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 μg/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 ± 4.1vs. 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). Inin 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 μM (65.6 ± 8.2 adhered neutrophils/mm², P < .05 vs.PAF-stimulated group) and 50 μM (56.6 ± 4.6 adhered neutrophils/mm², P < .05 vs.PAF-stimulated group). Superoxide anion production (cytochromec reduction) by activated neutrophils was reduced by CGS-21680 from 33.8 ± 5.0 to 8.9 ± 3.6 nmol/5 min/5 × 10⁶ 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.