Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice
Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice
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DOI：
10.1007/bf03402108
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发表时间：
2003-01-01
影响因子：
5.7
通讯作者：
Mizutani, S
中科院分区：
文献类型：
--
作者：
Mitsui, T;Nomura, S;Mizutani, S
血管加压肽血管紧张素II（AngII）的局部浓度取决于合成和降解之间的平衡。以往对血压调节的研究主要集中在血管紧张素II及其受体的产生上，而对血管紧张素的降解研究较少。氨肽酶A（阿帕，EC 3.4.11.7）负责AngII的N-末端裂解，这是一种水解事件，其在血管紧张素降解中充当限速步骤。为了评估阿帕的生理作用，我们研究了APA缺陷小鼠的BP稳态。采用尾袖法测定阿帕突变小鼠基础血压和持续输注AngII后的血压。我们还评估了AngII靶向器官的发育和组织学以及这些小鼠的尿液排泄。与杂合子突变和野生型同窝小鼠相比，纯合子阿帕突变小鼠的基础收缩压升高。输注血管紧张素II导致APA缺陷小鼠的收缩压反应增强。尽管阿帕敲除小鼠的血压持续升高，但其肾脏和心脏大小以及组织学外观与对照小鼠没有差异。此外，APA缺陷小鼠的尿量、渗透压和电解质含量均正常。阿帕缺乏会增加基线血压，并增强对AngII水平升高的高血压反应。这些发现表明阿帕在降低血压中的生理作用，并为高血压的发生机制提供了新的见解。
Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice. We measured basal BP and BP with continuous infusion of AngII in APA mutant mice by tail-cuff method. We also evaluated the development and histology of AngII-targeted organs as well as urine excretion in these mice. Homozygous APA mutant mice were found to have elevated basal systolic BP when compared with heterozygous mutant and wild-type littermate mice. Infusion of AngII led to an enhanced systolic BP response in the APA-deficient mice. Despite the sustained elevation of BP in APA knockout mice, neither their renal and cardiac sizes nor their histological appearances were not different from control mice. Moreover, the volume, osmolality, and electrolyte content of the urine were normal in APA-deficient mice. APA deficiency increased baseline BP and enhanced the hypertensive response to increased levels of AngII. These findings indicate a physiological role for APA in lowering BP and offer novel insight into the mechanisms for developing hypertension.