Tatlisumak T, Carano R A, Takano K, Opgenorth T J, Sotak C H, Fisher M
Department of Neurology, Helsinki University Central Hospital, Finland.
Stroke. 1998 Apr;29(4):850-7; discussion 857-8. doi: 10.1161/01.str.29.4.850.
Endothelins (ETs) are potent vasoconstrictors. Plasma ET levels increase during acute brain ischemia and may worsen the ischemic damage. Diffusion-weighted MRI (DWI) and perfusion imaging (PI) are powerful tools for evaluation of acute cerebral ischemia. We studied the effects of A-127722, a novel ET(A)-selective ET antagonist, on cerebral ischemic lesion size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem, on acute ischemic lesion development with DWI, and on the cerebral circulation using PI.
Twenty male Sprague-Dawley rats received either 5 mg/kg of A-127722 or vehicle (n=10 per group) intravenously 30 minutes and subcutaneously 4 hours after middle cerebral artery occlusion (MCAO). Whole-brain DWI and single-slice PI were done before initiation of treatment and repeated frequently thereafter up to 4 hours after MCAO. The animals were reperfused in the MRI scanner 90 minutes after the onset of MCAO. At 24 hours the animals were killed, and the brains were cut into six 2-mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV) was calculated for each animal.
Physiological parameters, body weight, neurological scores, and premature mortality (2 versus 2) did not differ between the two groups. No hypotension, abnormal behavior, or other adverse effects were seen. TTC-derived %HLV was 25.3+/-5.6% for controls and 16.2+/-9.6% for treated animals (36% reduction, P<.02). Six animals in each group had successful reperfusion as shown by PI. Among these animals, %HLV was 23.2+/-3.1% for controls and 9.3+/-4.4% for treated animals (60% reduction, P=.0001). The beneficial effect of A-127722 was limited to animals in which successful reperfusion was demonstrated. No difference in PI-detected perfusion deficit size was observed between the groups. DWI did not demonstrate significant in vivo lesion size differences.
A-127722 significantly reduced ischemic lesion size in rats without observable adverse effects. It is not clear whether the effect was due to vasodilatation of collateral arterioles not detectable by PI or whether A-127722 has neuroprotective properties that are independent of vascular effects.
内皮素（ETs）是强效血管收缩剂。急性脑缺血时血浆ET水平升高，可能会加重缺血性损伤。扩散加权磁共振成像（DWI）和灌注成像（PI）是评估急性脑缺血的有力工具。我们使用死后2,3,5-三苯基氯化四氮唑（TTC）染色研究了新型ET(A)选择性ET拮抗剂A-127722对脑缺血损伤大小的影响，使用DWI研究其对急性缺血性损伤发展的影响，并使用PI研究其对脑循环的影响。
20只雄性Sprague-Dawley大鼠在大脑中动脉闭塞（MCAO）后30分钟静脉注射5mg/kg的A-127722或赋形剂（每组n = 10），并在4小时后皮下注射。在开始治疗前进行全脑DWI和单层PI检查，此后在MCAO后长达4小时内频繁重复检查。在MCAO发作后90分钟在MRI扫描仪中对动物进行再灌注。在24小时时处死动物，将大脑切成6片2毫米厚的切片，并用2%TTC染色。计算每只动物的半球损伤体积百分比（%HLV）。
两组之间的生理参数、体重、神经学评分和过早死亡率（2比2）没有差异。未观察到低血压、异常行为或其他不良反应。对照组TTC衍生的%HLV为25.3±5.6%，治疗组动物为16.2±9.6%（降低36%，P<0.02）。如PI所示，每组中有6只动物成功再灌注。在这些动物中，对照组的%HLV为23.2±3.1%，治疗组动物为9.3±4.4%（降低60%，P = 0.0001）。A-127722的有益作用仅限于显示成功再灌注的动物。两组之间在PI检测到的灌注缺损大小上没有差异。DWI未显示体内损伤大小有显著差异。
A-127722可显著降低大鼠缺血性损伤大小，且未观察到不良反应。尚不清楚这种作用是由于PI无法检测到的侧支小动脉血管舒张，还是A-127722具有独立于血管作用的神经保护特性。
