Evidence that the acute phase of ischemic preconditioning does not require signaling by the A_2B adenosine receptor

Abstract 

Ischemic preconditioning (IPC) is a protective phenomenon in which brief ischemia renders the myocardium resistant to subsequent ischemic insults. Here, we used A_2BAR gene knock-out (A_2BKO)/β-galactosidase reporter gene knock-in mice and the A_2BAR antagonist ATL-801 to investigate the potential involvement of the A_2BAR in IPC, focusing on the acute phase of protection. Cardioprotection provided by acute IPC elicited by two 3-min occlusion/3-min reperfusion cycles was readily apparent in an isolated, Langendorff-perfused mouse heart model in studies using hearts from A_2BKO mice. IPC equivalently improved the recovery of contractile function following 20min of global ischemia and 45min of reperfusion in both WT and A_2BKO hearts by ~30–40%, and equivalently decreased the release of cardiac troponin I during the reperfusion period (from 5969±925 to 1595±674ng/g and 4376±739 to 2278±462ng/g using WT and A_2BKO hearts, respectively). Similarly, the infarct size-reducing capacity of acute IPC in an in vivo model of infarction was fully manifested in experiments using A_2BKO mice, as well as in experiments using rats pretreated with ATL-801. We did observe, however, a marked reduction in infarct size in rats following administration of the selective A_2BAR agonist BAY 60-6583 (~25% reduction at a dose of 1.0mg/kg). While supportive of its concept as a cardioprotective receptor, these experiments indicate that the mechanism of the early phase of IPC is not dependent on signaling by the A_2BAR. We present the idea that the A_2BAR may contribute to the later stages of IPC dependent on the induction of stress-responsive genes.

Keywords: Adenosine receptors, Myocardial infarction, Ischemia/reperfusion injury, Ischemic preconditioning, Adenosine