Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Cardiovasc Res. 2010 Jun 1;86(3):401-9. doi: 10.1093/cvr/cvq004. Epub 2010 Jan 12.
Our aim was to determine the contribution of the three angiotensin (Ang) II receptor subtypes (AT(1a), AT(1b), AT(2)) to coronary responsiveness, cardiac histopathology, and tissue Ang II levels using mice deficient for one, two, or all three Ang II receptors.
Hearts of knockout mice and their wild-type controls were collected for histochemistry or perfused according to Langendorff, and kidneys were removed to measure tissue Ang II. Ang II dose-dependently decreased coronary flow (CF) and left ventricular systolic pressure (LVSP), and these effects were absent in all genotypes deficient for AT(1a), independently of AT(1b) and AT(2). The deletion of Ang II receptors had an effect neither on the morphology of medium-sized vessels in the heart nor on the development of fibrosis. However, the lack of both AT(1) subtypes was associated with atrophic changes in the myocardium, a reduced CF and a reduced LVSP. AT(1a) deletion alone, independently of the presence or absence of AT(1b) and/or AT(2), reduced renal Ang II by 50% despite a five-fold rise of plasma Ang II. AT(1b) deletion, on top of AT(1a) deletion (but not alone), further decreased tissue Ang II, while increasing plasma Ang II. In mice deficient for all three Ang II receptors, renal Ang II was located only extracellularly.
The lack of both AT(1) subtypes led to a baseline reduction of CF and LVSP, and the effects of Ang II on CF and LVSP were found to be exclusively mediated via AT(1a). The lack of AT(1a) or AT(1b) does not influence the development or maintenance of normal cardiac morphology, whereas deficiency for both receptors led to atrophic changes in the heart. Renal Ang II levels largely depend on AT(1) binding of extracellularly generated Ang II, and in the absence of all three Ang II receptors, renal Ang II is only located extracellularly.
使用缺乏一种、两种或三种血管紧张素（Ang）II 受体亚型（AT(1a)、AT(1b)、AT(2)）的小鼠，确定这三种受体亚型对冠状动脉反应性、心脏组织病理学和组织 Ang II 水平的贡献。
收集敲除小鼠及其野生型对照的心脏进行组织化学检查，或根据 Langendorff 进行灌流，并取出肾脏以测量组织 Ang II。Ang II 呈剂量依赖性地降低冠状动脉流量（CF）和左心室收缩压（LVSP），而在缺乏 AT(1a)的所有基因型中，这些作用均不存在，而与 AT(1b)和 AT(2)无关。Ang II 受体的缺失对心脏中型血管的形态或纤维化的发展均无影响。然而，缺乏两种 AT(1)亚型与心肌萎缩变化、CF 降低和 LVSP 降低有关。单独缺失 AT(1a)，无论 AT(1b)和/或 AT(2)的存在与否，尽管血浆 Ang II 升高五倍，但仍使肾脏 Ang II 减少 50%。在缺乏 AT(1a)的基础上进一步缺失 AT(1b)（但不单独缺失），进一步降低组织 Ang II，同时增加血浆 Ang II。在缺乏三种 Ang II 受体的小鼠中，肾脏 Ang II 仅位于细胞外。
缺乏两种 AT(1)亚型导致 CF 和 LVSP 的基础降低，并且发现 Ang II 对 CF 和 LVSP 的作用仅通过 AT(1a)介导。缺乏 AT(1a)或 AT(1b)并不影响正常心脏形态的发育或维持，而缺乏两种受体则导致心脏萎缩变化。肾脏 Ang II 水平在很大程度上取决于细胞外产生的 Ang II 与 AT(1)的结合，在缺乏所有三种 Ang II 受体的情况下，肾脏 Ang II 仅位于细胞外。
