AMP579 binds to adenosine A2b receptors thus resolving longstanding mystery of its cardioprotective signaling

Abstract

The mixed A1/A2a adenosine agonist AMP579 given at reperfusion is very protective in animal models of myocardial infarction; however, neither A1‐ nor A2a‐selective agonists can duplicate its protection despite blocking studies indicating that the protection came from an A2‐type receptor. We recently noted that A2b‐selective agonists are very protective and wondered whether AMP579 might also be an A2b agonist. AMP579 (500nM) for 1h starting at reperfusion protected isolated rabbit hearts exposed to 30 min‐regional ischemia/2h‐reperfusion (12.9±2.2% infarction of risk zone vs 32.0±1.9% in control hearts). A highly selective A2b antagonist PSB1115 (500nM) given for the first 15 min of reperfusion blocked AMP579's protection (32.2±3.1% infarction). We then confirmed A2b binding of AMP579 in human embryonic kidney cells transfected with human A2b receptors in which A2b occupation causes phosphorylation of ERK. AMP579 induced ERK phosphorylation with an EC50 of 250nM. These studies resolve a longstanding mystery related to AMP579's mechanism of protection, and further support the primacy of adenosine A2b receptors in the cardioprotective signaling that can be implemented at reperfusion. Supported by HL‐20648