精氨酸加压素 V1 受体而非 V2 受体拮抗作用可调节实验性脑卒中后的梗死体积、脑含水量和水通道蛋白-4 的表达。
Arginine-vasopressin V1 but not V2 receptor antagonism modulates infarct volume, brain water content, and aquaporin-4 expression following experimental stroke.
机构信息
Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, OR, USA.
出版信息
Neurocrit Care. 2010 Feb;12(1):124-31. doi: 10.1007/s12028-009-9277-x.
BACKGROUND
Aquaporin-4 (AQP4) plays an important role in the evolution of ischemia-evoked cerebral edema. Experimental studies have also demonstrated anti-edema effects of arginine-vasopressin (AVP) antagonists. In a well-characterized murine model of ischemic stroke, we tested the hypotheses that treatment with selective AVP V(1) but not V(2) receptor antagonist (1) attenuates injury volume and ischemia-evoked cerebral edema; and (2) modulates ischemia-evoked AQP4 expression.
METHODS
Isoflurane-anesthetized adult male C57bl/6 mice were subjected to 60 min of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Mice were treated with intracerebroventricular injection of selective AVP V(1) and V(2) receptor antagonist or control vehicle (0.9% saline). Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios) and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments at 24 h of reperfusion.
RESULTS
Infarct volume (percentage of contralateral structure; mean +/- SEM) was significantly attenuated in mice treated with 500 ng V(1) receptor antagonist as well as at a dose of 1000 ng compared to controls. However, there was no difference in infarct volume following treatment with 1000 ng V(2) antagonist as compared to controls. Water content in the ischemic hemisphere was significantly attenuated with V(1) receptor antagonist (1000 ng) but not with V(2) receptor antagonist as compared to controls. Treatment with AVP V(1) receptor antagonist (1000 ng) but not V(2) receptor antagonist, significantly upregulated AQP4 protein expression (% beta-actin) compared to saline-treated mice in ipsilateral (ischemic) cerebral cortex.
CONCLUSIONS
These data demonstrate that following experimental stroke AVP V(1) receptor antagonism: (1) attenuates injury volume and ischemia-evoked cerebral edema; (2) modulates AQP4 expression; and (3) may serve as an important therapeutic target for neuroprotection and ischemia-evoked cerebral edema.
背景
水通道蛋白-4（AQP4）在缺血性脑水肿的演变中起着重要作用。实验研究还表明，精氨酸加压素（AVP）拮抗剂具有抗水肿作用。在一种特征明确的缺血性脑卒中小鼠模型中，我们检验了以下假设：（1）使用选择性 AVP V1 而不是 V2 受体拮抗剂治疗可减轻损伤体积和缺血性脑水肿；（2）调节缺血性 AQP4 表达。
方法
用异氟烷麻醉成年雄性 C57bl/6 小鼠，通过管腔内缝线技术进行 60 分钟的大脑中动脉闭塞（MCAO）。用激光多普勒血流仪监测对侧顶叶皮层的 MCAO 及再灌注情况。用脑室注射选择性 AVP V1 和 V2 受体拮抗剂或对照液（0.9%生理盐水）对小鼠进行治疗。在不同的治疗组中，用不同的方法，在再灌注 24 小时时，用四唑染色法确定梗死体积（% 对侧结构；平均值 +/- SEM）、脑水肿（干湿比）和 AQP4 蛋白表达（免疫印迹）。
结果
与对照组相比，用 500ng V1 受体拮抗剂和 1000ng 处理的小鼠的梗死体积明显减小。然而，用 1000ng V2 拮抗剂处理的小鼠的梗死体积与对照组相比没有差异。与对照组相比，缺血半球的水含量用 V1 受体拮抗剂（1000ng）处理后明显减少，但用 V2 受体拮抗剂处理后没有减少。与生理盐水处理的小鼠相比，用 AVP V1 受体拮抗剂（1000ng）治疗，但不用 V2 受体拮抗剂治疗，同侧（缺血）大脑皮质的 AQP4 蛋白表达（% beta-actin）明显上调。
结论
这些数据表明，在实验性脑卒中后，AVP V1 受体拮抗：（1）减轻损伤体积和缺血性脑水肿；（2）调节 AQP4 表达；（3）可能成为神经保护和缺血性脑水肿的重要治疗靶点。
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