精氨酸加压素受体阻断剂改善小鼠脑卒中后脑水肿和血脑屏障破坏

目的：探讨精氨酸加压素(arginine-vasopressin,AVP)受体阻滞剂盐酸考尼伐坦和托伐普坦是否可以减少小鼠卒中后脑水肿和血脑屏障(blood-brain barrier,BBB)破坏。方法：C57BL/6小鼠进行大脑中动脉阻塞后再灌注。盐酸考尼伐坦、托伐普坦或溶剂(vehicle)分别处理小鼠。再灌开始时静脉注射盐酸考尼伐坦48 h或口服托伐普坦。记录实验小鼠生理变量、神经功能缺损评分(neurological deficit score,NDS)和血、尿钠及渗透压。小鼠处死后评价脑水含量(brain water content,BWC)和伊万斯蓝(evans blue,EB)外渗。结果：盐酸考尼伐坦和托伐普坦均可引起血浆和尿液中钠含量变化。然而,仅盐酸考尼伐坦改变血浆和尿液渗透压。盐酸考尼伐坦改善NDS,降低同侧大脑半球BWC(vehicle：81.66±0.43% vs.盐酸考尼伐坦：78.28±0.48%,P<0.05)。盐酸考尼伐坦也减少EB外渗(vehicle：1.22±0.08 vs.盐酸考尼伐坦：1.01±0.02,P<0.05)。结论：小鼠脑卒中后持续静脉输入盐酸考尼伐坦减轻脑卒中引起的脑水肿和血脑屏障破坏。盐酸考尼伐坦可能用于预防脑卒中患者脑水肿。

Arginine-vasopressin receptor blocker improve brain edema and blood-brain barrier disruption after stroke in mice

Objective: To investigate if the arginine-vasopressin (AVP) receptor blockers conivaptan and tolvaptan can prevent brain edema and blood-brain barrier (BBB) disruption in mice after stroke.Methods: C57BL/6 mice underwent the filament model of middle cerebral artery occlusion with reperfusion. Mice were treated with conivaptan, tolvaptan, or vehicle. Treatments were initiated immediately at reperfusion and administered IV (conivaptan) or orally (tolvaptan) for 48 hours. Physiological variables, neurological deifcit scores (NDS), plasma and urine sodium and osmolality were recorded. Brain water content (BWC) and evans blue (EB) extravasation index were evaluated at the end point.Results: Both conivaptan and tolvaptan produced aquaresis as indicated by changes in plasma and urine sodium levels. However plasma and urine osmolality was changed only by conivaptan. Unlike tolvaptan, conivaptan improved NDS and reduced BWC in the ipsilateral hemisphere: from 81.66%±0.43% (vehicle) to 78.28%±0.48% (conivaptan, 0.2 mg,P<0.05 vs. vehicle). Conivaptan also attenuated the EB extravasation from 1.22%±0.08% (vehicle) to 1.01%±0.02% (conivaptan, 0.2 mg,P<0.05).Conclusion: Continuous IV infusion with conivaptan for 48 hours atfer experimental stroke reduces brain edema, and BBB disruption. Conivaptan may potentially be used to prevent brain edema atfer stroke.