Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5′-N- methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor

Zhi-Dong Ge, Jason N. Peart, Laura M. Kreckler, Tina C. Wan, Marlene A. Jacobson, Garrett J. Gross, John A. Auchampach*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


We used pharmacological agents and genetic methods to determine whether the potent A3 adenosine receptor (AR) agonist 2-chloro-N 6-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide (Cl-IB-MECA) protects against myocardial ischemia/ reperfusion injury in mice via the A 3AR or via interactions with other AR subtypes. Pretreating wild-type (WT) mice with Cl-IB-MECA reduced myocardial infarct size induced by 30 min of coronary occlusion and 24 h of reperfusion at doses (30 and 100 μg/kg) that concomitantly reduced blood pressure and stimulated systemic histamine release. The A3AR-selective antagonist MRS 1523 [3-propyl-6-ethyl- 5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine-carboxylate], but not the A2AAR antagonist ZM 241385 [4-{2-7-amino-2-(2-furyl)[1,2,4]triazolo- [2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol], blocked the reduction in infarct size provided by Cl-IB-MECA, suggesting a mechanism involving the A 3AR. To further examine the selectivity of Cl-IB-MECA, we assessed its cardioprotective effectiveness in A3AR gene "knock-out" (A3KO) mice. Cl-IB-MECA did not reduce myocardial infarct size in A3KO mice in vivo and did not protect isolated perfused hearts obtained from A3KO mice from injury induced by global ischemia and reperfusion. Additional studies using WT mice treated with compound 48/80 [condensation product of p-methoxyphenethyl methylamine with formaldehyde] to deplete mast cell contents excluded the possibility that Cl-IB-MECA was cardioprotective by releasing mediators from mast cells. These data demonstrate that Cl-IB-MECA protects against myocardial ischemia/reperfusion injury in mice principally by activating the A3AR.

Original languageEnglish (US)
Pages (from-to)1200-1210
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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