Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance

Melissa E. Reichelt, Laura Willems, Jose G. Molina, Chun Xiao Sun, Janci C. Noble, Kevin J. Ashton, Jurgen Schnermann, Michael R. Blackburn, John P. Headrick*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

53 Citations (Scopus)

Abstract

Adenosine receptors may be important determinants of intrinsic ischemic tolerance. Genetically modified mice were used to examine effects of global A1 adenosine receptor (A1AR) knockout (KO) on function and ischemic tolerance in perfused mouse hearts. Baseline contractile function and heart rate were unaltered by A1AR KO, which was shown to abolish the negative chronotropic effects of 2-chloroadenosine (A1AR-mediated) without altering A2 adenosine receptor-mediated coronary dilation. Tolerance to 25 minutes global normothermic ischemia (followed by 45 minutes reperfusion) was significantly limited by A1AR KO, with impaired contractile recovery (reduced by ≈25%) and enhanced lactate dehydrogenase (LDH) efflux (increased by ≈100%). Functional effects of A1AR KO involved worsened systolic pressure development with little to no change in diastolic dysfunction. In contrast, cardiac specific A1AR overexpression enhanced ischemic tolerance with a primary action on diastolic dysfunction. Nonselective receptor agonism (10 μmol/L 2-chloroadenosine) protected wild-type and also A1AR KO hearts (albeit to a lesser extent), implicating protection via subtypes additional to A1ARs. However, A1AR KO abrogated effects of 2-chloroadenosine on ischemic contracture and diastolic dysfunction. These data are the first demonstrating global deletion of the A1AR limits intrinsic myocardial resistance to ischemia. Data indicate the function of intrinsically activated A 1ARs appears primarily to be enhancement of postischemic contractility and limitation of cell death.

Original languageEnglish
Pages (from-to)363-367
Number of pages5
JournalCirculation Research
Volume96
Issue number3
DOIs
Publication statusPublished - 18 Feb 2005
Externally publishedYes

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    Reichelt, M. E., Willems, L., Molina, J. G., Sun, C. X., Noble, J. C., Ashton, K. J., ... Headrick, J. P. (2005). Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance. Circulation Research, 96(3), 363-367. https://doi.org/10.1161/01.RES.0000156075.00127.C3