Antagonists of the Vasopressin V1 Receptor and of the β(1)-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes - but the Mechanisms Differ.
Antagonists of the Vasopressin V1 Receptor and of the β(1)-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes - but the Mechanisms Differ.
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DOI：
10.2174/1570159x12666140828222723
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发表时间：
2014-07
影响因子：
5.3
通讯作者：
Du T
中科院分区：
文献类型：
--
作者：
Hertz L;Xu J;Chen Y;Gibbs ME;Du T;Hertz L;Xu J;Chen Y;Gibbs ME;Du T
脑水肿是缺血性中风的严重并发症，因为即使脑体积的相对较小的变化也会损害脑血流或导致重要脑结构的压缩，这是由于刚性颅骨的体积固定。文献数据表明，在缺血发作后给予V1血管加压素（AVP）受体或β 1-肾上腺素能受体拮抗剂能够减少水肿或梗死面积，这是可能的临床应用的关键优势。本综述讨论了可能的机制，重点是NKCC1，星形胶质细胞的Na+，K+，2Cl-和水的协同转运和其激活的高度增加的细胞外K+浓度的发展中的细胞毒性细胞肿胀的作用。然而，它还提到，由于Na+释放和驱动NKCC 1的Na+，K +-ATP酶的K+摄取之间的3/2比率，脑细胞外液可以变得高渗，这可能有助于水进入血脑屏障，这对水肿的发展至关重要。这表明脑水肿直到再灌注期间才发展，这可以通过缺血期间缺乏代谢能量来解释。V1拮抗剂可能通过抑制AVP增强NKCC 1介导的离子和水摄取来防止细胞毒性水肿形成，而β 1-肾上腺素能拮抗剂防止水肿形成，因为β 1-肾上腺素能刺激单独负责刺激驱动NKCC 1的Na+，K +-ATP酶，首先是由于细胞外Ca2+浓度降低。NKCC1的抑制也具有不利影响，例如对记忆力的影响，并且治疗可能应该是尽可能短的持续时间。
Brain edema is a serious complication in ischemic stroke because even relatively small changes in brain volume can compromise cerebral blood flow or result in compression of vital brain structures on account of the fixed volume of the rigid skull. Literature data indicate that administration of either antagonists of the V1 vasopressin (AVP) receptor or the β1-adrenergic receptor are able to reduce edema or infarct size when administered after the onset of ischemia, a key advantage for possible clinical use. The present review discusses possible mechanisms, focusing on the role of NKCC1, an astrocytic cotransporter of Na+, K+, 2Cl- and water and its activation by highly increased extracellular K+ concentrations in the development of cytotoxic cell swelling. However, it also mentions that due to a 3/2 ratio between Na+ release and K+ uptake by the Na+,K+-ATPase driving NKCC1 brain extracellular fluid can become hypertonic, which may facilitate water entry across the blood-brain barrier, essential for development of edema. It shows that brain edema does not develop until during reperfusion, which can be explained by lack of metabolic energy during ischemia. V1 antagonists are likely to protect against cytotoxic edema formation by inhibiting AVP enhancement of NKCC1-mediated uptake of ions and water, whereas β1-adrenergic antagonists prevent edema formation because β1-adrenergic stimulation alone is responsible for stimulation of the Na+,K+-ATPase driving NKCC1, first and foremost due to decrease in extracellular Ca2+ concentration. Inhibition of NKCC1 also has adverse effects, e.g. on memory and the treatment should probably be of shortest possible duration.