Received for publication July 21, 2006.
Revised September 16, 2006.
Accepted for publication September 18, 2006.

Cl-IB-MECA reduces ischemia/reperfusion injury in mice by activating the A₃ adenosine receptor

Abstract

We used pharmacological agents and genetic methods to determine whether the potent A₃ adenosine receptor (AR) agonist 2-chloro-N⁶-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) protects against myocardial ischemia/reperfusion injury in mice via the A₃AR 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, but not the A_2AAAR antagonist ZM 241385, blocked the reduction in infarct size provided by Cl-IB-MECA, suggesting a mechanism involving the A₃AR. 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 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.

Key words: adenosine, heart, infarction, ischemia, receptors, reperfusion

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