Cervenka Ludek, Horácek Vladislav, Vanecková Ivana, Hubácek Jaroslav A, Oliverio Michael I, Coffman Thomas M, Navar L Gabriel
Center for Experimental Cardiovascular Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Hypertension. 2002 Nov;40(5):735-41. doi: 10.1161/01.hyp.0000036452.28493.74.
The aims of this study were to delineate the relative contribution of angiotensin II (ANG II) subtype 1A (AT1A) and 1B (AT1B) receptors to the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in mice, to examine if increased nitric oxide synthase (NOS) activity counteracts the vasoconstrictor influences of ANG II in 2K1C hypertensive mice, and to determine the role of ANG II type 2 (AT2) receptors in 2K1C hypertension in mice. AT(1A) ANG II receptor knockout (AT1A-/-) and wild-type (AT1A+/+) mice underwent clipping of the right renal artery. Systolic blood pressure (SBP) was significantly lower in AT1A-/- compared with AT1A+/+ mice, and neither clip placement nor AT2 receptor blockade with PD 123319 (PD) altered SBP in AT1A-/- mice. A significant and sustained rise in SBP from 119+/-5 to 163+/-6 mm Hg was observed in the 2K1C AT1A+/+ mice from day 10 to day 26. Chronic PD infusion did not alter the course of hypertension in 2K1C/AT1A+/+. Acute PD infusion did not alter mean arterial pressure (MAP) in AT1A+/+, PD/AT1A+/+, 2K1C/AT1A+/+, PD/2K1C/AT1A+/+, AT1A-/-, PD/AT1A-/-, and PD/2K1C/AT1A-/- mice compared with basal levels. In contrast, acute PD infusion caused significant increases in MAP in 2K1C/AT1A-/- mice. The subsequent acute NOS inhibition caused greater increases in MAP in 2K1C/AT1A+/+ and PD/2K1C/AT1A+/+ mice than in AT1A+/+ and PD/AT1A+/+ mice. These results support the essential role of AT1A receptors in mediating 2K1C hypertension and support the hypothesis that augmented NO production serves as a counteracting system in this model of hypertension.
本研究的目的是阐明血管紧张素II（ANG II）1A亚型（AT1A）和1B亚型（AT1B）受体在小鼠二肾一夹（2K1C）型Goldblatt高血压发展过程中的相对作用，研究一氧化氮合酶（NOS）活性增加是否能抵消2K1C高血压小鼠中ANG II的血管收缩作用，并确定ANG II 2型（AT2）受体在小鼠2K1C高血压中的作用。将AT（1A）ANG II受体敲除（AT1A-/-）小鼠和野生型（AT1A+/+）小鼠的右肾动脉进行夹闭。与AT1A+/+小鼠相比，AT1A-/-小鼠的收缩压（SBP）显著降低，夹闭操作和用PD 123319（PD）阻断AT2受体均未改变AT1A-/-小鼠的SBP。在2K1C AT1A+/+小鼠中，从第10天到第26天观察到SBP从119±5显著持续升高至163±6 mmHg。慢性输注PD未改变2K1C/AT1A+/+小鼠的高血压病程。急性输注PD未改变AT1A+/+、PD/AT1A+/+、2K1C/AT1A+/+、PD/2K1C/AT1A+/+、AT1A-/-、PD/AT1A-/-和PD/2K1C/AT1A-/-小鼠的平均动脉压（MAP）与基础水平相比。相反，急性输注PD导致2K1C/AT1A-/-小鼠的MAP显著升高。随后的急性NOS抑制导致2K1C/AT1A+/+和PD/2K1C/AT1A+/+小鼠的MAP升高幅度大于AT1A+/+和PD/AT1A+/+小鼠。这些结果支持AT1A受体在介导2K1C高血压中的重要作用，并支持以下假设：在该高血压模型中，一氧化氮生成增加作为一种抵消系统。
