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Updated: Dec 30, 2025
The Superficial Inferior Epigastric Artery Axial Flap to Study Ischemic Preconditioning Effects in a Rat Model
Published on: January 27, 2023
Does ischemic preconditioning increase flap survival by ADORA2B receptor activation?
Pinar Ulker1, Ozlenen Ozkan2, Matteo Amoroso3
1Department of Physiology, Akdeniz University, Antalya, Turkey.
Background:
Ischemic preconditioning (IPC) is defined as raising tolerance to subsequent ischemic stress by exposing tissues to sub-lethal ischemia. Although many candidates have been suggested, recent studies have clearly demonstrated that adenosine-mediated ADORA2B receptor (ADORA2BR) activation is the main mechanism involved in IPC. While the tissue-protective role of this mechanism has been demonstrated in different ischemia/reperfusion (I/R) models, its role in flap surgery-derived I/R damage has not to date been investigated.
Objective:
To investigate the role of adenosine and ADORA2BR activation in IPC-mediated tissue protection in an epigastric flap model.
Methods:
Animals were divided into five main groups, all of which were then divided into two subgroups depending on whether or not they were exposed to IPC before the I/R procedure, which consisted of 6 hours of ischemia and 6 days of reperfusion. No drugs were administered in Group 1 (the control group). Animals in Group 2 were pretreated with CD73-inhibitor before IPC application or the ischemic period. Animals in Group 3 were pretreated with adenosine. Animals in Group 4 were pretreated with an ADORA2BR antagonist, and those in Group 5 with an ADORA2BR agonist. After 6 days of reperfusion, tissue survival was evaluated via histological and macroscopic analysis.
Results:
IPC application significantly enhanced CD73 expressions and adenosine concentrations (p < 0.01). Flap survivals were increased by IPC in Group 1 (p < 0.05). However, CD73 inhibition blocked this increase (Group 2). In Group 3, adenosine improved flap survival even in the absence of IPC (p < 0.01). While an ADORA2BR antagonist attenuated the tissue-protective effect of IPC (p < 0.01), the ADORA2BR agonist improved flap survival by mimicking IPC in groups 4 and 5.
Conclusion:
These results provide pharmacological evidence for a contribution of CD73 enzyme-dependent adenosine generation and signaling through ADORA2BR to IPC-mediated tissue protection. They also suggest for the first time that ADORA2BR agonists may be used as a potential preventive therapy against I/R injury in flap surgeries.
