Ability of CP-532,903 to protect mouse hearts from ischemia/reperfusion injury is dependent on expression of A3 adenosine receptors in cardiomyoyctes.

Abstract

A3 adenosine receptor (A3AR) agonists are effective at limiting injury caused by ischemia/reperfusion injury of the heart in experimental animal models. However, understanding of their mechanism of action, which is likely multifactorial, remains incomplete. In prior studies, it has been demonstrated that A3AR-mediated ischemic protection is blocked by glibenclamide and is absent in Kir6.2 gene ablated mice that lack the pore-forming subunit of the ATP-sensitive potassium (KATP) channel, suggesting one contributing mechanism may involve accelerated activation of KATP channels. However, presence of A3ARs in the myocardium has yet to be established. Utilizing a whole-cell recording technique, in this study we confirm functional expression of the A3AR in adult mouse ventricular cardiomyocytes, coupled to activation of ATP-dependent potassium (KATP) channels via Gi inhibitory proteins. We further show that ischemic protection provided by the selective A3AR agonist CP-532,903 in an isolated, buffer-perfused heart model is lost completely in Adora3LoxP/LoxP;Myh6-Cre mice, which is a newly developed model developed and comprehensively described herein whereby the A3AR gene (Adora3) is deleted exclusively in cardiomyocytes. Our findings, taken together with previously published work, are consistent with the hypothesis that A3AR agonists provide ischemic tolerance, at least in part, by facilitating opening of myocardial KATP channels.

• Authors: Tina C Wan, Akihito Tampo, Wai-Meng Kwok, John A Auchampach
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 163 Pg. 21-31 (05 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 30710517 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Adenosine A3 Receptor Agonists
• CP-532,903
• Cardiotonic Agents
• Furans
• Purines
• Receptor, Adenosine A3

Topics

• Adenosine A3 Receptor Agonists (pharmacology, therapeutic use)
• Animals
• Cardiotonic Agents (pharmacology, therapeutic use)
• Cells, Cultured
• Female
• Furans (pharmacology, therapeutic use)
• Gene Expression
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism)
• Purines (pharmacology, therapeutic use)
• Receptor, Adenosine A3 (biosynthesis, genetics)