Inverse agonist activity of angiotensin II type 1 receptor blockers

血管紧张素II (AngII) 1型（AT_1）受体是一种G蛋白偶联受体，在负荷性心肌肥厚的发展中起着至关重要的作用。我们之前报道过机械应力可以通过独立于AngII的激活AT_1受体来诱导肥厚反应，并且这种激活可以被具有逆激动剂活性的AT_1受体阻滞剂（ARB）抑制。在这项研究中，我们寻找了AT_1受体的关键区域，该区域负责机械拉伸诱导的激活。此外，我们还比较了具有双苯基四唑环结构的4种亲水性arb的逆激动剂活性，并探讨了arb的化学结构与逆激动剂活性的关系。我们首先构建了一系列由AT_1受体和内皮素-1 a型受体组成的嵌合体受体，内皮素-1 a型受体是一种对机械应力无反应的G蛋白偶联受体。嵌合体受体中更多的ERKs激活表明，从Lys199到Ser252的区域对血管内皮细胞诱导的受体激活至关重要。然而，同样的方法未能确定对机械应力诱导的受体激活至关重要的区域。我们推测二硫键可能在嵌合体受体中异常形成，机械应力可能引起嵌合体受体的不确定构象变化。在对AT_1- n111g突变体受体组成活性或机械应力诱导的AT_1受体激活的抑制作用中，氯沙坦表现出轻度的逆激动剂活性，而缬沙坦、坎地沙坦和奥美沙坦表现出中度至超逆激动剂活性。在强效反激动剂中，咪唑环上羧基的存在表明其化学结构在强效反激动剂活性的表现中起重要作用。进一步分析ARB中AT_1受体的结构与功能，探讨其化学结构与抗激动剂活性的关系，将有助于建立具有更强抗激动剂活性和抗器官损伤保护作用的理想ARB。少

The angiotensin II (AngII) type 1 (AT_1) receptor is a G protein-coupled receptor that plays a crucial role in the development of load-induced cardiac hypertrophy. We previously reported that mechanical stress can induce hypertrophic responses by activating AT_1 receptor independently of AngII, and that this activation can be inhibited by an AT_1 receptor blocker (ARB) with inverse agonist activity. In this study, we searched for the critical region of the AT_1 receptor, which is responsible for mechanical stretch-induced activation. In addition, we compared the inverse agonist activity in 4 kinds of hydrophilic ARBs, which share the bi-phenyl-tetrazole ring structure in common, and examined the relationship between the chemical structure and the inverse agonist activity in ARBs.We first constructed a series of chimera receptors consisting of the AT_1 receptor and the endothelin-1 type A receptor, which is a G protein-coupled receptor without responsiveness to mechanical stress. Examin … More ation of ERKs activation in chimera receptors revealed that a region ranging from Lys199 to Ser252 was critical for AngII-induced receptor activation. However, the same approach failed to identify the region that is critical for mechanical stress-induced receptor activation. We suppose that disulfide bonds might be aberrantly formed in chimera receptors, and that mechanical stress might induce undefined conformational change of chimera receptors.Losartan showed mild inverse agonist activity, while valsartan, candesartan, and olmesartan showed moderate to exceeding inverse agonist activities, when the inhibitory effects either on constitutive activity of the AT_1-N111G mutant receptor or on mechanical stress-induced activation of the AT_1 receptor were examined. The presence of the carboxyl group at the imidazole ring in the potent inverse agonists suggested that the chemical structure plays an important role in exhibiting the potent inverse agonist activity. Further analysis of structure-function of the AT_1 receptor and investigation of the relationship between the chemical structure and the inverse agonist activity in ARBs will be of help for the establishment of an ideal ARB with more potent inverse agonist activity and more protective effect against the organ damages. Less