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在组织型纤溶酶原激活剂存在的情况下,脑动脉反应性的缺血后衰减会增加。

Postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator.

作者信息

Cipolla M J, Lessov N, Clark W M, Haley E C

机构信息

Departments of Obstetrics/Gynecology, Pharmacology, and Neurology, University of Vermont College of Medicine, Burlington, VT, USA.

出版信息

Stroke. 2000 Apr;31(4):940-5. doi: 10.1161/01.str.31.4.940.

Abstract

BACKGROUND AND PURPOSE

We investigated the combined effect of tissue plasminogen activator and ischemia on middle cerebral artery (MCA) reactivity to determine whether abnormal MCA function after 2 hours of ischemia was worse in arteries perfused with recombinant tissue plasminogen activator (rtPA).

METHODS

The intraluminal suture model of focal cerebral ischemia was used to induce 2 hours of ischemia in rats, after which occluded MCAs were removed and studied in vitro with an arteriograph system that allowed control of transmural pressure (TMP) and measurement of lumen diameter. Arteries were either nonischemic (control; n=8), nonischemic and perfused with 400 microg/mL rtPA (rtPA; n=5), ischemic (ISC; n=6), or ischemic and perfused with 400 microg/mL rtPA (ISC-rtPA; n=6). After a 1-hour equilibration at 75 mm Hg, TMP was increased to 125 mm Hg and lumen diameter was recorded at each pressure. Reactivity to acetylcholine (ACh, 0.1 to 10.0 micromol/L) and serotonin (0.01 to 10 micromol/L) was then determined.

RESULTS

Control arteries responded myogenically to pressure and increased the amount of tone from 18.5+/-3.8% at 75 mm Hg to 24.8+/-3.0% at 125 mm Hg (P<0.05), which decreased diameter from 241+/-7 to 232+/-6 microm. In contrast, all other groups decreased tone at 125 mm Hg, which demonstrated a loss of myogenicity. The percent tone in each group at 75 versus 125 mm Hg was rtPA, 16.0+/-4.5% versus 11.8+/-3.8%; ISC, 23.5+/-4.5% versus 13. 5+/-3.1%; and ISC-rtPA, 23.5+/-4.2% versus 12.3+/-3.2% (P<0.05 for all). The percent increase in lumen diameter at each concentration of ACh was diminished in all groups compared with control; ISC-rtPA arteries responded the least, which suggests an additive effect of rtPA in ischemic arteries. The percent increase in lumen diameter at 10(-5)mol/L ACh was 23+/-4% for control versus 15+/-2% for rtPA; 17+/-3% for ISC arteries (P<0.05), and 8+/-2% for ISC-rtPA arteries (P<0.01). Sensitivity to serotonin was equally diminished in all groups compared with control: EC(50) (micromol/L) was 0.06+/-0.01 for control, 0.17+/-0.02 for rtPA, 0.22+/-0.07 for ISC, and 0.16+/-0. 04 for ISC-rtPA (P<0.05).

CONCLUSIONS

These results demonstrate that both ischemia and rtPA perfusion diminish cerebral artery reactivity and that the combination may produce an additive effect. This impaired reactivity may contribute to reperfusion-induced injury during or after thrombolysis by altering upstream cerebrovascular resistance.

摘要

背景与目的

我们研究了组织型纤溶酶原激活剂(tPA)与缺血对大脑中动脉(MCA)反应性的联合影响,以确定在缺血2小时后,用重组组织型纤溶酶原激活剂(rtPA)灌注的动脉中MCA功能异常是否更严重。

方法

采用局灶性脑缺血的腔内缝合模型在大鼠中诱导2小时缺血,之后取出闭塞的MCA,并用动脉造影系统在体外进行研究,该系统可控制跨壁压力(TMP)并测量管腔直径。动脉分为非缺血组(对照组;n = 8)、非缺血且用400μg/mL rtPA灌注组(rtPA组;n = 5)、缺血组(ISC组;n = 6)或缺血且用400μg/mL rtPA灌注组(ISC-rtPA组;n = 6)。在75mmHg平衡1小时后,将TMP增加到125mmHg,并在每个压力下记录管腔直径。然后测定对乙酰胆碱(ACh,0.1至10.0μmol/L)和5-羟色胺(0.01至10μmol/L)的反应性。

结果

对照动脉对压力产生肌源性反应,张力从75mmHg时的18.5±3.8%增加到125mmHg时的24.8±3.0%(P<0.05),管腔直径从241±7μm减小到232±6μm。相比之下,所有其他组在125mmHg时张力降低,这表明肌源性丧失。各rtPA组、ISC组、ISC-rtPA组在75mmHg与125mmHg时的张力百分比分别为16.0±4.5%与11.8±3.8%;23.5±4.5%与13.5±3.1%;23.5±4.2%与=12.3±3.2%(均P<0.05)。与对照组相比,所有组在各浓度ACh下管腔直径的增加百分比均降低;ISC-rtPA组动脉反应最小,这表明rtPA在缺血动脉中有累加效应。在10(-5)mol/L ACh时,对照组管腔直径增加百分比为23±4%,rtPA组为15±2%;ISC组为17±3%(P<0.05),ISC-rtPA组为8±2%(P<0.01)。与对照组相比,所有组对5-羟色胺的敏感性均同等降低:对照组半数有效浓度(EC(50),μmol/L)为0.06±0.01,rtPA组为0.17±0.02,ISC组为0.22±0.07,ISC-rtPA组为0.16±0.04(P<0.05)。

结论

这些结果表明,缺血和rtPA灌注均会降低脑动脉反应性,且两者联合可能产生累加效应。这种受损的反应性可能通过改变上游脑血管阻力,在溶栓期间或之后导致再灌注损伤。

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