INVESTIGATION OF ANG II/AT1 RECEPTORS WITH PET

描述（申请人提供）：血管紧张素II/AT 1受体亚型 (AT1受体）在血液的生理控制中起着重要作用 压力和体液平衡以及AT 1受体功能的增加可以 导致许多疾病的病理生理学，包括肾血管疾病， 高血压该项目的总体目标是调查 肾低灌注（两肾一夹模型）对AT 1调节的影响 犬的dAT 1受体。正电子发射断层扫描（PET）获得的数据 将与dAT 1蛋白和mRNA的生化分析相关 肾脏中的表达。 PET研究将使用放射性配体[11 C]L-159，884，这是一种AT 1 特异性受体拮抗剂。拟议的目标旨在测试 肾血流动力学改变主要致病因素假说 与肾动脉狭窄相关的是dAT 1受体的表达改变， [11 C]L-159，884在肾脏中的体内结合参数反映了这些 变化提出PET研究来测量以下物质的体内结合： [11 C]L-159，884在犬中造成单侧肾动脉狭窄后， 如果不用血管紧张素转化酶抑制剂赖诺普利治疗， 以及假手术动物。此外，dAT 1 mRNA水平将被 在体外定量，并与受体结合特性进行比较， 肾组织这将使研究潜在的 组织特异性和/或转录后调节机制 RAS的变化。 拟议的实验可以提供第一个体内证据， 肾血管中AT 1表达的组织特异性调节机制 高血压犬AT 1受体调节的研究 是使用这种非侵入性PET技术检查 人类AT 1受体，这项研究最终将导致更大的 了解在生理条件下人类AT 1受体的调节， 病理生理条件。建议的研究不仅有助于 阐明AT 1受体参与RVH，但可能 有助于区分肾血管性高血压患者， 可能会从血运重建中受益

Description (provided by applicant): The angiotensin II/AT1 receptor subtype (AT1 receptor) plays a fundamental role in the physiological control of blood pressure and fluid homeostasis and increased function of the AT1 receptor can contribute to the pathophysiology of numerous disorders including renovascular hypertension. The overall goal of this project is to investigate the effects of renal hypoperfusion (two-kidney one-clip model) on the regulation of the AT1 receptors in dogs (dAT1). Data obtained with positron emission tomography (PET) will be correlated with biochemical analysis of dAT1 protein and mRNA expression in the kidneys. PET studies will employ the radioligand, [11C]L-159,884, which is an AT1 specific receptor antagonist. The proposed aims are designed to test the hypothesis that a major pathogenetic factor of hemodynamic changes in kidneys with renal artery stensosi is altered expression of the dAT1 receptor and that in vivo binding parameters of [11C]L-159,884 in the kidney reflect these changes. PET studies are proposed to measure the in vivo binding of [11C]L-159,884 after creating unilateral renal artery stenosis in dogs with and without treatment with the angiotensin converting enzyme inhibitor, lisinopril, as well as in sham operated animals. In addition, dAT1 mRNA levels will be quantitated in vitro and compared with receptor binding characteristics in renal tissue. This will make it possible to investigate potential tissue-specific and/or post-transcriptional regulatory mechanisms during alterations in the RAS. The proposed experiments could provide the first in vivo evidence of tissue-specific regulatory mechanisms governing AT1 expression in renovascular hypertension. Investigations of the regulation of the AT1 receptor in the dog are a first step toward using this non-invasive PET technique to examine the human AT1 receptor and this research should ultimately lead to a greater understanding of the regulation of human AT1 receptors under physiological and pathophysiological conditions. The proposed studies will not only help elucidate the involvement of AT1 receptors in RVH but will potentially facilitate efforts to differentiate patients with renovascular hypertension who may benefit from revascularization.