in A 3 agonistmediated protection (Urmaliya et al, 2009;Methner et al, 2010). It was reported that A 1 and A 3 receptor agonists reduce hypoxic injury through the involvement of p38 MAPK (Leshem-Lev et al, 2010).…”

Cardiac purinergic signalling in health and disease

“…It has been claimed that A2AR and A2BR act in concert to induce strong protection against reperfusion injury in rat hearts [549] and co-operative activation of A1R and A2AR to produce cardioprotection in ischaemiareperfused mouse heart has also been reported [550]. Indeed, endogenous adenosine makes a significant contribution to A1R agonist-mediated prevention of necrosis in a cardiac cell model of ischaemia by co-operative interactions with both A2AR and A2BR, but does not play a role in A3R agonistmediated protection [551,552]. Figure 7 shows a simplified depiction of the impact of adenosine receptors in protecting against myocardial injury following ischaemia or hypoxia.…”