Faculty Collaboration Database

Ability of CP-532,903 to protect mouse hearts from ischemia/reperfusion injury is dependent on expression of A₃ adenosine receptors in cardiomyoyctes. Biochem Pharmacol 2019 May;163:21-31

Date

02/03/2019

Pubmed ID

30710517

Pubmed Central ID

PMC6470012

DOI

10.1016/j.bcp.2019.01.022

Scopus ID

2-s2.0-85061006338 (requires institutional sign-in at Scopus site)   9 Citations

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 (K_ATP) channel, suggesting one contributing mechanism may involve accelerated activation of K_ATP 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 (K_ATP) channels via G_i 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 Adora3^{LoxP/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 K_ATP channels.

Author List

Wan TC, Tampo A, Kwok WM, Auchampach JA

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Tina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine A3 Receptor Agonists
Animals
Cardiotonic Agents
Cells, Cultured
Female
Furans
Gene Expression
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myocardial Reperfusion Injury
Myocytes, Cardiac
Purines
Receptor, Adenosine A3