Divergent functions of angiotensin II receptor isoforms in the brain
Divergent functions of angiotensin II receptor isoforms in the brain
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DOI：
10.1172/jci10022
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发表时间：
2000-07-01
影响因子：
15.9
通讯作者：
Sigmund, CD
中科院分区：
文献类型：
--
作者：
Davisson, RL;Oliverio, MI;Sigmund, CD
肾素-血管紧张素系统(RAS)在心血管和体液动态平衡中起着重要作用。RAS的主要生物活性多肽是血管紧张素II，它通过AT(1)和AT(2)两个药理类别的G蛋白偶联受体发挥作用。AT(1)受体在脑和外周组织中表达，介导RAS的大多数经典公认的作用，包括血压稳态和调节饮水和水平衡。在啮齿动物中，两种高度同源的AT(1)受体亚型，称为AT(1A)和AT(1B)受体，在主要的前脑心血管和体液调节中枢不同程度地表达，其中AT(1A)的表达通常超过AT(1B)的表达，但这些受体亚型对中枢血管紧张素II反应的相对贡献尚不清楚。我们使用基因打靶和一种独特的维持清醒小鼠脑室导管的系统来测试AT(1A)和AT(1B)受体在大脑中血管紧张素II引发的反应中是否有不同的作用。在这里，我们表明，中枢应用血管紧张素II引起的血压升高可以选择性地归因于AT(1A)受体。然而，饮酒反应需要AT(1B)受体的存在。据我们所知，这是第一次证明AT(1B)受体的主要和非冗余的生理功能。
The renin-angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. The major biologically active peptide of the RAS is angiotensin II, which acts through G protein-coupled receptors of two pharmacological classes, AT(1) and AT(2). AT(1) receptors, expressed in brain and peripheral tissues, mediate most classically recognized actions of the RAS, including blood pressure homeostasis and regulation of drinking and water balance. In rodents, two highly homologous AT(1) receptor isoforms, termed AT(1A) and AT(1B) receptors, are expressed at different levels in major forebrain cardiovascular and fluid regulatory centers, with AT(1A) expression generally exceeding AT(1B) expression, but the relative contributions of these receptor subtypes to central angiotensin II responses are not known. We used gene targeting in combination with a unique system for maintaining catheters in the cerebral ventricles of conscious mice to test whether there are differential roles for AT(1A) and AT(1B) receptors in responses elicited by angiotensin II in the brain. Here we show that the blood pressure increase elicited by centrally administered angiotensin II can be selectively ascribed to the AT(1A) receptor. However, the drinking response requires the presence of AT(1B) receptors. To our knowledge, this is the first demonstration of a primary and nonredundant physiological function for AT(1B) receptors.