Nitric oxide reverses aspirin antagonism of t-PA thrombolysis in a rabbit model of thromboembolic stroke.
Nitric oxide reverses aspirin antagonism of t-PA thrombolysis in a rabbit model of thromboembolic stroke.
复制标题
在血栓栓塞性中风兔模型中，一氧化氮逆转阿司匹林对 t-PA 溶栓的拮抗作用。
DOI：
10.1006/exnr.1997.6568
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发表时间：
1997
影响因子：
5.3
通讯作者：
Thomas,GR
中科院分区：
文献类型：
--
作者：
Bednar,MM;Gross,CE;Howard,DB;Russell,SR;Thomas,GR
卒中溶栓治疗的随机试验报告了神经系统预后的改善；然而，在临床和动物研究中，阿司匹林的加入分别导致了死亡率的显著增加和血栓溶解的拮抗作用。这一发现与已知的阿司匹林和溶栓药物在降低心肌梗死死亡率方面的协同作用形成对比。据推测，阿司匹林对凝块溶解的拮抗作用与抑制一氧化氮（NO）有关，并可能通过提供NO来源而逆转。20只家兔在颈内动脉血栓栓塞前用阿司匹林（20mg /kg，静脉注射）治疗。栓塞后半小时，兔随机接受载药（n=5）、NO前体精氨酸（300 mg/kg，在栓塞后0.5和2.5 h静脉注射，n=5）或一氧化氮供体（硝普苷，1 mg/kg/h，静脉注射，或硝酸甘油，10 μg/kg/min，静脉注射，每种药物n=5）。栓塞后1 ~ 3 h给予组织型纤溶酶原激活剂（t-PA） 6.3 mg/kg。溶解锡标记的血块后进行连续X光检查和大体检查。对照组没有兔出现完全的凝块溶解。然而，精氨酸组的5只兔中有2只和一氧化氮供体（硝普塞和硝酸甘油）组的10只兔中有6只出现完全的凝块溶解（P<0.05， Fisher精确检验）。因此，给予NO供体（硝酸甘油或硝普塞）和精氨酸（在较小程度上），逆转了阿司匹林对t-PA溶栓的拮抗作用。这项研究可能有助于解释阿司匹林和溶栓药物的不同结果。
Randomized trials of thrombolytic therapy in stroke have reported an improvement in neurologic outcome; however, the addition of aspirin has resulted in a significantincreasein mortality and antagonism of clot lysis in clinical and animal studies, respectively. This finding is in contradistinction to the known synergy in mortality reduction for aspirin and thrombolytics in myocardial infarction. It is hypothesized that aspirin antagonism of clot lysis is related to inhibition of nitric oxide (NO) and may be reversed by providing a source of NO. Twenty rabbits were treated with aspirin (20 mg/kg, iv) prior to internal carotid clot embolization. One-half hour following embolization, rabbits were randomized to receive vehicle (n=5), the NO precursorl-arginine (300 mg/kg, iv bolus at 0.5 and 2.5 h postembolus;n=5), or a nitric oxide donor (nitroprusside, 1 mg/kg/h, ia, or nitroglycerin, 10 μg/kg/min, iv,n=5 each agent). Tissue plasminogen activator (t-PA) (6.3 mg/kg) was administered from 1 to 3 h after embolization. Lysis of the tin-tagged clot was followed with serial X rays and gross examination. No rabbit in the control group experienced complete clot lysis. However, 2 of 5 rabbits in thel-arginine group and 6 of 10 rabbits in the nitric oxide donor (nitroprusside and nitroglycerin) groups noted complete clot lysis (P<0.05, Fisher exact test). Thus, administration of an NO donor (nitroglycerin or nitroprusside) and, to a lesser extentl-arginine, reversed aspirin's antagonism of t-PA thrombolysis. This study may help explain the discrepant results seen with aspirin and thrombolytics.