Sim Meng-Kwoon, Chen Woei-Shin
Department of Pharmacology, Faculty of Medicine, National University of Singapore 117597, Singapore.
Regul Pept. 2006 Dec 10;137(3):140-6. doi: 10.1016/j.regpep.2006.07.002. Epub 2006 Aug 22.
The effects of losartan on angiotensin receptors in hypertrophic rat hearts were studied. The study was prompted by inconsistent findings of either an increase or decrease in the mRNA of the AT1 receptor in the hearts of cardiac hypertrophic rats treated with losartan, and a paucity of information on the effects of losartan on functional angiotensin receptors in the heart. Losartan, administered i.p. to aortic coarcted rats, dose-dependently attenuated the cardiac hypertrophy. Significant effect was observed with a dose of 2.72 micromol/kg/day for four days. Hypertrophy was accompanied by an increase in [125I]-Sar1-Ile8-angiotensin II binding sites (due mainly to an increase in AT2 binding) and AT2 receptor protein in cardiac ventricles of aortic coarcted rats. Treatment with effective anti-hypertrophic doses of losartan dose-dependently downregulated the [125I]-Sar1-Ile8-angiotensin II binding sites, constitutive AT1 receptor protein, and the over expressed AT2 receptor protein. It was suggested that the anti-cardiac hypertrophic action of losartan resulted from its ability to suppress the expression of both the basal and enhanced cardiac angiotensin receptors. This raises the question as to whether such drastic action could form the therapeutic basis for the use of losartan in cardiac pathologies.
研究了氯沙坦对肥厚型大鼠心脏中血管紧张素受体的影响。开展这项研究的起因是，在用氯沙坦治疗的心脏肥厚型大鼠心脏中，AT1受体的mRNA出现增加或减少的不一致研究结果，以及关于氯沙坦对心脏中功能性血管紧张素受体影响的信息匮乏。对主动脉缩窄大鼠腹腔注射氯沙坦，剂量依赖性地减轻了心脏肥厚。剂量为2.72微摩尔/千克/天，连续给药四天时观察到显著效果。主动脉缩窄大鼠心室的肥厚伴随着[125I]-Sar1-Ile8-血管紧张素II结合位点增加（主要由于AT2结合增加）以及AT2受体蛋白增加。用有效抗肥厚剂量的氯沙坦治疗，剂量依赖性地下调了[125I]-Sar1-Ile8-血管紧张素II结合位点、组成型AT1受体蛋白以及过度表达的AT2受体蛋白。提示氯沙坦的抗心脏肥厚作用源于其抑制基础和增强的心脏血管紧张素受体表达的能力。这就提出了一个问题，即这种剧烈作用是否可以构成氯沙坦用于心脏疾病治疗的基础。
