INVESTIGATION OF ANG II/AT1 RECEPTORS WITH PET

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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.