A(3) adenosine receptor activation during reperfusion reduces infarct size through actions on bone marrow-derived cells

J Mol Cell Cardiol. 2010 Aug;49(2):280-6. doi: 10.1016/j.yjmcc.2010.01.018. Epub 2010 Feb 2.


The goal of this study was to examine whether the A(3) adenosine receptor (A(3)AR) agonist Cl-IB-MECA protects against myocardial ischemia/reperfusion injury when administered at the time of reperfusion in an in vivo mouse model of infarction induced by 30min of coronary occlusion and 24h of reperfusion. Treating B6 wild-type with Cl-IB-MECA during the reperfusion phase (100microg/kg i.v. bolus+0.3microg/kg/min subcutaneously via implantation of Alzet mini-osmotic pumps) reduced myocardial infarct size approximately 37% from 50.1+/-2.5% in vehicle-treated mice to 31.6+/-2.8% in Cl-IB-MECA-treated mice, and significantly reduced the number of leukocytes that infiltrated into the ischemic-reperfused myocardium. Cl-IB-MECA did not reduce infarct size or limit leukocyte accumulation in studies using B6 congenic A(3)AR gene "knock-out" mice or in chimeric mice lacking the expression of A(3)ARs in bone marrow (BM)-derived cells. Subsequent mechanistic studies demonstrated that Cl-IB-MECA inhibited migration of mouse neutrophils isolated from BM towards the chemotactic substance c5a in trans-well migration assays, and inhibited leukocyte migration into the peritoneal cavity in a mouse model of thioglycollate-induced peritonitis. We conclude that treating with the A(3)AR agonist Cl-IB-MECA at the time of reperfusion provides effective protection from ischemia/reperfusion injury in the heart through activation of the A(3)AR expressed in BM-derived cells, potentially by suppressing the robust inflammatory reaction that occurs during reperfusion and neutrophil-mediated tissue injury.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Adenosine A3 Receptor Agonists
  • Animals
  • Blood Pressure / drug effects
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Transplantation
  • Cell Movement / drug effects
  • Histamine / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / blood
  • Myocardial Infarction / complications*
  • Myocardial Infarction / pathology*
  • Myocardial Infarction / physiopathology
  • Myocardial Reperfusion Injury / blood
  • Myocardial Reperfusion Injury / complications*
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / physiopathology
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Receptor, Adenosine A3 / metabolism*


  • Adenosine A3 Receptor Agonists
  • Receptor, Adenosine A3
  • Histamine
  • Adenosine
  • 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide