Visual Abstract -Adenosine Receptor Activation in the “Trigger” Limb of Remote Pre-Conditioning Mediates Human Endothelial Conditioning and Release of Circulating Cardioprotective Factor(s): 10.1016/j.jacbts.2016.06.002

• Pre-conditioning has emerged as a potentially powerful means of reducing ischemia-reperfusion injury.

• Several animal models have implicated adenosine in pre-conditioning pathways, but its role in human physiology is unknown.

• In human volunteers, the authors demonstrate that adenosine receptor activation in “trigger” tissue is an important step in initiating a pre-conditioning signal, but adenosine receptor blockade in “target” tissue does not block the protection afforded by pre-conditioning.

• The authors also demonstrate that pre-conditioning elaborates a transferrable cardioprotective factor(s) into the serum. This elaboration is prevented by adenosine receptor blockade but can be mirrored by the infusion of exogenous adenosine.

• An improved understanding of the physiological effectors of pre-conditioning may allow for better targeted clinical studies of pre-conditioning and pre-conditioning mimetics in the future.