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CARDIOVASCULAR

Cl-IB-MECA [2-Chloro-N⁶-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] Reduces Ischemia/Reperfusion Injury in Mice by Activating the A Adenosine Receptor

Department of Pharmacology and Toxicology and the Cardiovascular Center (Z.-D.G., J.N.P., L.M.K., T.C.W. G.J.G., J.A.A.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania (M.A.J.)

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 [3-propyl-6-ethyl-5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine-carboxylate], but not the A_2AAR 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 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 [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.

Address correspondence to: Dr. John A. Auchampach, Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Medical College of Wisconsin, Milwaukee, WI 53226. E-mail: jauchamp{at}mcw.edu

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