Jordan J E, Zhao Z Q, Sato H, Taft S, Vinten-Johansen J
Bowman Gray School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, North Carolina, USA.
J Pharmacol Exp Ther. 1997 Jan;280(1):301-9.
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.
在犬缺血再灌注模型中，腺苷A2受体激活通过抑制中性粒细胞来减轻再灌注损伤。在16只麻醉开胸犬中，结扎左前降支冠状动脉60分钟，然后再灌注3小时。在再灌注前5分钟开始冠状动脉内输注选择性腺苷A2激动剂CGS - 21680，剂量为0.2微克/千克/分钟（n = 8）或输注溶媒（n = 8），60分钟后停止。溶媒治疗组和CGS - 21680治疗组之间的危险面积相当（分别为左心室的39.6±4.1%和37.1±2.5%）。用氯化三苯基四氮唑测定的梗死面积，CGS - 21680治疗组小于溶媒治疗组（分别为危险面积的15.4±2.9%和29.8±2.3%，与溶媒治疗组相比P < 0.05）。与溶媒治疗组相比，CGS - 21680显著减少了危险组织非坏死区域的中性粒细胞聚集（髓过氧化物酶活性）（分别为2.12±0.5和6.47±0.6 U/g组织，与溶媒治疗组相比P < 0.05）。在体外研究中，CGS - 21680减少了血小板活化因子（PAF）激活的犬中性粒细胞对正常同源冠状动脉段内皮表面的黏附。与PAF刺激的中性粒细胞（188.4±9.4个黏附中性粒细胞/mm²）相比，CGS - 21680在10微摩尔浓度（65.6±8.2个黏附中性粒细胞/mm²，与PAF刺激组相比P < 0.05）和50微摩尔浓度（56.6±4.6个黏附中性粒细胞/mm²，与PAF刺激组相比P < 0.05）时将黏附减少至接近基线水平（46.6±5.8个黏附中性粒细胞/mm²）。CGS - 21680使活化中性粒细胞产生的超氧阴离子（细胞色素c还原）从33.8±5.0降至8.9±3.6纳摩尔/5分钟/5×10⁵个细胞（与PAF刺激组相比P < 0.05）。我们得出结论，再灌注时用CGS - 21680特异性刺激A2受体可通过抑制中性粒细胞相关过程减轻再灌注损伤。
