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(Circulation Research. 2005;96:363.)
© 2005 American Heart Association, Inc.

Integrative Physiology

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

From the Heart Foundation Research Center (M.E.R., L.W., K.J.A., J.P.H.), Griffith University, Southport, Australia; the Department of Biochemistry and Molecular Biology (J.G.M., C.-X.S., J.C.N., M.R.B.), University of Texas Health Science Center at Houston, Medical School, Houston; and the National Institute of Diabetes and Digestive and Kidney Diseases (J.S.), National Institutes of Health, Bethesda, Md.

Correspondence to John Headrick, Heart Foundation Research Centre, Griffith University, Southport, QLD 4217, Australia. E-mail J.Headrick{at}griffith.edu.au

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 A₁ARs appears primarily to be enhancement of postischemic contractility and limitation of cell death.

Key Words: adenosine • A₁ adenosine receptor • gene knockout • ischemia • reperfusion

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