From the Departments of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
Circ Res. 2014 Jul 18;115(3):388-99. doi: 10.1161/CIRCRESAHA.115.304110. Epub 2014 Jun 5.
Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist.
To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice.
In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial infusion of specific AT2R antagonist PD-123319. C-21 increased fractional excretion of Na(+) (P<0.05) and lithium (P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase. C-21-induced natriuresis was accompanied by an increase in renal interstitial cGMP (P<0.01); C-21-induced increases in urinary sodium excretion and renal interstitial cGMP were abolished by renal interstitial nitric oxide synthase inhibitor l-N(6)-nitroarginine methyl ester or bradykinin B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na(+) retention and lowered blood pressure in the angiotensin II infusion model of experimental hypertension.
AT2R activation initiates its translocation to the renal proximal tubule cell apical membrane and the internalization of Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase, inducing natriuresis in a bradykinin-nitric oxide-cGMP-dependent manner. Intrarenal AT2R activation prevents Na(+) retention and lowers blood pressure in angiotensin II-dependent hypertension. AT2R activation holds promise as a renal proximal tubule natriuretic/diuretic target for the treatment of fluid-retaining states and hypertension.
化合物 21（C-21）是一种高选择性的非肽类 AT2 受体（AT2R）激动剂。
验证假说，即肾近端小管 AT2R 可诱导 Sprague-Dawley 大鼠和小鼠产生利钠作用并降低血压。
在大鼠中，静脉内给予 C-21 可使尿钠排泄增加 10 倍（P<0.0001）；通过直接向肾间质输注特异性 AT2R 拮抗剂 PD-123319，可消除这种利钠作用。C-21 增加了肾近端小管细胞顶膜 AT2R 蛋白的分数排泄（P<0.05）和锂排泄（P<0.01），而不改变肾血流动力学功能。AT2R 激活增加了肾近端小管细胞顶膜 AT2R 蛋白（P<0.001），而不改变总 AT2R 表达以及内化/失活的 Na+-H+交换蛋白-3 和 Na+/K+ATP 酶。C-21 诱导的利钠作用伴随着肾间质 cGMP 的增加（P<0.01）；肾间质一氧化氮合酶抑制剂 l-N（6）-硝基精氨酸甲酯或缓激肽 B2 受体拮抗剂 icatibant 可消除 C-21 诱导的尿钠排泄增加和肾间质 cGMP 增加。用 C-21 激活肾 AT2R 可预防血管紧张素 II 输注模型中实验性高血压的钠潴留和降低血压。
AT2R 激活引发其向肾近端小管细胞顶膜的易位以及 Na+-H+交换蛋白-3 和 Na+/K+ATP 酶的内化，以依赖缓激肽-一氧化氮-cGMP 的方式诱导利钠作用。肾内 AT2R 激活可预防血管紧张素 II 依赖性高血压中的钠潴留和降低血压。AT2R 激活有望成为治疗保水状态和高血压的肾近端小管利钠/利尿的靶标。
