Evidence that the acute phase of ischemic preconditioning does not require signaling by the A 2B adenosine receptor.
Ischemic preconditioning (IPC) is a protective phenomenon in which brief ischemia renders the myocardium resistant to subsequent ischemic insults. Here, we used A(2B)AR gene knock-out (A(2B)KO)/β-galactosidase reporter gene knock-in mice and the A(2B)AR antagonist ATL-801 to investigate the potential involvement of the A(2B)AR 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(2B)KO mice. IPC equivalently improved the recovery of contractile function following 20 min of global ischemia and 45 min of reperfusion in both WT and A(2B)KO hearts by ~30-40%, and equivalently decreased the release of cardiac troponin I during the reperfusion period (from 5969 ± 925 to 1595 ± 674 ng/g and 4376 ± 739 to 2278 ± 462 ng/g using WT and A(2B)KO 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(2B)KO 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(2B)AR 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(2B)AR. We present the idea that the A(2B)AR may contribute to the later stages of IPC dependent on the induction of stress-responsive genes.
Maas
Jason E
JE
Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.
Wan
Tina C
TC
Figler
Robert A
RA
Gross
Garrett J
GJ
Auchampach
John A
JA
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000631:Aminopyridines; C518875:BAY 60-6583; D043704:Receptor, Adenosine A2B
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