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1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
* To whom correspondence should be addressed. E-mail: jauchamp{at}mcw.edu.
We examined the effect of the A3 adenosine receptor (AR) agonist IB-MECA on infarct size in an open-chest anesthetized dog model of myocardial ischemia/reperfusion injury. Dogs were subjected to 60 minutes of left anterior descending (LAD) coronary artery occlusion and 3 hours of reperfusion. Infarct size and regional myocardial blood flow were assessed by macrohistochemical staining with triphenyltetrazolium chloride and radioactive microspheres, respectively. Four experimental groups were studied: vehicle control (50% DMSO in normal saline), IB-MECA (100 µg/kg i.v. bolus) given 10 minutes before the coronary occlusion, IB-MECA (100 µg/kg i.v. bolus) given 5 minutes before initiation of reperfusion, and IB-MECA (100 µg/kg i.v. bolus)given 10 minutes before coronary occlusion in dogs pretreated 15 minutes earlier with the ATP-dependent potassium (KATP) channel antagonist glibenclamide (0.3 mg/kg i.v. bolus). Administration of IB-MECA had no effect on any hemodynamic parameter measured including heart rate, left ventricular pressure, left ventricular dP/dt, aortic pressure, LAD coronary blood flow, or coronary collateral blood flow. Nevertheless, pretreatment with IB-MECA before coronary occlusion produced a marked reduction in infarct size (~40% reduction) compared to the control group (13.0 ± 3.2% versus 25.2 ± 3.7% of the area-at-risk, respectively). This effect of IB-MECA was blocked completely in dogs pretreated with glibenclamide. An equivalent reduction in infarct size was also observed when IB-MECA was administered immediately before reperfusion (13.1 ± 3.9%). These results are the first to demonstrate efficacy of an A3AR agonist in a large animal model of myocardial infarction by mechanisms that are unrelated to changes in hemodynamic parameters. These results also demonstrate in an in vivo model that IB-MECA is effective as a cardioprotective agent when administered at the time of reperfusion.
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