Protection from myocardial ischemia/reperfusion injury by a positive allosteric modulator of the A₃ adenosine receptor. J Pharmacol Exp Ther 2012 Jan;340(1):210-7
Date
10/21/2011Pubmed ID
22011434Pubmed Central ID
PMC3251031DOI
10.1124/jpet.111.187559Scopus ID
2-s2.0-84055178004 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
Adenosine is increased in ischemic tissues where it serves a protective role by activating adenosine receptors (ARs), including the A₃ AR subtype. We investigated the effect of N-{2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarboxamide (LUF6096), a positive allosteric modulator of the A₃ AR, 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 before 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 A₃ AR in a guanosine 5'-[γ-[³⁵S]thio]triphosphate binding assay. LUF6096 increased the maximal efficacy of the partial A₃ AR agonist 2-chloro-N⁶-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide 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) compared with 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 A₃ AR allosteric enhancer in an in vivo model of infarction.
Author List
Du L, Gao ZG, Nithipatikom K, Ijzerman AP, Veldhoven JP, Jacobson KA, Gross GJ, Auchampach JAAuthor
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenosineAnimals
Blood Pressure
Cardiovascular Agents
Cell Membrane
Chromatography, High Pressure Liquid
Dogs
Female
Guanosine 5'-O-(3-Thiotriphosphate)
HEK293 Cells
Heart Rate
Humans
Male
Mass Spectrometry
Myocardial Reperfusion Injury
Radioligand Assay
Receptor, Adenosine A3
Ventricular Function, Left
