Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor.
Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor.
复制标题
增加肾血管扩张剂前列腺素类药物可预防缺乏血管紧张素 2 亚型受体的小鼠出现高血压。
DOI：
10.1172/jci6063
复制
发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Carey,RM
中科院分区：
文献类型：
--
作者：
Siragy,HM;Senbonmatsu,T;Ichiki,T;Inagami,T;Carey,RM
血管紧张素亚型1（AT 1）受体介导肾脏前列腺素E2（PGE 2）的产生，药物阻断血管紧张素亚型2（AT 2）受体可增强血管紧张素II（Ang II）增加PGE 2水平的作用。我们研究了AT 2受体在靶向缺失AT 2受体基因的小鼠前列腺素代谢中的作用。缺乏AT 2受体的小鼠（AT 2-null）的血压正常，与野生型（WT）对照小鼠相比略有升高。AT 2基因敲除小鼠的肾间质液（RIF）6-keto-PGF 1 α（前列环素[PGI 2]的稳定水解产物）和PGE 2水平高于WT小鼠，并且对饮食钠限制和Ang II输注的反应中PGE 2和6-keto-PGF 1 α的增加相似。相比之下，在基础条件下，AT 2-null小鼠的PGF 2 α水平低于WT小鼠，并对饮食钠限制或输注Ang II作出反应。在基础条件下和限钠或Ang II输注期间，AT 2缺失小鼠的RIF cAMP显著高于WT小鼠。用氯沙坦阻断AT 1受体可使PGE 2、PGI 2和cAMP降至WT小鼠中观察到的水平。为了确定增加的血管扩张剂前列腺素类是否能预防AT 2缺失小鼠的高血压，我们用吲哚美辛治疗AT 2缺失小鼠和WT小鼠14天。在WT和AT 2-null小鼠中，PGI 2、PGE 2和cAMP均显著降低。AT 2基因敲除小鼠的血压升高至高血压水平，但WT小鼠的血压无变化。这些结果表明，在AT 2受体的情况下，血管扩张剂前列腺素类的增加，防止高血压的发展。
The angiotensin subtype-1 (AT1) receptor mediates renal prostaglandin E2(PGE2) production, and pharmacological blockade of the angiotensin subtype-2 (AT2) receptor potentiates the action of angiotensin II (Ang II) to increase PGE2levels. We investigated the role of the AT2receptor in prostaglandin metabolism in mice with targeted deletion of the AT2receptor gene. Mice lacking the AT2receptor (AT2-null) had normal blood pressure that was slightly elevated compared with that of wild-type (WT) control mice. AT2-null mice had higher renal interstitial fluid (RIF) 6-keto-PGF1α(a stable hydrolysis product of prostacyclin [PGI2]) and PGE2levels than did WT mice, and had similar increases in PGE2and 6-keto-PGF1αin response to dietary sodium restriction and Ang II infusion. In contrast, AT2-null mice had lower PGF2αlevels compared with WT mice during basal conditions and in response to dietary sodium restriction or infusion of Ang II. RIF cAMP was markedly higher in AT2-null mice than in WT mice, both during basal conditions and during sodium restriction or Ang II infusion. AT1receptor blockade with losartan decreased PGE2, PGI2, and cAMP to levels observed in WT mice. To determine whether increased vasodilator prostanoids prevented hypertension in AT2-null mice, we treated AT2-null and WT mice with indomethacin for 14 days. PGI2, PGE2, and cAMP were markedly decreased in both WT and AT2-null mice. Blood pressure increased to hypertensive levels in AT2-null mice but was unchanged in WT. These results demonstrate that in the absence of the AT2receptor, increased vasodilator prostanoids protect against the development of hypertension.