Adenosine is increased in ischemic tissues where it serves a protective role by activating adenosine receptors (ARs) including the A3AR subtype. We investigated the effect of LUF6096, a positive allosteric modulator of the A3AR , on infarct size in a barbital-anesthetized dog model of myocardial ischemia/reperfusion injury. Dogs were subjected to 60 min of coronary artery occlusion and 3 h of reperfusion. Infarct size was assessed by macrohistochemical staining. Three experimental groups were included in the study. Groups I and II received two doses of vehicle or LUF6096 (0.5 mg/kg i.v. bolus), one administered prior to ischemia and the other immediately before reperfusion. Group III received a single dose of LUF6096 (1 mg/kg i.v. bolus) immediately before reperfusion. In preliminary in vitro studies, LUF6096 was found to exert potent enhancing activity (EC50=114.3±15.9 nM) with the canine A3AR using a [35S]GTPγS binding assay. LUF6096 increased the maximal efficacy of the partial A3AR agonist Cl-IB-MECA and the native agonist adenosine more than 2-fold while producing a slight decrease in potency. In the dog studies, administration of LUF6096 had no effect on any hemodynamic parameter measured. Pretreatment with LUF6096 before coronary occlusion and during reperfusion in Group II dogs produced a marked reduction in infarct size (~50% reduction) as compared to Group I vehicle-treated dogs. An equivalent reduction in infarct size was observed when LUF6096 was administered immediately before reperfusion in Group III dogs. This is the first study to demonstrate efficacy of an A3AR allosteric enhancer in an in vivo model of infarction.
- Received August 31, 2011.
- Revision received October 13, 2011.
- Accepted October 18, 2011.
- The American Society for Pharmacology and Experimental Therapeutics