College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA.
Surgery Department, University of Miami, Miami, FL, USA.
Physiol Rep. 2021 Apr;9(7):e14812. doi: 10.14814/phy2.14812.
Cardiovascular diseases are the principal cause of death worldwide, with hypertension being the most common cardiovascular disease risk factor. High blood pressure (BP) is also associated with an increased risk of poor cognitive performance and dementia including Alzheimer's disease. Angiotensin 1-7 (Ang 1-7), a product of the renin-angiotensin system (RAS), exhibits central and peripheral actions to reduce BP. Recent data from our lab reveals that the addition of a non-radioactive iodine molecule to the tyrosine in position 4 of Ang 1-7 (iodoAng 1-7) makes it 1000-fold more potent than Ang 1-7 in competing for the I-Ang 1-7 binding site (Stoyell-Conti et al., 2020). Moreover, the addition of the non-radioactive iodine molecule increases (4-fold) iodoAng 1-7's ability to bind to the AT1 receptor (AT1R), the primary receptor for Ang II. Preliminary data indicates that iodoAng 1-7 can also compete for the I-Ang IV binding site with a low micromolar IC50. Thus, our aims were to compare the effects of chronic treatment of the Spontaneously Hypertensive Rat (SHR) with iodoAng 1-7 (non-radioactive iodine isotope) and Ang 1-7 on arterial pressure, heart rate, and cognitive function. For this study, male SHRs were divided into three groups and treated with Saline, Ang 1-7, or iodoAng 1-7 administrated subcutaneously using a 28-day osmotic mini pump. Systolic BP was measured non-invasively by the tail-cuff technique. Cognitive function was assessed by Y-Maze test and novel object recognition (NOR) test. We have demonstrated in SHRs that subcutaneous administration of high doses of iodoAng 1-7 prevented the increase in heart rate with age, while Ang 1-7 showed a trend toward preventing the increase in heart rate, possibly by improving baroreflex control of the heart. Conversely, neither Ang 1-7 nor iodoAng 1-7 administered subcutaneously affected BP nor cognitive function.
心血管疾病是全球主要的死亡原因，高血压是最常见的心血管疾病危险因素。高血压（BP）也与认知表现不佳和痴呆症（包括阿尔茨海默病）的风险增加有关。血管紧张素 1-7（Ang 1-7）是肾素-血管紧张素系统（RAS）的产物，具有降低血压的中枢和外周作用。我们实验室的最新数据表明，在 Ang 1-7 的酪氨酸 4 位添加一个非放射性碘原子（碘代 Ang 1-7），使其与 I-Ang 1-7 结合位点的竞争能力比 Ang 1-7 强约 1000 倍（Stoyell-Conti 等人，2020 年）。此外，添加非放射性碘原子会增加（约 4 倍）碘代 Ang 1-7 与 AT1 受体（AT1R）的结合能力，AT1R 是 Ang II 的主要受体。初步数据表明，碘代 Ang 1-7 也可以与 I-Ang IV 结合位点竞争，IC50 为低微摩尔。因此，我们的目的是比较慢性给予 Spontaneously Hypertensive Rat（SHR）碘代 Ang 1-7（非放射性碘同位素）和 Ang 1-7 对动脉压、心率和认知功能的影响。在这项研究中，雄性 SHR 被分为三组，分别用生理盐水、Ang 1-7 或碘代 Ang 1-7 通过皮下 28 天渗透微型泵给药。通过尾套技术无创测量收缩压。通过 Y 迷宫测试和新物体识别（NOR）测试评估认知功能。我们已经在 SHR 中证明，皮下给予高剂量的碘代 Ang 1-7 可防止心率随年龄的增加，而 Ang 1-7 有降低心率增加的趋势，可能是通过改善心脏的压力反射控制。相反，皮下给予 Ang 1-7 或碘代 Ang 1-7 均不影响血压或认知功能。
