Olsen S B, Tang D B, Jackson M R, Gomez E R, Ayala B, Alving B M
Department of Hematology and Vascular Biology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Circulation. 1996 Jan 15;93(2):327-32. doi: 10.1161/01.cir.93.2.327.
Purified human cross-linked hemoglobin, which is now being used in clinical trials, increases mean arterial pressure through binding of nitric oxide (NO). We postulated that binding of NO by cross-linked hemoglobin (alpha alpha Hb) could also increase platelet deposition at sites of subintimal injury.
Male Sprague-Dawley rats were infused with alpha alpha Hb (0.88 g/kg, n = 8) or with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 30 mg/kg, n = 7) before undergoing microsurgical carotid endarterectomy. 111In-labeled platelets were infused after endarterectomy, and platelet deposition was measured 20 minutes later. In control endarterectomized rats (n = 8), mean platelet deposition was 7.7 +/- 0.7 x 10(6)/mm2. Platelet deposition was significantly increased above controls in rats that received alpha alpha Hb (13.2 +/- 0.9 x 10(6)/mm2, P = .0004) and in rats infused with L-NMMA (13.9 +/- 1.0 x 10(6)/mm2, P = .0002). The increase was prevented by infusion of L-arginine (150 mg/kg) immediately after alpha alpha Hb or L-NMMA. To determine whether aspirin (ASA) blocked the increased deposition induced by alpha alpha Hb, rats received oral ASA (10 mg/kg) 18 hours before endarterectomy. Platelet deposition in animals receiving ASA alone was 6.4 +/- 0.9 x 10(6)/mm2 (n = 8). This was significantly increased to 10.8 +/- 0.8 x 10(6)/mm2 (P = .002) for the ASA-treated group that received alpha alpha Hb at the time of endarterectomy (n = 8). The prolonged bleeding times induced by ASA were unaffected by the infusion of alpha alpha Hb.
These data suggest that in a rat endarterectomy model, alpha alpha Hb increases platelet deposition at sites of subintimal injury by binding NO. Increased deposition induced by alpha alpha Hb can be prevented by administration of L-arginine but not by pretreatment with aspirin.
目前正在临床试验中使用的纯化人交联血红蛋白，通过结合一氧化氮（NO）来升高平均动脉压。我们推测交联血红蛋白（ααHb）对NO的结合也可能增加血小板在血管内膜下损伤部位的沉积。
在接受显微外科颈动脉内膜切除术之前，给雄性Sprague-Dawley大鼠输注ααHb（0.88 g/kg，n = 8）或一氧化氮合酶抑制剂NG-单甲基-L-精氨酸（L-NMMA，30 mg/kg，n = 7）。内膜切除术后输注111In标记的血小板，20分钟后测量血小板沉积情况。在对照内膜切除大鼠（n = 8）中，平均血小板沉积为7.7±0.7×10(6)/mm2。接受ααHb的大鼠（13.2±0.9×10(6)/mm2，P = .0004）和输注L-NMMA的大鼠（13.9±1.0×10(6)/mm2，P = .0002）中，血小板沉积显著高于对照组。在输注ααHb或L-NMMA后立即输注L-精氨酸（150 mg/kg）可防止这种增加。为了确定阿司匹林（ASA）是否能阻止ααHb诱导的沉积增加，大鼠在动脉内膜切除术18小时前口服ASA（10 mg/kg）。单独接受ASA的动物的血小板沉积为6.4±0.9×10(6)/mm2（n = 8）。在内膜切除术时接受ααHb的ASA治疗组中，这一数值显著增加至10.8±0.8×10(6)/mm2（P = .002）（n = 8）。ASA诱导的延长出血时间不受输注ααHb的影响。
这些数据表明，在大鼠动脉内膜切除术模型中，ααHb通过结合NO增加血小板在血管内膜下损伤部位的沉积。给予L-精氨酸可防止ααHb诱导的沉积增加，但阿司匹林预处理则不能。
