Fan Xiaoqin, Liu Kaishan, Cui Wei, Huang Jiongmei, Wang Weina, Gao Yuan
Institution of Life and Health Engineering, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
Department of Laboratory, The Border Armed Police Central Hospital of Guangdong Province, Shenzhen, Guangdong 518023, P.R. China.
Mol Med Rep. 2014 Nov;10(5):2483-8. doi: 10.3892/mmr.2014.2492. Epub 2014 Aug 14.
The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar‑kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30 mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid‑inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the Ang II‑SGK1‑NHE3 of intra‑renal tissue.
本研究旨在探讨氯沙坦治疗高血压的分子药效学机制。将12只自发性高血压大鼠（SHR）随机分为生理盐水处理的SHR组和氯沙坦处理的LOS组。选取6只Wistar-kyoto大鼠（WKY）作为生理盐水处理的WKY组纳入研究。LOS组通过胃内注射给予30mg/kg/天的氯沙坦，而SHR组和WKY组给予相同体积的生理盐水。剂量根据每周体重进行调整。采用间接尾套法测量血压变化。采用免疫放射分析法测定血浆和肾组织中血管紧张素（Ang）II的产生。通过定量聚合酶链反应（qPCR）和蛋白质印迹分析评估钠/氢交换体（NHE）3以及血清和糖皮质激素诱导激酶（SGK）1。与WKY组相比，在给予氯沙坦治疗前，SHR组和LOS组的血压更高。两周后，血压降低，且在接下来的六周内持续下降。SHR组和LOS组血浆和肾组织中的Ang II水平显著高于WKY组。SHR组中NHE3和SGK1在mRNA和蛋白质水平均升高，而氯沙坦降低了它们二者的表达。结果表明，在高血压大鼠中，循环和组织肾素血管紧张素系统被激活，Ang II增加刺激了NHE3和SGK1的表达，而氯沙坦可使其降低。因此，氯沙坦治疗高血压的作用可能与肾组织中的Ang II-SGK1-NHE3有关。
