Angiotensin receptor agonism to promote recovery after stroke

描述（由申请人提供）：操纵肾素-血管紧张素-醛固酮（RAS）系统已被证明在减少心血管疾病的影响方面非常有效。特别是，血管紧张素受体阻滞剂（ARBs）已知可降低人类中风风险，并在实验性中风中具有强大的神经保护作用。血管紧张素II 2型（AT2）受体激动剂化合物21 （C21）可能显示出arb的所有神经血管益处，而没有这些AT1受体阻滞剂潜在的危险血压降低特征。本申请的目的是获得C21作为缺血性卒中候选治疗药物的临床前体内疗效数据。我们计划通过以下两个目标来实现这一目标：目标1：优化年轻雄性大鼠的C21方案，在不影响血压的情况下改善短期和长期卒中结局。我们将优化C21的给药频率、对血压和功能的影响。我们将使用这个方案进行第二阶段的测试。我们将通过遥测、脑血流量（CBF）、功能结局监测血压，并评估梗死面积和出血性转化（HT）。栓塞性脑卒中模型，有和没有tPA，将采用48小时和28天的终点。目的2：确定最佳C21方案对高血压大鼠的疗效。为了达到这个目的，我们将再次测量急性期对血压和脑血流的影响，以及28天的长期功能和组织学结果。我们将通过给药AT2受体激动剂（C21）和优化剂量、时间窗口和持续时间来实现这些目标，在临床相关的栓塞性卒中模型中，有和没有tPA。我们增加了用遥测法连续监测血压的方法，增加了对正常和高血压大鼠品系评估的严格程度。我们的团队拥有独特的跟踪记录和必要的专业知识来完成这个项目，并将化合物转移到人类的转化努力。

DESCRIPTION (provided by applicant): Manipulation of the renin-angiotensin-aldosterone (RAS) system has been shown to be extremely effective in reducing the impact of cardiovascular disease. In particular, angiotensin receptor blockers (ARBs) are known to reduce stroke risk in humans and be robustly neuroprotective in experimental stroke. The angiotensin II Type 2 (AT2) receptor agonist, compound 21 (C21) is likely to demonstrate all the neurovascular benefits of the ARBs without the potentially dangerous blood pressure (BP) lowering characteristic of these AT1 receptor blockers. The objective of this application is to obtain preclinical in vivo efficacy data on C21 as a candidate therapeutic in ischemic stroke. We plan to achieve this through the following two aims: AIM 1: Optimize the regimen of C21 in young male rats to improve short- and long-term stroke outcome without affecting BP. We will optimize the dosing of C21 with frequency, effects on BP and function. We will use this regimen to then test in Aim 2. We will monitor BP by telemetry, cerebral blood flow (CBF), functional outcome and assess infarct size and hemorrhagic transformation (HT). An embolic model of stroke, with and without tPA, will be employed with 48 hour and 28 day endpoints. AIM 2: Determine the effectiveness of the optimal C21 regimen in hypertensive rats. In this aim, we will again measure the effect on BP and CBF in the acute phase and long-term functional and histologic outcomes at 28 days. We will achieve these aims by administration of an AT2 receptor agonist (C21) and optimizing the dose, time window and duration, with and without tPA, in a clinically relevant embolic stroke model. Our addition of continuous monitoring of BP with telemetry adds an addition degree of rigor to the evaluation in both normotensive and hypertensive rat strains. Our group has the unique track record and expertise necessary to complete this project and move the compound on to a translational effort to humans.