Chang Chih-Zen, Yen Chin-Po, Winadi Daniel, Wu Shu-Chuan, Howng Sheng-Long, Lin Tze-Kan, Jeng Arco Y, Kassell Neal F, Kwan Aij-Lie
Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S487-9. doi: 10.1097/01.fjc.0000166307.86678.d1.
Endothelin-1 has been shown to aggravate the ischemic-reperfusion injury in the neocortex of rats. The purpose of this study was to examine the effect of an endothelin-converting enzyme inhibitor, CGS 26303, on neurological deficit, infarct size, and extent of edema after transient occlusion of the middle cerebral artery and bilateral common carotid arteries (triple vessel occlusion) in rats. In the pretreatment study, male Sprague-Dawley rats underwent a 90-minute triple vessel occlusion, and CGS 26303 was administered intravenously 30 minutes before triple vessel occlusion. The compound was subsequently administered at 6, 12 and 18 hours post-triple vessel occlusion, and neurological status was evaluated 1, 12 and 24 hours after triple vessel occlusion. Animals were sacrificed at 24 hours post-triple vessel occlusion, brains were perfusion-fixed, and infarct areas and brain swelling were determined. Total infarct areas were reduced when compared with vehicle-treated animals by 48%, 50%, and 57% in rats receiving CGS 26303 at 1, 3, and 10 mg/kg, respectively, while the neurological score was significantly improved in the highest-dose CGS 26303-treated group. In another study, CGS 26303 treatment was initiated 1 hour after triple vessel occlusion. Total infarct areas were reduced by an average of 42-50% in the CGS 26303 treatment group. Neurological scores of animals treated with CGS 26303 at 10 mg/kg were decreased by 59% and 45% upon evaluation at 12 and 24 hours post-triple vessel occlusion, respectively. These results demonstrate that CGS 26303 may have potential for the treatment of focal ischemic stroke.
内皮素 -1已被证明会加重大鼠新皮质的缺血再灌注损伤。本研究的目的是检测内皮素转换酶抑制剂CGS 26303对大鼠大脑中动脉和双侧颈总动脉短暂闭塞（三血管闭塞）后神经功能缺损、梗死面积和水肿程度的影响。在预处理研究中，雄性Sprague-Dawley大鼠接受90分钟的三血管闭塞，在三血管闭塞前30分钟静脉注射CGS 26303。该化合物随后在三血管闭塞后6、12和18小时给药，并在三血管闭塞后1、12和24小时评估神经状态。在三血管闭塞后24小时处死动物，对大脑进行灌注固定，并测定梗死面积和脑肿胀情况。与接受赋形剂处理的动物相比，分别接受1、3和10 mg/kg CGS 26303的大鼠的总梗死面积减少了48%、50%和57%，而最高剂量CGS 26303处理组的神经评分显著改善。在另一项研究中，在三血管闭塞后1小时开始CGS 26303治疗。CGS 26303治疗组的总梗死面积平均减少了42 - 50%。在三血管闭塞后12和24小时评估时，接受10 mg/kg CGS 26303治疗的动物的神经评分分别降低了59%和45%。这些结果表明，CGS 26303可能具有治疗局灶性缺血性中风的潜力。
