Endothelial dysfunction predisposes spontaneously hypertensive stroke prone rats to spreading depolarization and spreading ischemia

扩散性去极化（SD）是神经跨膜离子梯度几乎完全破裂引起脑灰质细胞毒性水肿的通称。SD连续体的范围从完整组织中的短SD到严重缺血组织中的中期SD到终末SD。SD诱导正常组织短暂性高灌注（正常反应）；或危险组织中严重的灌注不足（反向血流动力学反应=扩散性缺血）。我们之前在蛛网膜下腔出血（SAH）患者中发现，当硬膜下光电极直接放置在新发生的延迟性梗死上时，可以观察到持久的扩散性缺血，这表明它们导致了这些梗死。在之前的项目中，我们发表了世界上最大的SD研究，出院-1，在180名SAH患者中。之前的项目是翻译的。例如，使用出院-1数据并基于主成分和通径分析，一个重要的临床发现是SDs是蛛网膜下腔血容量和延迟性梗死容量之间的统计中介。在α2Na+/K+- atp酶（NaKA）功能失调的小鼠（Na +敏感性高血压的遗传模型）中，我们发现SD的易感性更高，血流动力学反应更逆向。我们检查了卒中易发自发性高血压大鼠（SHRsp），以确定SD阈值/血流动力学反应是否在其他Na+敏感性遗传模型中也发生了改变，结果发现确实如此。许多SAH患者医源性地暴露于静脉高渗盐水（HS），因为基于NaCl的渗透特性，这是目前被认为是控制颅内压（ICP）的一种经济有效的选择。三分之一的人对Na+敏感。在本项目中，我们前瞻性地收集了197例SAH患者的临床、神经监测、影像学和结局数据数据库，包括bbbb18000个血浆Na+值，这将使我们能够详细检查血浆Na+。在SHRsp和对照大鼠（WKY）中，(i)我们将继续研究半暗部扩张性缺血的药理学和使用增强灌注和氧饱和度（EPOS）的新技术对微循环进行深度表型分析，（ii）将确定HS是否会增强扩张性缺血，特别是在SHRsp中，以及这是否可能与SHRsp中α2NaKA功能障碍有关。（iii）将检查HS是否向大分子打开血脑屏障（BBB），而不向小分子打开，并通过Na+转运到脑脊液和淋巴系统导致脑间质Na+的延迟增加。我们的项目建立在先前工作的坚实证据的基础上，即SD和弥散性缺血具有显著的临床重要性，并专门研究了HS控制ICP的常见做法是否会加剧弥散性缺血和血脑屏障功能障碍，这可能解释了我们在临床数据中看到的与高中位血浆Na+水平相关的不良结果，尽管ICP控制良好。

Spreading depolarization (SD) is the generic term for waves of near-complete breakdown of neuronal transmembrane ion gradients causing cytotoxic edema in brain gray matter. The SD continuum ranges from short SDs in intact tissue to SDs of intermediate duration to terminal SD in severely ischemic tissue. SD induces either transient hyperperfusion in normal tissue (normal response); or severe hypoperfusion (inverse hemodynamic response=spreading ischemia) in tissue at risk. We previously found in patients with subarachnoid hemorrhage (SAH) that long-lasting spreading ischemias are observed when subdural optoelectrodes are located directly over newly developing delayed infarcts, suggesting that they cause these infarcts. In the previous project, we published the world's largest SD study, DISCHARGE-1, in 180 SAH patients. The previous project was translational. E.g., using DISCHARGE-1 data and based on principal component and path analyses, an important clinical finding was that SDs are a statistical mediator between subarachnoid blood volume and delayed infarct volume. In α2Na+/K+-ATPase (NaKA)-dysfunctional mice, a genetic model of Na+-sensitive hypertension, we found higher susceptibility to SD and a shift toward more inverse hemodynamic responses. We examined stroke-prone spontaneously hypertensive rats (SHRsp) to determine whether SD thresholds/hemodynamic responses are also altered in other genetic models of Na+ sensitivity and found that they are. Many SAH patients are iatrogenically exposed to intravenous hypertonic saline (HS), as this is currently considered a cost-effective option to control intracranial pressure (ICP) based on the osmotic properties of NaCl. One third of the population is Na+-sensitive. In the present project, our prospectively collected database of clinical, neuromonitoring, imaging and outcome data from 197 SAH patients, including >18,000 plasma Na+ values, will allow us to examine plasma Na+ in detail. In SHRsp and control rats (WKY), (i) we will continue a work package studying penumbral spreading ischemia pharmacologically and via deep phenotyping of the microcirculation using the novel technology of enhanced perfusion and O2 saturation (EPOS), (ii) will determine whether HS enhances spreading ischemia, particularly in SHRsp, and whether this might be related to α2NaKA dysfunction in SHRsp, and (iii) will examine whether HS opens the blood-brain barrier (BBB) to macromolecules but not to small molecules and yet leads to a delayed increase in brain interstitial Na+ by Na+ transport to the cerebrospinal fluid and glymphatic system. Our project builds on solid evidence from previous work that SD and spreading ischemia are of salient clinical importance and specifically addresses whether the common practice of ICP control with HS exacerbates spreading ischemia and BBB dysfunction, which may explain the poor outcome we see in our clinical data associated with high median plasma Na+ levels despite excellent ICP control.