, Volume 103, Issue 3, pp 203-215
Date: 12 Nov 2007

Adenosine: trigger and mediator of cardioprotection

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Adenosine, a purine nucleoside, is ubiquitous in the body, and is a critical component of ATP. Its concentration jumps 100-fold during periods of oxygen depletion and ischemia. There are four adenosine receptors: A1 and A3 coupled to Gi/o and the high-affinity A2A and low-affinity A2B coupled to Gs. Adenosine is one of three autacoids released by ischemic tissue which are important triggers of ischemic preconditioning (IPC). It is the A1 and to some extent A3 receptors which participate in the intracellular signaling that triggers cardioprotection. Unlike bradykinin and opioids, the other two autacoids, adenosine is not dependent on opening of mitochondrial KATP channels or release of reactive oxygen species (ROS), but rather activates phospholipase C and/or protein kinase C (PKC) directly. Another signaling cascade at reperfusion involves activated PKC which initiates binding to and activation of an A2 adenosine receptor that we believe is the A2B. Although the latter is the low-affinity receptor, its interaction with PKC increases its affinity and makes it responsive to the accumulated tissue adenosine. A2B agonists, but not adenosine or A1 agonists, infused at reperfusion can initiate this second signaling cascade and mimic preconditioning’s protection. The same A2B receptors are critical for postconditioning’s protection. Thus adenosine is both an important trigger and a mediator of cardioprotection.