Submitted on July 15, 2007
Accepted on October 1, 2007
Protective Roles of Adenosine A1, A2a, and A3 Receptors in Skeletal Muscle Ischemia and Reperfusion Injury
Jingang Zheng1, Ruibo Wang2, Edward Zambraski3, Dan Wu4, Kenneth A. Jacobson5, and Bruce T. Liang6*
1 Cardiology, University of Connecticut School of Medicine, Connecticut, United States
2 Dept of Cardiology, University of Connecticut Health Center, Farmington, Connecticut, United States; Cardiology, University of Connecticut School of Medicine, Connecticut, United States
3 Natick; US Army Research Institute of Environmental Medicine, Massachusetts, United States
4 Genetics, University of connecticut Health Center, Connecticut, United States
5 Molecular Recognition Section, NIDDK, NIH, Bethesda, Maryland, United States
6 Dept of Cardiology, University of Connecticut Health Center, Farmington, Connecticut, United States
* To whom correspondence should be addressed. E-mail: bliang{at}uchc.edu.
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 Cl-IBMECA (0.07 mg/kg, intraperitoneal) 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 (1840 U/L ± 910 U/L, n = 13 vs. vehicle-treated 12,600 U/L ± 3300 U/L, n = 14, P < 0.05), an effect that was selectively blocked by an A3 receptor antagonist MRS1191 (0.05 mg/kg). The A1 receptor agonist CCPA (0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A1 antagonist DPCPX (0.2 mg/kg). The A2A receptor agonist CGS21680 (0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A2A antagonist SCH 442416 (0.017 mg/kg). The protection induced by the A3 receptor was abrogated in phospholipase C 
2/3 null mice, but the protection mediated by the A1 or A2A receptor remained unaffected in these animals. The adenosine A3 receptor is a novel cytoprotective receptor that signals selectively via phospholipase C and represents a new target for ameliorating skeletal muscle injury.
