Morikawa E, Ginsberg M D, Dietrich W D, Duncan R C, Busto R
Cerebral Vascular Disease Research Center, University of Miami School of Medicine, Fla 33101.
Stroke. 1991 Mar;22(3):355-60. doi: 10.1161/01.str.22.3.355.
(S)-Emopamil is a calcium channel blocker of the phenylalkylamine class, having potent serotonin S2 antagonistic properties and high blood-brain barrier penetrability. Previous studies have documented cerebroprotective effect in animal models of both focal and global ischemia. The present study was undertaken to define the postischemic "window" of therapeutic efficacy for this agent. Sprague-Dawley rats were subjected to permanent proximal middle cerebral artery occlusion, combined with an initial 30-minute period of halothane-induced hypotension (50 mm Hg). (S)-Emopamil (20 mg/kg) was administered intraperitoneally either 20-30 minutes prior to middle cerebral artery occlusion or 1 hour, 2 hours, or 3 hours following occlusion. Treated groups received a second similar dose 2.5 hours later and twice daily for 2 days thereafter. Brains were perfusion-fixed on the third day. Planimetric analysis of hemotoxylin and eosin-stained coronal brain sections documented a cortical infarct averaging 72.9 +/- 33.3 mm3 (mean +/- SD) in untreated rats. Cortical infarct volume was reduced by 48% (to 37.6 +/- 27.6 mm3) when therapy was initiated 1 hour postischemia (p less than 0.05). When treatment was deferred to 2 hours postichemia, mean cortical infarct volume was reduced by 34%, but this difference did not attain statistical significance. Infarct volume in rats with treatment initiated at 3 hours postischemia was indistinguishable from that in controls. Striatal infarct volume was similar in all groups. These results document a postischemic therapeutic window of cerebroprotection for (S)-emopamil lying between 1 and 2 hours after middle cerebral artery occlusion.
（S）-埃莫帕米是一种苯烷基胺类钙通道阻滞剂，具有有效的5-羟色胺S2拮抗特性和高血脑屏障穿透性。先前的研究已证明其在局灶性和全脑缺血动物模型中具有脑保护作用。本研究旨在确定该药物缺血后治疗效果的“时间窗”。将Sprague-Dawley大鼠进行永久性大脑中动脉近端闭塞，并结合最初30分钟的氟烷诱导低血压（50毫米汞柱）。（S）-埃莫帕米（20毫克/千克）在大脑中动脉闭塞前20 - 30分钟或闭塞后1小时、2小时或3小时腹腔注射。治疗组在2.5小时后接受第二次相似剂量，此后每天两次，共2天。在第三天对大脑进行灌注固定。对苏木精和伊红染色的冠状脑切片进行平面测量分析，结果显示未治疗大鼠的皮质梗死灶平均为72.9±33.3立方毫米（平均值±标准差）。当在缺血后1小时开始治疗时，皮质梗死灶体积减少了48%（降至37.6±27.6立方毫米）（P<0.05）。当治疗推迟到缺血后2小时时，平均皮质梗死灶体积减少了34%，但这种差异未达到统计学显著性。在缺血后3小时开始治疗的大鼠中，梗死灶体积与对照组无差异。所有组的纹状体梗死灶体积相似。这些结果证明了（S）-埃莫帕米在大脑中动脉闭塞后1至2小时之间存在缺血后脑保护治疗时间窗。
