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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3685    most recent 00819.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zheng, J. Articles by Liang, B. T. Search for Related Content PubMed PubMed Citation Articles by Zheng, J. Articles by Liang, B. T.

Protective roles of adenosine A₁, A_2A, and A₃ receptors in skeletal muscle ischemia and reperfusion injury

¹Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, Connecticut; ²United States Army Research Institute of Environmental Medicine, Natick, Massachusetts; ³Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut; and ⁴Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Submitted 15 July 2007 ; accepted in final form 1 October 2007

Although adenosine exerts cardio-and vasculoprotective effects, the roles and signaling mechanisms of different adenosine receptors in mediating skeletal muscle protection are not well understood. We used a mouse hindlimb ischemia-reperfusion model to delineate the function of three adenosine receptor subtypes. Adenosine A₃ receptor-selective agonist 2-chloro-N⁶-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IBMECA; 0.07 mg/kg ip) reduced skeletal muscle injury with a significant decrease in both Evans blue dye staining (5.4 ± 2.6%, n = 8 mice vs. vehicle-treated 28 ± 6%, n = 7 mice, P < 0.05) and serum creatine kinase level (1,840 ± 910 U/l, n = 13 vs. vehicle-treated 12,600 ± 3,300 U/l, n = 14, P < 0.05), an effect that was selectively blocked by an A₃ receptor antagonist 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; 0.05 mg/kg). The adenosine A₁ receptor agonist 2-chloro-N⁶-cyclopentyladenosine (CCPA; 0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A₁ antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 mg/kg). The adenosine A_2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A_2A antagonist 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-C]pyrimidin-5-amine (SCH-442416; 0.017 mg/kg). The protection induced by the A₃ receptor was abrogated in phospholipase C-β2/β3 null mice, but the protection mediated by the A₁ or A_2A receptor remained unaffected in these animals. The adenosine A₃ receptor is a novel cytoprotective receptor that signals selectively via phospholipase C-β and represents a new target for ameliorating skeletal muscle injury.

wild-type mice; creatine kinase; phosolipase C