Kaul S, Makkar R R, Nakamura M, Litvack F I, Shah P K, Forrester J S, Hutsell T C, Eigler N L
Division of Cardiology, Cedars-Sinai Medical Center Research Institute, Los Angeles, CA, USA.
Circulation. 1996 Nov 1;94(9):2228-34. doi: 10.1161/01.cir.94.9.2228.
Coronary stenting is limited by subacute thrombosis, especially in smaller-diameter vessels, in which shear rates are high. The objective of the present study was to determine whether local delivery of a new type of NO donor, the NO adduct of N,N'-dimethylhexanediamine (DMHD/NO), inhibits acute stent thrombosis (ST) at high-shear flow.
Effects of local infusion of DMHD/NO; intravenous aspirin, and heparin on ST were evaluated in an ex vivo porcine AV shunt model. Nitinol stents (2 mum in diameter, n = 120) were placed in a tubular chamber and perfused with blood from pigs (n = 13) at a shear rate of 2100s-1 for 20 minutes. ST was quantified by measurement of dry thrombus weight(TW). Effects on platelet aggregation (PA), blood pressure, bleeding time, and activated clotting time (ACT) were also examined. There was a dose-dependent inhibition of ST and PA by DMHD/NO. TW was reduced by 95% (1 +/- 2 versus 16 +/- 4 mg control, mean +/- SD, P < .001), and PA was reduced by 75% (4 +/- 3 versus 14 +/- 9 omega/min control, P < .05) at the highest dose of 10 mumol/L. DMHD/NO had no effects on bleeding time, ACT, or blood pressure. In contrast, aspirin (10 mg/kg), despite inhibiting PA, had no effects on TW (12 +/- 5 versus 16 +/- 8 mg control, P = .3). Heparin (200 U/kg) reduced TW by 33% (14 +/- 4 versus 21 +/- 3 mg control, P < .05) and prolonged ACT.
Local delivery of DMHD/NO produced a 15-fold inhibition of acute ST at high-shear flow without producing adverse systemic hemostatic or hemodynamic effects. Thus, treatment with DMHD/NO may be an effective strategy for prevention of stent thrombosis.
冠状动脉支架置入术受亚急性血栓形成的限制，尤其是在小直径血管中，这些血管内的剪切率较高。本研究的目的是确定新型一氧化氮供体N，N'-二甲基己二胺的一氧化氮加合物（DMHD/NO）局部给药是否能抑制高剪切流状态下的急性支架内血栓形成（ST）。
在体外猪动静脉分流模型中评估了DMHD/NO局部输注、静脉注射阿司匹林和肝素对ST的影响。将镍钛合金支架（直径2毫米，n = 120）置于管状腔室中，并以2100秒-1的剪切率用来自猪（n = 13）的血液灌注20分钟。通过测量干血栓重量（TW）对ST进行定量。还检查了对血小板聚集（PA）、血压、出血时间和活化凝血时间（ACT）的影响。DMHD/NO对ST和PA有剂量依赖性抑制作用。在最高剂量10微摩尔/升时，TW降低了95%（对照组为16±4毫克，处理组为1±2毫克，平均值±标准差，P <.001），PA降低了75%（对照组为14±9欧姆/分钟，处理组为4±3欧姆/分钟，P <.05）。DMHD/NO对出血时间、ACT或血压无影响。相比之下，阿司匹林（10毫克/千克）尽管抑制了PA，但对TW无影响（对照组为16±8毫克，处理组为12±5毫克，P = 0.3）。肝素（200单位/千克）使TW降低了33%（对照组为21±3毫克，处理组为14±4毫克，P <.05）并延长了ACT。
DMHD/NO局部给药在高剪切流状态下对急性ST产生了15倍的抑制作用，且未产生不良的全身止血或血流动力学效应。因此，用DMHD/NO治疗可能是预防支架内血栓形成的有效策略。
