A novel hypertensive crisis rat model established by excessive norepinephrine infusion and the potential therapeutic effects of Rho-kinase inhibitors on it
A novel hypertensive crisis rat model established by excessive norepinephrine infusion and the potential therapeutic effects of Rho-kinase inhibitors on it
复制标题
过量去甲肾上腺素输注建立的新型高血压危象大鼠模型及Rho激酶抑制剂对其的潜在治疗作用
DOI：
10.1016/j.biopha.2018.11.061
复制
发表时间：
2019
影响因子：
7.5
通讯作者：
Du Guanhua
中科院分区：
文献类型：
--
作者：
Yuan Tianyi;Chen Di;Chen Yucai;Zhang Huifang;Niu Ziran;Jiao Xiaozhen;Xie Ping;Fang Lianhua;Du Guanhua
高血压危象是一种严重的疾病，临床上需要紧急处理。寻找稳定、快速降血压的新药是一个重要的课题。然而，筛选抗高血压危象药物的动物模型并不令人满意。本研究旨在建立一种新的高血压危象大鼠模型，并探讨三种Rho激酶抑制剂法舒地尔、DL 0805 -1和DL 0805 -2对该模型的治疗作用。用小剂量去甲肾上腺素（NE）皮下注射雄性Wistar大鼠10天，诱发高血压危象症状。然后通过过量NE输注诱导血压（BP）突然升高。当收缩压迅速升高时，立即将待测化合物静脉注射到大鼠体内。结果表明，小剂量NE给药后，大剂量NE给药后，大鼠血压可迅速升高至较高水平，而无猝死现象。法舒地尔、DL 0805 -1和DL 0805 -2均能迅速降低血压，并呈剂量依赖性，提高存活率。这些化合物还可以防止动物的器官损伤。总之，我们建立了一种新的高血压危象动物模型，可以在短时间内评估药物。在该模型中，我们发现三种Rho激酶抑制剂对高血压危象具有潜在的治疗作用。这一工作可能有助于发现和开发新的抗高血压危象药物。
Hypertension crisis is a severe disease and needs emergency treatment in clinic. It is an important task to discover novel drugs which could lower the blood pressure steadily and quickly. However, animal models for screening anti-hypertensive crisis agents are unsatisfactory. The present study aimed to establish a new hypertensive crisis rat model and then explore the therapeutic effects of three Rho-kinase inhibitors including Fasudil, DL0805-1 and DL0805-2 on such a disease model. The hypertensive crisis symptoms were developed on male Wistar rats by subcutaneously injecting small doses of norepinephrine (NE) for 10 days in the initial stage. A sudden increase in blood pressure (BP) was then induced by excessive NE infusion. Compounds to be tested were intravenously injected into the rats immediately when the rapidly increased systolic blood pressure appeared. The results have shown that after small dose administration with NE, the rats could obtain acute BP increase to a high level without sudden death when a large dose of NE was injected. Fasudil, DL0805-1 and DL0805-2 could lower the blood pressure quickly in a dose dependent manner and improve the survival rate. The compounds also prevent the animals from organ damage. In conclusion, we established a novel hypertensive crisis animal model which could evaluate agents within a short time. In this model, we found that three Rho-kinase inhibitors have potential therapeutic effects on hypertensive crisis. This work might contribute to the discovery and development of new anti-hypertensive crisis drugs.