title: Adenosine A2 receptor activation attenuates reperfusion injury by inhibiting neutrophil accumulation, superoxide generation and coronary endothelial adherence.
abstract: This study tests the hypothesis that adenosine A2 receptor activation reduces reperfusion injury by inhibiting neutrophils in a canine model of ischemia and reperfusion. In 16 anesthetized, open-chest dogs, the left anterior descending coronary artery was ligated for 60 min and reperfused for 3 hr. An intracoronary infusion of either the selective adenosine A2 agonist CGS-21680 at 0.2 microgram/kg/min (n = 8) or vehicle (n = 8) was started 5 min before reperfusion and discontinued after 60 min. The area at risk was comparable between vehicle-treated and CGS-21680-treated groups (39.6 +/- 4.1 vs. 37.1 +/- 2.5% of left ventricle). Infarction size, determined with triphenyltetrazolium chloride, was smaller in the CGS-21680-treated group than in the vehicle-treated group (15.4 +/- 2.9 vs. 29.8 +/- 2.3% of area at risk, P < .05 vs. vehicle-treated group). CGS-21680 significantly reduced neutrophil accumulation (myeloperoxidase activity) in the nonnecrotic area at risk tissue, compared with the vehicle-treated group (2.12 +/- 0.5 vs. 6.47 +/- 0.6 U/g of tissue, P < .05 vs. vehicle-treated group). In in vitro studies, CGS-21680 reduced platelet-activating factor (PAF)-activated canine neutrophil adherence to the endothelial surface of normal homologous coronary artery segments. Compared with PAF-stimulated neutrophils (188.4 +/- 9.4 adhered neutrophils/mm2), CGS-21680 reduced adherence close to base-line levels (46.6 +/- 5.8 adhered neutrophils/mm2) at concentrations of 10 microM (65.6 +/- 8.2 adhered neutrophils/mm2, P < .05 vs. PAF-stimulated group) and 50 microM (56.6 +/- 4.6 adhered neutrophils/mm2, P < .05 vs. PAF-stimulated group). Superoxide anion production (cytochrome c reduction) by activated neutrophils was reduced by CGS-21680 from 33.8 +/- 5.0 to 8.9 +/- 3.6 nmol/5 min/5 x 10(5) cells (P < .05 vs. PAF-stimulated group). We conclude that specific A2 receptor stimulation with CGS-21680 at reflow reduces reperfusion injury by inhibiting neutrophil-related processes.
authors.affiliation: Bowman Gray School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, North Carolina, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Jordan
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Taft
authors.forename: J
authors.initials: J
authors.lastname: Vinten-Johansen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion; D003331:Coronary Vessels / Q000502:physiology*; D003402:Creatine Kinase / Q000097:blood; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D010627:Phenethylamines; D018047:Receptors, Purinergic P1; D013481:Superoxides; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D009195:Peroxidase; D003402:Creatine Kinase; D000241:Adenosine