Protection from myocardial ischemia/reperfusion injury by a positive allosteric modulator of the A₃ adenosine receptor.
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.
Department of Pharmacology and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Lili
L
Du
Zhan-Guo
ZG
Gao
Kasem
K
Nithipatikom
Adriaan P
AP
Ijzerman
Jacobus P D van
JP
Veldhoven
Kenneth A
KA
Jacobson
Garrett J
GJ
Gross
John A
JA
Auchampach
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects
D002317:Cardiovascular Agents; D043684:Receptor, Adenosine A3; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide